Integrated Primary Care Information Research Articles

TreatmentPatterns: An R package to facilitate the standardized development and analysis of treatment patterns across disease domains

Background and objectivesThere is an increasing interest to use real-world data to illustrate how patients with specific medical conditions are treated in real life. Insight in the current treatment practices helps to improve and tailor patient care, but is often held back by a lack of data interoperability and a high-level of required resources. We aimed to provide an easy tool that overcomes these barriers to support the standardized development and analysis of treatment patterns for a wide variety of medical conditions. MethodsWe formally defined the process of constructing treatment pathways and implemented this in an open-source R package TreatmentPatterns (https://github.com/mi-erasmusmc/TreatmentPatterns) to enable a reproducible and timely analysis of treatment patterns. ResultsThe developed package supports the analysis of treatment patterns of a study population of interest. We demonstrate the functionality of the package by analyzing the treatment patterns of three common chronic diseases (type II diabetes mellitus, hypertension, and depression) in the Dutch Integrated Primary Care Information (IPCI) database. ConclusionTreatmentPatterns is a tool to make the analysis of treatment patterns more accessible, more standardized, and more interpretation friendly. We hope it thereby contributes to the accumulation of knowledge on real-world treatment patterns across disease domains. We encourage researchers to further adjust and add custom analysis to the R package based on their research needs.

Data Resource Profile: The Integrated Primary Care Information (IPCI) database, The Netherlands.

Data Resource Profile: The Integrated Primary Care Information (IPCI) database, The Netherlands.

Women are started on a lower daily dose of metoprolol than men irrespective of dose recommendations: A potential source of confounding by contraindication in pharmacoepidemiology.

PurposeCurrent guidelines have no sex‐specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population‐based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data.MethodsThe mean daily starting doses of metoprolol in both sexes were compared with independent‐samples t‐tests and a linear regression analysis was used to adjust in the RS for co‐variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI‐database, adjustment was for age only.ResultsThe mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI −7.8, −1.8) and 4.6 mg (95%CI −5.3,‐4.0), respectively. Statistical significance remained after adjustment in both databases.ConclusionsWomen received lower starting doses of metoprolol than men in two independent data collections despite non‐sex specific cardiovascular guideline recommendations. This example of real‐life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.

Trends of prescribing antimicrobial drugs for urinary tract infections in primary care in the Netherlands: a population-based cohort study

ObjectiveUrinary tract infections (UTIs) are an important reason to consult a general practitioner (GP). Here, we describe antimicrobial drug prescribing patterns for UTIs by GPs in relation to the Dutch...

The association of vascular disorders with incident dementia in different age groups

BackgroundThere is increasing evidence that dementia risk associated with vascular disorders is age dependent. Large population-based studies of incident dementia are necessary to further elucidate this effect. Therefore, the aim of the present study was to determine the association of vascular disorders with incident dementia in different age groups in a large primary care database.MethodsWe included 442,428 individuals without dementia aged ≥ 65 years from the longitudinal primary care Integrated Primary Care Information (IPCI) database. We determined in 6 age groups (from 65–70 to ≥ 90 years) the risk of hypertension, diabetes mellitus, dyslipidemia, stroke, myocardial infarction, heart failure, and atrial fibrillation for all-cause dementia using incidence rate ratios, Cox regression, and Fine and Gray regression models.ResultsThe mean age at inclusion of the total study sample was 72.4 years, 45.7% of the participants were male, and median follow-up was 3.6 years. During 1.4 million person-years of follow-up, 13,511 individuals were diagnosed with dementia. The risk for dementia decreased with increasing age for all risk factors and was no longer significant in individuals aged ≥ 90 years. Adjusting for mortality as a competing risk did not change the results.ConclusionsWe conclude that vascular disorders are no longer a risk factor for dementia at high age. Possible explanations include selective survival of individuals who are less susceptible to the negative consequences of vascular disorders and differences in follow-up time between individuals with and without a vascular disorder. Future research should focus on the identification of other risk factors than vascular disorders, for example, genetic or inflammatory processes, that can potentially explain the strong age-related increase in dementia risk.

Identifying Data Elements to Measure Frailty in a Dutch Nationwide Electronic Medical Record Database for Use in Postmarketing Safety Evaluation: An Exploratory Study.

The role of frailty in postmarketing drug safety is increasingly acknowledged. Few European electronic medical records (EMRs) have been used to explore frailty in observational drug safety research. The aim of this study was to identify data elements, beyond multimorbidity and polypharmacy, that could potentially contribute to measuring frailty among older adults in the Dutch nationwide Integrated Primary Care Information (IPCI) database. Persons aged between 65 and 90years in the IPCI database were identified from 2008 to 2013. Clinical non-disease, non-drug measurements that could potentially contribute to measuring frailty were identified and selected if they were recorded in > 0.005% of patients and could be included in at least one of three definitions of frailty: the frailty phenotype model, the cumulative deficit model, and direct evaluations of frailty through standardized frailty scores. The frequency of these measures was calculated. Overall, 314,191 (17% of the source population) elderly persons were identified. Of these, 7948 (2.53%) had one or more of 12 clinical measurements identified that could potentially contribute to measuring frailty, such as clinical evaluations of cognition, mobility, and cachexia, as well as direct measures of frailty, such as the Groningen Frailty Index. Three of five measurements required for the frailty phenotype were identified in < 0.5% of the population: cachexia, reduced walking speed, and reduced physical activity; weakness and fatigue were not identified. The measurements outlined above may be appropriate for the cumulative deficit definition of frailty, provided that at least 30 deficits, including comorbidities and drug utilization, are evaluated in total. The most commonly recorded item identified that could potentially be used in a cumulative frailty model was the Mini-Mental State Examination score (N= 2850; 0.91%); the only recorded direct measurement of frailty was the Groningen Frailty Index (N = 2382; 0.76%). Non-disease, non-drug clinical data that could potentially contribute to a frailty model was not commonly recorded in the IPCI; less than 3% of a cohort of elderly persons had these data recorded, suggesting that the use of these data in postmarketing drug safety evaluation may be limited.

Prescribing pattern of antipsychotic drugs during the years 1996-2010: a population-based database study in Europe with a focus on torsadogenic drugs.

Antipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs. The aim of the current study was to evaluate the use of APDs in five European countries during the years 1996-2010. A cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals. The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona-CERT list. All analyses were stratified by age, gender and calendar year. A total of 559 276 person-years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients. Substantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD.

Antidepressant use and the risk of suicide: A population-based cohort study

BackgroundThe existing literature provides contradictory evidence on antidepressant use and risk of suicide. Some studies have shown that the use of Selective Serotonin Reuptake Inhibitors (SSRIs) is associated with an increased risk of suicide, especially during the first months of treatment, whereas other studies did not confirm this association. For this reason, our objective was to investigate the association between antidepressant use and risk of suicide in incident antidepressant users in relation to time since starting therapy. MethodsWe conducted a population-based cohort study within the Dutch Integrated Primary Care Information (IPCI) database, in incident users of antidepressant therapy between 1994 and 2012 (n=27,712). Cox proportional hazard models were used to study the association between current use of SSRIs, tricyclic antidepressants (TCA) and other antidepressants and risk of suicide or attempted suicide. ResultsDuring follow-up, a total of 280 incident antidepressant users attempted or committed suicide. Current use of SSRIs (hazard ratio (HR): 0.78, 95% CI: 0.57–1.07), TCAs (HR: 0.82, 95% CI: 0.48–1.42) or other antidepressants (HR: 0.75, 95% CI: 0.47–1.18) was not statistically significantly associated with suicide compared to past use of any of the antidepressants. LimitationsAlthough a large healthcare database was used, the number of reported cases of suicide (attempt) was low. ConclusionsThis study did not indicate an increase in risk of suicide after starting treatment with SSRIs, TCAs or other antidepressants compared with past antidepressant use.

Risk of Hyponatremia with Diuretics: Chlorthalidone versus Hydrochlorothiazide

BackgroundChlorthalidone and hydrochlorothiazide are often considered as interchangeable. However, greater (nighttime) blood pressure reduction, and alleged pleiotropic effects have renewed the interest in chlorthalidone. A recent study showed an increased risk of adverse events with chlorthalidone, including hyponatremia. MethodsTo investigate differences in risk of hyponatremia between chlorthalidone and hydrochlorothiazide, adjusted for daily dose, we conducted a population-based case-control study within the Dutch IPCI (Integrated Primary Care Information) database. The study population included all subjects ≥18 years without diabetes mellitus, heart failure, liver failure, and malignancy, who were registered in the IPCI database from 1996 to 2011. Cases were subjects with a serum sodium <130 millimoles per liter or hospitalization due to hyponatremia. Controls were matched on practice, age within 5 years, sex, and date of onset. ResultsA total of 1033 cases of hyponatremia were identified. Hyponatremia was more common with chlorthalidone than with hydrochlorothiazide at equal dose per day: adjusted odds ratio was 2.09 (95% confidence interval [CI], 1.13-3.88) for 12.5 milligrams per day and 1.72 (95% CI, 1.15-2.57) for 25 milligrams per day. Risks were not significantly increased with chlorthalidone compared with twice the dose per day of hydrochlorothiazide. ConclusionsThis is the first study that shows an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. The need for a lower dose of chlorthalidone than hydrochlorothiazide to achieve similar blood pressure reduction likely compensates for the increased risk of hyponatremia at equal dose.

Validation study in four health-care databases: upper gastrointestinal bleeding misclassification affects precision but not magnitude of drug-related upper gastrointestinal bleeding risk

ObjectiveTo evaluate the accuracy of disease codes and free text in identifying upper gastrointestinal bleeding (UGIB) from electronic health-care records (EHRs). Study Design and SettingWe conducted a validation study in four European electronic health-care record (EHR) databases such as Integrated Primary Care Information (IPCI), Health Search/CSD Patient Database (HSD), ARS, and Aarhus, in which we identified UGIB cases using free text or disease codes: (1) International Classification of Disease (ICD)-9 (HSD, ARS); (2) ICD-10 (Aarhus); and (3) International Classification of Primary Care (ICPC) (IPCI). From each database, we randomly selected and manually reviewed 200 cases to calculate positive predictive values (PPVs). We employed different case definitions to assess the effect of outcome misclassification on estimation of risk of drug-related UGIB. ResultsPPV was 22% [95% confidence interval (CI): 16, 28] and 21% (95% CI: 16, 28) in IPCI for free text and ICPC codes, respectively. PPV was 91% (95% CI: 86, 95) for ICD-9 codes and 47% (95% CI: 35, 59) for free text in HSD. PPV for ICD-9 codes in ARS was 72% (95% CI: 65, 78) and 77% (95% CI: 69, 83) for ICD-10 codes (Aarhus). More specific definitions did not have significant impact on risk estimation of drug-related UGIB, except for wider CIs. ConclusionsICD-9-CM and ICD-10 disease codes have good PPV in identifying UGIB from EHR; less granular terminology (ICPC) may require additional strategies. Use of more specific UGIB definitions affects precision, but not magnitude, of risk estimates.

OP0187-PC Potentially harmful prescription of NSAIDS in a primary care population with musculoskeletal complaints

BackgroundTo reduce adverse drug events (ADEs), clinical guidelines recommend cautious prescription of non-steroidal anti-inflammatory drugs (NSAIDs) in patients known to be at a high risk of developing a serious ADE....

Automatic generation of case‐detection algorithms to identify children with asthma from large electronic health record databases

Most electronic health record databases contain unstructured free-text narratives, which cannot be easily analyzed. Case-detection algorithms are usually created manually and often rely only on using coded information such as International Classification of Diseases version 9 codes. We applied a machine-learning approach to generate and evaluate an automated case-detection algorithm that uses both free-text and coded information to identify asthma cases. The Integrated Primary Care Information (IPCI) database was searched for potential asthma patients aged 5-18 years using a broad query on asthma-related codes, drugs, and free text. A training set of 5032 patients was created by manually annotating the potential patients as definite, probable, or doubtful asthma cases or non-asthma cases. The rule-learning program RIPPER was then used to generate algorithms to distinguish cases from non-cases. An over-sampling method was used to balance the performance of the automated algorithm to meet our study requirements. Performance of the automated algorithm was evaluated against the manually annotated set. The selected algorithm yielded a positive predictive value (PPV) of 0.66, sensitivity of 0.98, and specificity of 0.95 when identifying only definite asthma cases; a PPV of 0.82, sensitivity of 0.96, and specificity of 0.90 when identifying both definite and probable asthma cases; and a PPV of 0.57, sensitivity of 0.95, and specificity of 0.67 for the scenario identifying definite, probable, and doubtful asthma cases. The automated algorithm shows good performance in detecting cases of asthma utilizing both free-text and coded data. This algorithm will facilitate large-scale studies of asthma in the IPCI database.

Incidence rates and risk factors of bipolar disorder in the general population: a population‐based cohort study

To estimate the incidence rates (IRs) of bipolar I and bipolar II disorders in the general population according to sociodemographic population characteristics. A cohort study (during the years 1996-2007) was conducted in a general practitioners research database with a longitudinal electronic record of 800000 patients throughout the Netherlands [the Integrated Primary Care Information (IPCI) database]. Cases of bipolar disorder were identified and classified by systematic review of medical records. Age- and gender-specific IRs were calculated per calendar year, degree of urbanization, and degree of deprivation. The overall IR of bipolar disorder was 0.70/10000 person-years (PY) [95% confidence interval (CI): 0.57-0.83]; the IR of bipolar I disorder was 0.43/10000 PY (95% CI: 0.34-0.55) and the IR of bipolar II disorder was 0.19/10000 PY (95% CI: 0.13-0.27). Two peaks in the age at onset of the disorder were noticed: one in early adulthood (15-24 years; 0.68/10000 PY) and a larger peak in later life (45-54 years; 1.2/10000 PY). In bipolar II disorder, only one peak, in the 45-54 year age category (IR 0.42/10000 PY), was found. The IRs of bipolar disorder were significantly higher in deprived areas. Similar rates were found for men compared to women and in urban compared to rural areas. No association was found between the onset of first (hypo)manic episode and month or season of birth. We found two peaks in the age at onset of bipolar disorder, one in early adulthood and one in later life, the former consisting mainly of bipolar I disorder subjects. The incidence of bipolar disorder is higher in deprived areas. The onset of bipolar disorder is not associated with gender, urbanization, or month or season of birth.

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

BackgroundNon-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. MethodsTwo 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. ResultsThe 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. ConclusionNon-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.

Domperidone and Ventricular Arrhythmia or Sudden Cardiac Death

Recently, a 4-fold increase in risk of sudden cardiac death (SCD) was reported for domperidone in a study that focused on corrected QT interval (QTc)-prolonging drugs as a class and their association with SCD. To evaluate the association between the use of domperidone and serious non-fatal ventricular arrhythmia (VA) and SCD in the general population. We performed a population-based, case-control study during 1996-2007 in the Integrated Primary Care Information (IPCI) database, a longitudinal general practice research database in the Netherlands. We included all patients aged ≥18 years without cancer in the source population. We studied the association between the use of domperidone by recency of use (current, past and none) and daily dose, and the risk of serious non-fatal VA or SCD. Cases were defined as a natural death due to cardiac causes heralded by abrupt loss of consciousness within 1 hour after the onset of acute symptoms or an unwitnessed, unexpected death of someone seen in a stable medical condition <24 hours previously with no evidence of a non-cardiac cause. Controls were randomly drawn from the source population and matched to cases on age, sex, practice and index date. We compared the exposure odds for SCD alone and VA plus SCD by means of conditional logistic regression while adjusting for all available confounders. In addition, we stratified by insurance type. The study population comprised 1366 cases (62 VA and 1304 SCD) and 14114 matched controls. Of all cases, ten patients were current domperidone users at the index date, all with SCD. The matched unadjusted odds ratio of domperidone and SCD was 3.72 (95% CI 1.72, 8.08). Daily doses >30 mg were associated with a significant increased risk of SCD (adjusted odds ratio [OR(adj)] 11.4 [95% CI 1.99, 65.2]). Since there was a near interaction with health insurance (p = 0.050), all analyses were stratified by insurance. In publicly insured patients, seven cases were current users at the index date. Current use was associated with a significant increased risk of SCD (OR(adj) 4.17 [95% CI 1.33, 13.1]). Amongst privately insured patients there was one domperidone-exposed case, and amongst non-insured there were two. Current use of domperidone, especially high doses, is associated with an increased risk of SCD. We could not demonstrate an effect of domperidone on non-fatal VA due to absence of exposed cases.

Inhaled anticholinergic drugs and risk of acute urinary retention

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

Incidence of facial pain in the general population

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 100,000PY. 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.

Population‐based studies of antithyroid drugs and sudden cardiac death

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. 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 (> or =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). 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). 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 association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS

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 (OR adjusted: 2.7, 95% CI: 1.1–6.8). The association was stronger if ACE inhibitors were used for a longer time period (OR adjusted: 3.0, 95% CI: 1.1–8.1) and in higher dosages (OR adjusted: 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.

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

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. 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). 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. 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.