Improving 10-year cardiovascular risk prediction in apparently healthy people: flexible addition of risk modifiers on top of SCORE2.

AIMS: In clinical practice, factors associated with cardiovascular disease (CVD) like albuminuria, education level, or coronary artery calcium (CAC) are often known, but not incorporated in cardiovascular risk prediction models. The aims of the current study were to evaluate a methodology for the flexible addition of risk modifying characteristics on top of SCORE2 and to quantify the added value of several clinically relevant risk modifying characteristics. METHODS AND RESULTS: Individuals without previous CVD or DM were included from the UK Biobank; Atherosclerosis Risk in Communities (ARIC); Multi-Ethnic Study of Atherosclerosis (MESA); European Prospective Investigation into Cancer, The Netherlands (EPIC-NL); and Heinz Nixdorf Recall (HNR) studies (n = 409 757) in whom 16 166 CVD events and 19 149 non-cardiovascular deaths were observed over exactly 10.0 years of follow-up. The effect of each possible risk modifying characteristic was derived using competing risk-adjusted Fine and Gray models. The risk modifying characteristics were applied to individual predictions with a flexible method using the population prevalence and the subdistribution hazard ratio (SHR) of the relevant predictor. Risk modifying characteristics that increased discrimination most were CAC percentile with 0.0198 [95% confidence interval (CI) 0.0115; 0.0281] and hs-Troponin-T with 0.0100 (95% CI 0.0063; 0.0137). External validation was performed in the Clinical Practice Research Datalink (CPRD) cohort (UK, n = 518 015, 12 675 CVD events). Adjustment of SCORE2-predicted risks with both single and multiple risk modifiers did not negatively affect calibration and led to a modest increase in discrimination [0.740 (95% CI 0.736-0.745) vs. unimproved SCORE2 risk C-index 0.737 (95% CI 0.732-0.741)]. CONCLUSION: The current paper presents a method on how to integrate possible risk modifying characteristics that are not included in existing CVD risk models for the prediction of CVD event risk in apparently healthy people. This flexible methodology improves the accuracy of predicted risks and increases applicability of prediction models for individuals with additional risk known modifiers.

Heart disease is a major health concern worldwide, and predicting an individual's risk for developing heart disease is an important tool for prevention. Current risk prediction models often use factors such as age, gender, smoking, and blood pressure, but other factors like education level, albuminuria (protein in the urine), and coronary artery calcium (CAC) may also affect an individual's risk. The aim of this study was to develop a new method for using these additional risk factors for predicting risk even more accurately. The researchers used data from several large studies that included over 400 000 apparently healthy individuals who were followed for 10 years. They examined the effect of various risk factors on cardiovascular disease (CVD) risk using a statistical model. They found that adding coronary scan ('CAC score'); NT-proBNP, a biomarker of heart strain; and hs-Troponin-T, a marker of heart damage, to the existing risk prediction model (SCORE2) improved the accuracy of predicted CVD risk. The key findings are: The methods presented in the current study can help to add additional risk factors to predictions of existing models, such as SCORE2. This flexible method may help identify individuals who are at higher risk for CVD and guide prevention strategies.

Predictive Value of SLCO1B1 c.521T>C Polymorphism on Observed Changes in the Treatment of 1136 Statin-Users.

Pharmacogenomic testing is a method to prevent adverse drug reactions. Pharmacogenomics could be relevant to optimize statin treatment, by identifying patients at high risk for adverse drug reactions. We aim to investigate the clinical validity and utility of pre-emptive pharmacogenomics screening in primary care, with SLCO1B1 c.521T>C as a risk factor for statin-induced adverse drug reactions. The focus was on changes in therapy as a proxy for adverse drug reactions observed in statin-users in a population-based Dutch cohort. In total, 1136 statin users were retrospectively genotyped for the SLCO1B1 c.521T>C polymorphism (rs4149056) and information on their statin dispensing was evaluated as cross-sectional research. Approximately half of the included participants discontinued or switched their statin treatment within three years. In our analyses, we could not confirm an association between the SLCO1B1 c.521T>C genotype and any change in statin therapy or arriving at a stable dose sooner in primary care. To be able to evaluate the predictive values of SLCO1B1 c.521T>C genotype on adverse drug reactions from statins, prospective data collection of actual adverse drug reactions and reasons to change statin treatment should be facilitated.

The incidence of fractures at various sites in newly treated patients with type 2 diabetes mellitus.

Purpose: In this descriptive study, we examined the incidence of fractures in patients with newly treated type 2 diabetes mellitus (T2D) compared to matched reference population. Methods: Participants from the UK Clinical Practice research datalink (CPRD) GOLD (1987-2017), aged ≥30 years, with a T2D diagnosis code and a first prescription for a non-insulin anti-diabetic drug (n = 124,328) were included. Cases with T2D were matched by year of birth, sex and practice to a reference population (n = 124,328), the mean follow-up was 7.7 years. Crude fracture incidence rates (IRs) and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex and additionally adjusted for BMI, smoking status, alcohol use and history of any fracture at index date. Results: The IR of all fractures and major osteoporotic fractures was lower in T2D compared to the reference population (IRR 0.97; 95%CI 0.94-0.99). The IRs were lower for clavicle (IRR 0.67; 0.56-0.80), radius/ulna (IRR 0.81; 0.75-0.86) and vertebral fractures (0.83; 0.75-0.92) and higher for ankle (IRR 1.16; 95%CI 1.06-1.28), foot (1.11; 1.01-1.22), tibia/fibula (1.17; 1.03-1.32) and humerus fractures (1.11; 1.03-1.20). Differences in IRs at various fracture sites between T2D and the reference population were more pronounced in women than in men. In contrast, BMI adjusted IRs for all fractures (IRR 1.07; 1.04-1.10) and most individual fracture sites were significantly higher in T2D, especially in women. Conclusion: The crude incidence of all fractures was marginally lower in patients with newly treated T2D compared to the matched reference population but differed according to fracture site, especially in women. BMI adjusted analyses resulted in higher incidence rates in T2D at almost all fracture sites compared to crude incidence rates and this was more pronounced in women than in men. This implies that BMI may have a protective impact on the crude incidence of fractures, especially in women with newly treated T2D.

Pioglitazone use in Australia and the United Kingdom following drug safety advisories on bladder cancer risk: An interrupted time series study.

PURPOSE: National regulators in Australia and the United Kingdom issued safety advisories on the association between pioglitazone use and bladder cancer in July 2011. The Australian advisory noted that males were at higher risk of bladder cancer than females, while the UK advisory highlighted a new recommendation, suggest careful consideration in the elderly due to increasing risk with age. This study examined whether these differences in the advisories had different age- and sex-based impacts in each country. METHODS: Interrupted time series analysis was used to compare pioglitazone use (prescriptions/100000 population) in Australia and the United Kingdom for the 24 months before and 11 months after the July 2011 safety advisories (study period July 2009-June 2012). Separate models were used to compare use by sex and age group (≥65 years vs. <65 years) in each country. RESULTS: Pioglitazone use fell in Australia (17%) and the United Kingdom (24%) following the safety advisories. Use of pioglitazone fell more for males (18%) than females (16%) in Australia, and more for females (25%) than males (23%) in the United Kingdom; however, neither difference was statistically significant (Australia p = 0.445, United Kingdom p = 0.462). Pioglitazone use fell to a similar extent among older people than younger people in the United Kingdom (23% vs. 26%, p = 0.354), and did not differ between age groups in Australia (both 18%, p = 0.772). CONCLUSIONS: The results indicate that differences in the Australian and UK safety advisories resulted in substantial reductions in pioglitazone use at the population level in both countries, however, differences by sub-groups were not observed.

Prescribers' compliance with summary of product characteristics of dabigatran, rivaroxaban and apixaban-A European comparative drug utilization study.

Despite a tremendous increase of direct oral anticoagulants (DOACs) prescriptions in recent years, only few data is available analysing prescribers' adherence to Summary of Product Characteristics (SmPC). We aimed to assess adherence to registered indications, contraindications, special warnings/precautions, and potential drug-drug interactions for three DOAC compounds (dabigatran, rivaroxaban, and apixaban) in six databases of five European countries (The Netherlands, United Kingdom, Spain, Denmark, and Germany). We included adult patients (≥18 years) initiating DOACs between 2008 and 2015. For several SmPC items, broad definitions were used due to ambiguous SmPC terms or lacking data in some databases. Within the study period, a DOAC was initiated in 407 576 patients (rivaroxaban: 240 985 (59.1%), dabigatran: 95 303 (23.4%), and apixaban: 71 288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common indication (>60% in most databases). For the whole study period, a substantial variation between the databases was found regarding the proportion of patients with at least one contraindication (inter-database range [IDR]: 8.2%-55.7%), with at least one special warning/precaution (IDR: 35.8%-75.2%) and with at least one potential drug-drug interaction (IDR: 22.4%-54.1%). In 2015, the most frequent contraindication was "malignant neoplasm" (IDR: 0.7%-21.3%) whereas the most frequent special warning/precaution was "prescribing to the elderly" (≥75 years; IDR: 25.0%-66.4%). The most common single compound class interaction was "concomitant use of non-steroidal anti-inflammatory drugs" (IDR: 3.0%-25.3%). Contraindications, special warnings/precautions, and potential drug-drug interactions were present in a relevant number of new DOAC users. Due to broad definitions used for some SmPC terms, overall proportions for contraindications are prone to overestimation. However, for unambiguous SmPC terms documented in the databases sufficiently, the respective estimates can be considered valid. Differences between databases might be related to "true" differences in prescription behaviour, but could also be partially due to differences in database characteristics.

Exploring the Association between Monoclonal Antibodies and Depression and Suicidal Ideation and Behavior: A VigiBase Study.

INTRODUCTION: Several monoclonal antibodies (mAbs) have been linked to neuropsychiatric adverse effects in patients, including depression and suicidal ideation and behavior. OBJECTIVE: The aim of this study was to quantify and characterize spontaneously reported adverse drug reactions (ADRs) of depression and suicidal ideation and behavior related to mAb users, and to explore a possible association with their mechanism of action. METHODS: We included mAb ADRs that were reported in VigiBase, and identified those related to depression and suicidal ideation and behavior. Reporting odds ratios (RORs) were estimated for each mAb (bevacizumab as the reference) and according to their influence on the immune system (not directly targeting [reference], stimulating, or suppressing). Those suppressing the immune system were further divided into their intended indication (auto-immune diseases, cancer). RESULTS: Overall, 2,924,319 ADRs for 44 mAbs were included; 9455 ADRs were related to depression and 1770 were related to suicidal ideation and behavior. The association was strongest for natalizumab and belimumab, both for depression (ROR 5.7, 95% confidence interval [CI] 5.0-6.4; and ROR 5.1, 95% CI 4.2-6.2) and suicidal ideation and behavior (ROR 12.0, 95% CI 7.9-18.3; and ROR 20.2, 95% CI 12.4-33.0). Those suppressing the immune system showed higher ROR, i.e. 1.9 (95% CI 1.8-2.0) for depression and 3.6 (95% CI 3.0-4.4) for suicidal ideation and behavior. This finding was only seen for mAbs used for treating autoimmune diseases. CONCLUSION: Depression and suicidal ideation and behavior are seen in patients using mAbs, particularly mAbs used for treating autoimmune diseases that suppress the immune system. For interpretation of these data, the indications for use and other characteristics require further consideration.

Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use.

BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low-frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene-based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta-analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 × 10-7) and rs8034191 (p = 6.31 × 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use.

Risk of community-acquired pneumonia in chronic obstructive pulmonary disease stratified by smoking status: a population-based cohort study in the United Kingdom.

BACKGROUND: Smoking increases the risk of community-acquired pneumonia (CAP) and is associated with the development of COPD. Until now, it is unclear whether CAP in COPD is due to smoking-related effects, or due to COPD pathophysiology itself. OBJECTIVE: To evaluate the association between COPD and CAP by smoking status. METHODS: In total, 62,621 COPD and 191,654 control subjects, matched by year of birth, gender and primary care practice, were extracted from the Clinical Practice Research Datalink (2005-2014). Incidence rates (IRs) were estimated by dividing the total number of CAP cases by the cumulative person-time at risk. Time-varying Cox proportional hazard models were used to estimate the hazard ratios (HRs) for CAP in COPD patients versus controls. HRs of CAP by smoking status were calculated by stratified analyses in COPD patients versus controls and within both subgroups with never smoking as reference. RESULTS: IRs of CAP in COPD patients (32.00/1,000 person-years) and controls (6.75/1,000 person-years) increased with age and female gender. The risk of CAP in COPD patients was higher than in controls (HR 4.51, 95% CI: 4.27-4.77). Current smoking COPD patients had comparable CAP risk (HR 0.92, 95% CI: 0.82-1.02) as never smoking COPD patients (reference), whereas current smoking controls had a higher risk (HR 1.23, 95% CI: 1.13-1.34) compared to never smoking controls. CONCLUSION: COPD patients have a fourfold increased risk to develop CAP, independent of smoking status. Identification of factors related with the increased risk of CAP in COPD is warranted, in order to improve the management of patients at risk.

Meta-analysis of genome-wide association studies on the intolerance of angiotensin-converting enzyme inhibitors.

OBJECTIVES: To identify single nucleotide polymorphisms (SNPs) associated with switching from an angiotensin-converting enzyme (ACE)-inhibitor to an angiotensin receptor blocker. METHODS: Two cohorts of patients starting ACE-inhibitors were identified within the Rotterdam Study in the Netherlands and the Genetics of Diabetes Audit and Research in Tayside Scotland study in Scotland. Cases were intolerant patients who switched from an ACE-inhibitor to an angiotensin receptor blocker and controls were individuals who used ACE-inhibitors continuously for at least 2 years and did not switch. Genome-wide association study (GWAS) using an additive model was run in these sets and the results were meta-analysed using Genome-Wide Association Meta Analysis software. RESULTS: A total of 972 cases out of 5161 ACE-inhibitor starters were identified. Eight SNPs within four genes reached the genome-wide association study significance level (P<5×10) in the meta-analysis [RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), γ-aminobutyric acid receptor subunit γ-2, sarcoma (Src) homology 2 (SH2) B adaptor protein 1 and membrane bound O-acyltransferase domain containing 1]. The strongest associated SNP was located in an intron of RNA binding protein, Fox-1 homolog (Caenorhabditis elegans), which contains an RNA binding protein [rs2061538: minor allele frequency=0.16, odds ratio=1.52 (95% confidence interval: 1.32-1.76), P=6.2×10]. CONCLUSION: These results indicate that genetic variation in the above-mentioned genes may increase the risk of ACE-inhibitor-induced adverse reactions.

Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials.

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.

Increasing trends in the incidence and prevalence rates of type 1 diabetes among children and adolescents in the Netherlands.

OBJECTIVE: To assess the trends in the incidence and prevalence rates of type 1 diabetes (T1D) among children and adolescents in the Netherlands. METHODS: A population-based cohort study was conducted in the Dutch PHARMO record linkage system (1998-2011). All children and adolescents aged ≤19 yr with at least one insulin dispensing (as a proxy for T1D) were identified and the numbers of incident and prevalent cases (numerators) were calculated. Overall age-adjusted (0-19 yr) incidence and prevalence rates together with age- and sex-specific rates of T1D and their 95% confidence intervals (CI) were calculated using data from the Dutch Central Bureau of Statistics as denominator. Trends over time were assessed using Joinpoint regression software (National Cancer Institute, Bethesda, MD, USA). RESULTS: In 2011, the overall age-adjusted incidence and prevalence rates of T1D were 25.2/100 000 (95% CI, 23.7-26.8) person-years (PY) and 174.4/100 000 (95% CI, 170.2-178.5) children, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence and prevalence rate was 3.7% (95% CI, 1.8-5.7) and 3.8% (95% CI, 2.4-5.2), respectively. While during the study period the largest increases in the incidence and prevalence rates of T1D were observed for the oldest age groups (10-14 and 15-19 yr), a decreasing trend was detected for the 0- to 4-yr-old category (with AAPCs of -1.8 (95% CI, -9.9 to 7.1) and -6.9% (95% CI, -11.5 to -2.1) for incidence and prevalence, respectively). CONCLUSION: Age-adjusted incidence (1999-2011) and prevalence rates (1998-2011) of T1D in Dutch children (aged 0-19 yr) continued to increase and a shift was observed to a later onset of the disease.

Chronic comorbidities in children with type 1 diabetes: a population-based cohort study.

OBJECTIVE: To determine the incidence of chronic comorbidities among children with type 1 diabetes (T1D) and to compare incidences with a group of children without diabetes. DESIGN: Population-based cohort study. SETTING: Dutch PHARMO database (1998-2010). PATIENTS: All patients (<19 years old) with T1D between 1999 and 2009 (T1D cohort) and a group of age- and sex-matched (ratio: 1-4) children without diabetes (reference cohort). MAIN OUTCOME MEASURE: The incidence of nine common chronic comorbidities was assessed on the basis that they were treated pharmacologically and/or resulted in hospital admission. Cox proportional hazard analysis was used to estimate the strength of the association between T1D and comorbidities, expressed as HRs and 95% CIs. RESULTS: A total of 915 patients with T1D and 3590 children in the reference cohort (51% boys, mean age of 10.1 (SD 4.5) years) were included. T1D was associated with an increased risk (HR; 95% CI) of hospitalisation for any comorbidity (3.7; 2.5 to 5.5), thyroid disease (14.2; 6.7 to 31.0), non-infectious enteritis and colitis (5.9; 3.0 to 11.5), cardiovascular disorders (3.1; 2.3 to 4.2), mental disorders (2.0; 1.4 to 3.1), epilepsy (2.0; 1.1 to 3.7) and (obstructive) pulmonary disease (1.5; 1.2 to 2.0). There was no significant difference in the incidences of other comorbidities (malignant disorders, anaemia and migraine) between the two cohorts. CONCLUSIONS: Our longitudinal study showed that incidences of six chronic diseases were significantly higher in T1D children during the early years of developing this disease compared with the reference children.

Long-term use of 5α-reductase inhibitors and the risk of male breast cancer.

BACKGROUND: The 5α-reductase inhibitors (5-ARI) finasteride and dutasteride are indicated for the treatment of lower urinary tract symptoms caused by benign prostatic hyperplasia. Case reports have suggested that 5-ARIs increase the risk for male breast cancer, with no conclusive evidence. The objective of this study was to quantify the association between use of 5-ARIs and the risk for male breast cancer. METHODS: A case-control study was conducted with data from the United Kingdom Clinical Practice Research Datalink database among all men aged 45 years and older in the period 1 January 1992 to 31 December 2011. Cases of men diagnosed with breast cancer were matched to up 10 controls on age and general practice. Crude and adjusted odds ratios were estimated for the risk of breast cancer associated with the use of 5-ARIs. RESULTS: Three hundred and ninety-eight cases were identified and matched to 3,930 controls. Ever use of 5-ARIs was associated with an adjusted odds ratio for breast cancer of 1.08 (95 % CI 0.62-1.87) compared to non-users. Increasing cumulative duration of treatment showed no increasing risks: adjusted odds ratios for use for less than 280, for 280 to 1,036 and for more than 1,036 days were 1.21 (95 % CI 0.47-3.10), 0.94 (95 % CI 0.36-2.41) and 1.29 (95 % CI 0.54-3.08), respectively. CONCLUSIONS: In this study, there was no evidence of an association between short- or long-term treatment with 5-ARIs and the risk for breast cancer in older men.

Age as a determinant of instability of serum lithium concentrations.

BACKGROUND: Lithium is used both in bipolar disorder and as augmentation in treatment-resistant unipolar depression. Long-term treatment is often indicated. Pharmacokinetic and pharmacodynamic changes in older age, as well as increasing comorbidities and polypharmacy, could result in instability of serum lithium concentrations. In this study, several parameters, considered proxy for instability, were compared between age groups. These parameters were derived from studies involving oral anticoagulants. METHODS: A retrospective study (1995-2004) was conducted using serum lithium concentrations from the laboratories of 3 hospitals in the Netherlands; 759 patients treated with lithium, 40 years or older, with at least 2 years' follow-up were identified. They were divided into 4 age groups: 40-49, 50-59, 60-69, and 70+ years; the youngest group was used as a reference group. The variance growth rate and percentage of time below, in, and above treatment range are all proxies for instability. They were analyzed between the age categories. RESULTS: There was no significant difference for these variables between the reference group and the older age groups. In a subgroup of 454 patients, the parameters considered as proxy for instability during titration, number of days and number of serum lithium concentration measurements during titration, were evaluated; no significant difference was found between the age groups. In a small group of 117 patients, titration and maintenance treatment for at least 2 years could be analyzed separately. Also in this group, there was no difference between the age groups. CONCLUSIONS: Age is not a determinant of serum lithium concentration instability. Therefore, age is not a reason to not initiate or discontinue lithium therapy.