Comparison of characteristics of patients with lung cancer in U.K. primary care databases: Clinical Practice Research Datalink Aurum and GOLD.

INTRODUCTION: In recent years, the number of general practices contributing to the Clinical Practice Research Datalink (CPRD) database GOLD is decreasing. Therefore, for research questions addressing for instance novel treatments requiring up-to-date data, sample size will become an important consideration in study feasibility. In recent years, CPRD Aurum, containing information of practices that use EMIS software, has become an additional data source that is being used for CPRD studies. In order to establish whether Aurum is suited to act as data source for future studies in the field of lung cancer research, we aimed to compare characteristics between patients with lung cancer in Aurum and GOLD. METHODS: A retrospective study was performed comparing characteristics and overall survival (OS) of patients with lung cancer in Aurum and GOLD. To further evaluate similarity, hypothetical eligibility of these patients in Aurum and GOLD was compared for 11 randomized clinical trials (RCTs). RESULTS: Baseline characteristics registered in Aurum and GOLD were largely similar, with some clinically irrelevant differences for previous malignancies, deviant laboratory values and drug use. Median OS was 9.8 and 9.0 months for patients in Aurum and GOLD, respectively. Potential RCT eligibility varied between 49.4% and 79.5% and 49.1% and 78.1% for patients in Aurum and GOLD, respectively. Mortality rates and the comparison of the obtained HRs per hypothetical eligibility cohort per RCT were similar in Aurum and GOLD. CONCLUSION: This study showed that data of patients with lung cancer in Aurum and GOLD are largely comparable, suggesting that Aurum is suitable for future epidemiological lung cancer research.

The pattern of incident fractures according to fracture site in people with T1D.

Higher incidences of fractures are seen in people with type 1 diabetes (T1D), but knowledge on different fracture sites is sparse. We found a higher incidence mainly for distal fracture sites in people with T1D compared to controls. It must be further studied which fractures attributed to the higher incidence rates (IRs) at specific sites. INTRODUCTION: People with T1D have a higher incidence of fractures compared to the general population. However, sparse knowledge exists on the incidence rates of individual fracture sites. Therefore, we examined the incidence of various fracture sites in people with newly treated T1D compared to matched controls. METHODS: All people from the UK Clinical Practice Research Datalink GOLD (1987-2017), of all ages with a T1D diagnosis code (n = 6381), were included. People with T1D were matched by year of birth, sex, and practice to controls (n = 6381). Fracture IRs and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex. RESULTS: The IR of all fractures was significantly higher in people with T1D compared to controls (IRR: 1.39 (CI95%: 1.24-1.55)). Compared to controls, the IRR for people with T1D was higher for several fracture sites including carpal (IRR: 1.41 (CI95%: 1.14-1.75)), clavicle (IRR: 2.10 (CI95%: 1.18-3.74)), foot (IRR: 1.70 (CI95%: 1.23-2.36)), humerus (IRR: 1.46 (CI95%: 1.04-2.05)), and tibia/fibula (IRR: 1.67 CI95%: 1.08-2.59)). In women with T1D, higher IRs were seen at the ankle (IRR: 2.25 (CI95%: 1.10-4.56)) and foot (IRR: 2.11 (CI95%: 1.27-3.50)), whereas in men with T1D, higher IRs were seen for carpal (IRR: 1.45 (CI95%: 1.14-1.86)), clavicle (IRR: 2.13 (CI95%: 1.13-4.02)), and humerus (IRR: 1.77 (CI95%: 1.10-2.83)) fractures. CONCLUSION: The incidence of carpal, clavicle, foot, humerus, and tibia/fibula fractures was higher in newly treated T1D, but there was no difference at other fracture sites compared to controls. Therefore, the higher incidence of fractures in newly treated people with T1D has been found mainly for distal fracture sites.

The risk of new fragility fractures in patients with chronic kidney disease and hip fracture-a population-based cohort study in the UK.

Chronic kidney disease (CKD) is a risk factor for fractures. However, in hip fracture patients, CKD G3-G5 was associated with a higher mortality risk and not associated with a higher risk of subsequent non-hip fractures compared to eGFR > 60 ml/min. The higher mortality risk may, as competing risk, explain our findings. INTRODUCTION: Chronic kidney disease (CKD) is a known risk factor for fragility fractures. Patients aged 50+ with a recent fragility fracture have an increased risk of subsequent fractures. Our aim was to evaluate the association between CKD stages G3-G5 versus estimated glomerular filtration rate (eGFR) > 60 ml/min and the risk of a new non-hip fracture or fragility fracture in patients with a first hip fracture. METHODS: Population-based cohort study using the UK general practices in the Clinical Practice Research Datalink. Associations between CKD stage and first subsequent fracture were determined using Cox proportional hazard analyses to estimate hazard ratios (HRs). To explore the potential competing risk of mortality, cause-specific (cs) HRs for mortality were estimated. RESULTS: CKD G3-G5 was associated with a lower risk of any subsequent non-hip fracture (HR: 0.90, 95%CI: 0.83-0.97), but not with the risk of subsequent major non-hip fragility fracture. CKD G3-G5 was associated with a higher mortality risk (cs-HR: 1.05, 95%CI: 1.01-1.09). Mortality risk was 1.5- to 3-fold higher in patients with CKD G4 (cs-HR: 1.50, 95%CI: 1.38-1.62) and G5 (cs-HR: 2.93, 95%CI: 2.48-3.46) compared to eGFR > 60 ml/min. CONCLUSIONS: The risk of a subsequent major non-hip fragility fractures following hip fracture was not increased in patients with CKD G3-G5 compared to eGFR > 60 ml/min. Mortality risk was higher in both hip fracture and non-hip fracture patients with CKD G4 and G5. The higher mortality risk may, as competing risk, explain our main finding of no increased or even decreased subsequent fracture risk after a hip fracture in patients with CKD G3-G5.

Use of proton pump inhibitors and risk of iron deficiency: a population-based case-control study.

BACKGROUND: Hypochlorhydric states are an important cause of iron deficiency (ID). Nevertheless, the association between therapy with proton pump inhibitors (PPIs) and ID has long been a subject of debate. This case-control study aimed to investigate the risk of ID associated with the use of PPIs using the UK Clinical Practice Research Datalink (CPRD) database. METHODS: Cases were patients aged 19 years or older with first-time diagnosis of ID between 2005 and 2016 (n = 26 806). The dates of first diagnosis of ID in cases defined the index dates. For each case, one control was matched by age, gender and general practice. A PPI "full" user (PFU) was defined as a subject who had received PPIs for a continuous duration of at least 1 year prior to the index date. A PPI "limited" users (PLU) was a subject who intermittently received PPI therapy. A PPI non-user (PNU) was a subject who received no PPI prescriptions prior to the index date. The odds ratio of ID in PFU and PLU compared to PNU was estimated using conditional logistic regression. RESULTS: Among cases, 2960 were PFU, 6607 PLU and 17 239 PNU. Among controls, 1091 were PFU, 5058 PLU and 20 657 PNU. Adjusted odds ratio of ID in PFU and PLU compared to PNU was 3.60 (95%CI, [3.32-3.91]) and 1.51 (95% CI, [1.44-1.58]). Positive dose-response and time-response relationships were observed. CONCLUSIONS: Chronic PPI use increases the risk of ID. Physicians should consider this when balancing the risks and benefits of chronic PPI prescription.

Long-term persistence with anti-osteoporosis drugs after fracture.

UNLABELLED: Long-term persistence with anti-osteoporosis drugs and determinants for discontinuation among fracture patients were examined. Persistence was 75.0 and 45.3 % after 1 and 5 years, respectively. Those aged ≥80 years were at increased risk of early discontinuation. Within 1 year after discontinuation, 24.3 % restarted therapy, yet 47.0 % persisted for 1 year. INTRODUCTION: The risk of osteoporotic fracture can effectively be reduced with use of anti-osteoporosis drugs. However, little is known about persistence with these drugs after fracture where subsequent fracture risk is high. The aims were to determine long-term persistence with anti-osteoporosis drugs among fracture patients, including its determinants, and to describe restart and subsequent persistence. METHODS: A cohort study was conducted within the Dutch PHARMO Database Network. Patients aged ≥50 years (n = 961) who received anti-osteoporosis drugs within 1 year after fracture, but not in the preceding year, were included (2002-2011). Persistence (defined as the proportion on treatment) and the proportion restarting after discontinuation were estimated using Kaplan-Meier analyses. Time-dependent Cox regression was used to identify determinants of non-persistence including age, sex, initial dosage regime, fracture type, comorbidities, and drug use. RESULTS: Persistence with anti-osteoporosis drugs was 75.0 % (95 % confidence interval (CI) 72.0-77.7) and 45.3 % (95 % CI 40.4-50.0) after 1 and 5 years, respectively. A significant determinant of non-persistence was age ≥80 years (reference 50-59 years: adjusted hazard ratio [adj. HR] 1.65; 95 % CI 1.15-2.38). This effect was not constant over time (≤360 days following initiation: adj. HR 2.07; 95 % CI 1.27-3.37; >360 days: adj. HR 1.08; 95 % CI 0.62-1.88). Within 1 year after discontinuation, 24.3 % (95 % CI 20.1-29.2) restarted therapy, yet 47.0 % persisted for 1 year. CONCLUSIONS: This study identified suboptimal persistence with anti-osteoporosis drugs among fracture patients. Major target groups for measures aimed to improve persistence may be those aged >80 years and those restarting therapy.

Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density.

UNLABELLED: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. INTRODUCTION: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. METHODS: We performed nested case-control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800-829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). RESULTS: Meta-analysis of the two nested case-control studies showed pooled odds ratios of 0.98 (0.91-1.05, p = 0.52), 1.04 (0.97-1.12, p = 0.28), and 1.16 (0.83-1.62, p = 0.38) for the associations between rs1042713, rs1042714, and rs1800888 per minor allele and fractures, respectively. There were no significant associations of the polymorphisms and BMD in GEFOS. CONCLUSION: In conclusion, polymorphisms in the beta-2 adrenergic receptor gene are not associated with fracture risk or BMD.

Long term trends in oral antidiabetic drug use among children and adolescents in the Netherlands.

AIM: The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. METHODS: A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. RESULTS: In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). CONCLUSIONS: Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity.

Incidence rates and trends of hip/femur fractures in five European countries: comparison using e-healthcare records databases.

Hip fractures represent a major public health challenge worldwide. Multinational studies using a common methodology are scarce. We aimed to estimate the incidence rates (IRs) and trends of hip/femur fractures over the period 2003-2009 in five European countries. The study was performed using seven electronic health-care records databases (DBs) from Denmark, The Netherlands, Germany, Spain, and the United Kingdom, based on the same protocol. Yearly IRs of hip/femur fractures were calculated for the general population and for those aged ≥50 years. Trends over time were evaluated using linear regression analysis for both crude and standardized IRs. Sex- and age-standardized IRs for the UK, Netherlands, and Spanish DBs varied from 9 to 11 per 10,000 person-years for the general population and from 22 to 26 for those ≥50 years old; the German DB showed slightly higher IRs (about 13 and 30, respectively), whereas the Danish DB yielded IRs twofold higher (19 and 52, respectively). IRs increased exponentially with age in both sexes. The ratio of females to males was ≥2 for patients aged ≥70-79 years in most DBs. Statistically significant trends over time were only shown for the UK DB (CPRD) (+0.7% per year, P < 0.01) and the Danish DB (-1.4% per year, P < 0.01). IRs of hip/femur fractures varied greatly across European countries. With the exception of Denmark, no decreasing trend was observed over the study period.

Short- and long-term effects of real-time medication monitoring with short message service (SMS) reminders for missed doses on the refill adherence of people with Type 2 diabetes: evidence from a randomized controlled trial.

AIMS: To investigate short- and long-term effects of real-time monitoring medication use combined with short message service (SMS) reminders for missed doses on refill adherence to oral anti-diabetic medication. METHODS: A randomized controlled trial with two intervention groups and one control group involving 161 participants with Type 2 diabetes with suboptimal adherence. For 6 months, participants in the SMS group (n = 56) were monitored and received SMS reminders if they missed their medication. Participants in the non-SMS group (n = 48) were only monitored. The control group (n = 57) was not exposed to any intervention. Primary outcome measure was refill adherence to oral anti-diabetic medication. Multi-level regression analyses were performed to examine intervention effects on adherence between and within groups after 1 and 2 years of follow-up. RESULTS: At baseline, mean refill adherence was comparable between the groups. After 1 year, adherence in the SMS group was significantly higher than in the control group (79.5% vs. 64.5%; P < 0.001) and showed a significant improvement from baseline (+16.3%; P < 0.001). Mean adherence in the non-SMS group reached 73.1% (+7.3%; P < 0.05), but did not differ from the control group (P = 0.06). After 2 years, the improved adherence in the SMS group persisted and remained significantly higher than in the control group (80.4% vs. 68.4%; P < .01), contrary to the non-SMS group whose adherence approached baseline level again (65.5%). CONCLUSIONS: This study shows the long-term effectiveness of real-time medication monitoring combined with SMS reminders in improving refill adherence. This new reminder system can strengthen the self-management of people with diabetes.

Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications.

PURPOSE: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. METHODS: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. RESULTS: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57% and 39-69% for depression respectively). CONCLUSION: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations.

Discontinuation of statins among patients with type 2 diabetes.

BACKGROUND: Statins play an important role in the prevention of cardiovascular disease in type 2 diabetes. Several studies have reported low adherence with statins among patients with type 2 diabetes. Studies comparing discontinuation of statins compared with discontinuation of oral anti-diabetics within the same individuals before and after initiation of oral anti-diabetic drugs are not available. The aim of this study was to describe discontinuation among patients with type 2 diabetes prescribed statins prior to and after initiation of oral anti-diabetics and to compare statin discontinuation with discontinuation of oral anti-diabetics. METHODS: We report an observational cohort study among patients initiating treatment with statins prior to or after initiation of oral anti-diabetics between 1999 and 2007. Patients were classified as starting statins prior to initiation (Prior users) or after initiation (After users) of anti-diabetics. Discontinuation was defined as an interval of 180 days or more between the theoretical end date of a statin/anti-diabetic prescription and the dispensing date of the next statin/anti-diabetic prescription. RESULTS AND CONCLUSIONS: We included 3323 starters with oral anti-diabetic drugs in our study; 2072 patients initiated statins in the period of observation. Discontinuation rates for statins were higher compared with oral anti-diabetics (52.1 vs 15.0%). After users discontinued statin therapy more frequently compared to prior users (62.8 vs 48.2%). Discontinuation of statins is higher compared with anti-diabetic discontinuation. Patients starting statins after the initiation of oral anti-diabetic treatment are more likely to discontinue treatment than patients who initiate statins before the start of oral anti-diabetics.

Indications related to antidepressant prescribing in the Nivel-PCD database and the SIDIAP database.

BACKGROUND: Antidepressant drug consumption has increased, mainly in the elderly. This trend could be explained by the use for indications other than depression. We aimed to describe the indications related to antidepressant drug new users in two primary care settings. METHODS: A longitudinal study of new antidepressant users aged ≥65 was conducted, with data from the Nivel-PCD (The Netherlands) and SIDIAP (Catalonia) databases (2010-2015). As a proxy for indication, diagnoses registered around the 3 months of antidepressant prescribing were collected. Indications were classified in seven categories and an additional one of non-selected indications. The percentage and incidence calculated over the total population registered was described. RESULTS: A total of 16,537 and 199,168 new antidepressant users were identified in the Nivel-PCD and SIDIAP databases, respectively (women aged 65-69 were the most prevalent). Depression was the most frequent indication (24.0% and 31.3%), followed by anxiety (12.5% and 19.5%) and sleep disorders (10.2% and 26.4%). Tricyclic antidepressants were the most commonly prescribed in Nivel-PCD (48.7%), mainly associated with neuropathic pain, and selective serotonin reuptake inhibitor antidepressants in SIDIAP (63.1%), associated with depression. The non-selected indications category showed an upward trend in the Nivel-PCD database while in the SIDIAP database it decreased. LIMITATIONS: It is not mandatory for physicians to register a diagnosis with each prescription. CONCLUSIONS: Depression was the most common prescribing indication in The Netherlands and Spain, followed by anxiety and sleep disorders. The most commonly prescribed antidepressant differed between the countries and is likely explained by differences in local guidelines.

Microbial evaluation of proton-pump inhibitors and the risk of pneumonia.

Recent initiation of proton-pump inhibitor (PPI) treatment may increase the risk of community-acquired pneumonia (CAP), hypothetically by allowing colonisation of the oropharynx by gastrointestinal bacteria. The aim of this study was to assess the causal pathway by considering microbial aetiology of pneumonia and indications for initiation of PPI treatment. This was a population-based, case-control study with 430 cases with pneumonia and 1,720 matched controls. An elaborate diagnostic protocol was used to identify the causative microorganism of pneumonia. For patients recently starting PPI treatment, indications for treatment were assessed. Recent initiation of PPI treatment (<30 days) was associated with an increased risk of CAP (adjusted OR 3.1, 95% CI 1.4-7.1). Oropharyngeal bacteria were evenly distributed among current users, past users and nonusers of PPIs (p=0.41). Gastrointestinal bacteria were identified in only five (1.2%) patients with pneumonia (two current users and three nonusers). Excluding patients who were possibly prescribed PPI treatment for early symptoms of pneumonia (protopathic bias) did not alter the study findings. This study reaffirmed that use of PPIs is associated with an increased risk of CAP, especially when treatment has recently been started. Neither protopathic bias nor shifts in microbial aetiology seem to explain the association.

Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study.

SUMMARY: The effect of dopaminergic medication on the risk of hip/femur fractures is not clear. Our results showed a nearly twofold increased risk of hip/femur fractures in current dopaminergic drug users. Concomitant use of antidepressants further increased this risk. Fracture risk assessment may be warranted in elderly users of dopaminergic drugs. INTRODUCTION: Dopaminergic drugs, often used in the treatment of Parkinson's disease, have several pharmacological effects that may increase or decrease the risk of falling and fractures. Thus, the effect of dopaminergic medication on the risk of hip/femur fractures is not clear. The objective of the study was to examine the effect of dopaminergic medication and concomitant use of psychotropics on the risk of hip/femur fractures taking into account the timing of dopaminergic drug use. METHODS: A population-based case-control study in the PHARMO database was conducted for the period 1991 to 2002. Cases were patients aged 18 years and older with a first hip or femur fracture and matched to four control patients by year of birth, sex and geographical region. RESULTS: The study population included 6,763 cases and 26,341 controls. Current use of dopaminergic drugs (1-30 days before the index date) was associated with an increased risk of hip/femur fractures compared to never use (OR(adj) 1.76, 95% CI = 1.39-2.22), but this excess risk rapidly dropped to baseline levels when treatment had been discontinued >1 year ago. Concomitant use of antidepressants among current dopaminergic drug users further increased the risk of hip/femur fractures (OR(adj) 3.51, 95% CI = 2.10-5.87) while there was no additional risk with concomitant use of other psychotropics. CONCLUSIONS: Although the observed association between dopaminergic drugs and fracture risk may not be entirely causal, due to absence of information on the (severity of the) underlying disease, fracture risk assessment may be warranted in elderly users of dopaminergic drugs.

Risk of drug-induced photosensitivity: focus on spectroscopic and molecular characteristics.

BACKGROUND: Drug-induced photosensitivity is difficult to predict and remains a challenge for both the dermatological clinical practice and pharmacovigilance. PURPOSE: To assess the association between spectroscopic and molecular characteristics and the occurrence of photosensitivity reactions. METHODS: For 143 well-known photosensitisers (e.g. tetracyclines, diuretics), we retrieved information on spectroscopic and molecular parameters, including: absorption maximum lambda(max), molar absorption coefficient epsilon, area under the absorption curve (AUC), molecular weight and configuration, hetero and aromatic halogen atoms, lipophilicity (log P) and acid/base status (pKa). In the WHO-ADR database, all reports with suspected adverse drug reactions of the study drugs were selected. We identified all reports on photosensitivity reactions and defined them as cases. All other reports were selected as non-cases. A case-non-case approach was performed to assess the spectroscopic and molecular exposure variables as a factor for photosensitivity reactions. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). RESULTS: A lambda(max) between 290 and 320 nm (OR 3.74, 95% CI 3.45-4.06), and an epsilon > 20,000 M(-1) cm(-1) (OR 5.49, 95% CI 5.10-5.92) were highly associated with the reporting of photosensitivity reactions. Risk of the photosensitivity reactions was significantly increased among intermediate or high AUCs compared to low AUC. Low molecular weight and aromatic halogen atoms were associated with photosensitivity reactions (OR 2.37, 95% CI 2.07-2.71 resp. OR 3.37, 95% CI 3.15-3.61) as were log p < 1 and pKa < 7. CONCLUSION: The reporting of photosensitivity reactions to established phototoxic drug classes is strongly influenced by spectroscopic and physicochemical characteristics of individual drugs.

Changes in outpatient lithium treatment in the Netherlands during 1996-2005.

BACKGROUND: The objectives of the present study were to investigate in outpatients in the Netherlands between 1996 and 2005, changes in 1) the incidence and prevalence of lithium use and 2) lithium use patterns (discontinuation, add-on, and switch). METHODS: Incidence and prevalence of lithium use were determined for each year between 1996 and 2005. In addition, we determined cumulative changes in lithium use (discontinuation, add-on, and switching) at three, six, 12 and 24 months for three separate time-cohorts (1998-1999, 2000-2001 and 2002-2003). Lastly, concomitant use of other drugs used in the treatment of bipolar disorders next to lithium during the 24 months after the first lithium prescription was determined for the three time-cohorts. RESULTS: Incidence of lithium use was constant at approximately 0.2 per 1000 person-years, prevalence increased with 26% from 0.95 to 1.2 per 1000 persons. The percentage of patients receiving an add-on drug used in the treatment of bipolar disorders was constant over the three time-cohorts, with a significant decrease in use of tricyclic antidepressants. Within the patient group that stopped using lithium, more patients switched from lithium to another agent used in the treatment of bipolar disorders over calendar time, and fewer patients discontinued lithium. There was a significant increase in the use of atypical antipsychotics and valproic acid next to lithium. LIMITATIONS: We did not know the specific diagnosis for which lithium treatment was instituted. CONCLUSION: The changes were in line with the increase in alternatives during the last decade and in line with Dutch guidelines.

Influence of antidepressants on glycaemic control in patients with diabetes mellitus.

PURPOSE: Anecdotal evidence suggests that antidepressants (ADs) may complicate glycaemic control. The objective of this longitudinal study was to investigate the influence of ADs on glycaemic control within diabetes patients. METHODS: From the pharmacy registry database PHARMO, we selected insulin users who did not use oral antidiabetics. The study population comprised: 133 patients with at least 12 months insulin use before and 6 months during an AD episode, including 56 patients with an additional 6 months of insulin use after the AD episode; 180 patients with 24 months insulin use without an AD episode. Glycaemic control was measured as the amount of insulin used, which was calculated intra-individually in 3-month periods. We stratified for selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). RESULTS: Mean age (s.d.) of the subjects was 53.9 (19) years; 46.9% were men. Overall, the amount of insulin used did not change during or after AD use. No-AD users showed an increase of 16% in amount of insulin used over a period of 2 years (p < 0.001). SSRI users showed a decrease of 13% in amount of insulin used during the AD episode (p = 0.029), while no change was seen in TCA users. Notable was the large intra- and interindividual variation in amount of insulin used across all groups. CONCLUSIONS: Overall, AD use did not influence glycaemic control in diabetes patients. The tendency for a difference between SSRIs and TCAs is suggestive for a pharmacologic effect of ADs rather than a general effect of depression on glycaemic control.

Risk of infections in patients with gout: a population-based cohort study.

To investigate the risk of various types of infections (pneumonia and urinary tract infection (UTI)), and infection-related mortality in patients with gout compared with population-based controls. A retrospective cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD). All patients with a first diagnosis of gout and aged >40 years between January 1987-July 2014, were included and matched with up to two controls. Time-varying Cox proportional hazards models were used to estimate the risk of infections and mortality. 131,565 patients and 252,763 controls (mean age: 64 years, 74% males, mean follow-up of 6.7 years) were included in the full cohort. After full statistical adjustment, the risk of pneumonia was increased (adj. HR 1.27, 95% CI 1.18 to 1.36), while the risk of UTI (adj. HR 0.99, 95% CI 0.97 to 1.01) was similar in patients compared to controls. No differences between patients and controls were observed for infection-related mortality due to pneumonia (adj. HR 1.03, 95% CI 0.93 to 1.14) or UTI (adj. HR 1.16, 95% CI 0.98 to 1.37). In conclusion, patients with gout did not have decreased risks of pneumonia, UTI or infection-related mortality compared to population-based controls.

[Non-publication is common among phase 1, single-center, not prospectively registered, or early terminated clinical drug trials]. / Hoeveel klinische geneesmiddelenstudies worden uiteindelijk gepubliceerd?

The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands. All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1-5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7-10.0), and trials not belonging to phase 1-4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1-2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1-4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0-4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3-0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1-0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.

Risk of acute myocardial infarction after discontinuation of antihypertensive agents: a case-control study.

We performed a nested case-control study in a cohort of antihypertensive drug users to assess the association between discontinuation of different antihypertensive agents and the risk of acute myocardial infarction (AMI). Cases and controls were drawn from the Utrecht Cardiovascular Pharmacogenetics database. Patients who were hospitalised for their first AMI were considered cases and controls were not hospitalised for AMI. Antihypertensive users were defined as current users if the index date (date of AMI) fell within the prescribed duration or as discontinuers if this date fell outside the prescribed duration. According to the recency of discontinuation, discontinuers were divided into the following: recent discontinuers (⩽90 days), intermediate-term discontinuers (91-180 days) and long-term discontinuers (>180 days). We found that the risk of AMI was significantly increased in discontinuers, regardless of time since discontinuation, of beta-blockers (adjusted odds ratio (OR) 1.54; 95% confidence interval (CI; 1.25-1.91), P-value<0.0005), calcium channel blockers (CCBs; adjusted OR 2.25; 95% CI (1.53-3.30), P-value<0.0005) and diuretics (adjusted OR 1.76; 95% CI (1.24-2.48), P-value=0.002) compared to current users of these drugs. Moreover, the risk of AMI was significantly increased in long-term discontinuers (beta-blockers, CCBs, angiotensin-converting enzyme inhibitors and diuretics) and intermediate-term discontinuers (beta-blockers and CCBs) versus current users of these drugs. There was no difference in AMI risk between recent discontinuers of antihypertensive drugs versus current users of these drugs. In conclusion, discontinuation of antihypertensive drugs increases the risk of AMI after >90 days of discontinuation. This further underlines the importance of persistence to antihypertensive drug therapy to reduce the risk of AMI in patients with hypertension.