Sturkenboom, M.C.J.M.

Academic output from EU-funded health research projects (Article)

2012-12-01T00:00:00Z

Burden of acute otitis media in primary care pediatrics in Italy: A secondary data analysis from the Pedianet database (Article)

2012-11-29T00:00:00Z

Background: The incidence of acute otitis media (AOM) vary from country to country. Geographical variations together with differences in study designs, reporting and settings play a role. We assessed the incidence of AOM in Italian children seen by primary care paediatricians (PCPs), and described the methods used to diagnose the disease.Methods: This secondary data analysis from the Pedianet database considered children aged 0 - 6 years between 01/2003 and 12/2007. The AOM episodes were identified and validated by means of patient diaries. Incidence rates/100 person-years (PY) were calculated for total AOM and for single or recurrent AOM.Results: The 92,373 children (52.1% males) were followed up for a total of 227,361 PY: 23,039 (24.9%) presented 38,241 episodes of AOM (94.6% single episodes and 5.4% recurrent episodes). The total incidence rate of AOM in the 5-year period was 16.8 episodes per 100 PY (95% CI: 16.7-16.9), including single AOM (15.9 episodes per 100 PY; 95% CI: 15.7-16.1) and recurrent AOM (0.9 episodes per 100 PY; 95% CI: 0.9-0.9). There was a slight and continuously negative trend decrease over time (annual percent change -4.6%; 95%CI: -5.3, -3.9%). The AOM incidence rate varied with age, peaking in children aged 3 to 4 years (22.2 episodes per 100 PY; 95% CI 21.8-22.7). The vast majority of the AOM episodes (36,842/38,241, 96.3%) were diagnosed using a static otoscope; a pneumatic otoscope was used in only 3.7%.Conclusions: Our data fill a gap in our knowledge of the incidence of AOM in Italy, and indicate that AOM represents a considerable burden for the Italian PCP system. Educational programmes concerning the diagnosis of AOM are needed, as are further studies to monitor the incidence in relation to the introduction of wider pneumococcal conjugate vaccines.

Using electronic health care records for drug safety signal detection: A comparative evaluation of statistical methods (Article)

2012-10-01T00:00:00Z

BACKGROUND: Drug safety monitoring relies primarily on spontaneous reporting, but electronic health care record databases offer a possible alternative for the detection of adverse drug reactions (ADRs). OBJECTIVES: To evaluate the relative performance of different statistical methods for detecting drug-adverse event associations in electronic health care record data representing potential ADRs. RESEARCH DESIGN: Data from 7 databases across 3 countries in Europe comprising over 20 million subjects were used to compute the relative risk estimates for drug-event pairs using 10 different methods, including those developed for spontaneous reporting systems, cohort methods such as the longitudinal gamma poisson shrinker, and case-based methods such as case-control. The newly developed method "longitudinal evaluation of observational profiles of adverse events related to drugs" (LEOPARD) was used to remove associations likely caused by protopathic bias. Data from the different databases were combined by pooling of data, and by meta-analysis for random effects. A reference standard of known ADRs and negative controls was created to evaluate the performance of the method. MEASURES: The area under the curve of the receiver operator characteristic curve was calculated for each method, both with and without LEOPARD filtering. RESULTS: The highest area under the curve (0.83) was achieved by the combination of either longitudinal gamma poisson shrinker or case-control with LEOPARD filtering, but the performance between methods differed little. LEOPARD increased the overall performance, but flagged several known ADRs as caused by protopathic bias. CONCLUSIONS: Combinations of methods demonstrate good performance in distinguishing known ADRs from negative controls, and we assume that these could also be used to detect new drug safety signals. Copyright

Prescription of nonselective NSAIDs, coxibs and gastroprotective agents in the era of rofecoxib withdrawal - A 617 400-patient study (Article)

2012-10-01T00:00:00Z

Background Gastroprotective strategies are recommended for nonsteroidal anti-inflammatory drug (NSAID) users at risk of upper gastrointestinal (UGI) complications. Aim To compare the use of gastroprotective strategies in NSAID users in three countries, and the subsequent impact of rofecoxib withdrawal. Methods We conducted a population-based cohort study in three general practice (GP) databases: (i) United Kingdom's (UK) GP Research Database (1998-2008); (ii) Italy's (IT) Health Search/CSD Longitudinal Patient Database (2000-2007); and (iii) the Dutch (NL) Integrated Primary Care Information database (1996-2006). Study cohorts comprised incident NSAID users ≥50 years. Preventive strategies included: (i) co-prescription of gastroprotective agents; or (ii) cyclooxygenase-2-selective inhibitor use. Under-use was defined as no gastroprotection in patients with ≥1 UGI risk factor (history of UGI event, age ≥65 years, concomitant use of anticoagulants, antiplatelets or glucocorticoids). Interrupted time-series analysis was performed to assess the impact of rofecoxib withdrawal on preventive strategies. Results The study populations consisted of 384 649 UK, 177 747 IT and 55 004 NL NSAID users. In UK, under-use of preventive strategies fell from 91% to 71% [linear trend (lt) P = 0.001], in NL from 92% to 58% (lt P < 0.001) and in IT from 90% to 76% (lt P = 0.38) in high-risk NSAID users. In 2000 and 2006, under-use was significantly lower in NL compared with UK and IT (P < 0.001) in high-risk users. After rofecoxib's withdrawal, under-use increased significantly in UK and NL. Conclusions The prescription of gastropreventive strategies followed a similar pattern across countries. Despite a temporary negative effect of rofecoxib withdrawal on under-use, improvement of gastroprotection with nonsteroidal anti-inflammatory drugs was observed.

The risk of new onset heart failure associated with dopamine agonist use in Parkinson's disease (Article)

2012-03-01T00:00:00Z

The aim of present study was to investigate the risk of heart failure associated with dopamine agonist use in patients with Parkinson's disease. The data sources of this study were four different population-based, healthcare databases in United Kingdom, Italy and Netherlands. A case control study nested within a cohort of Parkinson's disease patients who were new users of either dopamine agonist or levodopa was conducted. Incident cases of heart failure were identified and validated, using Framingham criteria. Controls were matched to cases on age, gender and database. To estimate the risk of newly diagnosed heart failure with ergot and non-ergot derived dopamine agonists, as compared to levodopa, odds ratios and 95% confidence intervals were calculated through conditional logistic regression. In the cohort of 25,459 Parkinson's disease patients (11,151 new users of dopamine agonists, 14,308 new users of levodopa), 518 incident heart failure cases were identified during follow-up. Compared to levodopa, no increased risk of heart failure was found for ergot dopamine agonists (odds ratio: 1.03; 95% confidence interval: 0.69-1.55). Among non-ergot dopamine agonists, only pramipexole was associated with an increased risk of heart failure (odds ratio: 1.61; 95%confidence interval: 1.09-2.38), especially in the first three months of therapy (odds ratio: 3.06; 95% confidence interval: 1.74-5.39) and in patients aged 80 years and older (odds ratio: 3.30; 95% confidence interval: 1.62-7.13). The results of this study indicate that ergot dopamine agonist use in Parkinson's disease patients was not associated with an increased risk of newly diagnosed heart failure. Among non-ergot dopamine agonists, we observed a statistically significant association between pramipexole use and heart failure, especially during the first months of therapy and in very old patients.

Safety of pandemic H1N1 vaccines in children and adolescents (Article)

2011-10-06T00:00:00Z

During the 2009 influenza A (H1N1) pandemic several pandemic H1N1 vaccines were licensed using fast track procedures, with relatively limited data on the safety in children and adolescents. Different extensive safety monitoring efforts were put in place to ensure timely detection of adverse events following immunization. These combined efforts have generated large amounts of data on the safety of the different pandemic H1N1 vaccines, also in children and adolescents. In this overview we shortly summarize the safety experience with seasonal influenza vaccines as a background and focus on the clinical and post marketing safety data of the pandemic H1N1 vaccines in children. We identified 25 different clinical studies including 10,505 children and adolescents, both healthy and with underlying medical conditions, between the ages of 6 months and 23 years. In addition, large monitoring efforts have resulted in large amounts of data, with almost 13,000 individual case reports in children and adolescents to the WHO. However, the diversity in methods and data presentation in clinical study publications and publications of spontaneous reports hampered the analysis of safety of the different vaccines. As a result, relatively little has been learned on the comparative safety of these pandemic H1N1 vaccines - particularly in children. It should be a collective effort to give added value to the enormous work going into the individual studies by adhering to available guidelines for the collection, analysis, and presentation of vaccine safety data in clinical studies and to guidance for the clinical investigation of medicinal products in the pediatric population. Importantly the pandemic has brought us the beginning of an infrastructure for collaborative vaccine safety studies in the EU, USA and globally.

Complications after hip arthroplasty and the association with hospital procedure volume: A nationwide retrospective cohort study on 50,080 total hip replacements with a follow-up of 3 months after surgery (Article)

2011-10-01T00:00:00Z

Background and purpose: It has been suggested that a higher procedure volume is associated with less complications after hip arthroplasty. In order to investigate the incidence of serious negative outcomes and a possible association with procedure volume, we performed a retrospective nationwide cohort study on total hip replacements in all Dutch hospitals. Methods: All total hip replacements (n = 50,080) that were identified as primary intervention in all general and university medical centers between January 1, 2002 and October 1, 2004 were included. Primary endpoints of follow-up were mortality and complications during admission, and re-admission within 3 months due to complications. Variables that were assessed as potential risk factor were age, sex, duration of (preoperative) admission, specific diagnosis, acute/non-planned admission, co-morbidity, and hospital procedure volume. Results: Age, sex, and comorbidity were associated with complications and mortality. Additionally, acute admission was a risk factor for mortality but not for complications. There was no linear trend indicating that decreasing volume led to an increasing number of complications, and no statistically sginificant effect for mortality was found. Interpretation: After adjustment for several risk factors, we found that the hospitals performing most hip procedures every year had fewer complications during index admission, but that they did not have a lower mortality than groups performing fewer procedures. The lack of a linear trend may be explained by the fact that almost all Dutch hospitals perform a high number of hip arthroplasties each year.

Guillain-Barré syndrome: Background incidence rates in the Netherlands (Article)

2011-09-01T00:00:00Z

Guillain-Barré syndrome (GBS) is a (sub)acute polyradiculoneuropathy, which may occur following immunization. To interpret the occurrence of GBS after introduction of large-scale immunization programmes, it is important to define recent background incidence rates (IRs) of GBS. We used a general practitioner electronic medical record database to assess age-specific GBS IRs between 1996 and 2008 in The Netherlands. All possible GBS cases were manually reviewed. Validated incident cases were reviewed by a neurologist (B. J.) for diagnostic certainty using the GBS case definition of the Brighton Collaboration (BC). In a population of 638,891 persons, we identified 23 validated incident GBS cases (mean age 46 years). IR was 1.14 per 100,000 person years (95% confidence interval [CI] 0.67-1.61) and was lower for people under 50 years (0.76; 95%CI 0.41-1.32) compared with elderly of 50 years or older (1.80; 95%CI 0.98-3.05). Only six cases fulfilled level 1 or 2 of diagnostic certainty of the BC case definition. IR of GBS increases with age. As vaccinations are often targeted at specific age groups, age-specific rates should be used to monitor GBS observed versus expected rates after introduction of large-scale vaccination programmes.

Effectiveness of a MF-59™-adjuvanted pandemic influenza vaccine to prevent 2009 A/H1N1 influenza-related hospitalisation; a matched case-control study (Article)

2011-07-18T00:00:00Z

Background: During the 2009 influenza A/H1N1 pandemic, adjuvanted influenza vaccines were used for the first time on a large scale. Results on the effectiveness of the vaccines in preventing 2009 influenza A/H1N1-related hospitalisation are scanty and varying.Methods: We conducted a matched case-control study in individuals with an indication for vaccination due to underlying medical conditions and/or age ≥ 60 years in the Netherlands. Cases were patients hospitalised with laboratory-confirmed 2009 A/H1N1 influenza infection between November 16, 2009 and January 15, 2010. Controls were matched to cases on age, sex and type of underlying medical condition(s) and drawn from an extensive general practitioner network. Conditional logistic regression was used to estimate the vaccine effectiveness (VE = 1 - OR). Different sensitivity analyses were used to assess confounding by severity of underlying medical condition(s) and the effect of different assumptions for missing dates of vaccination.Results: 149 cases and 28,238 matched controls were included. It was estimated that 22% of the cases and 28% of the controls received vaccination more than 7 days before the date of onset of symptoms in cases. A significant number of breakthrough infections were observed. The VE was estimated at 19% (95%CI -28-49). After restricting the analysis to cases with controls suffering from severe underlying medical conditions, the VE was 49% (95%CI 16-69).Conclusions: The number of breakthrough infections, resulting in modest VE estimates, suggests that the MF-59™ adjuvanted vaccine may have had only a limited impact on preventing 2009 influenza A/H1N1-related hospitalisation in this setting. As the main aim of influenza vaccination programmes is to reduce severe influenza-related morbidity and mortality from influenza in persons at high risk of complications, a more effective vaccine, or additional preventive measures, are needed.

Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: Multinational case-control study in Europe (Article)

2011-07-16T00:00:00Z

Objective: To assess the association between pandemic influenza A (H1N1) 2009 vaccine and Guillain-Barré syndrome. Design: Case-control study. Setting: Five European countries. Participants: 104 patients with Guillain-Barré syndrome and its variant Miller-Fisher syndrome matched to one or more controls. Case status was classified according to the Brighton Collaboration definition. Controls were matched to cases on age, sex, index date, and country. Main outcome measures: Relative risk estimate for Guillain-Barré syndrome after pandemic influenza vaccine. Results: Case recruitment and vaccine coverage varied considerably between countries; the most common vaccines used were adjuvanted (Pandemrix and Focetria). The unadjusted pooled risk estimate for all countries was 2.8 (95% confidence interval 1.3 to 6.0). After adjustment for influenza-like illness/upper respiratory tract infection and seasonal influenza vaccination, receipt of pandemic influenza vaccine was not associated with an increased risk of Guillain-Barré syndrome (adjusted odds ratio 1.0, 0.3 to 2.7). The 95% confidence interval shows that the absolute effect of vaccination could range from one avoided case of Guillain-Barré syndrome up to three excess cases within six weeks after vaccination in one million people. Conclusions: The risk of occurrence of Guillain-Barré syndrome is not increased after pandemic influenza vaccine, although the upper limit does not exclude a potential increase in risk up to 2.7-fold or three excess cases per one million vaccinated people. When assessing the association between pandemic influenza vaccines and Guillain-Barré syndrome it is important to account for the effects of influenza-like illness/upper respiratory tract infection, seasonal influenza vaccination, and calendar time.

Incidence, treatment, and case-fatality of non-traumatic subarachnoid haemorrhage in the Netherlands (Article)

2011-07-01T00:00:00Z

Background: Non-traumatic subarachnoid haemorrhage (SAH) is a devastating disorder and in the majority of cases it is caused by rupture of an intracranial aneurysm. No actual data are available on the incidence of non-traumatic SAH and aneursymal SAH (aSAH) in the Netherlands and little is known about treatment patterns of aSAH. Our purpose was therefore to assess the incidence, treatment patterns, and case-fatality of non-traumatic (a)SAH within the Dutch general population. Methods: Two population based data sources were used for this retrospective cohort study. One was the nationwide hospital discharge registry (National Medical Registration, LMR). Cases were patients hospitalized for SAH (ICD-9-code 430) in 2001-2005. The second source was the Integrated Primary Care Information (IPCI) database, a medical record database allowing for case validation. Cases were patients with validated non-traumatic (a)SAH in 1996-2006. Incidence, treatment, and case-fatality were assessed. Results: The incidence rate (IR) of non-traumatic SAH was 7.12 per 100,000 PY (95%CI: 6.94-7.31) and increased with age. The IR of aSAH was 3.78 (95%CI: 2.98-4.72). Women had a twofold increased risk of non-traumatic SAH; this difference appeared after the fourth decade. Non-traumatic SAH fatality was 30% (95%CI: 29-31%). Of aSAH patients 64% (95%CI: 53-74%) were treated with a clipping procedure, and 26% (95%CI: 17-37%) with coiling. Conclusion: Non-traumatic SAH is a rare disease with substantial case-fatality; rates in the Netherlands are similar to other countries. Case-fatality is also similar as well as age and sex patterns in incidence.

Suboptimal gastroprotective coverage of NSAID use and the risk of upper gastrointestinal bleeding and ulcers: An observational study using three European databases (Article)

2011-06-02T00:00:00Z

Background: Gastro-protective agents (GPA) are co-prescribed with non-steroidal anti-inflammatory drugs (NSAID) to lower the risk of upper gastrointestinal (UGI) events. It is unknown to what extent the protective effect is influenced by therapy adherence. Aim: To study the association between GPA adherence and UGI events among non-selective (ns) NSAID users. Methods: The General Practice Research Database (UK 1998e2008), the Integrated Primary Care Information database (the Netherlands 1996-2007) and the Health Search/CSD Longitudinal Patient Database (Italy 2000-2007) were used. A nested case-control design was employed within a cohort of nsNSAID users aged ≥50 years, who also used a GPA. UGI event cases (UGI bleeding and/or symptomatic ulcer with/without obstruction/perforation) were matched to event-free members of the cohort for age, sex, database and calendar time. Adherence to GPA was calculated as the proportion of nsNSAID treatment days covered by a GPA prescription. Adjusted OR with 95% CI were calculated. Results: The cohort consisted of 618 684 NSAID users, generating 1 107 266 nsNSAID episodes. Of these, 117 307 (10.6%) were (partly) covered by GPA, 4.9% of which with a GPA coverage <20% (non-adherence), and 68.1% with a GPA coverage >80% (full adherence). 339 patients experienced an event. Among non-adherers, the OR was 2.39 (95% CI 1.66 to 3.44) for all UGI events and 1.89 (95% CI 1.09 to 3.28) for UGI bleeding alone, compared to full adherers. Conclusions: The risk of UGI events was significantly higher in nsNSAID users with GPA non-adherence. This underlines the importance of strategies to improve GPA adherence. Copyright Article author (or their employer) 2011.

Cardiovascular and gastrointestinal safety of NSAIDs: A systematic review of meta-analyses of randomized clinical trials (Article)

2011-06-01T00:00:00Z

As part of the Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project, we reviewed the incidence of cardiovascular (CV) and gastrointestinal (GI) events associated with the use of this category of drugs. We collected data from published meta-analyses (MAs) of clinical trials of nonsteroidal anti-inflammatory drugs (NSAIDs). The Medline, Cochrane, ISI, and SCOPUS databases were systematically searched for MAs of NSAID clinical trials that could potentially contain data on adverse incidents such as myocardial infarction (MI), cerebrovascular events (CeVs), stroke, thromboembolic events (ThEs), heart failure (HF), gastrointestinal bleeding (GIB), and perforation, ulcer, and bleeding (PUB). From 1,733 identified references, 29 MAs were selected for the review. This allowed 109 estimations of incidence rates of CV adverse events and 26 estimations of incidence rates for GI adverse events. No data were found on hemorrhagic stroke or LGIB. Coxibs were studied in more MAs than traditional NSAIDs were (21 MAs for coxibs vs. 7 for traditional NSAIDs; one meta-analysis studied both). Many NSAIDs were not considered in any of the MAs. Our systematic review of MAs included information on the incidence of CV and GI events and identified important knowledge gaps regarding, in particular, the CV safety of traditional NSAIDs.

Effects of safety warnings on prescription rates of cough and cold medicines in children below 2 years of age (Article)

2011-06-01T00:00:00Z

AIM: The aim of the study was to assess the influence of national and international warnings on the prescription rates of cough and cold medicines (CCMs) in the youngest children (<2 years) in the Netherlands and Italy. METHODS: Analysis of outpatient electronic medical records of children <2 years in Italy and the Netherlands was carried out. Age and country specific prescription prevalence rates were calculated for the period 2005-08. Comparisons of prescription rates in 2005 (pre) and 2008 (post) warnings were done by means of a chi-square test. RESULTS: The cohort consisted of 99176 children <2 years of age. After international warnings, overall prescription rates for CCMs decreased slightly from 83 to 77/1000 person years (P= 0.05) in Italy and increased in the Netherlands from 74 to 92/1000 children per year. Despite the international warnings, prescription rates for nasal sympathomimetics and opium alkaloids increased in the Netherlands (P < 0.01). In Italy a significant decrease in the prescription rates of opium alkaloids and other cough suppressants (P < 0.01) was observed, and also a significant reduction in use of combinations of nasal sympathomimetics. CONCLUSION: Despite the international safety warnings and negative benefit-risk profiles, prescription rates of cough and cold medicines remain substantial and were hardly affected by the warnings, especially in the Netherlands where no warning was issued. The hazards of use of these medicines in young children should be explicitly stipulated by the European Medicines Agency and all national agencies, in order to increase awareness amongst physicians and caretakers and reduce heterogeneity across the EU. © 2011 The Authors. British Journal of Clinical Pharmacology

Inhaled anticholinergic drugs and risk of acute urinary retention (Article)

2011-04-01T00:00:00Z

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 (ORadj) 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 (ORadj1.40; 95% CI 0.99-1.98) compared with non-users. Among current users, the risk was highest for the recent starters (ORadj3.11; 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 (ORadj2.92; 95% CI 1.17-7.31). In men with COPD and benign prostatic hyperplasia (BPH) the association was strongest (ORadj4.67; 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.

A nationwide study of three invasive treatments for trigeminal neuralgia (Article)

2011-03-01T00:00:00Z

Invasive procedures for treatment of trigeminal neuralgia (TGN) include percutaneous radiofrequency thermocoagulation (PRT), partial sensory rhizotomy (PSR), and microvascular decompression (MVD). Using a nationwide discharge registry from The Netherlands, we assessed the frequency of use and patient characteristics, and evaluated treatment failure for each patient undergoing PRT, PSR, or MVD from January 2002 through December 2004. Only patients without a procedure in the year prior were included. Primary outcome was readmission for repeat procedures for TGN or known complications within 1 year. Comparability of patient populations was assessed through propensity scores based on hospital, age, sex, and comorbidity. Conditional logistic regression matched on propensity score was used to calculate relative risks (RR) with 95% confidence intervals (CIs) for repeat procedures or complications. During the study period, 672 patients with TGN underwent PRT, 39 underwent PSR, and 87 underwent MVD. Hospital type was the predominant determinant of procedure type; age, sex, and comorbidity were weak predictors. The RR for repeat procedures for PSR was 0.21 (95% CI: 0.07 to 0.65) and for MVD was 0.13 (95% CI: 0.05 to 0.35) compared with PRT (RR 1). For complications, the RR of PSR was 5.36 (95% CI: 1.46 to 19.64) and of MVD was 4.40 (95% CI: 1.44 to 13.42). Sex, urbanization, and comorbidity did not influence prognosis, but hospital and surgical volume did. In conclusion, although PSR and MVD are associated with a lower risk of repeat procedure than PRT, they seem to be more prone to complications requiring hospital readmission. Microvascular decompression and partial sensory rhizotomy are associated with a lower risk of undergoing a repeat procedure compared with percutaneous radiofrequency thermocoagulation but are more prone to complications requiring readmission to hospital.

Platelet aggregation inhibitors, vitamin K antagonists and risk of subarachnoid hemorrhage (Article)

2011-03-01T00:00:00Z

Background: Use of platelet aggregation inhibitors and vitamin K antagonists has been associated with an increased risk of intracranial hemorrhage (ICH). Whether the use of these antithrombotic drugs is associated with an increased risk of subarachnoid hemorrhage (SAH) remains unclear, especially as confounding by indication might play a role. Objective: The aim of the present study was to investigate whether use of platelet aggregation inhibitors or vitamin K antagonists increase the risk of SAH. Methods: We applied population-based case-control, case-crossover and case-time-control designs to estimate the risk of SAH while addressing issues both of confounding by indication and time varying exposure within the PHARMO Record Linkage System database. This system includes drug dispensing records from community pharmacies and hospital discharge records of more than 3million community-dwelling inhabitants in the Netherlands. Patients were considered a case if they were hospitalized for a first SAH (ICD-9-CM code 430) in the period between 1st January 1998 and 31st December 2006. Controls were selected from the source population, matched on age, gender and date of hospitalization. Conditional logistic regression was used to estimate multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of SAH during use of platelet aggregation inhibitors or vitamin K antagonists. In the case-crossover and case-time-control designs we selected 11 control periods preceding the index date in successive steps of 1month in the past. Results: In all, 1004 cases of SAH were identified. In the case-control analysis the adjusted OR for the risk of SAH in current use of platelet aggregation inhibitors was 1.32 (95% CI: 1.02-1.70) and in current use of vitamin K antagonists 1.29 (95% CI: 0.89-1.87) compared with no use. In the case-crossover analysis the ORs for the risk of SAH in current use of platelet aggregation inhibitors and vitamin K antagonists were 1.04 (95% CI: 0.56-1.94) and 2.46 (95% CI: 1.04-5.82), respectively. In the case-time-control analysis the OR for platelet aggregation inhibitors was 0.50 (95% CI: 0.26-0.98) and for vitamin K antagonists 1.98 (95% CI: 0.82-4.76). Conclusion: The use of platelet aggregation inhibitors was not associated with an increased SAH risk; the modest increase observed in the case-control analysis could be as a result of confounding. The use of vitamin K antagonists seemed to be associated with an increased risk of SAH. The increase was most pronounced in the case-crossover analysis and therefore cannot be explained by unmeasured confounding.

Non-cardiovascular drugs that inhibit hERG-encoded potassium channels and risk of sudden cardiac death (Article)

2011-02-01T00:00:00Z

Background: Virtually all QTc-prolonging drugs act by blocking the human ether a go-go-related gene (hERG)-encoded potassium channels (hERG channels), whereas not all QTc-prolonging drugs are associated with an increased risk of serious cardiac arrhythmias. This study assessed whether non-cardiovascular hERG channel blockers are associated with an increased risk of sudden cardiac death (SCD) and whether hERG-channel-inhibiting capacity is an indicator of the risk of SCD. Methods and results: The risk of SCD was studied in the Integrated Primary Care Information database, a longitudinal general practice research database. A case-control study was performed, matched for age, gender and calendar time. Odds ratios were calculated with conditional logistic regression, multivariably adjusted. In addition, the hERG-channel-inhibiting capacity of the different drugs was compared, defined as the effective free therapeutic plasma concentration (ETCPunbound) divided by the concentration that inhibits 50% of the potassium channels (IC50), with the risk of SCD. 1424 cases of SCD and 14 443 controls were identified. Current use of hERG channel blockers was associated with an increased risk of SCD. The risk of SCD was significantly increased in users of antipsychotic drugs. Patients using hERG channel blockers with a high ETCPunbound/IC50 ratio (≥0.033) had a higher risk of SCD than patients using drugs with a low ETCPunbound/IC50 ratio (<0.033). Conclusions: The current use of hERG channel blockers was associated with an increased risk of SCD in the general population. In addition, drugs with a high hERG-channel-inhibiting capacity had a higher risk of SCD than drugs with a low hERG-channel-inhibiting capacity.

A nationwide study of three invasive treatments for trigeminal neuralgia (Article)

2011-01-01T00:00:00Z

Risk of recurrent myocardial infarction with the concomitant use of clopidogrel and proton pump inhibitors (Article)

2011-01-01T00:00:00Z

Background: The association between myocardial infarction (MI) and co-administration of proton pump inhibitors (PPIs) and clopidogrel remains controversial. Aim: To quantify the association between concomitant use of PPIs and clopidogrel and occurrence of recurrent MI. Methods: We conducted a case-control study within a cohort of acute MI patients in PHARMO Record Linkage System (1999-2008). The cases were patients readmitted for MI. PPI exposure was categorized as current (3-1 days before MI), past (30-3 days before MI), or no use (>30 days before MI). We used conditional logistic regression analyses. Results: Among 23 655 patients hospitalized following MI, we identified 1247 patients readmitted for MI. Among clopidogrel users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.62, 95% CI: 1.15-2.27) when compared with no PPI use, but not when compared with past PPI use (OR: 0.95, 95% CI: 0.38-2.41). Among clopidogrel non-users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.38, 95% CI: 1.18-1.61) when compared with no PPI use. Conclusions The apparent association between recurrent MI and use of PPIs with clopidogrel depends on the design, and is affected by confounding by indication. The association is not present when (un)measured confounding is addressed by design.

Assessment of Pediatric asthma drug use in three European countries; A TEDDY study (Article)

2011-01-01T00:00:00Z

Asthma drugs are amongst the most frequently used drugs in childhood, but international comparisons on type and indication of use are lacking. The aim of this study was to describe asthma drug use in children with and without asthma in the Netherlands (NL), Italy (IT), and the United Kingdom (UK). We conducted a retrospective analysis of outpatient medical records of children 0-18 years from 1 January 2000 until 31 December 2005. For all children, prescription rates of asthma drugs were studied by country, age, asthma diagnosis, and off-label status. One-year prevalence rates were calculated per 100 children per patient-year (PY). The cohort consisted of 671,831 children of whom 49,442 had been diagnosed with asthma at any time during follow-up. 2-mimetics and inhaled steroids were the most frequently prescribed asthma drug classes in NL (4.9 and 4.1/100 PY), the UK (8.7 and 5.3/100 PY) and IT (7.2 and 16.2/100 PY), respectively. Xanthines, anticholinergics, leukotriene receptor antagonists, and anti-allergics were prescribed in less than one child per 100 per year. In patients without asthma, 2-mimetics were used most frequently. Country differences were highest for steroids, (Italy highest), and for 2-mimetics (the UK highest). Off-label use was low, and most pronounced for 2-mimetics in children <18 months (IT) and combined 2-mimetics + anticholinergics in children <6 years (NL). Conclusion: This study shows that among all asthma drugs, 2-mimetics and inhaled steroids are most often used, also in children without asthma, and with large variability between countries. Linking multi-country databases allows us to study country specific pediatric drug use in a systematic manner without being hampered by methodological differences. This study underlines the potency of healthcare databases in rapidly providing data on pediatric drug use and possibly safety.

Combining electronic healthcare databases in Europe to allow for large-scale drug safety monitoring: The EU-ADR Project (Article)

2011-01-01T00:00:00Z

Purpose: In this proof-of-concept paper we describe the framework, process, and preliminary results of combining data from European electronic healthcare record (EHR) databases for large-scale monitoring of drug safety. Methods: Aggregated demographic, clinical, and prescription data from eight databases in four countries (Denmark, Italy, Netherlands, the UK) were pooled using a distributed network approach by generation of common input data followed by local aggregation through custom-built software, Jerboa©. Comparison of incidence rates of upper gastrointestinal bleeding (UGIB) and nonsteroidal anti-inflammatory drug (NSAID) utilization patterns were used to evaluate data harmonization and quality across databases. The known association of NSAIDs and UGIB was employed to demonstrate sensitivity of the system by comparing incidence rate ratios (IRRs) of UGIB during NSAID use to UGIB during all other person-time. Results: The study population for this analysis comprised 19 647 445 individuals corresponding to 59 929 690 person-years of follow-up. 39 967 incident cases of UGIB were identified during the study period. Crude incidence rates varied between 38.8 and 109.5/100 000 person-years, depending on country and type of database, while age-standardized rates ranged from 25.1 to 65.4/100 000 person-years. NSAID use patterns were similar for databases within the same country but heterogeneous among different countries. A statistically significant age- and gender-adjusted association between use of any NSAID and increased risk for UGIB was confirmed in all databases, IRR from 2.0 (95%CI:1.7-2.2) to 4.3 (95%CI: 4.1-4.5). Conclusions: Combining data from EHR databases of different countries to identify drug-adverse event associations is feasible and can set the stage for changing and enlarging the scale for drug safety monitoring.

Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone (Article)

2010-12-01T00:00:00Z

The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study - SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35-0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self-harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups.

Intracranial aneurysm segmentation in 3D CT angiography: Method and quantitative validation (Article)

2010-12-01T00:00:00Z

Accurately quantifying aneurysm shape parameters is of clinical importance, as it is an important factor in choosing the right treatment modality (i.e. coiling or clipping), in predicting rupture risk and operative risk and for pre-surgical planning. The first step in aneurysm quantification is to segment it from other structures that are present in the image. As manual segmentation is a tedious procedure and prone to inter- and intra-observer variability, there is a need for an automated method which is accurate and reproducible. In this paper a novel semi-automated method for segmenting aneurysms in Computed Tomography Angiography (CTA) data based on Geodesic Active Contours is presented and quantitatively evaluated. Three different image features are used to steer the level set to the boundary of the aneurysm, namely intensity, gradient magnitude and variance in intensity. The method requires minimum user interaction, i.e. clicking a single seed point inside the aneurysm which is used to estimate the vessel intensity distribution and to initialize the level set. The results show that the developed method is reproducible, and performs in the range of interobserver variability in terms of accuracy.

Prescription data on orphan drugs (Article)

2010-11-08T00:00:00Z

Safety of sertindole versus risperidone in schizophrenia: Principal results of the sertindole cohort prospective study (SCoP) (Article)

2010-11-01T00:00:00Z

Objective: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. Method: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. Results: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). Conclusion: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

Drug-induced hepatic injury in children: A case/non-case study of suspected adverse drug reactions in VigiBase (Article)

2010-11-01T00:00:00Z

Aim: To identify which drugs are associated with reports of suspected hepatic injury in children and adolescents. Methods: Using a worldwide pharmacovigilance database, VigiBase, we conducted a case/non-case study on suspected adverse drug reactions (ADRs) occurring in the population <18 years old. Cases were all the records with hepatic ADRs and non-cases were all the other ADR records. Records regarding topically administered drugs were excluded from both groups. The association between drug and suspected hepatic ADRs was calculated using the reporting odds ratio (ROR) as a measure of disproportionality while adjusting for gender, country, reporter and calendar year. Sub-analyses were performed within therapeutic class and by excluding vaccination-related reports to reduce confounding. Results: Overall, 6595 (1%) out of 624 673 ADR records in children and adolescents concerned hepatic injury. Most of the reported hepatic injuries concerned children 12-17 years of age. Drugs that were most frequently reported as suspected cause and were associated with hepatic injury comprised paracetamol, valproic acid, carbamazepine, methotrexate, minocycline, zidovudine, pemoline, ceftriaxone, bosentan, ciclosporin, atomoxetine, olanzapine, basiliximab, erythromycin and voriconazole. The association between hepatotoxicity and all these drugs, except for basiliximab, is already known. Conclusions: Drug-induced hepatic injury is infrequently reported (only 1% of total) as a suspected ADR in children and adolescents. The drugs associated with reported hepatotoxicity (paracetamol, antiepileptic and anti-tuberculosis agents) are known to be hepatotoxic in adults as well, but age related changes in associations were observed. VigiBase is useful as a start to plan further drug safety studies in children.

How the European paediatric regulation is reducing the gap (Article)

2010-10-01T00:00:00Z

Prediction of two month modified Rankin Scale with an ordinal prediction model in patients with aneurysmal subarachnoid haemorrhage (Article)

2010-10-01T00:00:00Z

Background. Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with a frequently disabling outcome. Our aim was to develop a prognostic model to predict an ordinal clinical outcome at two months in patients with aSAH. Methods. We studied patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomized multicentre trial to compare coiling and clipping in aSAH patients. Several models were explored to estimate a patient's outcome according to the modified Rankin Scale (mRS) at two months after aSAH. Our final model was validated internally with bootstrapping techniques. Results. The study population comprised of 2,128 patients of whom 159 patients died within 2 months (8%). Multivariable proportional odds analysis identified World Federation of Neurosurgical Societies (WFNS) grade as the most important predictor, followed by age, sex, lumen size of the aneurysm, Fisher grade, vasospasm on angiography, and treatment modality. The model discriminated moderately between those with poor and good mRS scores (c statistic = 0.65), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.64). Conclusion. We presented a calibrated and internally validated ordinal prognostic model to predict two month mRS in aSAH patients who survived the early stage up till a treatment decision. Although generalizability of the model is limited due to the selected population in which it was developed, this model could eventually be used to support clinical decision making after external validation. Trial Registration. International Standard Randomised Controlled Trial, Number ISRCTN49866681.

Effectiveness of antibiotics for acute sinusitis in real-life medical practice (Article)

2010-09-01T00:00:00Z

AIMS To assess the effectiveness of antibiotics in acute bacterial sinusitis. METHODS This was a prospective cohort study with 2 months follow-up of 5640 patients with acute sinusitis included by a random sample from 1174 GPs and 120 ENT specialists. Main outcomes were short-term initial success, defined as the absence of prescription of (another) antibiotic or sinus lavage within 10 days, and lack of recurrence between the 11th and 60th day, after initial success. RESULTS Initial success was found in 88.7% (95% CI 85.1, 91.4%) of patients without antibiotic prescription at inclusion and 96.2% (95% CI 95.7, 96.7%) of patients prescribed antibiotics. The 10 day adjusted hazard ratio (HR) for treatment failure (new antibiotic prescription or sinus drainage) with initial antibiotics compared with no antibiotics was 0.30 (95% CI 0.21, 0.42) with no difference between antibiotics. Antibiotics were more effective in patients with poor oro-dental condition (HR 0.04, 95% CI 0.01, 0.20) and in patients who had already used antibiotics during the previous 2 months (HR 0.09, 95% CI 0.03, 0.28). For patients without failure at 10 days, recurrence between the 11th and 60th day was similar whether or not they had initially been prescribed an antibiotic, 94.1% (95% CI 93.4, 94.7%) and 93.4% (95%CI 90.3, 95.5%), respectively. CONCLUSION Most acute sinusitis cases not prescribed antibiotics resolve spontaneously. Antibiotics reduced by 3.3-fold the risk of failure within 10 days, without impact on later recurrence. The greatest benefit of antibiotics was found for patients with poor oro-dental condition or with antibiotic use within the previous 2 months.

Association between calcium channel blockers and gingival hyperplasia (Article)

2010-07-01T00:00:00Z

Aim: To study the effect of the dose and type of calcium channel blockers (CCBs) on the risk of gingival hyperplasia and to quantify this association. Methods: The study was conducted within the Integrated Primary Care Information Project in The Netherlands. A nested case-control study was designed within a cohort of all patients who were new users of either CCBs or drugs interacting with the renin-angiotensin system (RAS). Cases were all individuals with a validated diagnosis of gingival hyperplasia. Controls were matched on age, gender and index date. Results: Within the study population, 103 cases of gingival hyperplasia were identified and matched to 7677 controls. The risk of gingival hyperplasia was higher in current users of CCBs [adjusted odds ratio (ORadj) 2.2, 95% confidence intervals (95% CI): 1.4-3.4], especially in dihydropyridines (ORadj2.1, 95% CI: 1.3-3.5) and benzothiazepine derivatives (ORadj2.9, 95% CI: 1.3-6.5) than in RAS drug users. The risk increased in patients using more than the recommended daily dose (ORadj3.0, 95% CI: 1.6-5.5) and when the duration of current use was <1 month (ORadj5.2, 95% CI: 2.1-12.6). Conclusion: This study shows that the risk of gingival hyperplasia is twofold higher in current users of CCBs than in users of RAS drugs. The association was dose dependent and the highest for dihydropyridines or benzothiazepine derivates.

Time-trends in gastroprotection with nonsteroidal anti-inflammatory drugs (NSAIDs) (Article)

2010-06-01T00:00:00Z

Background Preventive strategies are advocated in patients at risk of upper-gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Aim To examine time-trends in preventive strategies. Methods In a study population comprising 50 126 NSAID users ≥50 years from the Integrated Primary Care Information database, we considered two preventive strategies: co-prescription of gastroprotective agents and prescription of a cyclooxygenase-2-selective inhibitor. In patients with ≥1 risk factor (history of upper-gastrointestinal bleeding/ulceration, age >65 years, use of anticoagulants, aspirin, or corticosteroids), correct prescription was defined as the presence of a preventive strategy and under-prescription as the absence of one. In patients with no risk factors, correct prescription was defined as the lack of a preventive strategy, and over-prescription as the presence of one. Results Correct prescription rose from 6.9% in 1996 to 39.4% in 2006 (P < 0.01) in high-risk NSAID users. Under-prescription fell from 93.1% to 59.9% (P < 0.01). In the complete cohort, over-prescription rose from 2.9% to 12.3% (P < 0.01). Conclusions Under-prescription of preventive strategies has steadily decreased between 1996 and 2006; however, 60% of NSAID users at increased risk of NSAID complications still do not receive adequate protection.

Risk of Ischemic Stroke Associated with Antidepressant Drug Use in Elderly Persons (Article)

2010-06-01T00:00:00Z

Competing hypotheses have been formulated about a possible association between selective serotonin reuptake inhibitors (SSRIs) and ischemic stroke. However, the relationship between antidepressant drug use and ischemic stroke is still unclear. The aim of the study was to assess the association between the use of different types of antidepressants and the risk of ischemic stroke in elderly outpatients.A population-based, nested, case-control study was conducted in persons 65 years and older in the Integrated Primary Care Information database (1996-2005). Cases were all patients with a validated first ischemic stroke. Controls were matched on year of birth, sex, and index date. Exposure to antidepressants was divided in current, past, and nonuse and further categorized by type (SSRI, tricyclic, and other antidepressants), dose, and duration. Conditional logistic regression was used to compare the risk of ischemic stroke between users of antidepressants and nonusers.Overall, 996 incident ischemic strokes were identified. Current use of SSRIs was associated with a significantly increased risk as compared with nonuse (odds ratio, 1.55; 95% confidence interval, 1.07-2.25) in elderly patients, particularly when used for less than six months. No associations were observed for current use of tricyclic and other antidepressant drugs.To summarize, compared with nonuse, only SSRI use seems to be associated with an increased risk of ischemic stroke in elderly patients, particularly as a short-term effect.

Genome-wide association study of intracranial aneurysm identifies three new risk loci (Article)

2010-05-01T00:00:00Z

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10 12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10 9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10 9). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 × 10 12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10 22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Comparison of antiepileptic drug prescribing in children in three European countries (Article)

2010-05-01T00:00:00Z

Purpose: Antiepileptic drug (AED) use in young people is increasing. However, evidence of its use at a multinational level is limited. This study aims to characterize AED prescribing in the young in three European countries and to assess the capacity of drug safety surveillance. Methods: A retrospective cohort study was conducted in 2001-2005 using primary care databases: PEDIANET (Italy, 0-11 years), IPCI (The Netherlands, 0-18 years), and IMS Disease Analyzer (United Kingdom, 0-18 years). Prescribing prevalence was calculated by country, patient age, and drug type. Results: In 2005, AED prevalence in children (0-11 years) was highest in Italy [3.9 subjects/1,000 person-years (PY)] followed by the United Kingdom (3.0 subjects/1,000 PY) and The Netherlands (2.2 subjects/1,000 PY). Over the study period, prescribing prevalence in 0-11 year olds was stable in all countries. In contrast, a steady rise of AED prevalence was observed in adolescents (12-18 years) in the United Kingdom (p = 0.0003) but not in The Netherlands (p = 0.88). All countries showed a slight increase in prevalence for newer AEDs. Simultaneously, the prevalence of conventional AEDs decreased in The Netherlands and Italy, but not in the United Kingdom. In 2005, lamotrigine use was highest in The Netherlands and the United Kingdom, whereas topiramate was favored in Italy. Discussion: In Europe, conventional AEDs are still the main treatment choice for children with epilepsy, and the use of newer AEDs remains low. Our study highlights a lack of research capacity to conduct multinational AED safety studies in children. Further work should explore large databases and other health care settings to meet these research needs.

Prediction of 60 day case-fatality after aneurysmal subarachnoid haemorrhage: results from the International Subarachnoid Aneurysm Trial (ISAT) (Article)

2010-04-01T00:00:00Z

Aneurysmal subarachnoid haemorrhage (aSAH) is a devastating event with substantial case-fatality. Our purpose was to examine which clinical and neuro-imaging characteristics, available on admission, predict 60 day case-fatality in aSAH and to evaluate performance of our prediction model. We performed a secondary analysis of patients enrolled in the International Subarachnoid Aneurysm Trial (ISAT), a randomised multicentre trial to compare coiling with clipping in aSAH patients. Multivariable logistic regression analysis was used to develop a prognostic model to estimate the risk of dying within 60 days from aSAH based on clinical and neuro-imaging characteristics. The model was internally validated with bootstrapping techniques. The study population comprised of 2,128 patients who had been randomised to either endovascular coiling or neurosurgical clipping. In this population 153 patients (7.2%) died within 60 days. World Federation of Neurosurgical Societies (WFNS) grade was the most important predictor of case-fatality, followed by age, lumen size of the aneurysm and Fisher grade. The model discriminated reasonably between those who died within 60 days and those who survived (c statistic = 0.73), with minor optimism according to bootstrap re-sampling (optimism corrected c statistic = 0.70). Several strong predictors are available to predict 60 day case-fatality in aSAH patients who survived the early stage up till a treatment decision; after external validation these predictors could eventually be used in clinical decision making.

In-label and off-label use of respiratory drugs in the Italian paediatric population (Article)

2010-04-01T00:00:00Z

Aim: To evaluate the prescription rate of respiratory drugs (ATC code R03) in an Italian community setting and to estimate the extent of off-label use by both age and indication. Methods: A cohort study aimed at evaluating prescriptions of drugs with ATC code R03 was conducted for the period 2002-2006. Data source was the PEDIANET Database. Results: Ninety percent of R03 prescriptions are covered by 11 active substances or combinations, corresponding to 67 medicinal products. Inhaled corticosteroids are the most prescribed anti-asthmatic agents, followed by short-acting β2 mimetics. The mean off-label rate is 19 and 56%, by age and indication respectively. The majority of off-label uses is among children under the age of 2. Five active substances are used at dosages not supported by adequate dose-finding studies. Conclusion: In Italy, many respiratory drugs are approved for the treatment of paediatric respiratory diseases, but a remarkable percentage of their prescriptions is off-label. This pharmaco-utilization study demonstrates that there is a need to perform clinical studies aimed at increasing the current knowledge on marketed paediatric drugs, and to revise and re-label the existing regulatory documents to reduce their off-label uses.

Intracranial aneurysm segmentation in 3D CT angiography: Method and quantitative validation with and without prior noise filtering (Article)

2010-03-25T00:00:00Z

Intracranial aneurysm volume and shape are important factors for predicting rupture risk, for pre-surgical planning and for follow-up studies. To obtain these parameters, manual segmentation can be employed; however, this is a tedious procedure, which is prone to inter- and intra-observer variability. Therefore there is a need for an automated method, which is accurate, reproducible and reliable. This study aims to develop and validate an automated method for segmenting intracranial aneurysms in Computed Tomography Angiography (CTA) data. Also, it is investigated whether prior smoothing improves segmentation robustness and accuracy. The proposed segmentation method is implemented in the level set framework, more specifically Geodesic Active Surfaces, in which a surface is evolved to capture the aneurysmal wall via an energy minimization approach. The energy term is composed of three different image features, namely; intensity, gradient magnitude and intensity variance. The method requires minimal user interaction, i.e. a single seed point inside the aneurysm needs to be placed, based on which image intensity statistics of the aneurysm are derived and used in defining the energy term. The method has been evaluated on 15 aneurysms in 11 CTA data sets by comparing the results to manual segmentations performed by two expert radiologists. Evaluation measures were Similarity Index, Average Surface Distance and Volume Difference. The results show that the automated aneurysm segmentation method is reproducible, and performs in the range of inter-observer variability in terms of accuracy. Smoothing by nonlinear diffusion with appropriate parameter settings prior to segmentation, slightly improves segmentation accuracy.

Pharmacological Treatment of Neuropathic Facial Pain in the Dutch General Population (Article)

2010-03-01T00:00:00Z

Few drugs are registered for treatment of neuropathic facial pain (NFP), and not much is known about treatment choices for NFP in daily practice. Patients with NFP were identified in the IPCI-database with longitudinal electronic general practitioner (GP) records. We described prescription patterns of pain medication following first symptoms. Off-label, off-guideline use, failure and reasons for failure were assessed. Failure was defined as treatment switch, exacerbation, adverse event, or invasive treatment for NFP. Of 203 NFP cases, 160 (79%) received pharmacological pain treatment. Most patients (90%) were initially treated by a GP with anti-epileptic drugs (55%) or NSAIDs (16%) as monotherapy. The median treatment delay was 0 days (range 0 to 2,478 days). Adverse events were experienced by 16 (10%) of patients. Sixty-two percent of first prescriptions were in adherence to guidelines and 59% were considered on-label while 34% of prescriptions were both off-label and off-guideline. Of the first therapy, 38% failed within 3 months. The median duration until failure was 251 days. General practitioners usually are the first to treat NFP. They usually prescribe drugs licensed for NFP and according to guidelines, but the extent of off-label use is substantial. Initial treatment often failed within a short period after starting therapy. Perspective: This drug-utilization study describes the pharmacological treatment of different forms of neuropathic facial pain in daily practice. Although treatment is mostly initiated rapidly by general practitioners in a correct way, it often contains off-label or off-guideline medication. Failure of the initial treatment is common and occurs rapidly as well.

Determination of non-treatment with statins of high risk patients in the Netherlands (Article)

2010-02-01T00:00:00Z

Objective: To determine in the Netherlands what proportions of high risk patients with established cardiovascular disease (CVD) or diabetes mellitus type 2 (DM2) who were not treated with statins on 1 January 2007 and which characteristics were associated with non-treatment. Methods: From the IPCI GP database patients were selected who were registered with a GP on 1 January 2007 who had a history of either CVD (CVD patients), DM2 (diabetics) or both (diabetics with CVD). The proportion of patients using statins around 1 January 2007 was determined. Associations of patient characteristics with non-treatment were quantified (CVD patients and diabetics only). Results: In all, 19 628 CVD patients, 5006 diabetics and 3767 diabetics with CVD were identified. Of these patients 71, 54 and 45, respectively did not use statins. These proportions were similar in the subgroups of patients with recent LDL-C measurements. Among these subgroups the vast majority of non-treated patients was eligible for statin treatment (LDL-C >2.5mmol/l). The proportion of statin-treated patients was larger among diabetics than among CVD patients. Among CVD patients, female gender, age below 40 years, living in a deprived area, a history of CVD of less than 1 year and arrhythmia were significantly associated with non-treatment. Among diabetics, significant associations were: living in a deprived area and specialist visits in the previous year. In 2003, treatment rates among diabetics were lower, but among CVD patients they were similar. This suggests that the higher treatment rates among diabetics compared to CVD patients in 2007 may be the result of disease-management programmes introduced for diabetics in 2004. Conclusion: The majority of patients with established CVD or DM2 were not treated with statins on 1 January 2007. Eligibility for statin treatment may have been overestimated due to unavailability of cholesterol levels among many non-treated patients. Implementation of care programmes for CVD patients may increase treatment rates among eligible CVD patients.

Serum glucose and insulin are associated with QTc and RR intervals in nondiabetic elderly (Article)

2010-02-01T00:00:00Z

Aims: To study whether nondiabetic persons with impaired fasting serum glucose and hyperinsulinemia have QTc/QT interval prolongation and RR interval shortening in the electrocardiogram (ECG), and whether these were associated with an increased risk of sudden cardiac death. Methods: This study consisted of two analyses. First, a cross-sectional analysis was used as part of the population-based Rotterdam Study including 1050 men and 1520 women (≥55 years) without diabetes mellitus. Participants in round 3 of the Rotterdam Study for whom an ECG and fasting serum glucose and fasting insulin measurements were available were eligible for the study. Participants using digoxin or QTc-prolonging drugs and participants with left ventricular hypertrophy and left and right bundle branch block were excluded. The endpoints of the study were the lengths of the QTc, QT, and RR intervals. The associations were examined by means of linear regression analysis. Secondly, in all 6020 participants of the Rotterdam Study with an ECG, the associations between the QTc, QT, and RR intervals and sudden cardiac death were examined by means of Cox regression analysis. Results: Overall, there was a significant association between impaired fasting serum glucose and the QTc interval with an increase of 2.6 ms (95% confidence interval (CI): 0.3; 5.0) in those with fasting glucose >6 mmol/l. Hyperinsulinemia was also associated with QTc prolongation (3.0 ms (0.8; 5.3)) in those with fasting insulin ≥100 pmol/l. Impaired fasting glucose (IFG) and hyperinsulinemia were significantly associated with a decrease of the RR interval (-33.7 ms (-48.8;-18.6) and -44.4 ms (-58.7; -30.0) respectively). Participants in the fourth quartile of the QTc and QT intervals had a significantly increased risk of sudden cardiac death compared to participants in the first quartile (hazard ratio (HR) 2.87 (95% CI: 2.02-4.06); HR 3.05 (1.99-4.67) respectively). Furthermore, there was a significant inverse association between the fourth quartile of the RR interval compared to the first quartile and the risk of sudden cardiac death (HR 0.49 (0.34-0.80)). Conclusion: In this population-based study, we demonstrated that IFG and hyperinsulinemia are associated with a significantly increased QTc interval and with significant shortening of the RR interval, the latter probably due to an increased sympathetic activity. In addition, we demonstrated that both a prolonged QTc interval and a shortened RR interval are associated with an increased risk of sudden cardiac death.

Study designs in paediatric pharmacoepidemiology (Article)

2010-01-01T00:00:00Z

Purpose: Few data on the efficacy and safety of drugs in children are available as in the past, these children were not included in randomized controlled trials (RCTs). Data on the efficacy and safety of drugs in children are extrapolated from adults. The EMA recognizes the need for long-term safety studies on various drugs, a need that can best be answered by pharmacoepidemiological studies. In this article, we provide currently available information on study designs within the field of paediatric drug research. Methods: A PubMed search was conducted on all pharmacoepidemiological studies in children. In addition, data from handbooks on pharmacoepidemiology were consulted. Data were reviewed and the relevant literature on study designs in paediatric pharmacoepidemiology is described. Results: The various study designs in pharmacoepidemiology have their specific indications, all with their specific limitations. Case reports and case series are mainly used for signal detection of safety issues whereas case control and cohort studies are used for safety hypothesis testing. Observational studies can be conducted using data from automated databases that guarantee large sample size and long-term follow-up, which is ideal for safety studies, especially in case of rare events. Conclusion: Pharmacoepidemiological studies are crucial in research on the safety of drugs in children. Knowledge of the different pharmacoepidemiological methods is important to guarantee optimal use and correct interpretation of the data.

The association of serum testosterone levels and ventricular repolarization (Article)

2010-01-01T00:00:00Z

It is assumed that testosterone is an important regulator of gender-related differences in ventricular repolarization. Therefore, our aim was to study whether serum levels of testosterone are associated with QTc, QT and RR interval variation. Setting: two independent population-based cohort studies. Participants: 445 male participants (≥ 55 years) from the Rotterdam study cohort and 1,428 male participants from the study of health in Pomerania (SHIP) with an electrocardiogram who were randomly sampled for assessment of serum testosterone at baseline, after exclusion of participants with testosterone altering drugs, QTc prolonging drugs or dig(it)oxin, left ventricular hypertrophy and left and right bundle branch block. Endpoints: length of the QTc, QT and RR intervals. Analysis: linear regression model, adjusted for the two individual studies and a pooled analysis of both studies. The pooled analysis of the Rotterdam study and SHIP showed that the QTc interval gradually decreased among the tertiles (P value for trend 0.024). The third tertile of serum testosterone was associated with a lower QTc interval compared to the first tertile [-3.4 ms (-6.5; -0.3)]. However, the third tertile of serum testosterone was not associated with a lower QT interval compared to the first tertile [-0.7 ms (-3.1; 1.8)]. The RR interval gradually increased among the tertiles (P value for trend 0.002) and the third tertile of serum testosterone showed an increased RR interval compared to the first tertile [33.5 ms (12.2; 54.8)]. In the pooled analysis of two population-based studies, serum testosterone levels were not associated with the QT interval, which could be due to a lack of power. Lower QTc intervals in men with higher serum testosterone levels could be due to the association of serum testosterone with prolongation of the RR interval.

Prescribing pattern of antipsychotic drugs in the Italian general population 2000-2005: A focus on elderly with dementia (Article)

2010-01-01T00:00:00Z

The objective of this study was to evaluate the antipsychotic drug prescribing pattern in the Italian general population, elderly, and especially elderly with dementia, in relation to the safety warnings issued by international regulatory agencies about the risk of cerebrovascular adverse events and mortality in 2004 and 2005. A cohort study was conducted using the electronic medical records of the Italian general practice database 'Health Search/Thales'. On the basis of prescription data, 1-year and monthly prevalence estimates were calculated for atypical and typical antipsychotic use in general population, elderly, and elderly demented outpatients. One-year prevalence of individual medication use in elderly demented patients was calculated as well. The prevalence of use of atypical agents in demented patients progressively increased from 2000 [0.2 (0.05-0.7) per 10000] until the beginning of 2004 [9.7 (8.1-11.6) per 10000], after which a slight decrease started, whereas the prevalence of use of typical antipsychotics decreased from 2001 [15.7 (13.5-18.2) per 10000] until 2004 [10.7 (9.0-12.7) per 10000], then slightly increased in December 2005 [12.1 (10.4-14.2) per 10000]. Monthly trends in general population and elderly were quite similar and differed significantly from the trend in elderly with dementia: stable use of atypicals from 2002 to 2005 and strong reduction of typicals from 2001 to the end of 2004. The recent safety warnings led to an increasing trend in the use of typical agents and decreasing trend in the use of atypical agents in elderly demented outpatients in Italy. Similar trends were not observed in general population and elderly as a whole.

Data mining on electronic health record databases for signal detection in pharmacovigilance: Which events to monitor? (Article)

2009-12-28T00:00:00Z

Purpose: Data mining on electronic health records (EHRs) has emerged as a promising complementary method for post-marketing drug safety surveillance. The EU-ADR project, funded by the European Commission, is developing techniques that allow mining of EHRs for adverse drug events across different countries in Europe. Since mining on all possible events was considered to unduly increase the number of spurious signals, we wanted to create a ranked list of high-priority events. Methods: Scientific literature, medical textbooks, and websites of regulatory agencies were reviewed to create a preliminary list of events that are deemed important in pharmacovigilance. Two teams of pharmacovigilance experts independently rated each event on five criteria: 'trigger for drug withdrawal', 'trigger for black box warning', 'leading to emergency department visit or hospital admission', 'probability of event to be drug-related', and 'likelihood of death'. In case of disagreement, a consensus score was obtained. Ordinal scales between 0 and 3 were used for rating the criteria, and an overall score was computed to rank the events. Results: An initial list comprising 23 adverse events was identified. After rating all the events and calculation of overall scores, a ranked list was established. The top-ranking events were: cutaneous bullous eruptions, acute renal failure, anaphylactic shock, acute myocardial infarction, and rhabdomyolysis. Conclusions: A ranked list of 23 adverse drug events judged as important in pharmacovigilance was created to permit focused data mining. The list will need to be updated periodically as knowledge on drug safety evolves and newissues in drug safety arise. Copyright

Incidence of facial pain in the general population (Article)

2009-12-15T00:00:00Z

Facial pain has a considerable impact on quality of life. Accurate incidence estimates in the general population are scant. The aim was therefore to estimate the incidence rate (IR) of trigeminal neuralgia (TGN), postherpetic neuralgia (PHN), cluster headache (CH), occipital neuralgia (ON), local neuralgia (LoN), atypical facial pain (AFP), glossopharyngeal neuralgia (GPN) and paroxysmal hemicrania (PH) in the Netherlands. In the population-based Integrated Primary Care Information (IPCI) medical record database potential facial pain cases were identified from codes and narratives. Two medical doctors reviewed medical records, questionnaires from general practitioners and specialist letters using criteria of the International Association for the Study of Pain. A pain specialist arbitrated if necessary and a random sample of all cases was evaluated by a neurologist. The date of onset was defined as date of first specific symptoms. The IR was calculated per 100,000 PY. Three hundred and sixty-two incident cases were ascertained. The overall IR [95% confidence interval] was 38.7 [34.9-42.9]. It was more common among women compared to men. Trigeminal neuralgia and cluster headache were the most common forms among the studied diseases. Paroxysmal hemicrania and glossopharyngeal neuralgia were among the rarer syndromes. The IR increased with age for all diseases except CH and ON, peaking in the 4th and 7th decade, respectively. Postherpetic neuralgia, CH and LoN were more common in men than women. From this we can conclude that facial pain is relatively rare, although more common than estimated previously based on hospital data.

Evaluation of serological trials submitted for annual re-licensure of influenza vaccines to regulatory authorities between 1992 and 2002 (Article)

2009-12-11T00:00:00Z

Background: As part of the regulatory requirements, serological evaluation of trivalent inactivated influenza vaccines must be performed before annual re-licensure in the European Union. These studies are typically set up as uncontrolled, open label trials including 2 groups of at least 50 healthy adults and healthy elderly. Methods: The serological data submitted to the Dutch Medicines Evaluation Board (MEB) for annual re-licensure purposes between 1992 and 2002, were analysed with respect to their ability to assess the immunogenic properties of the vaccines. The trials in this meta-analysis were selected by strictly applying the inclusion and exclusion criteria described in the Committee of Human Medicinal Products (CHMP) Note for Guidance on harmonisation of requirements for influenza vaccines. To select the final dataset additional exclusion criteria were defined: age outside the inclusion criterion of the trial, incomplete demographics, co-morbid conditions, antibody determination by SRH assay, incomplete dataset and sample size smaller than 50 subjects. Results: Out of 51 trials retrieved from the archives, 48 age-defined trials including 2510 adults and 2008 elderly fulfilled all the in- and exclusion criteria. A large proportion of vaccinees already met the threshold for seroprotection at baseline. Post-vaccination, the serological response was shown to be age dependent. Previous influenza vaccinations significantly affected pre-vaccination but not post-vaccination titres. Conclusions: The annual update trials performed for regulatory purposes have serious methodological limitations, which affect their ability to identify influenza vaccines with low immunogenicity. To establish clinical (protective) efficacy different trials and different assessment criteria are needed.

Increased Risk of Complex Regional Pain Syndrome in Siblings of Patients? (Article)

2009-12-01T00:00:00Z

An increased risk among siblings of probands with complex regional pain syndrome (CRPS) may be indicative of a genetic contribution. We calculated the sibling recurrence risk ratio (λsibling), a measure of familial aggregation. We surveyed 405 CRPS patients to collect information on the occurrence of CRPS in their siblings and compared this risk with the population risk to develop the syndrome. Information on disease status was collected from 1242 siblings, of which 24 were possibly affected according to their siblings. The diagnosis was confirmed in 16 patients, rejected in 2, and could not be verified in the remaining 6. Age-specific risk ratios were calculated for younger (<50 years) and older (≥50 years) age groups. The strongest effects were seen in the younger age group, with a λsiblingfor possibly affected and confirmed cases of 5.6 (95% CI, 3.0 to 9.8) and 3.4 (95% CI, 1.5 to 6.8), respectively. We concluded that this study yielded no indications for an overall increased risk of developing CRPS for siblings of CRPS patients but that the risk was significantly increased in siblings younger than 50, which may indicate that genetic factors play a more pronounced role in this subgroup. Perspective: We studied the risk of developing CRPS for siblings of patients with this syndrome. Although the overall risk for siblings was not increased compared with the population risk, the risk for younger siblings was elevated. To enhance chances of success, future genetic studies may consider restricting inclusion to younger-onset cases.

Role of NFκB in an Animal Model of Complex Regional Pain Syndrome-type I (CRPS-I) (Article)

2009-11-01T00:00:00Z

NFκB is involved in several pathogenic mechanisms that are believed to underlie the complex regional pain syndrome (CRPS), including ischemia, inflammation and sensitization. Chronic postischemia pain (CPIP) has been developed as an animal model that mimics the symptoms of CRPS-I. The possible involvement of NFκB in CRPS-I was studied using CPIP rats. Under sodium pentobarbital anesthesia, a tourniquet was placed around the rat left ankle joint, producing 3 hours of ischemia, followed by rapid reperfusion (IR injury). NFκB was measured in nuclear extracts of muscle and spinal cord tissue using ELISA. Moreover, the anti-allodynic (mechanical and cold) effect was tested for systemic, intrathecal, or intraplantar treatment with the NFκB inhibitor pyrrolidine dithiocarbamate (PDTC). At 2 and 48 hours after IR injury, NFκB was elevated in muscle and spinal cord of CPIP rats compared to shams. At 7 days, NFκB levels were normalized in muscle, but still elevated in spinal cord tissue. Systemic PDTC treatment relieved mechanical and cold allodynia in a dose-dependent manner, lasting for at least 3 hours. Intrathecal-but not intraplantar-administration also relieved mechanical allodynia. The results suggest that muscle and spinal NFκB plays a role in the pathogenesis of CPIP and potentially of human CRPS. Perspective: Using the CPIP model, we demonstrate that NFκB is involved in the development of allodynia after a physical injury (ischemia and reperfusion) without direct nerve trauma. Since CPIP animals exhibit many features of human CRPS-I, this observation indicates a potential role for NFκB in human CRPS.

Management of antihypertensive drugs in three European countries (Article)

2009-09-01T00:00:00Z

Objectives To compare rates of treatment discontinuation of and changes in initial antihypertensive drug therapy in the natural setting of treatment dispensation of Italy, Sweden and the Netherlands. Methods The cohorts included all the 23 715 (Italy), 20 289 (Sweden), and 5801 (the Netherlands) patients aged 40-70 years who received their first antihypertensive drug prescription from July 1, 2006 to September 30, 2006. Discontinuation was assumed if no antihypertensive drug was issued within 90 days following the end of the latest antihypertensive dispensation. Addition or replacement of the initial medication during the 90-day interval were defined as treatment combination or treatment switching. Results At 9 months after treatment initiation, the discontinuation rate of any antihypertensive drug was 24%. Compared with Italian patients, the discontinuation rate was significantly lower in Swedish [hazard ratios: 0.52, 95% confidence interval (CI): 0.50-0.54] and Dutch patients (hazard ratio: 0.79, 95% CI: 0.75-0.84). Almost 21 and 16% of patients who started on monotherapy respectively combined with and switched to another antihypertensive drug. Compared with Italian patients, the adjusted hazard rate of combining was lower in Swedish patients (hazard ratio: 0.83, 95% CI: 0.79-0.87). The hazard rate of switching was lower in Swedish and Dutch patients than in Italians (hazard ratios: 0.83, 95% CI: 0.79-0.88 and hazard ratio: 0.77, 95% CI: 0.71 -0.84 respectively). Conclusion Management of hypertension is unsatisfactory worldwide due to a very high rate of treatment discontinuation or insufficient use of proper treatment strategies.

Population-based studies of antithyroid drugs and sudden cardiac death (Article)

2009-09-01T00:00:00Z

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Thyroid hormone free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death. • The association between hyperthyroidism and ventricular arrhythmias or sudden cardiac death has been reported in several case reports. WHAT THIS STUDY ADDS • We investigated in a prospective population-based cohort study and in a case-control study whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of sudden cardiac death. • Use of antithyroid drugs was associated with a threefold increased risk of sudden cardiac death. • Although this might be due to antithyroid drug use, it could be more readily explained by underlying hyperthyroidism. AIM Thyroid free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death (SCD). Hyperthyroidism has been associated with SCD in case reports, but there are no population-based studies confirming this. The aim was to investigate whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of SCD. METHODS We studied the occurrence of SCD in a two-step procedure in two different Dutch populations. First, the prospective population-based Rotterdam Study including 7898 participants (≥55 years old). Second, we used the Integrated Primary Care Information (IPCI) database, which is a longitudinal general practice research database to see whether we could replicate results from the first study. Drug use at the index date was assessed with prescription information from automated pharmacies (Rotterdam Study) or drug prescriptions from general practices (IPCI). We used a Cox proportional hazards model in a cohort analysis, adjusted for age, gender and use of QTc prolonging drugs (Rotterdam Study) and conditional logistic regression analysis in a case-control analysis, matched for age, gender, practice and calendar time and adjusted for arrhythmia and cerebrovascular ischaemia (IPCI). RESULTS In the Rotterdam Study, 375 participants developed SCD during follow-up. Current use of antithyroid drugs was associated with SCD [adjusted hazard ratio 3.9; 95% confidence interval (CI) 1.7, 8.7]. IPCI included 1424 cases with SCD and 14 443 controls. Also in IPCI, current use of antithyroid drugs was associated with SCD (adjusted odds ratio 2.9; 95% CI 1.1, 7.4). CONCLUSIONS Use of antithyroid drugs was associated with a threefold increased risk of SCD. Although this might be directly caused by antithyroid drug use, it might be more readily explained by underlying poorly controlled hyperthyroidism, since treated patients who developed SCD still had low thyroid-stimulating hormone levels shortly before death.

The impact of electronic memory in the treatment of dyslipidemia (Article)

2009-09-01T00:00:00Z

Outcome of the complex regional pain syndrome (Article)

2009-09-01T00:00:00Z

Objectives: The outcome of complex regional pain syndrome (CRPS) is relatively unknown. High disease resolution rates have been reported, but also long-lasting impairments in many patients. This study aims to assess CRPS outcome in a population-based cohort of CRPS patients. Methods: CRPS patients were retrospectively identified (1996 to 2005) in a Dutch general practitioners database, the integrated primary care information project, and included if at onset (ie, in the past) they had complied with the International Association for the Study of Pain (IASP) diagnostic criteria. The disease status at minimum of 2 years since onset was assessed during visits using questionnaires, interviews, and physical examination. Symptoms and signs were compared with reference patients with an identical past injury but without CRPS. Actual fulfillment of the IASP criteria, treatment status, self-reported recovery, and working status were recorded. Moreover, to identify the potential prognostic factors, baseline patient characteristics were compared across subgroups according to the CRPS outcome. These subgroups were derived by cluster analysis on actual symptoms and signs. Results: One hundred and two CRPS patients were assessed at on average 5.8 years (range: 2.1 to 10.8) since onset. CRPS patients displayed higher symptom and sign prevalences in all categories (sensory, vasomotor, sudomotor, and motor/trophic) than controls. Sixteen percent (95% CI: 9-22) reported the CRPS as still progressive, whereas 31% (95% CI: 19-43) were incapable of working. Patients in the poorest outcome cluster more often had their upper extremity affected, event other than a fracture, and cold CRPS. Discussion: Severe CRPS outcome is rare, but a majority of patients has persistent impairments at 2 or more years since onset.

Cardiovascular and psychiatric risk profile and patterns of use in patients starting anti-obesity drugs (Article)

2009-08-27T00:00:00Z

Purpose: Real-life experience with anti-obesity drugs has shown that psychiatric and cardiovascular diseases may be reported as adverse drug reactions. For adequate risk assessment of these drugs knowledge on baseline risks of patients starting anti-obesity drugs and insight in patterns of use is needed. The aim was to assess whether baseline characteristics of patients starting anti-obesity drugs differ from those not being prescribed these drugs, and to study patterns of anti-obesity drug use. Methods: A population-based cohort study was conducted in the IPCI database (1995-2007). The index cohort comprised all persons who started an anti-obesity drug. The reference cohort comprised up to six randomly sampled patients from the same GP practice with same index date. Baseline characteristics were assessed for both cohorts. The index cohort was followed for 1 year to study patterns of drug use. Unconditional logistic regression was used to calculate crude odds ratios and 95% confidence intervals. Results: The index and reference cohort comprised 1471 and 8736 persons, respectively. Both cardiovascular and psychiatric co-morbidities were more prevalent among starters compared to non-starters. 77.7% of the patients stopped using anti-obesity drugs within 90 days. Users of amphetamine-like drugs differed from patients using orlistat or sibutramine, whereas users of orlistat and sibutramine were highly comparable. Conclusions: The increased prevalence of co-morbidities constitutes a baseline risk which may translate in higher occurrence of psychiatric and cardiovascular diseases during use of anti-obesity drugs, independent of the drugs. The limited period of use might reduce possible cardiovascular benefits of weight reduction induced by these drugs.

Withdrawal of statins and risk of subarachnoid hemorrhage (Article)

2009-08-01T00:00:00Z

BACKGROUND AND PURPOSE-: Vascular endothelium, which can be affected by statins, is believed to play a substantial role in subarachnoid hemorrhage (SAH). Our objective was to estimate the association between use and withdrawal of statins and the risk of SAH. METHODS-: We conducted a population-based case-control study within the PHARMO database. A case was defined as a person hospitalized for SAH (ICD-9-CM code 430) in the period January 1, 1998 to December 31, 2006. Ten randomly chosen controls were matched to each case on age, gender, and calendar date. RESULTS-: During the study period 1004 incident cases of SAH were identified. Current use of statins did not significantly decrease the risk of SAH (OR=0.77, 95% CI 0.55 to 1.07). The odds ratio for recent withdrawal compared to nonusers was 1.62 (95% CI 0.96 to 2.73). Compared to current use, recent withdrawal was associated with an increased risk of SAH (OR=2.34, 95% CI 1.35 to 4.05). Interaction analysis showed that the effect of statin withdrawal was highest in patients who had also recently stopped antihypertensive drugs (OR=6.77, 95% CI 2.10 to 21.8). CONCLUSIONS-: Current use of statins seems to lower the risk of SAH, although the reduction was not significant in new users. Statin withdrawal increased the risk of SAH by a factor 2, even more in patients who had also recently stopped their antihypertensive treatment.

Referral and treatment patterns for complex regional pain syndrome in the Netherlands (Article)

2009-07-01T00:00:00Z

Background: Patients with complex regional pain syndrome (CRPS) are seen and treated by a variety of physicians. The present study aims to describe referral and treatment patterns for CRPS patients in the Netherlands. Methods: Patients, who were selected (1996-2005) from an electronic general practice (GP) database (Integrated Primary Care Information Project), were invited for study participation, involving diagnosis verification (International Association for the Study of Pain criteria) and assessment of referrals and treatment through information retrieved from GP journals, patients' questionnaires, pharmacy dispensing lists and specialist letters if available. Results: One hundred and two patients were included. Sixty-one percent had presented first at the GP, while 80% subsequently consulted one or more medical specialists, most frequently an anesthetist (55% of the cases) or a specialist in rehabilitation medicine (41%). Over 90% of the patients received oral or topical pharmacotherapy, 45% received intravenous therapy, 89% received non-invasive therapy (i.e. physiotherapy) and 18% received nerve blocks. Analgesics and free radical scavengers were administered early during CRPS, while vasodilating drugs and drugs against neuropathic pain (antidepressants and anti-epileptics) were administered later on. Pharmacotherapy was usually initiated by a medical specialist. Conclusion: The Dutch treatment guidelines, issued in 2006, recommend free radical scavenger prescription (plus physiotherapy) as the initial treatment step for CRPS. Until 2005 only half of the patients received a scavenger within 3 months after disease onset, and the majority presents first at the GP, in particular GPs may be encouraged to initiate treatment with scavengers, while waiting for the results of further specialist consultation.

The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS (Article)

2009-04-01T00:00:00Z

Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (ORadjusted: 2.7, 95% CI: 1.1-6.8). The association was stronger if ACE inhibitors were used for a longer time period (ORadjusted: 3.0, 95% CI: 1.1-8.1) and in higher dosages (ORadjusted: 4.3, 95% CI: 1.4-13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation (Article)

2009-04-01T00:00:00Z

Objectives To study whether NOS1AP single nucleotide polymorphisms (SNPs), rs10494366 T>G and rs10918594 C>G, modify the heart-rate-corrected QT (QTc) prolonging effect of calcium channel blockers. Background Common variation in the NOS1AP gene has been associated with QT interval variation in several large population samples. NOS1 is presumed to influence intracellular calcium. Methods The prospective population-based Rotterdam Study includes 16 603 ECGs from 7565 participants (≥ 55 years), after exclusion of patients with left ventricular hypertrophy, left and right bundle branch block, as well as carriers of pacemakers. The endpoint was the length of the QTc interval in calcium channel blocker users and non-users with the minor alleles compared with the major alleles (wild type). We used a repeated-measurement analysis, adjusted for all known confounders. Results Use of verapamil was associated with a significant QTc interval prolongation [6.0 ms 95% confidence interval (CI) 1.7; 10.2] compared with non-users. Furthermore, users of verapamil with the rs10494366 GG genotype showed significantly more QTc prolongation than users with the TT genotype [25.4 ms (95% CI: 5.9-44.9)] (P value for multiplicative interaction 0.0038). Users of isradipine with the GG genotype showed more QTc prolongation than users with the TT genotype [19.8 ms (95% CI: 1.9-37.7)]; however, SNP rs10494366 did not modify the effect on QTc interval on a multiplicative scale (P= 0.3563). SNP rs10918594 showed similar results. Conclusion In conclusion, we showed that the minor alleles of both NOS1AP SNPs significantly potentiate the QTc prolonging effect of verapamil. Pharmacogenetics and Genomics 19:260-266

Current understandings on complex regional pain syndrome (Article)

2009-03-10T00:00:00Z

The mechanisms underlying complex regional pain syndrome (CRPS) have been increasingly studied over the past decade. Classically, this painful and disabling disorder was considered to emerge from pathology of the central nervous system. However, the involvement of additional peripheral disease mechanisms is likely, and recently these mechanisms have also attracted scientific attention. The present article provides an overview of the current understandings regarding pathology of the autonomic and somatic nervous system in CRPS, as well as the roles of neurogenic inflammation, hypoxia, and the contribution of psychological factors. Potential connections between the separate disease mechanisms will be discussed. Additionally, currently known risk factors for CRPS will be addressed. Insight into risk factors is of relevance as it facilitates early diagnosis and tailored treatment. Moreover, it may provide clues for further unraveling of the pathogenesis and etiology of CRPS.

An algorithm to identify antidepressant users with a diagnosis of depression from prescription data (Article)

2009-03-09T00:00:00Z

Purpose: Antidepressants are used for many indications besides depression. This makes investigating depression treatment outcomes in prescription databases problematic when the indication is unknown. The aim of our study is to develop an algorithm to identify antidepressant drug users from prescription data that suffer from depression. Methods: Data for deriving the algorithm were obtained from the Second Dutch National Survey of General Practice, carried out in 2001 by The Netherlands Institute for Health Services Research (NIVEL), and for validation the Integrated Primary Care Information (IPCI) database was used. Both sets included adults receiving their first antidepressant drug in 2001 (n = 1855 and 3321, respectively). The outcome was a registered diagnosis of depression. Covariates investigated for developing the algorithm were patient and prescribing characteristics, and co-medication. Results: The predictive algorithm included age, SSRI prescribed on the index date, prescribed dose, general practitioner as prescriber and the number of antidepressant prescriptions prescribed plus medication for treating acid related disorders, laxatives, cardiac therapy or hypnotics/ sedatives prescribed in the 6 months prior to index date. The probability that the algorithm correctly identified an antidepressant drug user as having a depression diagnosis was 79% with a sensitivity of 79.6% and a specificity of 66.9%. Conclusion: In conclusion, we developed and validated an algorithm that can be used to compose cohorts of patients treated with antidepressants for depression from prescription databases. Copyright

Estrogens and the risk of complex regional pain syndrome (CRPS) (Article)

2009-03-09T00:00:00Z

Objective: Since complex regional pain syndrome (CRPS) shows a clear female predominance, we investigated the association between the cumulative as well as current exposure to estrogens, and CRPS. Methods: A population-based case-control study was conducted in the Integrated Primary Care Information (IPCI) project in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during a visit (using International Association for the Study of Pain Criteria), or had been diagnosed by a specialist. Controls were matched to cases on gender, age, calendar time, and injury. Measures of cumulative endogenous estrogen exposure were obtained by questionnaire and included age of menarche and menopause, menstrual life, and cumulative months of pregnancy and breast-feeding. Current estrogen exposure at CRPS onset was retrieved from the electronic medical records and determined by current pregnancy or by the use of oral contraceptive (OC) drugs or hormonal replacement therapy (HRT). Results: Hundred and forty-three female cases (1493 controls) were included in analyses on drug use and pregnancies, while cumulative endogenous estrogen exposure was studied in 53 cases (58 controls) for whom questionnaire data were available. There was no association between CRPS and either cumulative endogenous estrogen exposure, OC, or HRT use. CRPS onset was increased during the first 6 months after pregnancy (OR: 5.6, 95%CI: 1.0-32.4), although based on small numbers. Discussion: We did not find an association between CRPS onset and cumulative endogenous estrogen exposure or current OC or HRT use, but more powered studies are needed to exclude potential minor associations. Copyright

Familial occurrence of complex regional pain syndrome (Article)

2009-02-01T00:00:00Z

Genetic factors are suggested to play a role in complex regional pain syndrome (CRPS), but familial occurrence has not been extensively studied. In the present study we evaluated familial occurrence in Dutch patients with CRPS. Families were recruited through the Dutch Association of CRPS patients and through referral by clinicians. The number of affected members per family, the phenotypic expression and inheritance were assessed. Demographic and clinical characteristics of familial CRPS (fCRPS) patients were compared with those of sporadic CRPS (sCRPS) patients from a Dutch population-based study and with a group of sCRPS patients that was proportionally matched for referral center of the fCRPS probandi to control for referral bias. Thirty-one CRPS families with two or more affected relatives were identified, including two families with five, four with four, eight with three and 17 with two affected relatives. In comparison with sCRPS patients, fCRPS patients had a younger age at onset and more often had multiple affected extremities and dystonia. We conclude that CRPS may occur in a familial form, but did not find a clear inheritance pattern. Patients with fCRPS develop the disease at a younger age and have a more severe phenotype than sporadic cases, suggesting a genetic predisposition to develop CRPS.

Psychotropic drugs associated with corrected QT interval prolongation (Article)

2009-02-01T00:00:00Z

AIMS:: To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drug effect, we conducted a prospective population-based cohort study. METHODS:: This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (ĝ‰¥55 years) who had triennial electrocardiograms (ECGs). The primary end points of the study were the length of the QTc interval at each ECG, the difference in QTc interval between consecutive ECGs within one person, and the risk of an abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age, sex, diabetes mellitus, hypertension, myocardial infarction, heart failure, and use of class 1 QTc-prolonging drugs. RESULTS:: Of the 8222 participants, 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison with consecutive ECGs of participants not using tricyclic antidepressants, in particular starting amitriptyline (8.5 milliseconds; 95% CI, 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds; 95% CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds; 95% CI, 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% CI, 4.8-32.4 milliseconds). CONCLUSIONS:: In this population-based prospective cohort study, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a significant intraindividual increase in the QTc interval in comparison to the change in nonusers. The tricyclic antidepressants seem to prolong the QTc interval as a class effect.

The Task-force in Europe for Drug Development for the Young (TEDDY) network of excellence (Article)

2009-01-14T00:00:00Z

The Task-force in Europe for Drug Development for the Young (TEDDY) was established in 2005 to contribute to the promotion of safe and efficacious medicines for children in the context of the impending European Paediatric Regulation that finally came into force in January 2007. The project includes seven objectives and 12 Work-Packages encompassing the main aspects of the development and use of pediatric drugs. TEDDY represents a new entity in the pediatric pharmaceutical field, differing from a Scientific Society, a network for developing research or trials, or a consultative regulatory body. The ambition of TEDDY is to support the existing pediatric networks, societies, and regulatory bodies in performing innovative initiatives, including those in areas in which such undertakings would not be feasible without supportive action. To accomplish its aim, TEDDY has focused on three different actions: (i) increasing awareness about the Paediatric Regulation revolution; (ii) reaching consensus on terms and instruments to be used for common research; and (iii) favoring close relationships among different stakeholders and partners from different EU Member States. After 3 years of activities, many results have been produced by the Network: surveys, databases, expert opinions, and recommendations. Linking together different stakeholders, including industry and patient associations, as well as academia and research centers, the Network has contributed to increasing awareness and participation in the Paediatric Regulation. In addition, many papers detailing original results have either been published or submitted for publication in peer-reviewed journals. TEDDY is an original Network whose identity and role as a catalyzer of initiatives related to the use and development of pediatric drugs needs to be better clarified in the near future. Of particular importance is the need to reach consensus on best practices. The lack of a common view on pediatric research requirements among stakeholders across Member States remains the main challenge to be overcome.

Databases for pediatric medicine research in Europe - Assessment and critical appraisal (Article)

2008-12-01T00:00:00Z

Purpose: To identify and describe European health care databases that can be used for pediatric pharmacoepidemiological research. Methods: A web-based survey was conducted among all European databases that were listed on the website of the International Society of Pharmacoepidemiology (ISPE)and/or known by an expert group. The survey comprised of questions regarding (a) the nature of the database, (b) database size, (c) demographic, clinical and drug related data provided, (d) cost, and (e) accessibility of the database. Results: A total of 25 data sources from 12 European countries were identified and invited to participate in the survey. Responses were obtained from 21 (84%) databases located in 10 different European countries. Seventeen databases were included in the assessment comprising a total of at least 9 million children aged 0-18 years. The majority of databases are based on outpatient data and all keep either prescription or drug dispensing data. Ten databases are based on electronic patient records from primary care physicians and five databases are predominantly claims oriented. Three databases do not belong to either of the above mentioned categories. Almost all of the databases can be used for pediatric drug utilization studies. For drug safety studies it is more appropriate to use electronic patient record databases because of the available clinical information and the potential to obtain additional information. Conclusions: There are many European healthcare databases providing an enormous potential for pediatric pharmacoepidemiological research. Future research should focus on methods to bring data from different databases together to use the full capacity effectively. Copyright

Defining off-label and unlicensed use of medicines for children: Results of a Delphi survey (Article)

2008-11-01T00:00:00Z

The aim of this Delphi survey is to develop common definitions for unlicensed and off-label drug use in children to be used for research and regulatory purposes. After a literature review on the current status of unlicensed/off-label definitions, a two-stage, web-based Delphi survey was conducted among experts in Europe. Their opinion on concerns, rules and scenarios regarding the unlicensed and off-label use of medicines were obtained. Results were then consulted with the European Medicines Agency (EMEA) before the final proposal was circulated to participants. Eighty-four experts were invited to participate (scientists, health professionals, pharmaceutical companies, regulatory agencies), 34 responded to the first round questionnaire and participated in subsequent rounds. Consensus was reached for the majority of questions. The lowest level of consensus reached was for questions related to a different formulation or if a drug was given although contraindicated. At the final step, 85% of the responding experts agreed on the proposed definition for off-label (use of a drug already covered by a Marketing Authorisation, in an unapproved way) and 80% on the definition for unlicensed (use of a drug not covered by a Marketing Authorisation as medicinal for human use), respectively. Results will facilitate the conduct of pharmacoepidemiological studies and allow comparison between different countries. The Delphi panel agreed that the definitions should be circulated within the scientific community and recommended to be adopted by relevant regulatory authorities.

Medical history and the onset of complex regional pain syndrome (CRPS) (Article)

2008-10-15T00:00:00Z

Knowledge concerning the medical history prior to the onset of complex regional pain syndrome (CRPS) might provide insight into its risk factors and potential underlying disease mechanisms. To evaluate prior to CRPS medical conditions, a case-control study was conducted in the Integrated Primary Care Information (IPCI) project, a general practice (GP) database in the Netherlands. CRPS patients were identified from the records and validated through examination by the investigator (IASP criteria) or through specialist confirmation. Cases were matched to controls on age, gender and injury type. All diagnoses prior to the index date were assessed by manual review of the medical records. Some pre-specified medical conditions were studied for their association with CRPS, whereas all other diagnoses, grouped by pathogenesis, were tested in a hypothesis-generating approach. Of the identified 259 CRPS patients, 186 cases (697 controls) were included, based on validation by the investigator during a visit (102 of 134 visited patients) or on specialist confirmation (84 of 125 unvisited patients). A medical history of migraine (OR: 2.43, 95% CI: 1.18-5.02) and osteoporosis (OR: 2.44, 95% CI: 1.17-5.14) was associated with CRPS. In a recent history (1-year before CRPS), cases had more menstrual cycle-related problems (OR: 2.60, 95% CI: 1.16-5.83) and neuropathies (OR: 5.7; 95% CI: 1.8-18.7). In a sensitivity analysis, including only visited cases, asthma (OR: 3.0; 95% CI: 1.3-6.9) and CRPS were related. Psychological factors were not associated with CRPS onset. Because of the hypothesis-generating character of this study, the findings should be confirmed by other studies.

A novel programme to evaluate and communicate 10-year risk of CHD reduces predicted risk and improves patients' modifiable risk factor profile (Article)

2008-10-01T00:00:00Z

Aims: We assessed whether a novel programme to evaluate/communicate predicted coronary heart disease (CHD) risk could lower patients' predicted Framingham CHD risk vs. usual care. Methods: The Risk Evaluation and Communication Health Outcomes and Utilization Trial was a prospective, controlled, cluster-randomised trial in nine European countries, among patients at moderate cardiovascular risk. Following baseline assessments, physicians in the intervention group calculated patients' predicted CHD risk and were instructed to advise patients according to a risk evaluation/communication programme. Usual care physicians did not calculate patients' risk and provided usual care only. The primary end-point was Framingham 10-year CHD risk at 6 months with intervention vs. usual care. Results: Of 1103 patients across 100 sites, 524 patients receiving intervention, and 461 receiving usual care, were analysed for efficacy. After 6 months, mean predicted risks were 12.5% with intervention, and 13.7% with usual care [odds ratio = 0.896; p = 0.001, adjusted for risk at baseline (17.2% intervention; 16.9% usual care) and other covariates]. The proportion of patients achieving both blood pressure and low-density lipoprotein cholesterol targets was significantly higher with intervention (25.4%) than usual care (14.1%; p < 0.001), and 29.3% of smokers in the intervention group quit smoking vs. 21.4% of those receiving usual care (p = 0.04). Conclusions: A physician-implemented CHD risk evaluation/ communication programme improved patients' modifiable risk factor profile, and lowered predicted CHD risk compared with usual care. By combining this strategy with more intensive treatment to reduce residual modifiable risk, we believe that substantial improvements in cardiovascular disease prevention could be achieved in clinical practice.

Prevalence and treatment of hypertensive patients with multiple concomitant cardiovascular risk factors in The Netherlands and Italy (Article)

2008-08-01T00:00:00Z

The Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA) trial demonstrated the benefits of combined antihypertensive/ lipid-lowering treatment over antihypertensive treatment alone in hypertensive patients with ≥3 additional cardiovascular (CV) risk factors. We assessed the prevalence and treatment of patients with hypertension and ≥3 additional CV risk factors in The Netherlands and Italy in a retrospective cohort study using the Integrated Primary Care Information (IPCI) database in The Netherlands and the Health Search/ Thales Database (HSD) in Italy. Patients aged ≥16 years, with 1 year of valid database history, diagnosed and/or treated for hypertension (>140/90 mmHg) during 2000-2002 were included in the study. The IPCI and HSD populations consisted of ∼175 000 and ∼325 000 patients, respectively. The prevalence of hypertension increased from 20.3 to 22.3% in the IPCI, and from 19.0 to 21.8% in the HSD during 2000-2002. The prevalence of ≥3 concomitant risk factors among hypertensive patients increased from 31.2 and 31.1% in 2000 to 34.2 and 39.3% in 2002 in the IPCI and HSD, respectively. From 2000 to 2002, among hypertensive patients with ≥3 CV risk factors and no prior symptomatic CV disease (CVD) approximately 54-57% in the IPCI and 80-83% in the HSD received antihypertensive treatment. In these patients, the use of combined antihypertensive and lipid-lowering treatment increased from 14.2 to 17.6% in the IPCI and from 15.5 to 17.4% in the HSD from 2000 to 2002. This study shows that primary prevention of CVD in hypertensive patients in The Netherlands and Italy could be improved.

Inappropriate benzodiazepine use in older adults and the risk of fracture (Article)

2008-08-01T00:00:00Z

AIMS: The Beers criteria for prescribing in elderly are well known and used for many drug utilization studies. We investigated the clinical value of the Beers criteria for benzodiazepine use, notably the association between inappropriate use and risk of fracture. METHODS: We performed a nested case-control study within the Rotterdam Study, a population-based cohort study in 7983 elderly. The proportion of 'inappropriate' benzodiazepine use according to the Beers criteria was compared between fracture patients and controls. 'Inappropriate' use for elderly implies use of some long-acting benzodiazepines and some intermediate/short-acting ones exceeding a suggested maximum daily dose. Also, alternative criteria were applied to compare the risk of fracture. Cases were defined as persons with incident fracture between 1991 and 2002 who were current benzodiazepine users on the fracture date. Controls were matched on fracture date and were also current benzodiazepine users. RESULTS: The risk of fracture in 'inappropriate' benzodiazepine users according to the Beers criteria was not significantly different from 'appropriate' users [odds ratio (OR) 1.07, 95% confidence interval (CI) 0.72, 1.60]. However, a significantly higher risk of fracture was found in 'high dose' users and a longer duration of use (14-90 days), irrespective of the type of benzodiazepine (OR 3.45, 95% CI 1.38, 8.59). CONCLUSIONS: These findings suggest that inappropriate benzodiazepine use according to the Beers criteria is not associated with increased risk of fracture. Daily dose and longer duration of use (>14 days) is associated with higher risk of fracture, irrespective of the type of benzodiazepine prescribed.

Mortality benefits of influenza vaccination in elderly people (Article)

2008-08-01T00:00:00Z

Incidence rates and treatment of neuropathic pain conditions in the general population (Article)

2008-07-31T00:00:00Z

Incidence rate estimates of neuropathic pain are scanty and mostly address single types whereas the scope of the disease is wide. We aimed to calculate the incidence rates of neuropathic pain conditions in the Dutch general population and to assess treatment strategies in primary care. The study population included persons registered for at least one year in the Integrated Primary Care Information (IPCI) database between 1996 and 2003. Neuropathic pain was ascertained and classified by systematic review of computerized longitudinal medical records. Incidence rates (IR) were calculated, and the treatment for pain was compared to age and gender matched controls. Among 362,693 persons contributing 1,116,215 person years (PY), we identified 9135 new cases of neuropathic pain (IR: 8.2/1000 PY, 95%CI: 8.0-8.4). Mononeuropathy and carpal tunnel syndrome were the most frequent types with 4.3 and 2.3 cases/1000 PY followed by diabetic peripheral neuropathy and post-herpetic neuralgia at 0.72 and 0.42/1000 PY. Neuropathic pain was 63% more common in women than in men and peaked between the ages 70 and 79. More than 50% of cases received pain medication within 6 months after diagnosis, mostly consisting of NSAIDs or aspirin. Anticonvulsants and tricyclic antidepressants were only used by 4.8 and 4.7% of cases. Neuropathic pain is a rather frequent condition with an annual incidence of almost 1% of the general population and affecting women and middle-aged persons more often. The treatment mostly consisted of regular analgesics suggesting that pharmacological treatment of neuropathic pain is suboptimal.

High free thyroxine levels are associated with QTc prolongation in males (Article)

2008-07-01T00:00:00Z

The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T4) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T4/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was no significant association between TSH and QTc interval (0.8 ms (95% confidence interval (Cl) -3.5, 5.2) in the first quintile compared with the fifth quintile). Subjects in the fifth quintile of free T4did not have an increased QTc interval (3.2 ms (95% Cl - 1.1, 7.6)); stratification on gender showed an increment of 10.9 ms (95% Cl 3.4, 18.3) in the fifth quintile in men and 1.1 ms (95% Cl - 4.2, 6.3) in the fifth quintile of free T4in women. When compared with subjects in the first quintile, male subjects in the fifth quintile of free T4had a significantly increased risk of a borderline QTc interval and QTc prolongation (odds ratio 2.40 (95% Cl 1.20, 4.80)). High levels of free T4are associated with substantial QTc prolongation in men of up to 10 ms. The fact that free T4is also associated with a significantly increased risk of borderline and prolonged QTc values with its risk of sudden cardiac death, endorses the clinical importance of our findings.

Gastro-oesophageal reflux, medical resource utilization and upper gastrointestinal endoscopy in patients at risk of oesophageal adenocarcinoma (Article)

2008-07-01T00:00:00Z

Background: Early identification of patients at risk of oesophageal adenocarcinoma (OAC) might improve survival. Aim: To assess the medical resource utilization in the 3 years before OAC diagnosis as potential markers for early identification and intervention. Methods: We identified 65 incident OAC within the Integrated Primary Care Information database. For comparison, we randomly selected 260 age- and gender-matched population controls. We abstracted the use of gastric acid inhibitors, general practitioner (GP) and specialist care, and gastroscopies in the 3 years before the detection of OAC. Results: Approximately 20% of the cases used gastric acid inhibitors in the third and second year before OAC, which increased to almost 50% in the last year, compared to approximately 10% among controls. Only in the 6 months before OAC, the proportion of patients visiting a GP (97%) or specialist (41%) increased compared to controls. Of 13 gastroscopies performed in the 3 years, six (46%) were not suspect for a malignancy. Conclusions: Only a minority of all OAC patients used acid inhibitors before diagnosis. The use of medical care between cases and controls differed only in the final year before OAC diagnosis. Detection of early neoplastic changes proves to be difficult.

Adverse drug reaction-related hospitalisations: A population-based cohort study (Article)

2008-04-01T00:00:00Z

Purpose: To evaluate the extent, charscteristics and determinants of adverse drug reaction (ADR)-related hospitalisations on a population-based level in 2003. Methods: We performed a cohort study in the Integrated Primary Care Information (IPCI) database, a general practitioners (GPs) research database with longitudinal data from electronic patient records of a group of 150 GP throughout the Netherlands. Hospital discharge letters and patient records were reviewed to evaluate ADR-related hospitalisations applying WHO causality criteria. The prevalence of ADR-related hospitalisations per total admissions and the incidence per drug group were calculated. Avoidability and seriousness of the ADRs causing admission were assessed applying the algorithm from Hallas. Results: We identified 3515 hospital admissions, 1277 elective and 2238 acute. Of the acute admissions, 115 were caused by an ADR giving a prevalence of 5.1% (95% confidence intervals (Cl): 4.3-6.1%). The prevalence of ADR-related acute admissions increased with age up to 9.8% (95%CI: 7.5-12.7) for persons >75 years. The ADRs that most frequently caused hospitalisations were gastro-intestinal bleeding with anti-thrombotics, bradycardia/hypotension with cardiovascular drugs and neutropenic fever with cytostatics. The incidence rate of ADR-related hospitalisations per drug group was highest for anti-thrombotics and anti-infectives and was relatively low for cardiovascular drugs. Fatality as a direct consequence of the ADR-related admission was 0.31 %. In elderly patients 40% of the ADRs causing hospitallisation werejudged to be avoidable. Conclusions: The extent and potential avoidability of ADR-related hospitalisations is still substantial, especially in elderly patients. Measures need to be put into place to reduce the burden of ADRs. Copyright

European commission consultation on pharmacovigilance (Article)

2008-02-01T00:00:00Z

Electronic alerts versus on-demand decision support to improve dyslipidemia treatment: A cluster randomized controlled trial (Article)

2008-01-01T00:00:00Z

BACKGROUND - Indirect evidence shows that alerting users with clinical decision support systems seems to change behavior more than requiring users to actively initiate the system. However, randomized trials comparing these methods in a clinical setting are lacking. We studied the effect of both alerting and on-demand decision support with respect to screening and treatment of dyslipidemia based on the guidelines of the Dutch College of General Practitioners. METHODS AND RESULTS - In a clustered randomized trial design, 38 Dutch general practices (77 physicians) and 87 886 of their patients (39 433 men 18 to 70 years of age and 48 453 women 18 to 75 years of age) who used the ELIAS electronic health record participated. Each practice was assigned to receive alerts, on-demand support, or no intervention. We measured the percentage of patients screened and treated after 12 months of follow-up. In the alerting group, 65% of the patients requiring screening were screened (relative risk versus control=1.76; 95% confidence interval, 1.41 to 2.20) compared with 35% of patients in the on-demand group (relative risk versus control=1.28; 95% confidence interval, 0.98 to 1.68) and 25% of patients in the control group. In the alerting group, 66% of patients requiring treatment were treated (relative risk versus control=1.40; 95% confidence interval, 1.15 to 1.70) compared with 40% of patients (relative risk versus control=1.19; 95% confidence interval, 0.94 to 1.50) in the on-demand group and 36% of patients in the control group. CONCLUSION - The alerting version of the clinical decision support systems significantly improved screening and treatment performance for dyslipidemia by general practitioners.

Incidence and outcomes of acute gastroenteritis in Italian children (Article)

2008-01-01T00:00:00Z

BACKGROUND AND AIMS: Little is known about the epidemiology of acute gastroenteritis (AGE) and intussusception (IS) or gastrointestinal obstruction (GO) in Italy. We conducted a retrospective study to assess AGE incidence and symptoms, 1-month hospitalization risk, and IS incidence among Italian children. METHODS: A dynamic cohort study was conducted using the PEDIANET general practice research database. The study population comprised 79,949 children aged <10 years, from September 2001 to September 2004. AGE, GO, and IS cases were identified from diagnoses, hospitalizations, and free-text searches in patient diaries, and were individually validated. AGE outcomes were assessed. Episodes with ascertained rotavirus (RV) infection and incidence rates with 95% confidence intervals (CIs) were calculated. RESULTS: Overall, 13,978 AGE episodes were identified, and 20 cases of GO including 9 IS cases. The overall AGE incidence rate was 76.1 (74.8-77.4) per 1000 person-years (PY), dropping with age from 124/1000 PY among 0-12 months old to 97/1000 PY among 13-48 months old, and 45/1000 PY among 5-10 years old. Male/female AGE rates were similar. The overall rate of GO including IS was 11.2 per 100,000 PY (95% CI: 7.1-16.9). The overall rate of IS alone was 5.0 per 100,000 PY (95% CI: 2.5-9.2). The rate of GO decreased substantially with increasing age from 32 per 100,000 PY (95% CI 17-56) among children 0-12 months of age to 5.5 per 100,000 PY (95% CI 2.1-12.1) among children 5-10 years of age. Most children with AGE presented with diarrhea (91%), about 30% had vomiting, and 29% had fever. The hospitalization risk for children with AGE was 3.0% (95% CI: 2.70-3.27) within 30 days after start of AGE. CONCLUSIONS: AGE is a substantial disease burden in primary care, especially among children aged <5 years. AGE etiology is rarely identified. Most of the cases occurred during the winter period and in children of 6-24 months of age, suggesting that rotavirus could be frequently involved. IS constitutes a rare event in this population, although underreporting might have occurred.

Mortality in men admitted to hospital with acute urinary retention (Article)

2007-12-08T00:00:00Z

Tricyclic antidepressants and the risk of reflux esophagitis (Article)

2007-09-01T00:00:00Z

OBJECTIVE: Incompetence of the lower esophageal sphincter (LES) is a key factor in the pathogenesis of gastroesophageal reflux disease (GERD). Drugs with anticholinergic properties, such as tricyclic antidepressants (TCAs), may facilitate GERD by a relaxing effect on the LES. AIM: To investigate whether the use of TCAs is associated with an increased risk of reflux esophagitis (RE). METHOD: A population-based case-control study was conducted within a large Dutch primary care database over the period 1996-2005. Cases with endoscopy-confirmed RE were identified and matched with up to 10 controls on gender, age, GP practice, and calendar time. Exposure to TCAs was assessed in the year prior to diagnosis and categorized as current (last prescription covered or ended within one month prior to the index date), past, and no use. The relative risk of RE was estimated by odds ratios (OR) with 95% confidence intervals (95% CI) using multivariate conditional logistic regression analysis. RESULTS: During the study period, 1,462 cases with endoscopy-confirmed RE were identified. The risk of RE was increased in current TCA users (ORadj1.61, 95% CI 1.04-2.50). Drug-specific analyses revealed that only clomipramine was associated with an increased risk of RE (ORadj4.6, 95% CI 2.0-10.6) in a duration- and dose-dependent manner (ORadj7.1, 95% CI 2.7-19.2 for use >180 days and ORadj9.2, 95% CI 1.6-51.5 for >1 DDD equivalent/day). CONCLUSION: No association was observed between the risk of RE and the use of TCAs other than clomipramine. The association between RE and clomipramine might be drug-related or a result of the underlying indication.

The effect of antihypertensive drugs and drug combinations on the incidence of new-onset type-2 diabetes mellitus (Article)

2007-09-01T00:00:00Z

Purpose: To evaluate the effect of antihypertensive drugs on new-onset type-2 diabetes. Methods: This was a cohort study using the UK General Practice Research Database (GPRD). Patients newly diagnosed with hypertension between 1991 and 2001, and treated with antihypertensive drugs, were included. Type-2 diabetes mellitus was identified based on a physician diagnosis or an anti-diabetic drug prescription. Antihypertensive treatments were classified as: ACE inhibitors (ACE-Is), β blockers, calcium channel blockers (CCB), thiazides, all other drugs, and their combinations. Results: A total of 2706 incident diabetes cases were identified in 98 629 hypertensive patients during 307 356 patient years (8.8/1000 patient years). New-onset diabetes was lower for ACE-I regimens compared with non-ACE inhibitor regimens (HR = 0.90; 95%CI: 0.82-0.99). CCB monotherapy (HR = 1.27; 95%CI: 1.07-1.51) had an increased risk of diabetes compared with ACE-I monotherapy. ACE-I plus thiazide had the lowest risk of diabetes among double combinations, followed by ACE-I plus β blocker, and ACE-I plus CCB. Double combinations with an ACE-I had 0.79 (95%CI: 0.67-0.92) times the risk compared with non-ACE inhibitor combinations. The risk of new-onset diabetes was significantly higher for β blocker plus thiazide (HR = 1.37; 1.10-1.70), CCB plus thiazide (HR = 1.44; 95%CI: 1.13-1.83), but not β blocker plus CCB (HR = 1.30; 95%CI: 0.99-1.70) compared with ACE-I plus thiazide. Conclusions: Antihypertensive drug combinations including an ACE-I had a significantly lower risk of new-onset diabetes than antihypertensive drug combinations without an ACE-I. Copyright

Rationale, design, and methods for the risk evaluation and communication health outcomes and utilization trial (REACH OUT) (Article)

2007-09-01T00:00:00Z

Objective: To test the primary study hypothesis that a physician-delivered coronary heart disease risk evaluation and communication program can lower patients' predicted 10-year risk of myocardial infarction or death due to coronary heart disease by 10% within 6 months compared to usual care. Design: Prospective, parallel group, open-label, controlled, cluster-randomized multinational trial; the study site is the unit of randomization. Setting: Patients were recruited from 106 general practices located in nine European countries. Patients: Men and women aged 45 to 64 (N = 1500) with a documented history of hypertension (treated or untreated), systolic blood pressure ≥ 140 mmHg (or ≥ 130 mmHg in the presence of renal or kidney disease), no history of cardiovascular disease, and a predicted 10-year risk of myocardial infarction or death due to coronary heart disease ≥ 10%. Intervention: Sites were randomized to deliver a physician-directed coronary heart disease risk communication and education program or usual care. The intervention program included informing patients of their 10-year risk of myocardial infarction or death due to coronary heart disease, educating patients about modifiable risk factors and their control, and three follow-up phone calls by a physician or study nurse. Main outcome measure: Predicted 10-year risk of myocardial infarction or death due to coronary heart disease at 6 months. Conclusions: REACH OUT will evaluate a novel, patient-focused, physician-implemented application of coronary heart disease risk equations. Results of the study will be of practical relevance to physicians, health care organizations, and those who issue clinical guidelines for the reduction of cardiovascular risk.

Channelling of COX-2 inhibitors to patients at higher gastrointestinal risk but not at lower cardiovascular risk: The Cox2 inhibitors and tNSAIDs description of users (CADEUS) study (Article)

2007-08-01T00:00:00Z

Purpose: To describe the characteristics of users of cyclo-oxygenase (COX)-2 inhibitors and traditional nonselective non-steroidal anti-inflammatory drugs (tNSAIDs) in France. Methods: Between 1 August 2003 and 31 July 2004, patients who received at least one dispensing of celecoxib, rofecoxib or tNSAIDs were randomly sampled with a 1:1:2 target ratio within the French National Healthcare Insurance database. Patients and prescribers were asked to fill a questionnaire on socio-demographic characteristics, NSAID indication and use and previous medical history. For each respondent, healthcare resources used in the 6 months before inclusion were extracted from the database. Multivariate logistic regression was used to study the determinants of a first COX-2 inhibitor dispensing. Results: Of the 45 217 patients included, 13 065 COX-2 inhibitors and 13 553 tNSAID users had prescriber data. Ninety seven per cent of COX-2 inhibitor prescriptions were for 'rheumatological' indications, whereas 37% of tNSAIDs use was for benign diseases (n = 2643) or analgesia (n = 2318). Among patients with rheumatological indications (n = 4730) and a first COX-2 inhibitor (n = 2427) or tNSAID (n = 2303) dispensing, multivariate analysis of factors associated with COX-2 inhibitors dispensing showed that, compared to new tNSAID users, new COX-2 inhibitor users were older, more often female, on sick leave or unemployed. COX-2 use was also associated with previous gastrointestinal history and previous gastroprotective agent dispensing, but not with previous cardiovascular (CV) history. Conclusion: The choice of NSAID depended largely on indication and on previous gastrointestinal history, in line with the recommendations of the French health authorities. Possible knowledge of CV risk associated with COX-2 inhibitors did not influence prescribing. Copyright

Adherence to gastroprotection and the risk of NSAID-related upper gastrointestinal ulcers and haemorrhage (Article)

2007-07-01T00:00:00Z

Background: Upper gastrointestinal (UGI) complications are a well-recognized risk of NSAID treatment, requiring preventive measures in high-risk patients. Adherence to gastroprotective agents (GPAs) in NSAID users has been suggested to be suboptimal. Aim: To investigate the association between adherence to GPAs (proton pump inhibitors or H2-receptor antagonists) and the risk of NSAID-related UGI ulcers or haemorrhage in high-risk patients. Methods: A population-based nested case-control study was conducted within a cohort of new NSAID users with at least one risk factor for a NSAID-related UGI complication, identified in the Dutch IPCI database during 1996-2005. Adherence to GPAs was calculated as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Multivariate conditional logistic regression analysis was used to calculate odds ratios with 95% confidence intervals (95% CI). Results: Fifteen percent of the non-selective NSAID users received GPAs. The risk of a NSAID-related UGI complication among NSAID users increased 16% for every 10% decrease in adherence. Compared to patients with a PDC of >80%, patients with PDCs of 20-80% and <20% had a 2.5-fold (95% CI: 1.0-6.7) respectively 4.0-fold (95% CI: 1.2-13.0) increased risk. Conclusion: There is a strong inverse relationship between adherence to GPAs and the risk of UGI complications in high-risk NSAID users.

Of new times, new opportunities, and old problems (Article)

2007-05-01T00:00:00Z

The incidence of complex regional pain syndrome: A population-based study (Article)

2007-05-01T00:00:00Z

The complex regional pain syndrome (CRPS) is a painful disorder that can occur in an extremity after any type of injury, or even spontaneously. Data on the incidence of CRPS are scarce and mostly hospital based. Therefore the size of the problem and its burden on health care and society are unknown. The objective of the present study was to estimate the incidence of CRPS in the general population. A retrospective cohort study was conducted during 1996-2005 in the Integrated Primary Care Information (IPCI) project, a general practice research database with electronic patient record data from 600,000 patients throughout the Netherlands. Potential CRPS cases were identified by a sensitive search algorithm including synonyms and abbreviations for CRPS. Subsequently, cases were validated by electronic record review, supplemented with original specialist letters and information from an enquiry of general practitioners. The estimated overall incidence rate of CRPS was 26.2 per 100,000 person years (95% CI: 23.0-29.7). Females were affected at least three times more often than males (ratio: 3.4). The highest incidence occurred in females in the age category of 61-70 years. The upper extremity was affected more frequently than the lower extremity and a fracture was the most common precipitating event (44%). The observed incidence rate of CRPS is more as four times higher than the incidence rate observed in the only other population-based study, performed in Olmsted County, USA. Postmenopausal woman appeared to be at the highest risk for the development of CRPS.

All-cause mortality associated with atypical and typical antipsychotics in demented outpatients (Article)

2007-05-01T00:00:00Z

Purpose: To estimate the association between use of typical and atypical antipsychotics and all-cause mortality in a population of demented outpatients. Methods: The study cohort comprised all demented patients older than 65 years and registered in the Integrated Primary Care Information (IPCI) database, during 1996-2004. First, mortality rates were calculated during use of atypical and typical antipsychotics. Second, we assessed the association between use of atypical and typical antipsychotics and all-cause mortality through a nested case-control study in the cohort of demented patients. Each case was matched to all eligible controls at the date of death by age and duration of dementia. Odds ratios were estimated through conditional logistic regression analyses. Results: The crude mortality rate was 30.1 (95%CI: 18.2-47.1) and 25.2 (21.0-29.8) per 100 person-years (PY) during use of atypical and typical antipsychotics, respectively. No significant difference in risk of death was observed between current users of atypical and typical antipsychotics (OR = 1.3; 95%CI: 0.7-2.4). Both types of antipsychotics were associated with a significantly increased risk of death as compared to non-users (OR= 2.2, 1.2-3.9 for atypical antipsychotics; OR= 1.7, 1.3-2.2 for typical antipsychotics). Conclusions: Conventional antipsychotic drug should be included in the FDA's Public Health advisory, which currently warns only of the increased risk of death with the use of atypical antipsychotics in elderly demented persons. Copyright

Spironolactone and risk of upper gastrointestinal events: population based case-control study (Article)

2006-01-01T00:00:00Z

OBJECTIVE: To confirm and quantify any association between spironolactone and upper gastrointestinal bleeding and ulcers. DESIGN: Population based case-control study. SETTING: A primary care information database in the Netherlands. PARTICIPANTS: All people on the database who were aged 18 or more between 1 January 1996 and 30 September 2003. Patients with a history of alcoholism or gastrointestinal cancer were excluded. Ten controls were matched to each case of gastroduodenal ulcer or upper gastrointestinal bleeding by age (year of birth), sex, and index date. MAIN OUTCOME MEASURES: The occurrence of an upper gastrointestinal event (bleeding or ulcers), adjusted for potential confounders with conditional logistic regression analysis. RESULTS: Within the source population of 306 645 patients, 523 cases of gastric or duodenal ulcer or upper gastrointestinal bleeding were identified and matched to 5230 controls. Current use of spironolactone was associated with a 2.7-fold (95% confidence interval 1.2 to 6.0) increased risk of a gastrointestinal event. CONCLUSION: The risk of gastroduodenal ulcers or upper gastrointestinal bleeding is significantly increased in patients using spironolactone.

Incidence of mucocutaneous reactions in children treated with niflumic acid, other nonsteroidal antiinflammatory drugs, or nonopioid analgesics. (Article)

2005-12-01T00:00:00Z

Background and OBJECTIVE: Results from a relatively small case-control study recently showed that niflumic acid increases the risk of serious mucocutaneous reactions in children. As a consequence, the Italian Ministry of Health sent a "Dear Doctor" letter in June 2001 to warn pediatricians about the alleged adverse effects. The objective of this study was to estimate and compare the incidence of mild and severe mucocutaneous reactions among children using niflumic acid, other nonsteroidal antiinflammatory drugs (NSAIDs), or nonopioid analgesics. DESIGN: Retrospective cohort study. SETTING: Italy is one of the few countries in which a specific primary care system is devoted to children up to 14 years of age: every child is registered at birth and receives free medical care from 1 of the approximately 6000 family pediatricians working for the National Health Service. This study was conducted with the Pedianet network of Italian family pediatricians who use computerized electronic patient records for routine care; 185 pediatricians participated in the study. The patient records comprise information on demographics, diagnoses, symptoms, prescriptions, referrals, laboratory examinations, and hospitalizations. PARTICIPANTS: Children aged 0 to 14 years and registered with 1 of the collaborating pediatricians between January 1, 1998, and May 31, 2001. MAIN OUTCOME MEASURES: The incidence rate of severe (hospitalized or referred) and mild mucocutaneous reactions (exanthema, disseminated or localized pruritus, urticaria, angioedema, fixed eruption, dermatitis, erythema multiforme, vesicles, bullae, pustules, toxic epidermal necrolysis, purpura, and vasculitis) was estimated during use of niflumic acid, other NSAIDs, or nonopioid analgesics. For each episode of drug use, the following covariates were assessed: age, gender, region, year, indication for study drug, use of antibiotics, antimycotic agents, glucocorticoids, and other NSAIDs. Multivariate Poisson regression analysis was used to estimate the adjusted relative risk of mucocutaneous disorders during use of niflumic acid compared with use of other NSAIDs or use of acetaminophen alone. RESULTS: The population included 193727 children, 45351 of whom received at least 1 of the study drugs. The most frequently prescribed drugs were niflumic acid, acetaminophen, and propionic acid derivatives (ketoprofen and flurbiprofen). Users of niflumic acid (n = 32150) were younger and slightly more often had otitis media or upper respiratory tract infections as an indication compared with the other NSAIDs. During use of the various study drugs we identified 1451 mild mucocutaneous events and 42 severe reactions. The incidence rates of severe and mild mucocutaneous reactions after the administration of any study drug were 10.3 per 100000 exposure person-days and 3.7 per 1000 exposure person-days, respectively. Both incidence rates decreased strongly with increasing age. In comparison with other NSAIDs, the adjusted relative risks of niflumic acid were 0.5 (95% confidence interval: 0.23-1.27) for severe and 0.9 (95% confidence interval: 0.79-1.11) for mild mucocutaneous reactions. The use of acetaminophen as a reference category instead of other NSAIDs, restriction of the children to those who received NSAIDs for respiratory tract infections, or restriction to those who did not use antibiotics never revealed an increased risk of serious or mild mucocutaneous reactions during use of niflumic acid. CONCLUSIONS: In comparison with other NSAIDs or acetaminophen, niflumic acid is not associated with an increased risk of severe or mild mucocutaneous reactions in children. This was true for the different age groups and various types of mucocutaneous reactions, was independent of the concomitant use of antibiotics, and was not sensitive to changes in our assumptions regarding exposure and outcomes.

Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. (Article)

2005-10-01T00:00:00Z

AIMS: To assess the association between the use of non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. METHODS AND RESULTS: A population-based case-control study was performed in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from more than 500,000 persons. All deaths between 1 January 1995 and 1 September 2003 were reviewed. Sudden cardiac death was classified based on the time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, gender, date of sudden death, and general practice. The exposure of interest was the use of non-cardiac QTc-prolonging drugs. Exposure at the index date was categorized into three mutually exclusive groups of current use, past use, and non-use. The study population comprised 775 cases of sudden cardiac death and 6297 matched controls. Current use of any non-cardiac QTc-prolonging drug was associated with a significantly increased risk of sudden cardiac death (adjusted OR: 2.7; 95% CI: 1.6-4.7). The risk of death was highest in women and in recent starters. CONCLUSION: The use of non-cardiac QTc-prolonging drugs in a general population is associated with an increased risk of sudden cardiac death.

Identification of the four conventional cardiovascular disease risk factors by Dutch general practitioners. (Article)

2005-10-01T00:00:00Z

BACKGROUND: Detecting and managing the four major conventional risk factors, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, is pivotal in the primary and secondary prevention of cardiovascular disease (CVD). OBJECTIVE: To assess the preventive activities of general practitioners (GPs) regarding the four conventional risk factors and the associated measurements for cardiovascular risk factors by GPs in relation to the time of the first clinical presence of CVD. SETTING: Large longitudinal general practice research database (the Integrated Primary Care Information database) in the Netherlands from September 1999 to August 2003. PARTICIPANTS AND METHODS: Patients > 18 year of age with newly diagnosed CVD with a valid history of at least 1 year before and after the first clinical diagnosis of CVD. Details on conventional risk factors and associated measurements for the four cardiovascular risk factors were assessed in relation to the first clinical diagnosis of CVD. RESULTS: In total, 157,716 patients met the study inclusion criteria. Of the 2,594 patients with newly diagnosed CVD, at least one of the four investigated risk factors was observed in 76% of women and 73% of men. In 40% of cases, no risk factor was recorded before the date of the first CVD diagnosis. In 16% of cases, no associated measurements were present before the first CVD diagnosis. CONCLUSION: In daily practice, GPs seem to focus on the secondary prevention of CVD. Intervention strategies that aim to influence GPs' case finding behavior should focus on increasing the awareness of physicians in performing risk factor-associated measurements in patients who are eligible for the primary prevention of CVD. Further research will have to show the feasibility and effectiveness of such intervention strategies.

Increasing incidence of Barrett's oesophagus in the general population (Article)

2005-01-01T00:00:00Z

BACKGROUND: Barrett's oesophagus (BO) predisposes to oesophageal adenocarcinoma. Epidemiological data suggest that the incidence of BO is rising but it is unclear whether this reflects a true rise in incidence of BO or an increase in detection secondary to more upper gastrointestinal endoscopies performed. This study aimed to examine the changes in BO incidence relative to the number of upper gastrointestinal endoscopies performed in the general population. METHODS: We conducted a cohort study using the Integrated Primary Care Information database. This general practice research database contains the complete and longitudinal electronic medical records of more than 500,000 persons. RESULTS: In total, 260 incident cases of BO were identified during the study period. The incidence of BO increased from 14.3/100,000 person years in 1997 (95% confidence interval (CI) 8.6-22.4) to 23.1/100,000 person years (95% CI 17.2-30.6) in 2002 (r2 = 0.87). The number of upper gastrointestinal endoscopies decreased from 7.2/1000 person years (95% CI 6.7-7.7) to 5.7/1000 person years (95% CI 5.4-6.1) over the same time period. This resulted in an overall increase in detected BO per 1000 endoscopies from 19.8 (95% CI 12.0-31.0) in 1997 to 40.5 (95% CI 30.0-53.5) in 2002 (r2 = 0.93). The incidence of adenocarcinoma increased from 1.7/100,000 person years (95% CI 0.3-5.4) in 1997 to 6.0/100,000 person years (95% CI 3.3-10.2) in 2002 (r2 = 0.87). CONCLUSION: The incidence of diagnosed BO is increasing, independent of the number of upper gastrointestinal endoscopies that are being performed. This increase in BO incidence will likely result in a further increase in the incidence of oesophageal adenocarcinomas in the near future.

A promoter polymorphism of the insulin-like growth factor-I gene is associated with left ventricular hypertrophy (Article)

2005-01-01T00:00:00Z

Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. (Article)

2004-11-03T00:00:00Z

CONTEXT: Although large-scale observational studies have demonstrated the effectiveness of influenza vaccination, no large studies have systematically addressed the clinical benefit of annual revaccinations. OBJECTIVE: To investigate the effect of annual influenza revaccination on mortality in community-dwelling elderly persons. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study using the computerized Integrated Primary Care Information (IPCI) database in the Netherlands including community-dwelling individuals aged 65 years or older from 1996 through 2002. For each year, we computed the individual cumulative exposure to influenza vaccination since study start. MAIN OUTCOME MEASURE: Association between the number of consecutive influenza vaccinations and all-cause mortality vs no vaccination after adjusting for age, sex, chronic respiratory and cardiovascular disease, hypertension, diabetes mellitus, renal failure, and cancer. RESULTS: The study population included 26,071 individuals, of whom 3485 died during follow-up. Overall, a first vaccination was associated with a nonsignificant annual reduction of mortality risk of 10% (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.78-1.03) while revaccination was associated with a reduced mortality risk of 24% (HR, 0.76; 95% CI, 0.70-0.83). Compared with a first vaccination, revaccination was associated with a reduced annual mortality risk of 15% (HR, 0.85; 95% CI, 0.75-0.96). During the epidemic periods this reduction was 28% (HR, 0.72; 95% CI, 0.53-0.96). Similar estimates were obtained for persons with and without chronic comorbidity and those aged 70 years or older at baseline. Overall, influenza vaccination is estimated to prevent 1 death for every 302 vaccinees at a vaccination coverage that varied between 64% and 74%. CONCLUSION: Annual influenza vaccination is associated with a reduction in all-cause mortality risk in a population of community-dwelling elderly persons, particularly in older individuals.

Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. (Article)

2004-09-01T00:00:00Z

AIMS: To determine the prevalence, incidence rate, lifetime risk and prognosis of heart failure. METHODS AND RESULTS: The Rotterdam Study is a prospective population-based cohort study in 7983 participants aged > or =55. Heart failure was defined according to criteria of the European Society of Cardiology. Prevalence was higher in men and increased with age from 0.9% in subjects aged 55-64 to 17.4% in those aged > or =85. Incidence rate of heart failure was 14.4/1000 person-years (95% CI 13.4-15.5) and was higher in men (17.6/1000 man-years, 95% CI 15.8-19.5) than in women (12.5/1000 woman-years, 95% CI 11.3-13.8). Incidence rate increased with age from 1.4/1000 person-years in those aged 55-59 to 47.4/1000 person-years in those aged > or =90. Lifetime risk was 33% for men and 29% for women at the age of 55. Survival after incident heart failure was 86% at 30 days, 63% at 1 year, 51% at 2 years and 35% at 5 years of follow-up. CONCLUSION: Prevalence and incidence rates of heart failure are high. In individuals aged 55, almost 1 in 3 will develop heart failure during their remaining lifespan. Heart failure continues to be a fatal disease, with only 35% surviving 5 years after the first diagnosis.

Unlicensed and off-label prescription of respiratory drugs to children (Article)

2004-01-01T00:00:00Z

Many respiratory drugs are not available in formulations suitable for infants and toddlers. Efficacy and safety research is mostly restricted to older children. However, respiratory drugs are frequently used in children for common diseases like asthma, upper and lower respiratory tract infections, rhinitis and sinusitis. The unlicensed and off-label use of respiratory drugs in children were studied. A population-based cohort study was conducted by using the computerised medical records in the Integrated Primary Care Information project. The study population comprised a random sample from all children aged 0-16 yrs who were registered with a general practitioner in 1998. All prescriptions for respiratory drugs during the study period were classified according to their licensing and off-label status. The study population comprised 13,426 patients (51.7% male, median age 8.7 yrs), of whom 2,502 (19%) received 5,253 prescriptions for respiratory drugs in 1998. A total of 3,306 (62.9%) prescriptions concerned licensed drugs. Of the remaining 1,947 prescriptions (37.1%), 882 (16.8%) were unlicensed for use in children, and 1,065 (20.3%) were prescribed off-label. The 1-yr cumulative risk of receiving an unlicensed or off-label prescription was 45% among children with at least one prescription for a respiratory drug. This population-based study showed that a large proportion of respiratory drugs prescribed by the general practitioner are unlicensed for use in children, or licensed but prescribed in an off-label manner. Results have to be interpreted with caution because they may unjustly suggest inaccurate prescribing, whereas it may be difficult to treat children with respiratory symptoms and diseases, because for many respiratory drugs paediatric data on safety and efficacy are insufficient. These findings underline the importance of research on suitable formulations, dosages and efficacy of respiratory drugs in children.

Marketing in the lay media and prescriptions of terbinafine in primary care: Dutch cohort study (Article)

2004-01-01T00:00:00Z

Underutilization of preventive strategies in patients receiving NSAIDs. (Article)

2003-01-01T00:00:00Z

BACKGROUND: Multiple treatment guidelines for non-steroidal anti-inflammatory drugs (NSAIDs) suggest that patients with one or more risk factors for NSAID-associated upper gastrointestinal (UGI) ulcer complications should be prescribed preventive strategies such as acid-suppressive drugs, misoprostol or cyclooxygenase (COX)-2-specific inhibitors to reduce their risk of serious ulcer complications. The purpose of the present study was to evaluate the extent to which new NSAID users receive recommended preventive strategies and to assess the association between risk factors and a prescription of acid suppressive drugs or misoprostol. METHOD: A retrospective observational cohort study was conducted using the Integrated Primary Care Information (IPCI) database, a longitudinal database of electronic general practitioner patient records in The Netherlands. The study population comprised all new NSAID users, defined as users of non-specific NSAIDs, COX-2-preferential NSAIDs and COX-2-specific inhibitors, during the period from January 1996 to April 2002. Subjects were excluded if they had an H2-receptor antagonist (H2RA), proton pump inhibitor (PPI) or misoprostol prescription in the 3 months prior to the first NSAID prescription. Preventive use of acid-suppressive drugs or misoprostol was identified by the coprescription for these drugs on the same day (+/-2 days) as the NSAID prescription. The drug use for each patient was validated as having a preventive indication by reviewing the physician-recorded symptoms and diagnoses. Risk factors for UGI ulcer events were defined as age >65 yr, UGI history (gastroduodenal ulcer, UGI bleeding, dyspepsia) and concomitant medications (anticoagulants, aspirin, oral corticosteroids). The study population comprised 69 648 new NSAID users. RESULTS: Overall, 7.9% of NSAID users received a preventive strategy (6.6% received a gastroprotective agent and an additional 1.3% received COX-2-specific inhibitors). Patients using preventive drugs had higher odds of having one or more UGI risk factors than patients without preventive drugs [adjusted odds ratio (OR) 1.78, 95% confidence interval 1.66-1.92]. Despite the greater rate of preventive drug prescriptions in patients who may have been at higher risk, 86.6% of patients with one risk factor and 81.2% with two or more risk factors received no preventive strategies. In contrast to non-specific NSAIDs, patients who received a prescription for a COX-2-specific inhibitor had significantly lower adjusted odds (OR = 0.22) of having H2RA/PPI or misoprostol coprescribed. CONCLUSIONS: Although patients who are treated with preventive strategies have higher odds of having gastrointestinal risk factors than those not prescribed preventive therapies, the majority (>80%) of patients with one or more gastrointestinal risk factors do not receive the recommended NSAID treatment regimen of a COX-2-specific inhibitor or NSAID + H2RA/PPI or misoprostol and are therefore undertreated.

Unlicensed and off label prescription of drugs to children: population based cohort study (Article)

2002-01-01T00:00:00Z

Fluoroquinolones and risk of Achilles tendon disorders: case-control study (Article)

2002-01-01T00:00:00Z