Assessing the relationship between serum potassium variability and the risk of hyperkalaemia and adverse clinical outcomes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P McEwan ◽  
K Badora ◽  
D Sugrue ◽  
G James ◽  
M Hurst ◽  
...  
Keyword(s):  
Serum Potassium ◽  
Index Date ◽  
Adverse Outcomes ◽  
Practice Research ◽  
Major Adverse Cardiovascular Events ◽  
Clinical Practice Research Datalink ◽  
Funding Source ◽  
Private Company ◽  
Increased Risk

Abstract Background Serum potassium (SK+) is a vital electrolyte, which level is maintained by adjusting renal K+ excretion. Variability in SK+ has been linked to increased risk of mortality and other adverse clinical events in patients in intensive care and/or receiving haemodialysis, prompting a similar investigation in cardiovascular patients. Purpose To examine the effect of SK+ variability on all-cause mortality (ACM) and the incidence of major adverse cardiovascular events (MACE), comprising arrhythmia, [subsequent records of] HF, myocardial infarction, or stroke, in patients with heart failure (HF) or resistant hypertension (RHTN). Methods Patients aged ≥18 years with HF or RHTN were identified from the UK Clinical Practice Research Datalink (CPRD, primary care data) and linked Hospital Episode Statistics (HES, secondary care data). HF and RHTN were defined through READ codes recorded during the study period (2008-June 2018) or the five-year look-back period (2003–2007). Index date was set to 1st January 2008 or initial diagnosis; whichever occurred later. Mean SK+ and variability of measurements (quantified as standard deviation [SD] and each patient categorised as low or highly variable based on the median SD of the cohort), and crude incidence rates of ACM and MACE were estimated over a follow-up period from index date to event or end of follow-up (death, loss to follow-up or end of study, whichever was earlier). Results The eligible population included 317,135 RHTN patients and 84,210 HF patients with a mean follow-up of 6.37 (SD 3.06) and 5.01 (SD 3.20) years, respectively. In both cohorts, higher mean SK+ ≥5.0 mmol/L was associated with increased rates of ACM and MACE relative to a mean SK+ of 3.5–5 mmol/L (Table 1). High SK+ variability was associated with increased incidence of adverse outcomes, with rates consistently higher in the high SK+ variability group compared to low-variability patients with the same diagnosis and mean SK+ category (Table 1); all comparisons were statistically significant except for ACM in HF patients with mean SK+ ≥5 mmol/L. Conclusion Independently of mean SK+, increased variability in SK+ levels was associated with an increased rate of mortality and MACE in patients with RHTN or HF. Careful SK+ monitoring and management to maintain SK+ concentrations may improve the outcomes of patients with RHTN and HF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): AstraZeneca

The relationship between duration of heart failure, serum potassium concentration and adverse clinical outcomes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P McEwan ◽  
M Hurst ◽  
L Hoskin ◽  
K Badora ◽  
D Sugrue ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Outcomes ◽  
Serum Potassium ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Funding Source ◽  
Private Company ◽  
Increased Risk ◽  
Ckd Stage ◽  
The Relationship

Abstract Background Hyper- and hypokalaemia are frequent complications in patients with heart failure (HF). The association between all-cause mortality (ACM), major adverse cardiovascular events (MACE) and serum potassium (K+) has previously been characterised in a UK incident HF population, with hypo- and hyperkalaemic patients being at increased risk of adverse clinical outcomes. Purpose This study aimed to assess the generalisability and findings of previously published risk equations in a broader HF population, spanning both incident and prevalent HF cases regardless of chronic kidney disease (CKD), and to explore the relationship between duration of HF and elevated risk associated with hypo- or hyperkalaemia. Methods A retrospective cohort study was conducted using linked UK Clinical Practice Research Datalink (CPRD) GOLD and Hospital Episode Statistics (HES) data. Eligible patients included individuals ≥18 years with HF (identified using READ codes) during the study period (January 2008 to June 2018) or five-year lookback period (2003 to 2007). Patients' index date was set to 1st January 2008 for prevalent patients or date of HF diagnosis for incident patients. Adverse clinical outcomes included ACM and MACE, a composite of arrhythmia, HF, myocardial infarction and stroke. Published risk equations for ACM and MACE for incident HF without CKD were refitted to this broader study population using original covariates and model forms. Coefficient values were adjusted for the inclusion of HF duration (≤5 and >5 years). Incidence rate ratios (IRRs) were recalculated with K+ concentration 4.5 to <5.0 mmol/L as the reference category. Results The HF cohort consisted of 84,210 patients with a mean follow-up of 5.01 years. The cohort was predominantly male (53.0%), with a mean age of 77.3 years at index. Ischaemic heart disease, hypertension, atrial fibrillation and type 2 diabetes were present in 42.24%, 61.39%, 40.89% and 20.38% of the population, respectively. CKD stage 3+ was present in 39.13% of patients, with a cohort mean estimated glomerular filtration rate of 56.9 mL/min/1.73m2 at index. Crude ACM and MACE event rates were 159.5 (95% confidence interval (CI): 157.9–161.0) and 575.8 (95% CI: 572.8–578.7) per 1,000 patient years, respectively. Hypo- and hyperkalaemia were generally associated with increased risk of ACM and MACE in comparison with patients with K+ concentrations of 4.5 to <5.0 mmol/L (figure 1); these associations were maintained irrespective of the duration of HF. Conclusion A real-world analysis of UK patients suggests that previously published associations between hypo- and hyperkalaemia and increased risk of adverse clinical outcomes in an incident HF population are generalisable to a cohort of incident and prevalent HF patients, irrespective of HF duration and the presence of comorbid CKD. Improved monitoring and management of K+ may have the potential to improve outcomes in these patients. Figure 1. IRRs of ACM and MACE Funding Acknowledgement Type of funding source: Private company. Main funding source(s): AstraZeneca

scholarly journals Serum uric acid, influence of sacubitril/valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Selvaraj ◽  
B.L Claggett ◽  
D.V Veldhuisen ◽  
I.S Anand ◽  
B Pieske ◽  
...  
Keyword(s):  
Heart Failure ◽  
Uric Acid ◽  
Ejection Fraction ◽  
Serum Uric Acid ◽  
Primary Outcome ◽  
Adverse Outcomes ◽  
Funding Source ◽  
Preserved Ejection Fraction ◽  
Private Company ◽  
Increased Risk

Abstract Background Serum uric acid (SUA) is a biomarker of several pathobiologies relevant to the pathogenesis of heart failure with preserved ejection fraction (HFpEF), though by itself may also worsen outcomes. In HF with reduced EF, SUA is independently associated with adverse outcomes and sacubitril/valsartan reduces SUA compared to enalapril. These effects in HFpEF have not been delineated. Purpose To determine the prognostic value of SUA, relationship of change in SUA to quality of life and outcomes, and influence of sacubitril/valsartan on SUA in HFpEF. Methods We analyzed 4,795 participants from the Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial. We related baseline hyperuricemia to the primary outcome (CV death and total HF hospitalization), its components, myocardial infarction or stroke, and a renal composite outcome. At the 4-month visit, the relationship between SUA change and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and several biomarkers including N-terminal pro-B-type natriuretic peptide (NT-proBNP) were also assessed. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. Results Average age was 73±8 years and 52% were women. After multivariable adjustment, hyperuricemia was associated with increased risk for most outcomes (primary outcome HR 1.61, 95% CI 1.37, 1.90, Fig 1A). The treatment effect of sacubitril/valsartan for the primary outcome was not modified by baseline SUA (interaction p=0.11). Sacubitril/valsartan reduced SUA −0.38 mg/dL (95% CI: −0.45, −0.31) compared with valsartan (Fig 1B), with greater effect in those with baseline hyperuricemia (−0.50 mg/dL) (interaction p=0.013). Change in SUA was independently and inversely associated with change in KCCQ-OSS (p=0.019) and eGFR (p<0.001), but not NT-proBNP (p=0.52). Time-updated SUA was a stronger predictor of adverse outcomes over baseline SUA. Conclusions SUA independently predicts adverse outcomes in HFpEF. Sacubitril/valsartan significantly reduces SUA compared to valsartan, an effect that was stronger in those with higher baseline SUA, and reducing SUA was associated with improved outcomes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Novartis

Relationship between frailty and all-cause mortality in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational research programme AF general long-term registry

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Proietti ◽  
M Vitolo ◽  
S Harrison ◽  
G.A Dan ◽  
A.P Maggioni ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Frailty Index ◽  
Primary Study ◽  
Funding Source ◽  
Private Company ◽  
Kaplan Meier ◽  
Increased Risk ◽  
All Cause Mortality

Abstract Introduction Frailty is a major health determinant for cardiovascular disease. Thus far, data on frailty in patients with atrial fibrillation (AF) are limited. Aims To evaluate frailty in a large contemporary cohort of European AF patients, the relationship with oral anticoagulant (OAC) prescription and with risk of all-cause death. Methods We analyzed patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. A 38-items frailty index (FI) was derived from baseline characteristics according to the accumulation of deficits model proposed by Rockwood and Mitnitsky. All-cause mortality was the primary study outcome. Results Out of the 11096 AF enrolled patients, data for evaluating frailty were available for 6557 (59.1%) patients who have been included in this analysis (mean [SD] age 68.9 [11.5], 37.7% females). Baseline median [IQR] CHA2DS2-VASc and HAS-BLED were 3 [2–4] and 1 [1–2], respectively. At baseline, median [IQR] FI was 0.16 (0.12–0.23), with 1276 (19.5%) patients considered “not-frail” (FI<0.10), 4033 (61.5%) considered “pre-frail” (FI 0.10–0.25) and 1248 (19.0%) considered “frail” (FI≥0.25). Age, female prevalence, CHA2DS2-VASc and HAS-BLED progressively increased across the FI classes (all p<0.001). Use of OAC progressively increased among FI classes; after adjustments FI was not associated with OAC prescription (odds ratio [OR]: 1.09, 95% confidence interval [CI]: 0.98–1.19 for each 0.10 FI increase). Conversely, FI was directly associated with vitamin K antagonist (VKA) use (OR: 1.26, 95% CI: 1.18–1.34 for each 0.10 FI increase) and inversely associated with non-VKA OACs (NOACs) use (OR: 0.82, 95% CI: 0.77–0.88). FI was significantly correlated with CHA2DS2-VASc (Rho= 0.516, p<0.001). Over a median [IQR] follow-up of 731 [704–749] days, there were 569 (8.7%) all-cause death events. Kaplan-Meier curves [Figure] showed an increasing cumulative risk for all-cause death according to FI categories. A Cox multivariable analysis, adjusted for age, sex, type of AF and use of OAC, found that increasing FI as a continuous variable was associated with an increased risk of all-cause death (hazard ratio [HR]: 1.56, 95% CI: 1.40–1.73 for each 0.10 FI increase). An association with all-cause death risk was found across the FI categories (HR: 1.71, 95% CI: 1.23–2.38 and HR: 2.88, 95% CI: 2.02–4.12, respectively for pre-frail and frail patients compared to non-frail ones). FI was also predictive of all-cause death (c-index: 0.660, 95% CI: 0.637–0.682; p<0.001). Conclusions In a European contemporary cohort of AF patients the burden of frailty is significant, with almost 1 out of 5 patients found to be “frail”. Frailty influenced significantly the choice of OAC therapy and was associated with (and predictive of) all-cause death at follow-up. Kaplan-Meier Curves Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Since the start of EORP programme, several companies have supported it with unrestricted grants.

ACE inhibitor use and risk of cataract: a case–control analysis

2019 ◽  
Vol 103 (11) ◽  
pp. 1561-1565 ◽  
Author(s):  
Claudia Becker ◽  
Susan S Jick ◽  
Christoph R Meier
Keyword(s):  
Observational Study ◽  
Index Date ◽  
Antihypertensive Drugs ◽  
Conditional Logistic Regression ◽  
Case Control ◽  
Sensitivity Analyses ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Control Analysis ◽  
Increased Risk

Background/AimUse of ACE inhibitors (ACEIs) has been associated with an increased risk of cataract in a previous observational study in humans. In contrast, ACEIs were associated with beneficial effects on cataract development in experimental studies. We assessed the risk of cataract in relation to exposure to ACEI and other antihypertensive drugs.MethodsThis is a case-control study based on data from the UK-based Clinical Practice Research Datalink (CPRD). We included first-time cataract patients aged ≥40 years between 1995 and 2015 and an equal number of cataract-free controls. We matched the controls to cases on age, sex, general practice, date of first cataract (ie, index date) and years of history in the CPRD prior to the index date. We assessed the number of prescriptions for ACEI and other antihypertensive drugs in detail and explored the use of single ACEI substances. We performed conditional logistic regression and conducted various sensitivity analyses to test the robustness of our findings. We calculated the risk of cataract associated with previous exposure to ACEI, measured as OR with 95% CIs, and adjusted the multivariable model for body mass index, smoking, diabetes, hypertension, prescriptions of systemic corticosteroids and other antihypertensive drugs.ResultsWe identified 206 931 cataract cases and the same number of matched controls. Use of ACEI was not associated with a materially altered risk of cataract compared with non-use of ACEI, neither in the main analysis (OR 1.06, 95% CI 1.04 to 1.08) nor in any of the sensitivity or stratified analyses.ConclusionIn our large observational study, use of ACEI was not associated with an altered risk of cataract.

scholarly journals P203 Oral glucocorticoid use is associated with hypertension in patients with RA

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Ruth E Costello ◽  
Meghna Jani ◽  
Belay B Yimer ◽  
William G Dixon
Keyword(s):  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Incident Hypertension ◽  
Increased Risk ◽  
Risk Attribution ◽  
Predominantly Female ◽  
Oral Glucocorticoids

Abstract Background Oral glucocorticoids (GC) are frequently prescribed to patients with rheumatoid arthritis (RA), however GC use is associated with several potential side effects. Hypertension is cited as a possible side effect, but few studies have specifically investigated GC-associated hypertension in patients with RA with conflicting results. The aim of this study was to determine whether GCs were associated with an increased risk of incident hypertension in a cohort of patients with RA. Methods A retrospective cohort of patients with incident RA and no hypertension at RA diagnosis were identified from UK primary care electronic health records (Clinical Practice Research Datalink). GC prescriptions were used to determine time-varying GC use and dose, categorised as: no use, >0-4.9 mg/day, 5-7.4 mg/day, 7.5-14.9 mg/day, ≥15mg/day. A 3-month risk attribution model was used where patients continued to remain at risk for 3 months after the end of prescriptions. Hypertension was identified if a patient had either: 1) 2 consecutive systolic blood pressure (BP) measurements >140mmHg within a year, 2) 2 consecutive diastolic BP measurements >90mmHg within a year or 3) antihypertensive prescriptions on at least two occasions and a Read code for hypertension. Unadjusted and adjusted Cox proportional hazards (PH) regression models were fitted to determine if there was an association between GC use and hypertension. Results There were 17,760 patients with incident RA and no hypertension. The cohort had a mean age of 56.3 ± 12.7 years and were predominantly female (68%). 7,421 (42%) were prescribed GCs during follow-up. There were 6,243 cases of incident hypertension. The Cox PH model indicated that recent GC use was associated with a 17% increased hazard of hypertension (hazard ratio: 1.17 (95% CI 1.10 to 1.24)). When categorised by dose, only doses above 7.5mg were significantly associated with hypertension (Table 1). Conclusion In this large cohort of patients with RA and without hypertension, recent GC use was associated with incident hypertension. Doses ≥7.5mg were associated with hypertension while the association with lower doses was inconclusive. Clinicians need to consider cardiovascular risk when prescribing GCs and ensure BP is regularly monitored. Disclosures R.E. Costello None. M. Jani None. B.B. Yimer None. W.G. Dixon None.

The prevalence and patient outcomes of adult primary hypercholesterolaemia and dyslipidaemia in the UK: a longitudinal retrospective study using a primary care dataset from 2008 to 2018

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Bilitou ◽  
A Rabe ◽  
L Inema ◽  
G Alamgir ◽  
K Dunton
Keyword(s):  
Primary Care ◽  
Adult Population ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Funding Source ◽  
Private Company ◽  
Primary Hypercholesterolaemia ◽  
The Uk

Abstract Background Cardiovascular disease (CVD) remains the leading cause of death and morbidity in Europe and United Kingdom (UK). Increased low-density lipoprotein cholesterol (LDL-C), implicated in primary hypercholesterolaemia and mixed dyslipidaemia (PH/MD), is an extensively studied risk factor, with proven direct and linear causality of CVD. Lowering LDL-C remains a primary goal in the treatment and prevention of atherosclerotic CVD. Objectives This study aimed to quantify adult prevalence and incidence of PH/MD in the UK. Methods We used an anonymised dataset covering primary care practices across the UK, accessed through the Clinical Practice Research Datalink (CPRD GOLD). Ethics approval was sought and provided (Protocol 19_238R). Using a validated set of clinical codes as well as pre-treatment lipid profile levels for total cholesterol (TC) (>8 mmol/L), LDL-C (>4.9 mmol/L), we calculated prevalent and new adult cases starting from 2009 to 2018. Our denominator population was the CPRD GOLD GP-registered adult population each calendar year, adjusted for mortality. Results There were 1,514,916 adults in the CPRD GOLD GP register for the period from 2009 to 2018. During that period there were 354,444 patients diagnosed with PH/MD. Males comprised 46.5%, mean age on diagnosis was 58.2 years. Mean follow-up time was 104 months. The annual prevalence of PH/MD increased from 2009 to 2019 (see graph). The overall prevalence across the period was 22.7%. Mean annual incidence across the decade was 1.7%. Mean LDL-C levels were 4.7 mmol/L and mean TC level was 6.8 mmol/L. In this cohort, 15.9% experienced cardiovascular events (see table). Nearly all patients have used lipid lowering therapies. Only 2.2% achieved at least 40% reduction of LDL-C from baseline. Conclusions The prevalence of PH/MD has been increasing despite the availability of interventions. Considering guidelines, only a small proportion of patients have achieved LDL-C goals. Est prevalence of PH/MD in the UK Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo Europe, Health iQ Ltd

scholarly journals Sex, Age, and Socioeconomic Differences in Nonfatal Stroke Incidence and Subsequent Major Adverse Outcomes

Stroke ◽  
2021 ◽  
Vol 52 (2) ◽  
pp. 396-405
Author(s):  
Ralph K. Akyea ◽  
Yana Vinogradova ◽  
Nadeem Qureshi ◽  
Riyaz S. Patel ◽  
Evangelos Kontopantelis ◽  
...  
Keyword(s):  
Socioeconomic Status ◽  
United Kingdom ◽  
Adverse Outcomes ◽  
Nonfatal Stroke ◽  
Practice Research ◽  
Major Adverse Cardiovascular Events ◽  
Clinical Practice Research Datalink ◽  
Socioeconomic Differences ◽  
Stroke Incidence ◽  
The United Kingdom

Background and Purpose: Data about variations in stroke incidence and subsequent major adverse outcomes are essential to inform secondary prevention and prioritizing resources to those at the greatest risk of major adverse end points. We aimed to describe the age, sex, and socioeconomic differences in the rates of first nonfatal stroke and subsequent major adverse outcomes. Methods: The cohort study used linked Clinical Practice Research Datalink and Hospital Episode Statistics data from the United Kingdom. The incidence rate (IR) ratio of first nonfatal stroke and subsequent major adverse outcomes (composite major adverse cardiovascular events, recurrent stroke, cardiovascular disease-related, and all-cause mortality) were calculated and presented by year, sex, age group, and socioeconomic status based on an individual’s location of residence, in adults with incident nonfatal stroke diagnosis between 1998 and 2017. Results: A total of 82 774 first nonfatal stroke events were recorded in either primary care or hospital data—an IR of 109.20 per 100 000 person-years (95% CI, 108.46–109.95). Incidence was significantly higher in women compared with men (IR ratio, 1.13 [95% CI, 1.12–1.15]; P <0.001). Rates adjusted for age and sex were higher in the lowest compared with the highest socioeconomic status group (IR ratio, 1.10 [95% CI, 1.08–1.13]; P <0.001). For subsequent major adverse outcomes, the overall incidence for major adverse cardiovascular event was 38.05 per 100 person-years (95% CI, 37.71–38.39) with a slightly higher incidence in women compared with men (38.42 versus 37.62; IR ratio, 1.02 [95% CI, 1.00–1.04]; P =0.0229). Age and socioeconomic status largely accounted for the observed higher incidence of adverse outcomes in women. Conclusions: In the United Kingdom, incidence of initial stroke and subsequent major adverse outcomes are higher in women, older populations, and people living in socially deprived areas.

scholarly journals Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

Heart ◽  
2019 ◽  
Vol 105 (13) ◽  
pp. 975-981 ◽  
Author(s):  
Ralph Kwame Akyea ◽  
Joe Kai ◽  
Nadeem Qureshi ◽  
Barbara Iyen ◽  
Stephen F Weng
Keyword(s):  
Cardiovascular Disease ◽  
Statin Therapy ◽  
Competing Risks ◽  
Density Lipoprotein ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
National Guidelines ◽  
Increased Risk ◽  
Future Risk

ObjectiveTo assess low-density lipoprotein cholesterol (LDL-C) response in patients after initiation of statins, and future risk of cardiovascular disease (CVD).MethodsProspective cohort study of 165 411 primary care patients, from the UK Clinical Practice Research Datalink, who were free of CVD before statin initiation, and had at least one pre-treatment LDL-C within 12 months before, and one post-treatment LDL-C within 24 months after, statin initiation. Based on current national guidelines, <40% reduction in baseline LDL-C within 24 months was classified as a sub-optimal statin response. Cox proportional regression and competing-risks survival regression models were used to determine adjusted hazard ratios (HRs) and sub-HRs for incident CVD outcomes for LDL-C response to statins.Results84 609 (51.2%) patients had a sub-optimal LDL-C response to initiated statin therapy within 24 months. During 1 077 299 person-years of follow-up (median follow-up 6.2 years), there were 22 798 CVD events (12 142 in sub-optimal responders and 10 656 in optimal responders). In sub-optimal responders, compared with optimal responders, the HR for incident CVD was 1.17 (95% CI 1.13 to 1.20) and 1.22 (95% CI 1.19 to 1.25) after adjusting for age and baseline untreated LDL-C. Considering competing risks resulted in lower but similar sub-HRs for both unadjusted (1.13, 95% CI 1.10 to 1.16) and adjusted (1.19, 95% CI 1.16 to 1.23) cumulative incidence function of CVD.ConclusionsOptimal lowering of LDL-C is not achieved within 2 years in over half of patients in the general population initiated on statin therapy, and these patients will experience significantly increased risk of future CVD.

scholarly journals Infectious Disease Burden and the Risk of Alzheimer’s Disease: A Population-Based Study

2021 ◽  
pp. 1-10
Author(s):  
Antonios Douros ◽  
Christina Santella ◽  
Sophie Dell’Aniello ◽  
Laurent Azoulay ◽  
Christel Renoux ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Burden ◽  
Population Based ◽  
Practice Research ◽  
Clinical Practice Research Datalink ◽  
Cumulative Number ◽  
Increased Risk

Background: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer’s disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor. Objective: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD. Methods: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed >  2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections. Results: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12–30 years (OR, 1.11; 95% CI, 1.05–1.17). The risk did not increase with cumulative number of infections. Conclusion: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection.

scholarly journals RNA interference targeting apolipoprotein C-III with ARO-APOC3 in healthy volunteers mimics lipid and lipoprotein findings seen in subjects with inherited apolipoprotein C-III deficiency

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Schwabe ◽  
R Scott ◽  
D Sullivan ◽  
J Baker ◽  
P Clifton ◽  
...  
Keyword(s):  
Rna Interference ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Funding Source ◽  
Private Company ◽  
Good Tolerability ◽  
Genetic Studies ◽  
Apolipoprotein C ◽  
Increased Risk

Abstract Background Individuals with triglycerides (TGs) ≥1,000 mg/dL (11.1 mmol/L) are at increased risk of acute pancreatitis. Genetic studies indicate that individuals with apolipoprotein C-3 (APOC3) loss-of-function mutations have low TGs, reduced cardiovascular risk and no observed adverse phenotype. RNA interference (RNAi) with ARO-APOC3 has shown deep and durable knockdown (KD) of APOC3 after single doses in healthy volunteers (HVs, presented at AHA 2019) with good tolerability. We report here initial results using multiple doses of ARO-APOC3 to silence APOC3 expression in HVs. Methods ARO-APOC3 was administered subcutaneously to HVs on days 1 and 29 at doses of 10, 25 or 50 mg (n=4 per group). Measured parameters included plasma concentrations of APOC3, LDL-C, TGs, VLDL-C and HDL-C. Results All HVs have received both doses and follow-up for most parameters is available through week (wk) 14 (10 wks after second dose) for the 10 and 25 mg doses and through wk 10 for 50 mg. Mean nadir for APOC3 levels occurred at wk 3 for 10 mg (−73%) and remained similar at wk 10 (−66%), at wk 6 for 25 mg (−90%) with no change at wk 10 and at wk 2 for 50 mg (−94%) unchanged at wk 8. TGs fell faster in the 50 mg group (wk 1: 10 mg −41%; 25 mg −47%; 50 mg −72%). By wk 6 the 25 and 50 mg results were similar (−68% and −74%, respectively) and remained similar through wk 14. 10 mg was less active with a nadir of −56% and mean reductions between 42% and 56% post-nadir. VLDL-C values mirrored TGs. LDL-C reductions were more modest and did not manifest a dose response. Mean nadirs (−23–26%) occurred 4–6 wks after the first dose, again with minimal change through 10–14 wks of follow-up. Consistent with genetic studies, HDL-C increased to a maximum at approximately wk 8 (10 mg +42%, 25 mg +48%, 50 mg +84%). ARO-APOC3 was well tolerated without serious or severe adverse events or dropouts related to drug. The most common adverse events were mild injection site AEs and headache. Conclusions Genetic deficiency of APOC3 is associated with substantial reductions in TGs, VLDL-C and increases in HDL-C without an adverse phenotype. Using RNAi to selectively suppress APOC3 production mimics these lipid and lipoprotein effects, with a duration of at least 10 weeks following a second dose and with good tolerability over 16 wks using doses ranging from 10 to 50 mg. Investigation of optimal dosing regimen is ongoing, especially with respect to dosing interval. This therapeutic approach has potential for treating patients with chylomicronemia at risk of pancreatitis. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Arrowhead Pharmaceuticals

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