Matrix metalloproteinase 10 is linked to the risk of progression to dementia of the Alzheimer's type.

Alzheimer's disease has a long asymptomatic phase that offers a substantial time window for intervention. Using this window of opportunity will require early diagnostic and prognostic biomarkers to detect Alzheimer's disease pathology at predementia stages, thus allowing identification of patients who will most probably progress to dementia of the Alzheimer's type and benefit from specific disease-modifying therapies. Consequently, we searched for CSF proteins associated with disease progression along with the clinical disease staging. We measured the levels of 184 proteins in CSF samples from 556 subjective cognitive decline and mild cognitive impairment patients from three independent memory clinic longitudinal studies (Spanish ACE, n = 410; German DCN, n = 93; German Mannheim, n = 53). We evaluated the association between protein levels and clinical stage, and the effect of protein levels on the progression from mild cognitive impairment to dementia of the Alzheimer's type. Mild cognitive impairment subjects with increased CSF level of matrix metalloproteinase 10 (MMP-10) showed a higher probability of progressing to dementia of the Alzheimer's type and a faster cognitive decline. CSF MMP-10 increased the prediction accuracy of CSF amyloid-ß 42 (Aß42), phospho-tau 181 (P-tau181) and total tau (T-tau) for conversion to dementia of the Alzheimer's type. Including MMP-10 to the [A/T/(N)] scheme improved considerably the prognostic value in mild cognitive impairment patients with abnormal Aß42, but normal P-tau181 and T-tau, and in mild cognitive impairment patients with abnormal Aß42, P-tau181 and T-tau. MMP-10 was correlated with age in subjects with normal Aß42, P-tau181 and T-tau levels. Our findings support the use of CSF MMP-10 as a prognostic marker for dementia of the Alzheimer's type and its inclusion in the [A/T/(N)] scheme to incorporate pathologic aspects beyond amyloid and tau. CSF level of MMP-10 may reflect ageing and neuroinflammation.

Higher Risk of Ischemic Stroke After an Intracerebral Hemorrhage Than in General Population: A Cohort Study From the United Kingdom.

[Figure: see text].

Identification of undiagnosed dementia cases using a web-based pre-screening tool: The MOPEAD project.

INTRODUCTION: Innovative patient engagement models are required to identify people with prodromal and mild Alzheimer's disease who are "hidden" in their communities and not normally found in a memory clinic setting. METHODS: A marketing campaign and a web-based pre-screening tool were used to identify individuals at risk of dementia in five European countries. Harmonized clinical evaluation of these patients was performed in participating memory clinics within the MOPEAD project. RESULTS: A total of 1487 individuals completed the pre-screening, with 547 of them found to be at risk of dementia (36.8%). Among the subset of 91 patients with a positive pre-screening result that underwent full clinical evaluation, 49 (53.8%) were diagnosed with either mild cognitive impairment or Alzheimer's disease. CONCLUSION: This novel web-based pre-screening tool showed to be a valid strategy to identify undiagnosed people with cognitive impairment.

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aß1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aß1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

Hormonal contraception is not associated with increased risk for seizures in the general population: results from a cohort study using The Health Improvement Network.

PURPOSE: Endogenous human gonadal steroids and especially female sex hormones modulate the risk of developing epileptic seizures. In most circumstances, estrogens increase excitability, while progesterone bears substantial anticonvulsive properties. We questioned whether exogenous gonadal steroids used as hormonal contraception are associated with risk of seizures. METHODS: In a dynamic cohort ascertained within The Health Improvement Network database, we identified 2201 female patients aged 20-44 years with seizures during follow-up. In a nested case-control analysis, we matched these cases to 10,143 controls. Using logistic regression, we calculated the risk of seizure associated with use of contraceptives and adjusted for potential confounders. We performed same analyses among women with no prior hormonal contraception use ("new user" analyses) and in patients with a history of epilepsy. RESULTS: Unadjusted data suggested a lower risk for seizures in patients taking exogenous gonadal steroids irrespective of type of contraception used. After adjustment for potential confounders, neither use of combined oral contraceptives nor progestin-only oral contraceptives was associated with the risk for seizures overall. Analyses of "new users" of oral contraceptives produced similar risk estimates. CONCLUSIONS: We found no evidence supporting an effect of oral exogenous gonadal steroids used for hormonal contraception on the risk of seizures in the general female population.

Mortality in patients who discontinue low-dose acetylsalicylic acid therapy after upper gastrointestinal bleeding.

PURPOSE: Discontinuing low-dose acetylsalicylic acid (ASA) therapy after upper gastrointestinal bleeding (UGIB) may increase the risk of cardiovascular-related death. Our aim was to compare mortality in UK primary care patients who discontinue ASA after UGIB with that in patients who continue therapy. METHODS: ASA users at the time of UGIB and who were alive 30 days after were selected using The Health Improvement Network. Predictors of survival were assessed using adjusted Cox proportional hazards regression models. RESULTS: Of 547 ASA users, half did not re-initiate ASA during a mean follow-up of 4.1 years. Increasing age (a 10% increased risk for each yearly increase in age; hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.07-1.14), female sex (HR: 1.61; 95%CI: 1.09-2.38), current smoking (HR: 2.11; 95%CI: 1.23-3.63), heavy alcohol use (HR: 3.31; 95%CI: 1.50-7.31), diabetes mellitus (HR: 1.93; 95%CI: 1.25-3.00), and chronic obstructive pulmonary disease (HR: 1.75; 95%CI: 1.03-2.99) were significantly associated with increased mortality. Most deaths (115/139) occurred in patients taking ASA for secondary prevention. In these patients, mortality tended to be lower among ASA continuer periods (HR: 0.74; 95%CI: 0.34-1.62) and higher among discontinuer periods (HR: 1.37; 95%CI: 0.81-2.30) than among non-users. Current use of clopidogrel was associated with decreased mortality in this population (HR: 0.49; 95%CI: 0.28-0.86). CONCLUSIONS: ASA therapy for secondary prevention should continue after UGIB because the risk of death tends to increase when ASA is stopped. However, a significantly increased risk was not found in these patients, likely owing to the relatively small number of ASA users and deaths that occurred during follow-up. Further studies with larger samples sizes are needed to confirm these findings among UGIB survivors taking ASA at the time of UGIB. Copyright © 2016 John Wiley & Sons, Ltd.

Risk of seizure associated with use of acid-suppressive drugs: An observational cohort study.

OBJECTIVES: Previous, large, prescription-event monitoring studies in patients receiving PPI therapy recorded instances of convulsion or seizure. The objective of this study was to quantify the relative risk of seizure associated with the use of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) in a general population, overall and stratified by epilepsy status, and to determine the effects of demographics and comorbidities. METHODS: In this observational study (NCT01744301), patients aged 20-84years in the study period from 1 January 2005 to 31 December 2011 were identified from The Health Improvement Network. In a nested case-control analysis, 8605 patients with seizure were matched to 40000 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. RESULTS: After adjustment, there were no associations between current PPI use and seizure risk in the overall population (OR: 1.05; 95% CI: 0.87-1.27), the subcohort with epilepsy (OR: 0.87; 95% CI: 0.49-1.53), and the subcohort without epilepsy (OR: 1.05; 95% CI: 0.87-1.28). There were no associations between current H2RA use and seizure risk in the overall population (OR: 1.16; 95% CI: 0.62-2.18) and the subcohort without epilepsy (OR: 1.02; 95% CI: 0.51-2.01). Seizures were less frequent in women than in men. Dementia/psychosis, anxiety, depression, and use of anxiolytics, antidepressants, and paracetamol were associated with an increased seizure risk. CONCLUSIONS: Our study revealed that the use of PPIs and the use of H2RAs were not associated with an increased risk of seizures in the overall population or in the cohorts stratified by epilepsy status.

Risk of bleeding after hospitalization for a serious coronary event: a retrospective cohort study with nested case-control analyses.

BACKGROUND: Bleeding events have been associated with the use of antiplatelet agents. This study estimated the incidence of bleeding events in patients previously hospitalized for a serious coronary event and determined the risks of bleeding associated with the use of acetylsalicylic acid (ASA) and/or clopidogrel. METHODS: A UK primary care database was used to identify 27,707 patients aged 50 to 84 years, hospitalized for a serious coronary event during 2000 to 2007 and who were alive 30 days later (start date). Patients were followed up until they reached an endpoint (hemorrhagic stroke, upper or lower gastrointestinal bleeding [UGIB/LGIB]), death or end of study [June 30, 2011]) or met an exclusion criterion. Risk factors for bleeding were determined in a nested case-control analysis. RESULTS: Incidences of hemorrhagic stroke, UGIB, and LGIB were 5.0, 11.9, and 25.5 events per 10,000 person-years, respectively, and increased with age. UGIB and LGIB led to hospitalization in 73 and 23 % of patients, respectively. Non-users of ASA, who were mostly discontinuers, and current users of ASA had similar risks of hemorrhagic stroke, UGIB, and LGIB. Users of combined antithrombotic therapy (warfarin and antiplatelets) experienced an increased risk of hemorrhagic stroke (odds ratio [OR], 6.36; 95 % confidence interval [CI], 1.34-30.16), whereas users of combined antiplatelet therapy (clopidogrel and ASA) experienced an increased risk of UGIB (OR, 2.42; 95 % CI, 1.09-5.36). An increased risk of LGIB (OR, 1.86; 95 % CI, 1.34-2.57) was also observed in users of clopidogrel. CONCLUSIONS: In patients previously hospitalized for a serious coronary event, combined antithrombotic therapy was associated with an increased risk of hemorrhagic stroke, whereas combined antiplatelet therapy was associated with an increased risk of UGIB.Non-use of ASA was rare in this population and use of ASA was not associated with a significantly increased risk of hemorrhagic stroke, UGIB, or LGIB.

New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer.

BACKGROUND: Associations between type 2 diabetes, anti-diabetic medications and pancreatic cancer are controversial. This study aims to clarify such associations with new-onset type 2 diabetes and repeated measurements of glycated haemoglobin (HbA1c) levels. METHODS: A nested case-control study was initiated from the Health Improvement Network (THIN) in UK from 1996 to 2010. Information of pancreatic cancer cases was retrieved electronically from the medical records and manually validated. Control subjects were randomly selected and frequency-matched to the cases on sex, age, and calendar years. Multivariable unconditional logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI), and adjusted for potential confounders. RESULTS: Among 1,574,768 person-years of follow-up, 529 pancreatic cancer cases and 5000 controls were identified. Type 2 diabetes, or changed HbA1c levels (rather than HbA1c levels at diabetes diagnosis) in diabetes patients (⩾4 mmol mol(-1) compared with <0 mmol mol(-1)) were followed by an increased OR of pancreatic cancer (OR, 2.16, 95% CI 1.72-2.72 and OR, 5.06, 95% CI 1.52-16.87, respectively). Among the anti-diabetic medications in diabetes patients, the OR for insulin users was 25.57 (95% CI 11.55-56.60), sulphonylureas 2.22 (95% CI 1.13, 4.40), and metformin users 1.46 (95% CI 0.85-2.52), compared with no use of any anti-diabetic medications. CONCLUSIONS: New-onset type 2 diabetes and, particularly, diabetes with rising HbA1c seem to be independent risk factors for pancreatic cancer. The relation between different anti-diabetic medications and pancreatic cancer seems to vary in strength, with the highest risk among users of insulin.

A new risk variant for multiple sclerosis at the immunoglobulin heavy chain locus associates with intrathecal IgG, IgM index and oligoclonal bands.

BACKGROUND: Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS). OBJECTIVES: The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters. METHODS: We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls. Associations of intrathecal IgG and IgM indexes with rs11621145 were analysed by linear regression analysis in 538 MS patients. RESULTS: We found that rs11621145 showed statistically significant evidence for association with susceptibility to MS (odds ratio = 0.69, p = 1.053E-09), though validation of this result in additional cohorts would be desirable. We confirmed the association between the IgG index and the rs11621145 (p = 6.85E-07, Beta = 0.207). Furthermore, rs11621145 was inversely correlated with IgM index (p = 7.24E-04, Beta = -0.277), and therefore marks a decreased likelihood of presenting IgM oligoclonal bands (odds ratio = 0.38, p = 2.35E-06). CONCLUSIONS: Our results suggest that the polymorphism of the IGHC locus could be altering the switching of the Ig isotype in B cells and it may be interfering with T-dependent and T-independent antibody responses.

Incidence and Predictors of Hemorrhagic Stroke in Users of Low-Dose Acetylsalicylic Acid.

BACKGROUND: The use of antithrombotic drugs (anticoagulants and antiplatelet drugs) has been reported to increase the risk of hemorrhagic stroke (HS) relative to no treatment. This study was performed to characterize the incidence and predictors of HS in users of acetylsalicylic acid (ASA) for the secondary prevention of cardiovascular events. METHODS: A cohort of 36,775 ASA users aged 50-84 years in 2000-2007 was identified from The Health Improvement Network database. The incidence of HS was calculated, and a nested case-control analysis, adjusted for potential confounding factors, was performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association of potential risk factors with HS in current users of ASA. RESULTS: The overall incidence of HS was 5.70 cases per 10,000 person-years and increased with age. In current ASA users, the incidence of HS was 4.91 cases per 10,000 person-years. Predictors of HS in patients taking ASA for secondary prevention included a history of HS (OR, 4.84; 95% CI, 1.48-15.88), a history of atrial fibrillation (OR, 4.03; 95% CI, 1.53-10.62), and hypnotic/anxiolytic drug use (OR, 2.67; 95% CI, 1.17-6.05). The small number of patients using warfarin also had an increased risk of HS (OR, 23.42; 95% CI, 4.89-112.10). CONCLUSIONS: Physicians should consider additional risk factors for HS, such as a history of HS or atrial fibrillation, and the use of warfarin, before prescribing ASA for the secondary prevention of cardiovascular events.

Migraine and risk of hemorrhagic stroke: a study based on data from general practice.

BACKGROUND: We investigated the association between hemorrhagic stroke and migraine using data from The Health Improvement Network database. FINDINGS: We ascertained 1,797 incident cases of intracerebral hemorrhage (ICH) and 1,340 of subarachnoid hemorrhage (SAH). Density-based sampling was used to select 10,000 controls free from hemorrhagic stroke. Using unconditional logistic regression models, we calculated the risk of hemorrhagic stroke associated with migraine, adjusting for age, sex, calendar year, alcohol, body mass index, hypertension, previous cerebrovascular disease, oral contraceptive use, and health services utilization.The risk (odds ratio [OR]) of ICH among migraineurs was 1.2 (95% confidence interval [CI] 0.9-1.5), and of SAH was (1.2, 95% CI 0.9-1.5). The association with ICH was stronger for migraine diagnosed ≥20 years prior to ICH (OR 1.6, 95% CI 1.0-2.4), but not with SAH (OR 1.1, 95% CI 0.6-2.1). In analyses stratified by migraine type and gender, the OR of ICH in women with migraine with aura was 1.7 (95% CI 0.9-3.4) and the corresponding OR of SAH in women was 1.2 (95% CI 0.6-2.3). CONCLUSION: No clear increased risk of ICH or SAH was observed in migraineurs.

An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Incidence of hemorrhagic stroke in the general population: validation of data from The Health Improvement Network.

PURPOSE: The Health Improvement Network (THIN) is a UK healthcare database composed of computerized information from primary care physicians (PCPs). We analyzed the validity of our method for identifying cases of intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) within THIN and assessed the incidence of these events. METHODS: Patients aged 20-89 years were identified and followed until (i) ICH or SAH was detected, (ii) the patient reached 90 years old (iii) death, or (iv) the end of the study. Computerized patient profiles were reviewed manually; those not discarded became potential cases. A validation study was undertaken in 400 computer-detected cases (333 confirmed as potential cases; 67 discarded). PCPs completed a questionnaire to determine the actual incidence of ICH and SAH among these cases. We also assessed the incidence of ICH and SAH in the total cohort. RESULTS: A total of 4330 patients with a READ code suggesting hemorrhagic stroke were identified. Computerized profiles with free-text comments were reviewed manually to identify 3633 potential cases. Responses to the PCP questionnaire were received for 306 potential cases and 63 discarded cases (92% response rate); 82% of potential cases were confirmed. Finally, we identified 3137 cases of hemorrhagic stroke. Crude incidence was 15 per 100,000 person-years for ICH and 11 per 100,000 person-years for SAH; the overall incidence increased sharply with age. CONCLUSIONS: Computer detection of cases of hemorrhagic stroke in THIN followed by manual review of clinical profiles is a valid method. The incidence of hemorrhagic stroke increases sharply with age.

Cardiovascular and renal outcomes among patients with type 2 diabetes using SGLT2 inhibitors added to metformin: a population-based cohort study from the UK.

INTRODUCTION: Large numbers of patients with type 2 diabetes receive treatment with a sodium-glucose co-transporter-2 inhibitor (SGLT2i). We investigated whether the cardiorenal preventative effects found in clinical trials are also seen in clinical practice where patient characteristics and adherence to treatment differ. RESEARCH DESIGN AND METHODS: Using UK primary care electronic health records, we followed two cohorts of patients with type 2 diabetes prescribed metformin: SGLT2is (N=12 978) and a matched comparator of patients not using an SGLT2i at the start of follow-up (N=44 286). Independent follow-ups were performed to identify the study outcomes: cardiovascular (CV) composite (comprising non-fatal myocardial infarction (MI)/ischemic stroke (IS) requiring hospitalization and CV death), severe renal disease, and all-cause mortality. Cox regression was used to estimate adjusted HRs. RESULTS: Mean follow-up was 2.3 years (SGLT2i cohort) and 2.1 years (comparison cohort). Mean age was 59.6 years (SD ±10.2, SGLT2i cohort) and 60.4 years (SD ±10.0, comparison cohort). SGLT2i new users were associated with a reduced risk of the CV composite (HR 0.75, 95% CI: 0.61 to 0.93), severe renal disease (HR 0.55, 95% CI: 0.46 to 0.67), and all-cause mortality (HR 0.56, 95% CI: 0.49 to 0.63), with risk reductions similar irrespective of baseline chronic kidney disease. Reduced risks were seen for IS (HR 0.51, 95% CI: 0.36 to 0.74) but not MI (HR 0.98, 95% CI: 0.74 to 1.28). Results were consistent in sensitivity analyses. CONCLUSIONS: In this population-based study, SGLT2is were associated with significant CV, renal and survival benefits among individuals with type 2 diabetes on metformin; the CV benefit was driven by a reduced risk of ischemic stroke.

A metagenome-wide association study of HIV disease progression in HIV controllers.

Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Renal decline in patients with non-valvular atrial fibrillation treated with rivaroxaban or warfarin: A population-based study from the United Kingdom.

BACKGROUND: Reports suggest that renal decline is greater among patients with non-valvular atrial fibrillation (NVAF) treated chronically with warfarin vs. some non-vitamin K antagonist oral anticoagulants. METHODS AND RESULTS: Using primary care electronic health records from the United Kingdom we followed adults with NVAF and who started rivaroxaban (20 mg/day, N = 5338) or warfarin (N = 6314), excluding those with estimated glomerular filtration rate (eGFR) <50 ml/min/1.73m2, end-stage renal disease (ESRD) or no eGFR or serum creatinine (SCr) values recorded in the previous year. Outcomes were: doubling SCr levels, ≥30% decline in eGFR and progression to ESRD. We calculated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome. Average eGFR slope was estimated using mixed model regression. After a mean follow-up 2.5 years, the number of incident cases of adverse renal events within the two cohorts was: doubling SCr (n = 322), ≥30% decline in eGFR (n = 1179), and progression to ESRD (n = 22). Adjusted HRs (95% CIs) for the renal outcomes among rivaroxaban vs. warfarin users were: doubling SCr, 0.63 (0.49-0.81); ≥30% decline in eGFR, 0.76 (0.67-0.86); ESRD, 0.77 (0.29-2.04). Similar results were observed among patients with diabetes or heart failure. Estimated mean decline in renal function over the study period was 2.03 ml/min/1.73 m2/year among warfarin users and 1.65 ml/min/1.73 m2/year among rivaroxaban users (p = 0.03). CONCLUSIONS: We found clear evidence that patients with NVAF, preserved renal function at baseline and treated with rivaroxaban had a markedly reduced risk and rate of renal decline compared with those treated with warfarin.

Acute Kidney Injury in Patients with Non-Valvular Atrial Fibrillation Treated with Rivaroxaban or Warfarin: A Population-Based Study from the United Kingdom.

Purpose: To compare the risk of acute kidney injury (AKI) among users of rivaroxaban vs warfarin. Patients and Methods: We identified two cohorts of patients with non-valvular atrial fibrillation (NVAF) who initiated rivaroxaban (15/20 mg/day, N = 6436) or warfarin (N = 7129) excluding those without estimated glomerular filtration rate values recorded in the year before oral anticoagulant (OAC) initiation and those with a history of end-stage renal disease or AKI. We used two methods to define AKI during follow-up (mean 2.5 years): coded entries (method A) and the Aberdeen AKI phenotyping algorithm (method B) using recorded renal function laboratory values during the study period to identify a sudden renal deterioration event. Cox regression was used to calculate hazard ratios (HRs) for AKI with rivaroxaban vs warfarin use, adjusted for confounders. Results: The number of identified incident AKI cases was 249 (method A) and 723 (method B). Of the latter, 104 (14.4%) were also identified by method A. After adjusting for age, sex, baseline renal function and comorbidity, HRs (95% CIs) for AKI were 1.19 (0.92-1.54; p=0.18) using method A and 0.80 (0.68-0.93; p<0.01) using method B. Estimates stratified by baseline level of chronic kidney disease were largely consistent with the main estimates. Conclusion: Our results support a beneficial effect of rivaroxaban over warfarin in terms of AKI occurrence in patients with NVAF. More research into how best to define AKI using primary care records would be valuable for future studies.

Safety and effectiveness of appropriately and inappropriately dosed rivaroxaban or apixaban versus warfarin in patients with atrial fibrillation: a cohort study with nested case-control analyses from UK primary care.

OBJECTIVES: To investigate effects of appropriately and inappropriately dosed apixaban/rivaroxaban versus warfarin on effectiveness and safety outcomes in patients with non-valvular atrial fibrillation (NVAF). DESIGN: Cohort study with nested case-control analyses using primary care electronic health records (IQVIA Medical Research Data UK database). SETTING: UK primary care. PARTICIPANTS: Patients aged ≥18 years with NVAF newly prescribed apixaban (N=14 701), rivaroxaban (N=14 288) or warfarin (N=16 175) between 1 January 2012 and 30 June 2018, and followed up to 31 December 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident cases of ischaemic stroke/systemic embolism (IS/SE) and intracranial bleeding (ICB). Cases were matched to controls on age, sex and OAC naïve status. Using logistic regression, adjusted ORs with 95% CIs were calculated for the outcomes comparing apixaban/rivaroxaban use (appropriate or inappropriate dosing based on the product label criteria) and warfarin. RESULTS: For IS/SE, ORs (95% CIs) for apixaban versus warfarin were 1.19 (0.92-1.52) for appropriate dose and 1.01 (0.67-1.51) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 1.07 (0.83-1.37) for appropriate dose and 1.21 (0.78-1.88) for inappropriate dose. For ICB, ORs (95% CIs) for apixaban versus warfarin were 0.67 (0.44-1.00) for appropriate dose and 0.45 (0.21-0.95) for inappropriate dose; for rivaroxaban versus warfarin, estimates were 0.81 (0.55-1.20) for appropriate dose and 1.14 (0.56-2.31) for inappropriate dose. CONCLUSIONS: Dosing appropriateness in NVAF was not associated with a significant difference in IS/SE risk or increase in ICB risk versus warfarin. These findings may reflect residual confounding and biases that were difficult to control, as also seen in other observational studies. They should, therefore, be interpreted with caution, and prescribers should adhere to the dosing instructions in the respective Summary of Product Characteristics. Further studies on this topic from real-world populations are needed.