Risk of death and cardiovascular outcomes with thiazolidinediones: a study with the general practice research database and secondary care data.

OBJECTIVE: To describe the likely extent of confounding in evaluating the risks of cardiovascular (CV) events and mortality in patients using diabetes medication. METHODS: The General Practice Research Database was used to identify inception cohorts of insulin and different oral antidiabetics. An analysis of bias and incidence of mortality, acute coronary syndrome, stroke and heart failure were analysed in GPRD, Hospital Episode Statistics and death certificates. RESULTS: 206,940 patients were identified. The bias analysis showed that past thiazolidinedione users had a lower mortality risk compared to past metformin users. There were no differences between past users of rosiglitazone and pioglitazone (adjusted RR of 1.04; 95% CI 0.93-1.18). Current rosiglitazone users had an increased risk of death (adjusted RR 1.20; 95% CI 1.08-1.34) and of hospitalisation for heart failure (adjusted RR of 1.73; 95% CI 1.19-2.51) compared to current pioglitazone users. Risk of mortality was increased two-fold shortly after starting rosiglitazone. Excess risk of death over 3 years with rosiglitazone was 0.3 per 100 in those aged 50-64 years, 2.0 aged 65-74, 3.0 aged 75-84, and 7.0 aged 85+. The cause of death with rosiglitazone was more likely to be due to a disease of the circulatory system. CONCLUSIONS: Higher risks for death (overall and due to cardiovascular disease) and heart failure were found for rosiglitazone compared to pioglitazone. These excess risks were largest in patients aged 65 years or older. The European regulatory decision to suspend rosiglitazone is supported by this study

Could NICE guidance on the choice of blood pressure lowering drugs be simplified?

Reecha Sofat and colleagues argue that prescribing advice needs updating in the light of recent evidence that all classes of blood pressure lowering drugs are broadly equivalen

Risk of stroke following herpes zoster: a self-controlled case-series study.

BACKGROUND: Herpes zoster is common and vaccine preventable. Stroke risk may be increased following zoster, but evidence is sparse and could be explained by differences between people with and without zoster. Our objective was to determine if stroke risk is increased following zoster. METHODS: Within-person comparisons were undertaken using the self-controlled case-series method and data from the UK Clinical Practice Research Datalink (1987-2012). Participants had a first-ever diagnosis of zoster and stroke within the study period. Stroke incidence in periods following zoster was compared with incidence in other time periods. Age-adjusted incidence ratios (IRs) and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 6584 individuals were included. Stroke rate was increased following zoster compared with the baseline unexposed period, then gradually reduced over 6 months: weeks 1-4 (age-adjusted IR, 1.63; 95% CI, 1.32-2.02), weeks 5-12 (IR, 1.42; 95% CI, 1.21-1.68), and weeks 13-26 (IR, 1.23; 95% CI, 1.07-1.42), with no increase thereafter. A stronger effect was observed for individuals with zoster ophthalmicus, rising to a >3-fold rate 5-12 weeks after zoster. Oral antivirals were given to 55% of individuals: IRs for stroke were lower among those receiving antivirals compared with those not treated, suggesting a protective effect. CONCLUSIONS: We have established an increased stroke rate within 6 months following zoster. Findings have implications for zoster vaccination programs, which may reduce stroke risk following zoster. The low antiviral prescribing rate needs to be improved; our data suggest that antiviral therapy may lead to a reduced stroke risk following zoster

Association between eczema and major cardiovascular outcomes in population-based studies: a systematic review protocol.

INTRODUCTION: Chronic inflammatory diseases such as eczema (also known as atopic dermatitis) have been inconsistently linked to cardiovascular disease and stroke in both mechanistic and epidemiological studies. There is a need to review the existing epidemiological data examining the association between eczema and major cardiovascular outcomes, including angina, myocardial infarction, coronary revascularisation, heart failure, cardiac arrhythmias, stroke and cardiovascular death, in order to improve our understanding of the comorbidities of eczema. METHODS AND ANALYSIS: We will systematically review population-based studies, including cohort, case-control and cross-sectional studies, reporting on the association between eczema and cardiovascular outcomes. We will search Medline, Embase and Global Health, from their date of inception to April 2017, using a comprehensive search strategy formulated with the help of a librarian. Two reviewers will independently screen titles and abstracts in duplicate, followed by independent data extraction and quality assessment. We will group studies by the cardiovascular outcome under study and synthesise them narratively. If sufficient numbers of homogeneous studies are returned, we will perform meta-analyses to obtain pooled effect estimates. Preferred Reporting Items for Systematic Review and Meta-Analysis will be used to inform the reporting of this study. TRIAL REGISTRATION NUMBER: CRD42017060359

Association between eczema and major cardiovascular outcomes in population-based studies: a systematic review protocol.

INTRODUCTION: Chronic inflammatory diseases such as eczema (also known as atopic dermatitis) have been inconsistently linked to cardiovascular disease and stroke in both mechanistic and epidemiological studies. There is a need to review the existing epidemiological data examining the association between eczema and major cardiovascular outcomes, including angina, myocardial infarction, coronary revascularisation, heart failure, cardiac arrhythmias, stroke and cardiovascular death, in order to improve our understanding of the comorbidities of eczema. METHODS AND ANALYSIS: We will systematically review population-based studies, including cohort, case-control and cross-sectional studies, reporting on the association between eczema and cardiovascular outcomes. We will search Medline, Embase and Global Health, from their date of inception to April 2017, using a comprehensive search strategy formulated with the help of a librarian. Two reviewers will independently screen titles and abstracts in duplicate, followed by independent data extraction and quality assessment. We will group studies by the cardiovascular outcome under study and synthesise them narratively. If sufficient numbers of homogeneous studies are returned, we will perform meta-analyses to obtain pooled effect estimates. Preferred Reporting Items for Systematic Review and Meta-Analysis will be used to inform the reporting of this study. TRIAL REGISTRATION NUMBER: CRD42017060359

Zoster vaccination is associated with a reduction of zoster in elderly patients with chronic kidney disease.

BACKGROUND: Growing epidemiological evidence demonstrates increased zoster risks in people with chronic kidney disease (CKD). Study objectives were to determine zoster vaccine effectiveness in individuals with CKD in pragmatic use. METHODS: A population-based cohort study was undertaken in a 5% random sample of US Medicare from 2007 to 2009 involving 766 330 eligible individuals aged ≥65 years who were (29 785) and were not (736 545) exposed to the zoster vaccine. Incidence rates for zoster in vaccinated and unvaccinated individuals and hazard ratios for zoster comparing vaccinated with unvaccinated were determined for individuals with CKD. Time-updated Cox proportional hazards models were used, adjusting for relevant confounders. RESULTS: CKD was present in 183 762 (24%) of individuals (15% of vaccinees). Adjusted vaccine effectiveness [95% confidence intervals (CIs)] in individuals with CKD was 0.49 (0.36-0.65). The adjusted vaccine effectiveness in participants with both CKD and diabetes mellitus was 0.46 (95% CI 0.09-0.68). Vaccine effectiveness estimates were similar to those previously reported for the general population [vaccine effectiveness 0.48 (95% CI 0.39-0.56)]. CONCLUSIONS: Zoster vaccine is effective against incident zoster in older individuals with CKD. Extra efforts are warranted to increase vaccine uptake in individuals with CKD given the known low uptake in these higher risk individuals

Phosphodiesterase Type 5 Inhibitors and Risk of Malignant Melanoma: Matched Cohort Study Using Primary Care Data from the UK Clinical Practice Research Datalink.

BACKGROUND: Laboratory evidence suggests that reduced phosphodiesterase type 5 (PDE5) expression increases the invasiveness of melanoma cells; hence, pharmacological inhibition of PDE5 could affect melanoma risk. Two major epidemiological studies have investigated this and come to differing conclusions. We therefore aimed to investigate whether PDE5 inhibitor use is associated with an increased risk of malignant melanoma, and whether any increase in risk is likely to represent a causal relationship. METHODS AND FINDINGS: We conducted a matched cohort study using primary care data from the UK Clinical Practice Research Datalink. All men initiating a PDE5 inhibitor and with no prior cancer diagnosis were identified and matched on age, diabetes status, and general practice to up to four unexposed controls. Ever use of a PDE5 inhibitor and time-updated cumulative number of PDE5 inhibitor prescriptions were investigated as exposures, and the primary outcome was malignant melanoma. Basal cell carcinoma, solar keratosis, and colorectal cancer were investigated as negative control outcomes to exclude bias. Hazard ratios (HRs) were estimated from Cox models stratified by matched set and adjusted for potential confounders. 145,104 men with ≥1 PDE5 inhibitor prescription, and 560,933 unexposed matched controls were included. In total, 1,315 incident malignant melanoma diagnoses were observed during 3.44 million person-years of follow-up (mean 4.9 y per person). After adjusting for potential confounders, there was weak evidence of a small positive association between PDE5 inhibitor use and melanoma risk (HR = 1.14, 95% CI 1.01-1.29, p = 0.04). A similar increase in risk was seen for the two negative control outcomes related to sun exposure (HR = 1.15, 95% CI 1.11-1.19, p < 0.001, for basal cell carcinoma; HR = 1.21, 95% CI 1.17-1.25, p < 0.001, for solar keratosis), but there was no increased risk for colorectal cancer (HR = 0.91, 95% CI 0.85-0.98, p = 0.01). There was no evidence that risk increased with number of prescriptions received (p-trend = 0.83). In a post hoc analysis, there was strong evidence that solar keratosis was associated with future PDE5 inhibitor use (odds ratio = 1.28, 95% CI 1.23-1.34, p < 0.001), suggesting that men with higher sun exposure were more likely to become PDE5 inhibitor users. However, a limitation of our study was that we did not have individual-level data on sun exposure, so we could not directly control for this in the primary analysis. CONCLUSIONS: Our results were not consistent with PDE5 inhibitors being causally associated with melanoma risk, and strongly suggest that observed risk increases are driven by greater sun exposure among patients exposed to a PDE5 inhibitor

Effects of War Exposure on Pubertal Development in Refugee Children

Increasing research shows pubertal development accelerates following threats while it decelerates following deprivation. Yet, these environmental stressors are unlikely to occur in isolation. We investigated how war exposure and energetic stress impact pubertal development using data from the longitudinal Biological Pathways of Risk and Resilience in Syrian Refugee Children study. Our sample included 1,600 male and female Syrian refugee children and their caregivers who lived in temporary settlements in Lebanon. We hypothesized that (a) energetic stress suppresses pubertal development; (b) war exposure accelerates pubertal timing in boys and increases risk of menarche in girls, but only when energetic stress is low; and (c) when energetic stress is elevated, effects of war exposure on pubertal development will be attenuated. Among boys, we did not find support for Hypothesis 1, but Hypotheses 2 and 3 were supported. Exposure to morbidity/mortality threats accelerated pubertal timing; this effect was attenuated under conditions of elevated energetic stress. Among girls, we found support for Hypothesis 1, but not for Hypotheses 2 and 3. Elevated energetic stress decreased the risk of menarche in girls. Neither war exposure, nor any interactions with energetic stress, predicted risk of menarche. Sensitivity analyses revealed a significant interaction between bombing exposure and the amount of time since leaving Syria. Bombing decreased the risk of menarche, but only for girls who had left Syria four or more years prior to data collection. We discuss implications for translational efforts advocating for puberty screening in medical and mental health settings to identify trauma-exposed youth