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

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

How to assess pharmacogenomic tests for implementation in the NHS in England

AIMS: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost-effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England. METHODS: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests. RESULTS: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10-point checklist that is proposed as a tool to aid evidence-based implementation of pharmacogenomic testing into routine clinical care within the NHS. CONCLUSION: Our 10-point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence-based framework for adoption. Such an approach could also be applied to other health systems

Complex disease genetics: present and future translational applications

A report on the British Atherosclerosis Society autumn meeting 'Genetics of Complex Diseases', Cambridge, UK, 17-18 September 2009

Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank

Background: Most people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention. Objective: To evaluate the performance of two-stage adult population screening for FH. Design: Using data from UK Biobank, we estimated the screening performance of different low-density lipoprotein cholesterol (LDL-C) cut-offs (stage 1) to select adults for DNA sequencing (stage 2) to identify individuals with FH-causing variants inLDLR, APOB, PCSK9andAPOE. We estimated the number of additional FH cases detected by cascade testing of first-degree relatives of index cases and compared the overall approach with screening in childhood. Setting: UK Biobank. Participants: 140 439 unrelated participants of European ancestry from UK Biobank with information on circulating LDL-C concentration and exome sequence. Main outcome measures: For different LDL-C cut-offs, we estimated the detection and false-positive rate, the proportion of individuals who would be referred for DNA sequencing (stage 1 screen positive rate), and the number of FH cases identified by population screening followed by cascade testing. Results: We identified 488 individuals with an FH-causing variant and 139 951 without (prevalence 1 in 288). An LDL-C cut-off of >4.8 mmol/L had a stage 1 detection rate (sensitivity) of 40% (95% CI 36 to 44%) for a false-positive rate of 10% (95% CI 10 to 11%). Detection rate increased at lower LDL-C cut-offs but at the expense of higher false-positive and screen positive rates, and vice versa. Two-stage screening of 100 000 adults using an LDL-C cut-off of 4.8 mmol/L would generate 10 398 stage 1 screen positives for sequencing, detect 138 FH cases and miss 209. Up to 207 additional cases could be detected throughtwo-generationcascade testing of first-degree relatives. By comparison, based on previously published data, childhood screening followed by cascade testing was estimated to detect nearly three times as many affected individuals for around half the sequencing burden. Conclusions: Two-stage adult population screening for FH could help achieve the 25% FH case detection target set in the National Health Service Long Term Plan, but less efficiently than childhood screening and with a greater sequencing requirement

Pharmacogenomic alerts: Developing guidance for use by healthcare professionals.

Funder: NHS England; Id: http://dx.doi.org/10.13039/100013963Funder: NIHR UCLH Biomedical Centre; Id: http://dx.doi.org/10.13039/501100012317AIMS: For diseases with a genetic cause, genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age, it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines. METHODS: The Professional Record Standards Body commissioned by NHS England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach. RESULTS: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices. CONCLUSION: Ensuring pharmacogenetics information is available to make safer use of medicines will require a major effort, of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and at the right times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing

Antipsychotic drug prescribing and mortality in people with dementia before and during the COVID-19 pandemic:a retrospective cohort study in Wales, UK

BackgroundConcerns have been raised that antipsychotic drug prescribing, which has been associated with increased mortality in people with dementia, might have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of SARS-CoV-2. We used multisource, routinely collected health-care data from Wales, UK to investigate prescribing and mortality variations in people with dementia before and during the COVID-19 pandemic.MethodsIn this retrospective cohort study, we used individual-level, anonymised, population-scale linked health data to identify adults aged 60 years and older with a diagnosis of dementia in Wales, UK. We used the CVD-COVID-UK initiative to access Welsh routinely collected electronic health record data from the Secure Anonymised Information Linkage (SAIL) Databank. Patients who were alive and registered with a SAIL general practice on Jan 1, 2016, and who received a dementia diagnosis before the age of 60 years and before or during the study period were included. We explored antipsychotic drug prescribing rate changes over 67 months, between Jan 1, 2016, and Aug 1, 2021, overall and stratified by age and dementia subtype. We used time-series analyses to examine all-cause and myocardial infarction and stroke mortality over the study period and identified the leading causes of death in people with dementia between Jan 1, 2020, and Aug 1, 2021.FindingsOf 3 106 690 participants in SAIL between Jan 1, 2016 and Aug 1, 2021, 57 396 people (35 148 [61·2%] women and 22 248 [38·8%] men) met inclusion criteria for this study and contributed 101 428 person-years of follow-up. Of the 57 396 people with dementia, 11 929 (20·8%) were prescribed an antipsychotic drug at any point during follow-up. Accounting for seasonality, antipsychotic drug prescribing increased during the second half of 2019 and throughout 2020. However, the absolute difference in prescribing rates was small, ranging from 1253 prescriptions per 10 000 person-months in March, 2019, to 1305 per 10 000 person-months in September, 2020. All-cause mortality and stroke mortality increased throughout 2020, while myocardial infarction mortality declined. From Jan 1, 2020, to Aug 1, 2021, 1286 (17·1%) of 7508 participants who died had COVID-19 recorded as the underlying cause of death.InterpretationDuring the COVID-19 pandemic, antipsychotic drug prescribing in people with dementia in the UK increased slightly; however, it is unlikely that this was solely related to the pandemic and this increase was unlikely to be a major factor in the substantial increase in mortality during 2020. The long-term increase in antipsychotic drug prescribing in younger people and in those with Alzheimer's disease warrants further investigation using resources with access to more granular clinical data. Although deprescribing antipsychotic medications remains an essential aspect of dementia care, the results of this study suggest that changes in prescribing and deprescribing practices as a result of the COVID-19 pandemic are not required.FundingBritish Heart Foundation (via the British Heart Foundation Data Science Centre led by Health Data Research UK), and the Scottish Neurological Research Fund

Performance of polygenic risk scores in screening, prediction, and risk stratification: secondary analysis of data in the Polygenic Score Catalog

OBJECTIVE: To clarify the performance of polygenic risk scores in population screening, individual risk prediction, and population risk stratification. DESIGN: Secondary analysis of data in the Polygenic Score Catalog. SETTING: Polygenic Score Catalog, April 2022. Secondary analysis of 3915 performance metric estimates for 926 polygenic risk scores for 310 diseases to generate estimates of performance in population screening, individual risk, and population risk stratification. PARTICIPANTS: Individuals contributing to the published studies in the Polygenic Score Catalog. MAIN OUTCOME MEASURES: Detection rate for a 5% false positive rate (DR5) and the population odds of becoming affected given a positive result; individual odds of becoming affected for a person with a particular polygenic score; and odds of becoming affected for groups of individuals in different portions of a polygenic risk score distribution. Coronary artery disease and breast cancer were used as illustrative examples. RESULTS: For performance in population screening, median DR5 for all polygenic risk scores and all diseases studied was 11% (interquartile range 8-18%). Median DR5 was 12% (9-19%) for polygenic risk scores for coronary artery disease and 10% (9-12%) for breast cancer. The population odds of becoming affected given a positive results were 1:8 for coronary artery disease and 1:21 for breast cancer, with background 10 year odds of 1:19 and 1:41, respectively, which are typical for these diseases at age 50. For individual risk prediction, the corresponding 10 year odds of becoming affected for individuals aged 50 with a polygenic risk score at the 2.5th, 25th, 75th, and 97.5th centiles were 1:54, 1:29, 1:15, and 1:8 for coronary artery disease and 1:91, 1:56, 1:34, and 1:21 for breast cancer. In terms of population risk stratification, at age 50, the risk of coronary artery disease was divided into five groups, with 10 year odds of 1:41 and 1:11 for the lowest and highest quintile groups, respectively. The 10 year odds was 1:7 for the upper 2.5% of the polygenic risk score distribution for coronary artery disease, a group that contributed 7% of cases. The corresponding estimates for breast cancer were 1:72 and 1:26 for the lowest and highest quintile groups, and 1:19 for the upper 2.5% of the distribution, which contributed 6% of cases. CONCLUSION: Polygenic risk scores performed poorly in population screening, individual risk prediction, and population risk stratification. Strong claims about the effect of polygenic risk scores on healthcare seem to be disproportionate to their performance

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

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

Authors’ Response to Peer Reviews of “Why We Are Losing the War Against COVID-19 on the Data Front and How to Reverse the Situation”

No abstract available - Author's response