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BACKGROUND: Diabetic retinopathy (DR) is a major sight-threatening microvascular complication in individuals with diabetes. Systemic inflammation combined with oxidative stress is thought to capture most of the complexities involved in the pathology of diabetic retinopathy. A high level of neutrophil-lymphocyte ratio (NLR) is an indicator of abnormal immune system activity. Current estimates of the association of NLR with diabetes and its complications are almost entirely derived from cross-sectional studies, suggesting that the nature of the reported association may be more diagnostic than prognostic. Therefore, in the present study, we examined the utility of NLR as a biomarker to predict the incidence of DR in the Scottish population. METHODS: The incidence of DR was defined as the time to the first diagnosis of R1 or above grade in the Scottish retinopathy grading scheme from type 2 diabetes diagnosis. The effect of NLR and its interactions were explored using a competing risks survival model adjusting for other risk factors and accounting for deaths. The Fine and Gray subdistribution hazard model (FGR) was used to predict the effect of NLR on the incidence of DR. RESULTS: We analysed data from 23,531 individuals with complete covariate information. At 10 years, 8416 (35.8%) had developed DR and 2989 (12.7%) were lost to competing events (death) without developing DR and 12,126 individuals did not have DR. The median (interquartile range) level of NLR was 2.04 (1.5 to 2.7). The optimal NLR cut-off value to predict retinopathy incidence was 3.04. After accounting for competing risks at 10 years, the cumulative incidence of DR and deaths without DR were 50.7% and 21.9%, respectively. NLR was associated with incident DR in both Cause-specific hazard (CSH = 1.63; 95% CI: 1.28-2.07) and FGR models the subdistribution hazard (sHR = 2.24; 95% CI: 1.70-2.94). Both age and HbA1c were found to modulate the association between NLR and the risk of DR. CONCLUSIONS: The current study suggests that NLR has a promising potential to predict DR incidence in the Scottish population, especially in individuals less than 65 years and in those with well-controlled glycaemic status.
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Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Humanos , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/epidemiología , Neutrófilos , Diabetes Mellitus Tipo 2/epidemiología , Incidencia , Estudios Transversales , Linfocitos/patología , Factores de Riesgo , Escocia/epidemiologíaRESUMEN
OBJECTIVE: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. METHOD: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. RESULTS: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark -0.08%, 95%CI -0.13, -0.03; England -0.09%, 95%CI -0.13 to -0.06%; the Netherlands -1.84%, 95%CI -2.51 to -1.17%; Scotland -0.34%, 95%CI -0.38 to -0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (-0.12%, 95%CI -0.19 to -0.04), PAD (-0.13%, 95%CI -0.22 to -0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (-0.01%, 95%CI -0.02 to -0.007%), IHD (-0.017, 95%CI -0.02, -0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. CONCLUSION: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings.
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Enfermedades Cardiovasculares , Diclofenaco , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/epidemiología , Diclofenaco/efectos adversos , Inglaterra , Europa (Continente) , Humanos , Análisis de Series de Tiempo Interrumpido , Países Bajos , Análisis de Regresión , EscociaRESUMEN
BACKGROUND: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. METHOD: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression. RESULTS: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (-12.05, 95%CI -18.47 to -5.63) and Scotland (-19.01, 95%CI -26.99 to -11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (-1.72, 95%CI -2.69 to -0.75) and Scotland (-2.38, 95%CI -3.32 to -1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country. CONCLUSION: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants.
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Hidroxizina , Dinamarca , Inglaterra , Humanos , Análisis de Series de Tiempo Interrumpido , Países Bajos , Análisis de Regresión , EscociaRESUMEN
OBJECTIVE: The retina may provide readily accessible imaging biomarkers of global cardiovascular health. Increasing evidence suggests variation in retinal vascular traits is highly heritable. This study aimed to identify the genetic determinants of retinal vascular traits. Approach and Results: We conducted a meta-analysis of genome-wide association studies for quantitative retinal vascular traits derived using semi-automatic image analysis of digital retinal photographs from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside; N=1736) and ORCADES (Orkney Complex Disease Study; N=1358) cohorts. We identified a novel genome-wide significant locus at 19q13 (ACTN4/CAPN12) for retinal venular tortuosity (TortV), and one at 13q34 (COL4A2) for retinal arteriolar tortuosity (TortA); these 2 loci were subsequently confirmed in 3 independent cohorts (Ntotal=1413). In the combined analysis of discovery and replication cohorts, the lead single-nucleotide polymorphism in ACTN4/CAPN12 was rs1808382 (ßs.d.=-0.109; SE=0.015; P=2.39×10-13) and in COL4A2 was rs7991229 (ßs.d.=0.103; SE=0.015; P=4.66×10-12). Notably, the ACTN4/CAPN12 locus associated with TortV is also associated with coronary artery disease, heart rate, and atrial fibrillation. CONCLUSIONS: Genetic determinants of retinal vascular tortuosity are also linked to cardiovascular health. These findings provide a molecular pathophysiological foundation for the use of retinal vascular traits as biomarkers for cardiovascular diseases.
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Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Enfermedades de la Retina/genética , Vasos Retinianos/anomalías , Vénulas/anomalías , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/etiología , Humanos , Fenotipo , Enfermedades de la Retina/complicaciones , Enfermedades de la Retina/diagnóstico , Vasos Retinianos/diagnóstico por imagen , Factores de RiesgoRESUMEN
PURPOSE: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. METHODS: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. RESULTS: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be a more limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (-0.42%, 95% CI, -0.66% to -0.18%), England (-0.09%, 95% CI, -0.11% to -0.08%), and Scotland (-0.67%, 95% CI, -0.79% to -0.55%); and falling trends in diclofenac initiation in the Netherlands (-0.03%, 95% CI, -0.06% to -0.01% per quarter) and Scotland (-0.04%, 95% CI, -0.05% to -0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. CONCLUSIONS: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching.
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Diclofenaco/uso terapéutico , Etiquetado de Medicamentos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Analgésicos/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Dolor Crónico/tratamiento farmacológico , Dinamarca , Inglaterra , Humanos , Países Bajos , Escocia/epidemiologíaRESUMEN
AIMS/HYPOTHESIS: The aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade. METHODS: This was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (n = 1364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades. RESULTS: The hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively. CONCLUSIONS/INTERPRETATION: Higher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2.
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1-Alquil-2-acetilglicerofosfocolina Esterasa/sangre , Diabetes Mellitus Tipo 2/sangre , Retinopatía Diabética/sangre , Anciano , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/complicaciones , Retinopatía Diabética/diagnóstico , Progresión de la Enfermedad , Registros Electrónicos de Salud , Femenino , Humanos , Estudios Longitudinales , Masculino , Microcirculación , Persona de Mediana Edad , Factores de Riesgo , Escocia , Resultado del TratamientoRESUMEN
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.
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Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Diabetes Mellitus/tratamiento farmacológico , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Acetiltransferasas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antígenos Nucleares/genética , Diabetes Mellitus/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Oportunidad Relativa , Receptores de GABA-A/genéticaAsunto(s)
Enfermedad de la Arteria Coronaria/genética , Insuficiencia Cardíaca/genética , Polimorfismo de Nucleótido Simple , Volumen Sistólico/genética , Función Ventricular Izquierda/genética , Anciano , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/fisiopatología , Progresión de la Enfermedad , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Incidencia , Estudios Longitudinales , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Fenotipo , Medición de Riesgo , Factores de Riesgo , Escocia/epidemiologíaRESUMEN
BACKGROUND: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. METHODS AND FINDINGS: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (nâ =â 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (pâ = â0.001). CONCLUSIONS: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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Adiposidad/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Análisis de la Aleatorización Mendeliana , Carácter Cuantitativo Heredable , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Índice de Masa Corporal , Estudios de Casos y Controles , Factores de Confusión Epidemiológicos , Estudios de Asociación Genética , Humanos , Metaanálisis como Asunto , Polimorfismo de Nucleótido Simple/genética , Proteínas/genéticaRESUMEN
OBJECTIVE: South Asians are diagnosed with type 2 diabetes (T2D) more than a decade earlier in life than seen in European populations. We hypothesized that studying the genomics of age of diagnosis in these populations may give insight into the earlier age diagnosis of T2D among individuals of South Asian descent. RESEARCH DESIGN AND METHODS: We conducted a meta-analysis of genome-wide association studies (GWAS) of age at diagnosis of T2D in 34,001 individuals from four independent cohorts of European and South Asian Indians. RESULTS: We identified two signals near the TCF7L2 and CDKAL1 genes associated with age at the onset of T2D. The strongest genome-wide significant variants at chromosome 10q25.3 in TCF7L2 (rs7903146; P = 2.4 × 10-12, ß = -0.436; SE 0.02) and chromosome 6p22.3 in CDKAL1 (rs9368219; P = 2.29 × 10-8; ß = -0.053; SE 0.01) were directionally consistent across ethnic groups and present at similar frequencies; however, both loci harbored additional independent signals that were only present in the South Indian cohorts. A genome-wide signal was also obtained at chromosome 10q26.12 in WDR11 (rs3011366; P = 3.255 × 10-8; ß = 1.44; SE 0.25), specifically in the South Indian cohorts. Heritability estimates for the age at diagnosis were much stronger in South Indians than Europeans, and a polygenic risk score constructed based on South Indian GWAS explained â¼2% trait variance. CONCLUSIONS: Our findings provide a better understanding of ethnic differences in the age at diagnosis and indicate the potential importance of ethnic differences in the genetic architecture underpinning T2D.
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Diabetes Mellitus Tipo 2 , Pueblo Europeo , Personas del Sur de Asia , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/genética , Etnicidad , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Edad de Inicio , Factores de Edad , Pueblo Europeo/genética , Personas del Sur de Asia/genéticaRESUMEN
Background/Aims: Statin intolerance leads to poor adherence to statin therapy, resulting in a failure to achieve desired cholesterol reduction and adverse outcomes. The LILRB5 Asp247Gly genotype has been identified as being associated with statin intolerance and statin-induced myalgia. We conducted a randomized clinical trial to examine its role in immune response through T regulatory cell aggregation and in achieving cholesterol reduction targets. Methods: A double-blind, cross-over, recruit-by-genotype trial was undertaken. A total of 18 participants who had either the Asp247Asp (T/T) genotype or the Gly247Gly (C/C) genotype were recruited to the study. Participants were randomised to receive placebo or atorvastatin 80 mg daily for 28 days. Following a washout period of 3 weeks, they were then switched to the opposite treatment. Biochemical and immunological measurements as well as interviews were performed prior to and after both treatment periods. Within genotype group comparisons were performed using repeated measures Wilcoxon tests. Two-way repeated measures ANOVA with genotype and treatment as factors were used to compare changes in biochemical parameters between groups during placebo and atorvastatin periods. Results: Individuals with the Asp247Asp genotype had a greater increase in creatine kinase (CK) compared to those with Gly247Gly genotype in response to atorvastatin (p = 0.03). Those with Gly247Gly genotype had a mean non-HDL cholesterol reduction of 2.44 (95% CI:1.59 - 3.29) mmol/L while in Asp247Asp genotype group the mean reduction was 1.28 (95%CI: 0.48 - 2.07) mmol/L. The interaction between the genotype and atorvastatin treatment for total cholesterol (p = 0.007) and non-HDL cholesterol response was significant (p = 0.025). Immunological assessment showed no significant changes in aggregation of T regulatory cells by genotype. Conclusion: The Asp247Gly variant in LILRB5, previously associated with statin intolerance, was associated with differential increases in creatine kinase and total cholesterol and non-HDL cholesterol-lowering response to atorvastatin. Taken together, these results suggest that this variant could have utility in precision cardiovascular therapy.
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BACKGROUND: Co-prescribed aspirin and dipyridamole are more effective than aspirin alone following cerebral infarction; however, patients may struggle with this more complex regimen. The objectives of this study were: (1) to describe postdischarge prescribing of antiplatelet regimens, (2) to measure patient persistence with different antiplatelet regimens, and (3) to measure whether persistence impacts on outcomes. METHODS: We used record linkage of the Tayside Stroke Cohort with community dispensed prescribing data from 1994 to 2005. All patients had suffered a radiologically confirmed cerebral infarction and were excluded if they had previously used or had other indications for antiplatelet agents. We measured persistence to initial and any antiplatelet regimen using survival analysis. To assess the impact of therapy we used survival analysis to follow up until the APTC endpoint of serious vascular event (myocardial infarction, stroke or vascular death) or censored. Antiplatelet regimen was entered as a time-dependent covariate in a Cox model that also adjusted for age, sex, history of diabetes and baseline use of nitrates and statins. RESULTS: The study cohort contained 1,407 stroke patients (mean age 70.3 years, 46.8% male), with a total follow-up of 4,243 patient-years. Patients initiated on aspirin with dipyridamole had a worse persistence to their initial regimen compared with those initiated on aspirin alone (hazard ratio for non-persistence 1.62; 95% CI 1.37-1.92), but better persistence with any antiplatelet medication long term (hazard ratio 0.86; 95% CI 0.73-1.02). Compared to aspirin monotherapy, receiving no antiplatelet therapy was associated with significantly worse patient outcomes (hazard ratio 1.50; 95% CI 1.21-1.87), whilst receiving prescribed aspirin with dipyridamole was associated with better outcomes (hazard ratio 0.75; 95% CI 0.56-0.99). Only a few patients received clopidogrel or other antiplatelet regimens. CONCLUSIONS: Patients discharged on dual therapy have worse adherence to their initial regimen but better persistence to any antiplatelet agents in the long term. Continued exposure to antiplatelet regimens predicts good outcomes in patients with cerebral infarction.
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Infarto Cerebral/tratamiento farmacológico , Cumplimiento de la Medicación , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pautas de la Práctica en Medicina , Anciano , Aspirina/uso terapéutico , Infarto Cerebral/diagnóstico por imagen , Infarto Cerebral/mortalidad , Clopidogrel , Estudios de Cohortes , Dipiridamol/uso terapéutico , Prescripciones de Medicamentos , Quimioterapia Combinada , Utilización de Medicamentos , Femenino , Humanos , Masculino , Registro Médico Coordinado , Sistemas de Registros Médicos Computarizados , Pautas de la Práctica en Medicina/estadística & datos numéricos , Modelos de Riesgos Proporcionales , Radiografía , Medición de Riesgo , Factores de Riesgo , Escocia/epidemiología , Análisis de Supervivencia , Ticlopidina/análogos & derivados , Ticlopidina/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
Objective: Patients with diabetes have an increased risk of dementia. Improved prediction of dementia is an important goal in developing future prevention strategies. Diabetic retinopathy screening (DRS) photographs may be a convenient source of imaging biomarkers of brain health. We therefore investigated the association of retinal vascular measures (RVMs) from DRS photographs in patients with type 2 diabetes with dementia risk. Research Design and Methods: RVMs were obtained from 6,111 patients in the GoDARTS bioresource (635 incident cases) using VAMPIRE software. Their association, independent of Apo E4 genotype and clinical parameters, was determined for incident all cause dementia (ACD) and separately Alzheimer's disease (AD) and vascular dementia (VD). We used Cox's proportional hazards with competing risk of death without dementia. The potential value of RVMs to increase the accuracy of risk prediction was evaluated. Results: Increased retinal arteriolar fractal dimension associated with increased risk of ACD (csHR 1.17; 1.08-1.26) and AD (HR 1.33; 1.16-1.52), whereas increased venular fractal dimension (FDV) was associated with reduced risk of AD (csHR 0.85; 0.74-0.96). Conversely, FDV was associated with increased risk of VD (csHR 1.22; 1.07-1.40). Wider arteriolar calibre was associated with a reduced risk of ACD (csHR 0.9; 0.83-0.98) and wider venular calibre was associated with a reduced risk of AD (csHR 0.87; 0.78-0.97). Accounting for competing risk did not substantially alter these findings. RVMs significantly increased the accuracy of prediction. Conclusions: Conventional DRS photographs could enhance stratifying patients with diabetes at increased risk of dementia facilitating the development of future prevention strategies.
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BACKGROUND: Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence. In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK. METHODS: Patients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating general practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalisation and death data in the NHS will be used to compare cardiovascular event rates between the two policies. RESULTS: This pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients) and 15 to bendroflumethiazide (3437 patients), a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch. CONCLUSION: The pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study; currently, 102 GP practices (> 12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN46635087 . Registered on 11 August 2017.
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Aim: To assess the prescribing patterns and response to different classes of antihyperglycemic agents in novel clusters of type 2 diabetes (T2D) described in India. Materials and Methods: We attempted to replicate the earlier described clusters of T2D, in 32,867 individuals with new-onset T2D (within 2 years of diagnosis) registered between October 2013 and December 2020 at 15 diabetes clinics located across India, by means of k-means clustering utilizing 6 clinically relevant variables. Individuals who had follow-up glycated hemoglobin (HbA1c) up to 2 years were included for the drug response analysis (n = 13,247). Results: Among the 32,867 participants included in the study, 20,779 (63.2%) were males. The average age at diagnosis was 45 years and mean HbA1c at baseline was 8.9%. The same four clusters described in India earlier were replicated. Forty percent of the study participants belonged to the mild age-related diabetes cluster, followed by insulin-resistant obese diabetes (27%), severe insulin-deficient diabetes (21%), and combined insulin-resistant and insulin-deficient diabetes (12%) clusters. The most frequently used antihyperglycemic agents were sulfonylureas, metformin, and dipeptidyl peptidase-4 inhibitors apart from insulin. While there were significant differences in HbA1c reduction between drugs across clusters, these were largely driven by differences in the baseline (pretreatment) HbA1c. Conclusions: In this new cohort, we were able to reliably replicate the four subtypes of T2D earlier described in Asian Indians. Prescribing patterns show limited usage of newer antihyperglycemic agents across all clusters. Randomized clinical trials are required to establish differential drug responses between clusters.
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Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Metformina , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana EdadRESUMEN
BACKGROUND AND PURPOSE: Antiplatelet medicines are commonly perceived as contraindicated after intracerebral hemorrhage (ICH). Many ICH patients have or will have indications for antiplatelet therapy. This observational study describes the level of antiplatelet prescribing and rate of subsequent events after ICH in Tayside, Scotland. METHODS: This study used record-linkage of an existing stroke cohort with antiplatelet prescribing data from 1994 to 2005. Patients were followed-up from discharge after index event. The primary outcome was recurrent ICH. Other outcomes were subsequent ischemic stroke and a composite of ischemic stroke or myocardial infarction. Event rates were calculated as the number of events divided by patient-years of exposure. Univariate hazard ratios associated with antiplatelet exposure were derived from a Cox model using a time-dependent covariate. RESULTS: There were 417 ICH patients who survived to discharge. Of these, 120 patients were prescribed subsequent antiplatelet medicines (28.8%). The median time from discharge to antiplatelet use was 14.8 months (range, 2 days-7.5 years). Among all survivors, there were 14 recurrent ICH (rate, 9.7 per 1000 patient-years; 95% confidence interval [CI], 5.3-16.4), 29 subsequent ischemic strokes (rate, 20.6; 95% CI, 13.8-29.6), and 40 subsequent ischemic strokes or myocardial infarctions (rate, 28.7; 95% CI, 20.5-39.0). Hazard ratios associated with antiplatelet exposure were 1.07 (95% CI, 0.24-4.84) for recurrent ICH, 0.23 (95% CI, 0.03-1.68) for ischemic stroke, and 0.72 (95% CI, 0.25-2.02) for ischemic strokes or myocardial infarction. CONCLUSIONS: Antiplatelet prescribing was common after ICH. Subsequent ischemic strokes or myocardial infarctions were more common than recurrent ICH. Antiplatelet prescribing did not appear to have a clinically significant impact on outcomes measured. Despite being contraindicated, antiplatelet use was not a major hazard for recurrent ICH.
Asunto(s)
Hemorragia Cerebral/prevención & control , Infarto del Miocardio/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Accidente Cerebrovascular/prevención & control , Anciano , Hemorragia Cerebral/epidemiología , Estudios de Cohortes , Contraindicaciones , Femenino , Estudios de Seguimiento , Humanos , Masculino , Infarto del Miocardio/epidemiología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Escocia , Prevención Secundaria , Accidente Cerebrovascular/epidemiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: Much potentially useful clinical information for pharmacoepidemiological research is contained in unstructured free-text documents and is not readily available for analysis. Routine health data such as Scottish Morbidity Records (SMR01) frequently use generic 'stroke' codes. Free-text Computerised Radiology Information System (CRIS) reports have potential to provide this missing detail. We aimed to increase the number of stroke-type-specific diagnoses by augmenting SMR01 with data derived from CRIS reports and to assess the accuracy of this methodology. METHODS: SMR01 codes describing first-ever-stroke admissions in Tayside, Scotland from 1994 to 2005 were linked to CRIS CT-brain scan reports occurring with 14 days of admission. Software was developed to parse the text and elicit details of stroke type using keyword matching. An algorithm was iteratively developed to differentiate intracerebral haemorrhage (ICH) from ischaemic stroke (IS) against a training set of reports with pathophysiologically precise SMR01 codes. This algorithm was then applied to CRIS reports associated with generic SMR01 codes. To establish the accuracy of the algorithm a sample of 150 ICH and 150 IS reports were independently classified by a stroke physician. RESULTS: There were 8419 SMR01 coded first-ever strokes. The proportion of patients with pathophysiologically clear diagnoses doubled from 2745 (32.6%) to 5614 (66.7%). The positive predictive value was 94.7% (95%CI 89.8-97.3) for IS and 76.7% (95%CI 69.3-82.7) for haemorrhagic stroke. CONCLUSIONS: A free-text processing approach was acceptably accurate at identifying IS, but not ICH. This approach could be adapted to other studies where radiology reports may be informative.
Asunto(s)
Hemorragia Cerebral , Registros Electrónicos de Salud , Sistemas de Información Radiológica , Accidente Cerebrovascular , Algoritmos , Hemorragia Cerebral/diagnóstico , Femenino , Hospitales , Humanos , Pacientes Internos , Masculino , Radiología , Accidente Cerebrovascular/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: Observational studies can provide valuable information where data from randomised controlled trials is lacking. We aimed to generate a region-wide longitudinal register of stroke patients using record-linkage of existing clinical and research datasets. METHODS: The population were residents of Tayside, Scotland from 1994-2005. Stroke cases were identified from hospital inpatient admission records, death certificates and prescribing data. These were augmented with data derived from free-text CT-brain scan reports. Strokes were classified as intracerebral haemorrhage (ICH), subarachnoid haemorrhage (SAH) or ischaemic stroke (IS). The methodology was validated by audit of patient case-records. The incidence was calculated using direct standardisation to the standard European population for ages 45-84. Twenty-eight day case-fatality rates were calculated as percentages. RESULTS: There were 12 620 all-cause incident strokes (ICH 1057; SAH 511; IS 6257; undetermined 4795). Standardised incidences per 100 000 by subtypes of stroke were: ICH 35 (95%CI 33-38), SAH 19 (17-22) and IS 210 (205-217). The 28-day case-fatality rates were: ICH 49% (95%CI 46-52), SAH 38% (34-43) and IS 19% (18-20). Comparisons with previous studies were favourable for ICH and SAH. For IS the incidence was lower and fatality rate higher than elsewhere. Three hundred and three sets of patient case records were audited. The positive predictive value (PPV) for identifying cases of stroke was 94.7% (95%CI 91.6-96.7). CONCLUSIONS: The case ascertainment in the TSC compares favourably to established stroke cohorts. This cost effective resource can now be linked with multiple other clinical and research datasets in Tayside to further understanding of stroke and its treatment.
Asunto(s)
Bases de Datos Factuales/estadística & datos numéricos , Aplicaciones de la Informática Médica , Farmacoepidemiología/métodos , Accidente Cerebrovascular/epidemiología , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/epidemiología , Hemorragia Cerebral/epidemiología , Humanos , Estudios Longitudinales , Registro Médico Coordinado , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sistema de Registros , Escocia/epidemiología , Hemorragia Subaracnoidea/epidemiologíaRESUMEN
AIMS: Identification of patients with type 2 diabetes (T2D) at increased risk of incident heart failure (HF) beyond traditional risk factors such as prior myocardial infarction (MI) might allow selection of patients who would benefit from preventative treatment. Microvascular disease (MiVD) is thought to play a pathophysiological role in the development of HF in T2D; however, its association with new-onset HF with reduced or preserved ejection fraction has not been specifically defined. METHODS AND RESULTS: Patients in the Genetics of Diabetes Audit and Research Tayside Scotland study were linked to echocardiography, prescriptions, and clinical outcomes. In total, 9141 patients with T2D were identified for analysis. Clinical variables and the presence of retinopathy, nephropathy, and neuropathy were assessed. Cumulative incidence was calculated for the association of both individual and the total number of MiVD states and incident HF. Median follow-up was 9.3 years. In total, there were 900 HF events. The presence of any MiVD was independently associated with both HF with reduced ejection fraction (hazard ratio 1.40; 95% confidence interval 1.11-1.76, P = 0.004) and HF with preserved ejection fraction (hazard ratio 1.38; 95% confidence interval 1.10-1.72, P = 0.005), with a stepwise association between the number of MiVD states and risk of incident HF (P for trend <0.001). Similar associations were found in sensitivity analyses limited to patients without a prior MI, and using competing risks analysis. CONCLUSIONS: Individuals with T2D and with MiVD are at risk of incident HF independent of a history of prior HF or MI. Patients with MiVD could benefit from screening for HF and individualized therapy with treatments that lower HF risk.