Publications by authors named "Reecha Sofat"

70 Publications

Association of Smoking, Alcohol Consumption, Blood Pressure, Body Mass Index, and Glycemic Risk Factors With Age-Related Macular Degeneration: A Mendelian Randomization Study.

JAMA Ophthalmol 2021 Nov 4. Epub 2021 Nov 4.

Institute of Health Informatics, University College London, London, United Kingdom.

Importance: Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD.

Objective: To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD.

Design, Setting, Participants: This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021.

Exposures: Smoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin.

Main Outcomes And Measures: Advanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD.

Results: A 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD.

Conclusions And Relevance: This study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.4601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569599PMC
November 2021

Validation of lipid-related therapeutic targets for coronary heart disease prevention using human genetics.

Nat Commun 2021 10 21;12(1):6120. Epub 2021 Oct 21.

Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, WC1E 6BT, UK.

Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter the target's expression or function, as a tool to anticipate the effect of drug action on the same target. Here we apply MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets are further prioritized using independent replication, co-localization, protein expression profiles and data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with blood lipids (HDL-C, LDL-C and triglycerides), we robustly prioritize 30 targets that might elicit beneficial effects in the prevention or treatment of CHD, including NPC1L1 and PCSK9, the targets of drugs used in CHD prevention. We discuss how this approach can be generalized to other targets, disease biomarkers and endpoints to help prioritize and validate targets during the drug development process.
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http://dx.doi.org/10.1038/s41467-021-25731-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531035PMC
October 2021

An informatics consult approach for generating clinical evidence for treatment decisions.

BMC Med Inform Decis Mak 2021 10 12;21(1):281. Epub 2021 Oct 12.

Institute of Health Informatics, University College London, London, UK.

Background: An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis.

Methods: We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems.

Results: We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39-1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49-0.76) and ischaemic stroke (HR = 0.27, CI 0.08-0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results.

Conclusion: We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on 'patients like me'. We identify the key challenges in offering such an Informatics Consult as a service.
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http://dx.doi.org/10.1186/s12911-021-01638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506488PMC
October 2021

Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease.

Nat Commun 2021 09 24;12(1):5640. Epub 2021 Sep 24.

Institute of Cardiovascular Science, Faculty of Population Health, University College London, London, UK.

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.
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http://dx.doi.org/10.1038/s41467-021-25703-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463530PMC
September 2021

Free-of-charge medicine schemes in the NHS: A local and regional drug and therapeutic committee's experience.

Br J Clin Pharmacol 2021 Sep 23. Epub 2021 Sep 23.

Centre of Clinical Pharmacology and Therapeutics, Institute of Health Informatics, University College London, London, UK.

Introduction: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning.

Methods: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available Medicines and Healthcare products Regulatory Agency Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised.

Results: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes, 37% had phase 2 data and 19% were supported only by phase 1 data, retrospective observational studies or preclinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS schemes showed little growth.

Conclusion: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or to allow generation of further evidence.
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http://dx.doi.org/10.1111/bcp.15094DOI Listing
September 2021

Atrial fibrillation epidemiology, disparity and healthcare contacts: a population-wide study of 5.6 million individuals.

Lancet Reg Health Eur 2021 Aug;7:100157

Barts Heart Centre, Barts Health NHS Trust, London, UK.

We aimed to evaluate atrial fibrillation occurrence, reasons for healthcare visits, mortality, causes of death and examined patterns by relative deprivation in the UK. To study the atrial fibrillation (AF) incidence, mortality and case-fatality, we implemented a prospective cohort study with the linked electronic health records of 5.6 million population in the United Kingdom Clinical Practice Research Datalink from 1998 to 2016. A matched case-control study was used to investigate causes of hospitalisation and death comparing individuals with and without incident AF. During a median follow-up of 10.3 years, 199,433(3.6%) patients developed incident AF. Increased risk of hospitalisation for heart failure, cardiovascular conditions and infection was present among patients who later developed AF. Following an AF diagnosis, patients were frequently admitted to the hospital for heart failure, lower respiratory tract infection, chronic obstructive pulmonary disease and ischemic heart disease. One in 5 AF patients died during the first year after diagnosis, and the mortality increased to 42.7% at the fifth year. The excess deaths in AF cases compared to controls may result from cardiovascular diseases, infection and metabolic disorders. Individuals from areas with higher deprivation in socioeconomic and living status had both higher AF incidence and fatality. We observed an elevated risk of hospitalisation for cardiovascular or respiratory diseases among incident AF patients, and the considerable disparity in AF burden by socioeconomic deprivation informs priorities for prevention and provision of patient care. The study was supported by the GlaxoSmithKline, University College London Hospital and National Institute for Health Research. The funders did not have any role in study design, data collection, data analysis, interpretation, and writing of the report.
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http://dx.doi.org/10.1016/j.lanepe.2021.100157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351189PMC
August 2021

Why We Are Losing the War Against COVID-19 on the Data Front and How to Reverse the Situation.

JMIRx Med 2021 Apr-Jun;2(2):e20617. Epub 2021 May 5.

Institute of Health Informatics University College London London United Kingdom.

With over 117 million COVID-19-positive cases declared and the death count approaching 3 million, we would expect that the highly digitalized health systems of high-income countries would have collected, processed, and analyzed large quantities of clinical data from patients with COVID-19. Those data should have served to answer important clinical questions such as: what are the risk factors for becoming infected? What are good clinical variables to predict prognosis? What kinds of patients are more likely to survive mechanical ventilation? Are there clinical subphenotypes of the disease? All these, and many more, are crucial questions to improve our clinical strategies against the epidemic and save as many lives as possible. One might assume that in the era of big data and machine learning, there would be an army of scientists crunching petabytes of clinical data to answer these questions. However, nothing could be further from the truth. Our health systems have proven to be completely unprepared to generate, in a timely manner, a flow of clinical data that could feed these analyses. Despite gigabytes of data being generated every day, the vast quantity is locked in secure hospital data servers and is not being made available for analysis. Routinely collected clinical data are, by and large, regarded as a tool to inform decisions about individual patients, and not as a key resource to answer clinical questions through statistical analysis. The initiatives to extract COVID-19 clinical data are often promoted by private groups of individuals and not by health systems, and are uncoordinated and inefficient. The consequence is that we have more clinical data on COVID-19 than on any other epidemic in history, but we have failed to analyze this information quickly enough to make a difference. In this viewpoint, we expose this situation and suggest concrete ideas that health systems could implement to dynamically analyze their routine clinical data, becoming learning health systems and reversing the current situation.
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http://dx.doi.org/10.2196/20617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104306PMC
May 2021

Data-driven identification of ageing-related diseases from electronic health records.

Sci Rep 2021 02 3;11(1):2938. Epub 2021 Feb 3.

Health Data Research UK London, University College London, London, UK.

Reducing the burden of late-life morbidity requires an understanding of the mechanisms of ageing-related diseases (ARDs), defined as diseases that accumulate with increasing age. This has been hampered by the lack of formal criteria to identify ARDs. Here, we present a framework to identify ARDs using two complementary methods consisting of unsupervised machine learning and actuarial techniques, which we applied to electronic health records (EHRs) from 3,009,048 individuals in England using primary care data from the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics admitted patient care dataset between 1 April 2010 and 31 March 2015 (mean age 49.7 years (s.d. 18.6), 51% female, 70% white ethnicity). We grouped 278 high-burden diseases into nine main clusters according to their patterns of disease onset, using a hierarchical agglomerative clustering algorithm. Four of these clusters, encompassing 207 diseases spanning diverse organ systems and clinical specialties, had rates of disease onset that clearly increased with chronological age. However, the ages of onset for these four clusters were strikingly different, with median age of onset 82 years (IQR 82-83) for Cluster 1, 77 years (IQR 75-77) for Cluster 2, 69 years (IQR 66-71) for Cluster 3 and 57 years (IQR 54-59) for Cluster 4. Fitting to ageing-related actuarial models confirmed that the vast majority of these 207 diseases had a high probability of being ageing-related. Cardiovascular diseases and cancers were highly represented, while benign neoplastic, skin and psychiatric conditions were largely absent from the four ageing-related clusters. Our framework identifies and clusters ARDs and can form the basis for fundamental and translational research into ageing pathways.
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http://dx.doi.org/10.1038/s41598-021-82459-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859412PMC
February 2021

Remdesivir for COVID-19 in Europe: will it provide value for money?

Lancet Respir Med 2021 02 17;9(2):127-128. Epub 2020 Dec 17.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.

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http://dx.doi.org/10.1016/S2213-2600(20)30568-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836228PMC
February 2021

Metabolic profiles of socio-economic position: a multi-cohort analysis.

Int J Epidemiol 2021 07;50(3):768-782

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Background: Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear.

Methods: We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies.

Results: In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids.

Conclusions: Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.
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http://dx.doi.org/10.1093/ije/dyaa188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271201PMC
July 2021

Establishing a service to tackle problematic polypharmacy.

Future Healthc J 2020 Oct;7(3):208-211

University College London, London, UK.

Introduction: Polypharmacy is increasingly common and can increase the risk of adverse drug reactions (ADRs), accounting for a significant proportion of hospital admissions. It may also impair functional status and quality of life. Current efforts to improve polypharmacy take place largely in primary care, but there may be a role for increased support from medicines specialists in the secondary care setting.

Methods: We developed a pilot polypharmacy clinic in secondary care, led by clinical pharmacologists and pharmacists. Medicines were deprescribed as appropriate, based on clinical need and symptoms suspected of being ADRs. An ADR symptom burden was recorded pre- and post-intervention to identify any clinical changes following deprescribing.

Results: Twenty-four individuals were reviewed. The total number of medicines prescribed to each patient was reduced by a median of 4 (interquartile range (IQR) 2-5), resulting in annual savings in discontinued medicines of £4,957.44. The ADR burden fell from a median of 15 (IQR 14-17) to a median of 7 (IQR 4-11).

Conclusion: Our pilot clinic reviewed a small number of patients, but demonstrated the potential of such a service to offer both clinical improvements and cost savings. This service could be extended, integrated and sustained to improve care for people taking multiple medicines.
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http://dx.doi.org/10.7861/fhj.2019-0048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571722PMC
October 2020

Monitoring indirect impact of COVID-19 pandemic on services for cardiovascular diseases in the UK.

Heart 2020 12 5;106(24):1890-1897. Epub 2020 Oct 5.

The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK

Objective: To monitor hospital activity for presentation, diagnosis and treatment of cardiovascular diseases during the COVID-19) pandemic to inform on indirect effects.

Methods: Retrospective serial cross-sectional study in nine UK hospitals using hospital activity data from 28 October 2019 (pre-COVID-19) to 10 May 2020 (pre-easing of lockdown) and for the same weeks during 2018-2019. We analysed aggregate data for selected cardiovascular diseases before and during the epidemic. We produced an online visualisation tool to enable near real-time monitoring of trends.

Results: Across nine hospitals, total admissions and emergency department (ED) attendances decreased after lockdown (23 March 2020) by 57.9% (57.1%-58.6%) and 52.9% (52.2%-53.5%), respectively, compared with the previous year. Activity for cardiac, cerebrovascular and other vascular conditions started to decline 1-2 weeks before lockdown and fell by 31%-88% after lockdown, with the greatest reductions observed for coronary artery bypass grafts, carotid endarterectomy, aortic aneurysm repair and peripheral arterial disease procedures. Compared with before the first UK COVID-19 (31 January 2020), activity declined across diseases and specialties between the first case and lockdown (total ED attendances relative reduction (RR) 0.94, 0.93-0.95; total hospital admissions RR 0.96, 0.95-0.97) and after lockdown (attendances RR 0.63, 0.62-0.64; admissions RR 0.59, 0.57-0.60). There was limited recovery towards usual levels of some activities from mid-April 2020.

Conclusions: Substantial reductions in total and cardiovascular activities are likely to contribute to a major burden of indirect effects of the pandemic, suggesting they should be monitored and mitigated urgently.
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http://dx.doi.org/10.1136/heartjnl-2020-317870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536637PMC
December 2020

Beyond dexamethasone, emerging immuno-thrombotic therapies for COVID-19.

Br J Clin Pharmacol 2021 03 14;87(3):845-857. Epub 2020 Oct 14.

Centre for Clinical Pharmacology and Therapeutics, UCL, London, UK.

Host immunity is required to clear SARS-CoV-2, and inability to clear the virus because of host or pathogen factors renders those infected at risk of poor outcomes. Estimates of those who are able to clear the virus with asymptomatic or paucisymptomatic COVID-19 remain unclear, and dependent on widespread testing. However, evidence is emerging that in severe cases, pathological mechanisms of hyperinflammation and coagulopathy ensue, the former supported by results from the RECOVERY trial demonstrating a reduction in mortality with dexamethasone in advanced COVID-19. It remains unclear whether these pathogenic pathways are secondary to a failure to clear the virus because of maladaptive immune responses or if these are sequential COVID-19 defining illnesses. Understanding the pathophysiological mechanisms underpinning these cascades is essential to formulating rationale therapeutic approaches beyond the use of dexamethasone. Here, we review the pathophysiology thought to underlie COVID-19 with clinical correlates and the current therapeutic approaches being investigated.
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http://dx.doi.org/10.1111/bcp.14540DOI Listing
March 2021

Are high-cost drug funding mechanisms fit for purpose? A retrospective study of individual funding requests in an NHS tertiary hospital.

Br J Clin Pharmacol 2020 Jun 5. Epub 2020 Jun 5.

Centre for Clinical Pharmacology, Division of Medicine, University College London, UK.

Aims: To report on a retrospective study of individual funding request (IFR) submissions from a large tertiary hospital and describe gaps in current mechanisms for funding of high-cost medicines in England.

Methods: Data on the number and outcome of IFR submissions submitted to commissioners between 2014/15 and 2018/19 was extracted from the electronic patient health record and a local high-cost drug database.

Results: In total, 230 IFRs were submitted: 112 to NHS England and 118 to a Clinical Commissioning Group (CCG). The decline rate for IFRs was 71% for NHS England and 34% for CCGs. Lack of exceptionality was the primary reason cited for declining IFRs submitted between 2016-18 (n = 42/45; 93%). Half of the patients whose IFR was declined received treatment funded through other routes, the majority (13/23; 57%) from internal hospital budget. This was governed via a local high-cost drug panel. Positive clinical outcomes were observed in 50% (4/8) of patients who received NHS England IFR-funded treatment, 54% (19/35) who received CCG IFR-funded treatment and 91% (21/23) who were funded via other routes.

Conclusion: The high rate of IFR decline signals inefficient use of resource expended in the IFR process. Gaps in access to high-cost medicines remain for patients with rare and refractory disease requiring urgent treatment, largely due to the demand for exceptionality from NHS commissioners. Local mechanisms address this unmet need but have limitations. An outcomes-based evaluation approach to commissioning and greater transparency of previous funding decisions by commissioners may improve efficiency and equity in the IFR system.
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http://dx.doi.org/10.1111/bcp.14409DOI Listing
June 2020

Polypharmacy: the whys, the so whats and the what nexts.

Br J Hosp Med (Lond) 2020 May 11;81(5):1-7. Epub 2020 May 11.

Department of Clinical Pharmacology, University College London Hospital Foundation Trust, London, UK.

There is an increasing awareness that polypharmacy - the use of multiple medicines by one individual - may bring harm as well as benefit. This has been termed 'problematic polypharmacy' and is associated with increased risk of admission to hospital, decreased quality of life and psychological harm. This article addresses the factors that may be contributing to the global rise of polypharmacy (the whys), the problems it can cause (the so whats), and some opportunities and strategies for improving and avoiding problematic polypharmacy in the future (the what nexts).
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http://dx.doi.org/10.12968/hmed.2019.0383DOI Listing
May 2020

Association between Angiotensin Blockade and Incidence of Influenza in the United Kingdom.

N Engl J Med 2020 07 8;383(4):397-400. Epub 2020 May 8.

University College London, London, United Kingdom

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http://dx.doi.org/10.1056/NEJMc2005396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233186PMC
July 2020

Overprescribing and rational therapeutics: Barriers to change and opportunities to improve.

Br J Clin Pharmacol 2021 01 14;87(1):34-38. Epub 2020 Apr 14.

Department of Clinical Pharmacology, University College London Hospital Foundation Trust, UK.

There is increasing national and international interest in overprescribing and polypharmacy, and the burden that the inappropriate use of multiple medicines can place on individual patients and on society as a whole. This paper explores the challenges faced by prescribers and pharmacists wishing to reduce polypharmacy, including the uncertainties about the risks and benefits of continuing or stopping individual drugs. We discuss the factors influencing us to prescribe-which may lead to overprescribing-including the increasing number of guidelines, perceived patient pressure and advertising. We offer a critical appraisal of the tools currently available to clinicians and pharmacists aiming to rationalise medicines, and finally a systems-wide approach to improving overprescribing and problematic polypharmacy.
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http://dx.doi.org/10.1111/bcp.14291DOI Listing
January 2021

RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.

J Inherit Metab Dis 2020 09 16;43(5):1002-1013. Epub 2020 Apr 16.

Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.
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http://dx.doi.org/10.1002/jimd.12234DOI Listing
September 2020

Improving the odds of drug development success through human genomics: modelling study.

Sci Rep 2019 12 11;9(1):18911. Epub 2019 Dec 11.

Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Veterans Administration, Boston, MA, USA.

Lack of efficacy in the intended disease indication is the major cause of clinical phase drug development failure. Explanations could include the poor external validity of pre-clinical (cell, tissue, and animal) models of human disease and the high false discovery rate (FDR) in preclinical science. FDR is related to the proportion of true relationships available for discovery (γ), and the type 1 (false-positive) and type 2 (false negative) error rates of the experiments designed to uncover them. We estimated the FDR in preclinical science, its effect on drug development success rates, and improvements expected from use of human genomics rather than preclinical studies as the primary source of evidence for drug target identification. Calculations were based on a sample space defined by all human diseases - the 'disease-ome' - represented as columns; and all protein coding genes - 'the protein-coding genome'- represented as rows, producing a matrix of unique gene- (or protein-) disease pairings. We parameterised the space based on 10,000 diseases, 20,000 protein-coding genes, 100 causal genes per disease and 4000 genes encoding druggable targets, examining the effect of varying the parameters and a range of underlying assumptions, on the inferences drawn. We estimated γ, defined mathematical relationships between preclinical FDR and drug development success rates, and estimated improvements in success rates based on human genomics (rather than orthodox preclinical studies). Around one in every 200 protein-disease pairings was estimated to be causal (γ = 0.005) giving an FDR in preclinical research of 92.6%, which likely makes a major contribution to the reported drug development failure rate of 96%. Observed success rate was only slightly greater than expected for a random pick from the sample space. Values for γ back-calculated from reported preclinical and clinical drug development success rates were also close to the a priori estimates. Substituting genome wide (or druggable genome wide) association studies for preclinical studies as the major information source for drug target identification was estimated to reverse the probability of late stage failure because of the more stringent type 1 error rate employed and the ability to interrogate every potential druggable target in the same experiment. Genetic studies conducted at much larger scale, with greater resolution of disease end-points, e.g. by connecting genomics and electronic health record data within healthcare systems has the potential to produce radical improvement in drug development success rate.
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http://dx.doi.org/10.1038/s41598-019-54849-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906499PMC
December 2019

Bleeding in cardiac patients prescribed antithrombotic drugs: electronic health record phenotyping algorithms, incidence, trends and prognosis.

BMC Med 2019 11 20;17(1):206. Epub 2019 Nov 20.

Health Data Research UK, University College London, 222 Euston Road, London, NW1 2DA, UK.

Background: Clinical guidelines and public health authorities lack recommendations on scalable approaches to defining and monitoring the occurrence and severity of bleeding in populations prescribed antithrombotic therapy.

Methods: We examined linked primary care, hospital admission and death registry electronic health records (CALIBER 1998-2010, England) of patients with newly diagnosed atrial fibrillation, acute myocardial infarction, unstable angina or stable angina with the aim to develop algorithms for bleeding events. Using the developed bleeding phenotypes, Kaplan-Meier plots were used to estimate the incidence of bleeding events and we used Cox regression models to assess the prognosis for all-cause mortality, atherothrombotic events and further bleeding.

Results: We present electronic health record phenotyping algorithms for bleeding based on bleeding diagnosis in primary or hospital care, symptoms, transfusion, surgical procedures and haemoglobin values. In validation of the phenotype, we estimated a positive predictive value of 0.88 (95% CI 0.64, 0.99) for hospitalised bleeding. Amongst 128,815 patients, 27,259 (21.2%) had at least 1 bleeding event, with 5-year risks of bleeding of 29.1%, 21.9%, 25.3% and 23.4% following diagnoses of atrial fibrillation, acute myocardial infarction, unstable angina and stable angina, respectively. Rates of hospitalised bleeding per 1000 patients more than doubled from 1.02 (95% CI 0.83, 1.22) in January 1998 to 2.68 (95% CI 2.49, 2.88) in December 2009 coinciding with the increased rates of antiplatelet and vitamin K antagonist prescribing. Patients with hospitalised bleeding and primary care bleeding, with or without markers of severity, were at increased risk of all-cause mortality and atherothrombotic events compared to those with no bleeding. For example, the hazard ratio for all-cause mortality was 1.98 (95% CI 1.86, 2.11) for primary care bleeding with markers of severity and 1.99 (95% CI 1.92, 2.05) for hospitalised bleeding without markers of severity, compared to patients with no bleeding.

Conclusions: Electronic health record bleeding phenotyping algorithms offer a scalable approach to monitoring bleeding in the population. Incidence of bleeding has doubled in incidence since 1998, affects one in four cardiovascular disease patients, and is associated with poor prognosis. Efforts are required to tackle this iatrogenic epidemic.
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http://dx.doi.org/10.1186/s12916-019-1438-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864929PMC
November 2019

A novel approach to support implementation of biosimilars within a UK tertiary hospital.

Br J Clin Pharmacol 2020 01 20;86(1):23-28. Epub 2019 Dec 20.

University College London Hospital, London, UK.

Aims To assess the transfer of patients treated with originator biological therapies to biosimilar products in a large UK tertiary referral hospital reflecting practice within the National Health Service (NHS) using prospectively collected data by a hospital-based registry administered by the Biologics Steering Group (BSG).

Methods: We analysed data collected prospectively in a hospital-based registry in a large NHS tertiary referral hospital in the UK. The registry was administered by the hospital's BSG, which considered requests for patients to remain on or revert to originator products. The registry contained prospectively collected data on patients switching therapy from an originator to a biosimilar. The data included clinical circumstances or rationale for each request, whether it was granted, and the results of clinical reviews at 3-6 months.

Results: In a 12-month period, we identified 1299 patients who could switch to the respective biosimilar and, of these, 1196 (92%) did so. Of the 260 patients taking infliximab, 250 (96%) switched to infliximab biosimilar; of the 390 patients taking etanercept 50 mg, 298 (76%) switched to etanercept 50 mg biosimilar; and of the 649 patients taking rituximab, 648 (99%) switched to rituximab biosimilar. The BSG received 39 applications: 12 (out of 39) applications were to remain on the originator and 27 (out of 39) were to switch back to the originator. Of the applications to remain on the originator 10 (out of 12) were approved. At 3-6 month review, 2 of these approvals reported continued efficacy, 3 switched to the biosimilar, 3 switched to an alternative therapy and 2 stopped treatment. Two (out of 10) applications were not approved, both applicants reported efficacy with the biosimilar at follow up. Of the 27 applications to switch back to the originator, 16 (out of 27) applications were approved. At 3-6 months, 9 (out of 16) applicants reported regain of efficacy, 6 (out of 16) reported cessation of reported adverse effects and 1 (out of 16) switched to alternative therapy. Eight (out of 27) applications were not approved, and, at point of follow up, 50% reported efficacy with the biosimilar and 50% had switched to an alternative therapy. Three (out of 27) applications were withdrawn by the clinical team as efficacy was achieved with the biosimilar.

Conclusion: We have set up a system within a busy NHS clinical practice to successfully switch patients to biosimilars, and established a mechanism to guide decisions on continuing with or reverting back to the originator. Such a system could be of use more broadly within the NHS and other health care systems.
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http://dx.doi.org/10.1111/bcp.14150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983502PMC
January 2020

A chronological map of 308 physical and mental health conditions from 4 million individuals in the English National Health Service.

Lancet Digit Health 2019 06 20;1(2):e63-e77. Epub 2019 May 20.

Institute of Cardiovascular Science, London.

Background: To effectively prevent, detect, and treat health conditions that affect people during their lifecourse, health-care professionals and researchers need to know which sections of the population are susceptible to which health conditions and at which ages. Hence, we aimed to map the course of human health by identifying the 50 most common health conditions in each decade of life and estimating the median age at first diagnosis.

Methods: We developed phenotyping algorithms and codelists for physical and mental health conditions that involve intensive use of health-care resources. Individuals older than 1 year were included in the study if their primary-care and hospital-admission records met research standards set by the Clinical Practice Research Datalink and they had been registered in a general practice in England contributing up-to-standard data for at least 1 year during the study period. We used linked records of individuals from the CALIBER platform to calculate the sex-standardised cumulative incidence for these conditions by 10-year age groups between April 1, 2010, and March 31, 2015. We also derived the median age at diagnosis and prevalence estimates stratified by age, sex, and ethnicity (black, white, south Asian) over the study period from the primary-care and secondary-care records of patients.

Findings: We developed case definitions for 308 disease phenotypes. We used records of 2 784 138 patients for the calculation of cumulative incidence and of 3 872 451 patients for the calculation of period prevalence and median age at diagnosis of these conditions. Conditions that first gained prominence at key stages of life were: atopic conditions and infections that led to hospital admission in children (<10 years); acne and menstrual disorders in the teenage years (10-19 years); mental health conditions, obesity, and migraine in individuals aged 20-29 years; soft-tissue disorders and gastro-oesophageal reflux disease in individuals aged 30-39 years; dyslipidaemia, hypertension, and erectile dysfunction in individuals aged 40-59 years; cancer, osteoarthritis, benign prostatic hyperplasia, cataract, diverticular disease, type 2 diabetes, and deafness in individuals aged 60-79 years; and atrial fibrillation, dementia, acute and chronic kidney disease, heart failure, ischaemic heart disease, anaemia, and osteoporosis in individuals aged 80 years or older. Black or south-Asian individuals were diagnosed earlier than white individuals for 258 (84%) of the 308 conditions. Bone fractures and atopic conditions were recorded earlier in male individuals, whereas female individuals were diagnosed at younger ages with nutritional anaemias, tubulointerstitial nephritis, and urinary disorders.

Interpretation: We have produced the first chronological map of human health with cumulative-incidence and period-prevalence estimates for multiple morbidities in parallel from birth to advanced age. This can guide clinicians, policy makers, and researchers on how to formulate differential diagnoses, allocate resources, and target research priorities on the basis of the knowledge of who gets which diseases when. We have published our phenotyping algorithms on the CALIBER open-access Portal which will facilitate future research by providing a curated list of reusable case definitions.

Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council, Arthritis Research UK, British Heart Foundation, Cancer Research UK, Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Department of Health and Social Care (England), Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), Economic and Social Research Council, Engineering and Physical Sciences Research Council, National Institute for Social Care and Health Research, and The Alan Turing Institute.
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http://dx.doi.org/10.1016/S2589-7500(19)30012-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798263PMC
June 2019

Drug and therapeutics committees as guardians of safe and rational medicines use.

Br J Clin Pharmacol 2020 01 18;86(1):10-12. Epub 2019 Oct 18.

Institute of Clinical Sciences, University of Birmingham, Birmingham, UK.

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http://dx.doi.org/10.1111/bcp.14088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983503PMC
January 2020

Evaluation of cardiovascular risk in a lung cancer screening cohort.

Thorax 2019 12 26;74(12):1140-1146. Epub 2019 Sep 26.

Lungs for Living Research Centre, UCL Respiratory, University College London, London, UK

Introduction: Lung cancer screening (LCS) by low-dose computed tomography (LDCT) offers an opportunity to impact both lung cancer and coronary heart disease mortality through detection of coronary artery calcification (CAC). Here, we explore the value of CAC and cardiovascular disease (CVD) risk assessment in LCS participants in the Lung Screen Uptake Trial (LSUT).

Methods: In this cross-sectional study, current and ex-smokers aged 60-75 were invited to a 'lung health check'. Data collection included a CVD risk assessment enabling estimation of 10 year CVD risk using the QRISK2 score. Participants meeting the required lung cancer risk underwent an ungated, non-contrast LDCT. Descriptive data, bivariate associations and a multivariate analysis of predictors of statin use are presented.

Results: Of 1005 individuals enrolled, 680 were included in the final analysis. 421 (61.9%) had CAC present and in 49 (7.2%), this was heavy. 668 (98%) of participants had a QRISK2≥10% and QRISK2 was positively associated with increasing CAC grade (OR 4.29 (CI 0.93 to 19.88) for QRISK2=10%-20% and 12.29 (CI 2.68 to 56.1) for QRISK2≥20% respectively). Of those who qualified for statin primary prevention (QRISK2≥10%), 56.8% did not report a history of statin use. In the multivariate analysis statin use was associated with age, body mass index and history of hypertension and diabetes.

Conclusions: LCS offers an important opportunity for instituting CVD risk assessment in all LCS participants irrespective of the presence of LDCT-detected CAC. Further studies are needed to determine whether CAC could enhance uptake and adherence to primary preventative strategies.
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http://dx.doi.org/10.1136/thoraxjnl-2018-212812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902068PMC
December 2019

Directly Acting Oral Anticoagulants for the Prevention of Stroke in Atrial Fibrillation in England and Wales: Cost-Effectiveness Model and Value of Information Analysis.

MDM Policy Pract 2019 Jul-Dec;4(2):2381468319866828. Epub 2019 Aug 17.

Bristol Medical School, University of Bristol, Bristol, UK.

Determine the optimal, licensed, first-line anticoagulant for prevention of ischemic stroke in patients with non-valvular atrial fibrillation (AF) in England and Wales from the UK National Health Service (NHS) perspective and estimate value to decision making of further research. We developed a cost-effectiveness model to compare warfarin (international normalized ratio target range 2-3) with directly acting (or non-vitamin K antagonist) oral anticoagulants (DOACs) apixaban 5 mg, dabigatran 150 mg, edoxaban 60 mg, and rivaroxaban 20 mg, over 30 years post treatment initiation. In addition to death, the 17-state Markov model included the events stroke, bleed, myocardial infarction, and intracranial hemorrhage. Input parameters were informed by systematic literature reviews and network meta-analysis. Expected value of perfect information (EVPI) and expected value of partial perfect information (EVPPI) were estimated to provide an upper bound on value of further research. At willingness-to-pay threshold £20,000, all DOACs have positive expected incremental net benefit compared to warfarin, suggesting they are likely cost-effective. Apixaban has highest expected incremental net benefit (£7533), followed by dabigatran (£6365), rivaroxaban (£5279), and edoxaban (£5212). There was considerable uncertainty as to the optimal DOAC, with the probability apixaban has highest net benefit only 60%. Total estimated population EVPI was £17.94 million (17.85 million, 18.03 million), with relative effect between apixaban versus dabigatran making the largest contribution with EVPPI of £7.95 million (7.66 million, 8.24 million). At willingness-to-pay threshold £20,000, all DOACs have higher expected net benefit than warfarin but there is considerable uncertainty between the DOACs. Apixaban had the highest expected net benefit and greatest probability of having highest net benefit, but there is considerable uncertainty between DOACs. A head-to-head apixaban versus dabigatran trial may be of value.
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http://dx.doi.org/10.1177/2381468319866828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699015PMC
August 2019

Eligibility and subsequent burden of cardiovascular disease of four strategies for blood pressure-lowering treatment: a retrospective cohort study.

Lancet 2019 08 25;394(10199):663-671. Epub 2019 Jul 25.

Department of Non-Communicable Diseases Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; Health Data Research UK, London, UK.

Background: Worldwide treatment recommendations for lowering blood pressure continue to be guided predominantly by blood pressure thresholds, despite strong evidence that the benefits of blood pressure reduction are observed in patients across the blood pressure spectrum. In this study, we aimed to investigate the implications of alternative strategies for offering blood pressure treatment, using the UK as an illustrative example.

Methods: We did a retrospective cohort study in primary care patients aged 30-79 years without cardiovascular disease, using data from the UK's Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality. We assessed and compared four different strategies to determine eligibility for treatment: using 2011 UK National Institute for Health and Care Excellence (NICE) guideline, or proposed 2019 NICE guideline, or blood pressure alone (threshold ≥140/90 mm Hg), or predicted 10-year cardiovascular risk alone (QRISK2 score ≥10%). Patients were followed up until the earliest occurrence of a cardiovascular disease diagnosis, death, or end of follow-up period (March 31, 2016). For each strategy, we estimated the proportion of patients eligible for treatment and number of cardiovascular events that could be prevented with treatment. We then estimated eligibility and number of events that would occur during 10 years in the UK general population.

Findings: Between Jan 1, 2011, and March 31, 2016, 1 222 670 patients in the cohort were followed up for a median of 4·3 years (IQR 2·5-5·2). 271 963 (22·2%) patients were eligible for treatment under the 2011 NICE guideline, 327 429 (26·8%) under the proposed 2019 NICE guideline, 481 859 (39·4%) on the basis of a blood pressure threshold of 140/90 mm Hg or higher, and 357 840 (29·3%) on the basis of a QRISK2 threshold of 10% or higher. During follow-up, 32 183 patients were diagnosed with cardiovascular disease (overall rate 7·1 per 1000 person-years, 95% CI 7·0-7·2). Cardiovascular event rates in patients eligible for each strategy were 15·2 per 1000 person-years (95% CI 15·0-15·5) under the 2011 NICE guideline, 14·9 (14·7-15·1) under the proposed 2019 NICE guideline, 11·4 (11·3-11·6) with blood pressure threshold alone, and 16·9 (16·7-17·1) with QRISK2 threshold alone. Scaled to the UK population, we estimated that 233 152 events would be avoided under the 2011 NICE guideline (28 patients needed to treat for 10 years to avoid one event), 270 233 under the 2019 NICE guideline (29 patients), 301 523 using a blood pressure threshold (38 patients), and 322 921 using QRISK2 threshold (27 patients).

Interpretation: A cardiovascular risk-based strategy (QRISK2 ≥10%) could prevent over a third more cardiovascular disease events than the 2011 NICE guideline and a fifth more than the 2019 NICE guideline, with similar efficiency regarding number treated per event avoided.

Funding: National Institute for Health Research.
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http://dx.doi.org/10.1016/S0140-6736(19)31359-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717081PMC
August 2019

24-Hour vs. Spot Urinary Sodium and Potassium Measurements in Adult Hypertensive Patients: A Cohort Validation Study.

Am J Hypertens 2019 09;32(10):983-991

Complex Hypertension Service, UCL Department of Renal Medicine, University College London, London, UK.

Background: Sodium intake is correlated with the development of hypertension. Guyton's principals suggest that the 24-hour urinary sodium excretion reflects sodium ingestion over the same period. 24-hour urine collections are arduous to collect, so many centers use spot urinary measurements instead. We compared spot to matched 24-hour urinary electrolyte measurements.

Methods: We examined 419 hypertensive patients from the UCL Complex Hypertension Clinic. 77 had matched and complete 24-hour and spot urinary and serum biochemistry to examine.We compared the spot and 24-hour urinary; sodium concentration, Na/Cr ratio, FENa, Kawasaki and Tanaka estimated sodium excretion as well as the potassium concentration, K/Cr ratio, Kawasaki and Tanaka potassium excretion.

Results: Our cohort was 58% male and the median age was 41 years. The 24-hour and spot Na concentrations correlated moderately (r = 0.4633, P < 0.0001). The 24-hour and spot Na/creatinine ratios correlated weakly (r = 0.2625, P = 0.0194). The 24-hour and spot FENa results showed a weak negative correlation (r = -0.222, P = ns). The 24-hour sodium excretion and the Kawasaki-derived spot urine sodium excretion correlated moderately (r = 0.3118, P = 0.0052). All Bland-Altman analyses showed poor agreement.The 24-hour and spot potassium concentrations correlated very poorly (r = 0.1158, P = ns). The 24-hour and spot urinary K/creatinine ratios correlated weakly (r = 0.47, P ≤ 0.0001). 24-hour and Kawasaki and Tanaka estimated potassium excretions correlated much better (r = 0.58, P < 0.0001).

Conclusions: Spot urinary measurements of sodium give a very poor understanding of the natriuresis occurring over the same 24-hour period. The Kawasaki and Tanaka estimations of the 24-hour sodium excretion showed a much lower correlation than previously reported.
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http://dx.doi.org/10.1093/ajh/hpz104DOI Listing
September 2019

Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial.

Br J Pharmacol 2019 05 31;176(9):1251-1267. Epub 2019 Mar 31.

Dorset County Hospital NHS Foundation Trust, Dorset, UK.

Background And Purpose: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodelling, and right ventricular failure. In preclinical models, the combination of a PDE5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cGMP signalling, and reverses the structural and haemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH.

Experimental Approach: Twenty-one PAH patients stable on PDE5i therapy were recruited. Acute haemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14-day safety and efficacy evaluation. The primary endpoint in both steps was the maximum change in circulating atrial natriuretic peptide (ANP) concentration (Δ ), with secondary outcomes including pulmonary and systemic haemodynamics plus mechanistic biomarkers.

Key Results: Acute administration of racecadotril (100 mg) resulted in a 79% increase in the plasma ANP concentration and a 106% increase in plasma cGMP levels, with a concomitant 14% fall in pulmonary vascular resistance. Racecadotril (100 mg; t.i.d.) treatment for 14 days resulted in a 19% rise in plasma ANP concentration. Neither acute nor chronic administration of racecadotril resulted in a significant drop in mean arterial BP or any serious adverse effects.

Conclusions And Implications: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger scale prospective trial.
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http://dx.doi.org/10.1111/bph.14621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651846PMC
May 2019

Mendelian randomization study shows no causal relationship between circulating urate levels and Parkinson's disease.

Ann Neurol 2018 08;84(2):191-199

Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.

Objective: Observational studies have shown that increased plasma urate is associated with lower risk of Parkinson's disease (PD), but these studies were not designed to test causality. If a causal relationship exists, then modulating plasma urate levels could be a potential preventive avenue for PD. We used a large two-sample Mendelian randomization (MR) design to assess for a causal relationship between plasma urate and PD risk.

Methods: We used a genetic instrument consisting of 31 independent loci for plasma urate on a case-control genome-wide association study data set, which included 13,708 PD cases and 95,282 controls. Individual effect estimates for each SNP were combined using the inverse-variance weighted (IVW) method. Two additional methods, MR-Egger and a penalized weighted median (PWM)-based approach, were used to assess potential bias attributed to pleiotropy or invalid instruments.

Results: We found no evidence for a causal relationship between urate and PD, with an effect estimate from the IVW method of odds ratio (OR) 1.03 (95% confidence interval [CI], 0.88-1.20) per 1-standard-deviation increase in plasma urate levels. MR Egger and PWM analyses yielded similar estimates (OR, 0.99 [95% CI, 0.83-1.17] and 0.99 [95% CI, 0.86-1.14], respectively).

Interpretation: We did not find evidence for a linear causal protective effect by urate on PD risk. The associations observed in previous observational studies may be, in part, attributed to confounding or reverse causality. In the context of the present findings, strategies to elevate circulating urate levels may not reduce overall PD risk. Ann Neurol 2018;84:191-199.
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http://dx.doi.org/10.1002/ana.25294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481555PMC
August 2018

Resistant Hypertension: Trials and Tribulations.

Hypertension 2018 05 2;71(5):772-780. Epub 2018 Apr 2.

From the Department of Clinical Pharmacology, University College London Hospital NHS Foundation Trust, United Kingdom (M.J.G., R.S., J.M., A.H.); Centre for Molecular Medicine, University College London, United Kingdom (D.J.B.M.); Nephrology, Royal Free London NHS Foundation Trust, United Kingdom (T.R.); Silver Creek Pharmaceuticals, San Francisco, CA (R.B.); Dorset County Hospital, Dorchester, United Kingdom (R.M.); Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (R.M.T.); Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium (J.A.S.); Hadassah-Hebrew University Medical Center, Mount-Scopus, Jerusalem, Israel (M.B.); Department of Nephrology, Galway University Hospitals, Ireland (D.L.); and University Paris Descartes, AP-HP, Hypertension Unit, Hospital European Georges Pompidou, France (M.B.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.10864DOI Listing
May 2018
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