Impact case study database

Colorectal cancer is the second commonest cause of cancer death in both sexes, killing ~1,600 people in Scotland each year. The Scottish Bowel Screening Programme, of which Steele has been Clinical Director since its implementation, started in 2007; between 2008 and 2018 colorectal cancer mortality in Scotland fell by 8%. By October 2018 ~6,000 colorectal cancers had been diagnosed through screening [E1].

Steele is the Independent Chair of the UK National Screening Committee (UKNSC), which advises UK  ministers and the NHS on population screening. In this role “he has been particularly helpful in navigating the policy positions in bowel screening… and facilitated an excellent and evidence-based outcome.” [E2].

The Scottish Bowel Screening Programme has been exemplary for similar programmes in other countries. The European Guidelines for Quality Assurance in Colorectal Cancer Screening and the International Agency for Research on Cancer (IARC) Handbook of Colorectal Cancer Screening [E3], to both of which Steele made major contributions, drew heavily on experience gained in Scotland and the rest of the UK. Steele’s evidence contributed to the IARC conclusion “There is sufficient evidence that biennial screening with the faecal immunochemical test (FIT) reduces colorectal cancer mortality. …[and]… that the benefits of biennial screening with FIT outweigh the harms when the screening programme can be delivered with high quality.” [E3, p298]. This evidence has been used to support use of the FIT in colorectal cancer screening programmes across the world.

Introduction of the FIT in Scotland and the UK

From 2007-2017 the FIT was used to follow up weak positive faecal occult blood test results in Scotland, Wales and Northern Ireland. In January 2016 the UKNSC recommended quantitative FIT as the primary method for colorectal cancer screening nationwide. The Scottish Bowel Screening Programme made this change in November 2017 [E4]; by the end of 2020 England, Wales and Northern Ireland had also adopted the FIT for their national bowel cancer screening programmes [E5].

Uptake of screening invitations increased by ~10% in the year following introduction of quantitative FIT screening in Scotland. This was associated with a 64.8% increase in the detection rate for adenomas (1.02% vs 0.62% of the screening population with an adenoma) and a small increase in the detection rate for carcinomas (0.12% vs 0.11% of the screening population with a carcinoma) [E1].

Contribution of the FIT to diagnosis in symptomatic patients

The presenting symptoms of colorectal cancer resemble those of numerous benign, self-limiting conditions. The challenge, therefore, is to achieve early diagnosis of neoplasia against this background of non-cancerous disease, thus avoiding unnecessary investigation which can cause trauma and discomfort to patients, is a drain on resources and puts pressure on service providers.

Demand on colonoscopy services has recently increased enormously, driven by increasing awareness of these symptoms and waiting time targets. This has not, however, translated into improved early detection. Non-endoscopic methods which can identify all, but only, those patients who require full investigation are therefore essential. Steele’s group has demonstrated that quantitative FIT can be used to rule out colorectal neoplasia in symptomatic patients. This concept was incorporated into NICE guidelines in 2017 [E6].

Research on this use of quantitative FIT demonstrated, over the first year of its implementation in NHS Tayside, a 20% reduction in colonoscopy referrals without appreciable failure to detect neoplasia. The quantitative FIT was added to the diagnostic process for symptomatic individuals across Scotland in July 2020 [E7]; this has been particularly valuable in reducing the need for face-to-face appointments during the COVID-19 pandemic.

Moving away from flexible sigmoidoscopy for colorectal cancer screening

Flexible sigmoidoscopy is an effective screening method for colorectal neoplasia. In England it used to be offered at age 55 before the faecal occult blood test (now replaced by the FIT) was offered at 60; however, significant uptake, delivery and quality issues were experienced. The benefits of population-based endoscopic screening were therefore questioned, especially given that the UKNSC now recommends FIT screening from age 50 (i.e. including the age at which endoscopy is offered) [E8]. A randomized trial by Steele’s group demonstrated that the benefits of flexible sigmoidoscopy as an adjunct to faecal occult blood test screening did not justify its introduction into the Scottish Bowel Screening Programme [E9]. Flexible sigmoidoscopy was not, therefore, adopted for screening in Scotland and in July 2020 the UKNSC recommended the permanent discontinuation of endoscopic screening in England [E10].

In summary, Steele and his team have driven improvements in colorectal cancer screening in Scotland and across the UK. They championed the FIT, which is easier to use and more sensitive than the faecal occult blood test, enabling signs of colorectal cancer to be detected earlier, saving more lives. They have also provided evidence against the need for endoscopy in screening and early diagnosis; as well as avoiding the need for an intrusive and often uninformative procedure, this could ”save the NHS millions, as each colonoscopy costs the NHS £372 compared to about £5 for the FIT test” (2017 figures) [E11].

The iLFT approach provides a rapid, reliable means of identifying abnormal LFTs which require specialist follow-up, thus improving patient outcomes through timely intervention and NHS infrastructure through the exploitation and adaptation of existing clinical tools and processes. By identifying the highest priority patients it facilitates workload management in hepatology specialist services and builds the confidence of GPs in handling a previously complex and unwieldy diagnostic pathway. This has contributed to better diagnosis of liver disease, often at an early stage when lifestyle interventions are effective, with minimal workload implications for GPs and inconvenience to patients.

Benefits to patients and population health

In August 2018, NHS Tayside adopted iLFT as standard care accessible to all its GP practices. During its first year, iLFT generated >2000 diagnoses from 1824 samples with an abnormality in their initial LFTs [E1]. Compared with current real-world practice it did not increase overall GP workload; indeed, 21/23 GPs involved in the trial felt that iLFT reduced their workload. Since July 2020, NHS Tayside has performed Enhanced Liver Fibrosis testing, a further refinement of iLFT, on >500 patients; of these, 44% had a score which showed they could safely be managed in the community, thus reducing pressure on in-patient services [E2].

By testing all samples for viral hepatitis, iLFT made it possible to identify unsuspected carriers of hepatitis C and target them for treatment, preventing wider community transmission and contributing to the elimination of hepatitis C in Tayside by the end of 2019. Having become the first region in the world to effectively eradicate the virus, Tayside has already met the WHO target of eliminating hepatitis C as a public health threat by 2030 [E3].

National adoption in Scotland and the wider UK

Following the success of iLFT in Tayside the Scottish Access Collaborative (part of the Scottish Government’s Directorate for Health Performance and Delivery) recommended national roll-out [E4]. Implementation groups have been established in NHS Greater Glasgow and Clyde, Fife, Lothian and Lanarkshire; when roll-out is complete the service will be available to 1.6 million people. The Clinical Lead for the introduction of iLFTs in the Modern Patient Pathways Programme writes [E5]:

The introduction of iLFTs in Tayside resulted in the correct patients being seen by the correct staff, in the correct setting, at the correct time……The Scottish Government has adopted this as being an area where there is not only the potential for better patient management but also for significant financial benefit to the NHS.

The Lancet Commission for Liver Disease has recommended iLFT for implementation to reduce the burden of liver disease [E6] and it is now being adopted across the UK. North Cumbria Integrated Care NHS Foundation was the first to have a working system [E7] and iLFT is under consideration by the Wales Liver Disease Delivery Plan [E8].

Global recognition

In 2019 the Dillon team’s achievements in integrated clinical care were rewarded with the UNIVANTS Healthcare Excellence Award; this award recognises teams who collaborate across disciplines to transform healthcare delivery and patient lives, and involves a rigorous selection process conducted by seven leading international healthcare organizations including The International Federation of Clinical Chemistry and Laboratory Medicine [E9]. The iFLT has also won accolades for innovation from the British Society of Gastroenterology and the Royal Colleges of Physicians and Pathologists.

Benefit to GPs

One reason for the low follow-up rate for abnormal LFTs is that many GPs lack confidence in interpreting these findings and using them to inform referral decisions, partly because of the lack of a quantitative relationship between abnormal LFT findings and severity of disease: very high serum enzyme levels may resolve spontaneously whereas lower levels often persist and can lead to chronic liver disease. Referring everybody with an abnormal LFT is unnecessary and would overwhelm specialist hepatology services; by providing a rapid and reliable triage process, iLFT ensures that only those individuals requiring specialist services are referred.

Following roll-out of iLFT in Tayside, Dillon surveyed the views of 100 GPs, over a third of the workforce [E10]. The opinions expressed were overwhelmingly positive (Table 1).

Table 1: Outcomes of a survey of GP opinion on iLFT

The features most liked by respondents were the automatic calculation of fibrosis scores and information around referral criteria (80 respondents) and the reduction in number of consultations required before arriving at a diagnosis (77 respondents).

The benefits of iLFT to healthcare providers are succinctly summarized by North Cumbria Integrated Care NHS Foundation Trust [E7]:

The journey to date has been truly transformational, empowering primary care to have the confidence in managing low risk liver disease, expediting care for those with significant liver disease who truly need secondary care input and undoubtedly shortening the timescales in the assessment and management of liver disease across the health economy.

Before 2013 the risks of long-term consumption of sodium-containing effervescent, soluble and dispersible medications had not been characterised and manufacturers were not required to highlight the sodium content of prescription or over-the-counter medications. George’s work [R2] therefore highlighted an important but overlooked source of ingested sodium. Subsequently, information campaigns, regulatory action and lobbying ensured proper labelling of sodium-containing formulations to help prescribing professionals and consumers of over-the-counter products make informed decisions when choosing which products to use.

Changes in prescribing as a direct result of George’s work

Analysis of prescribing trends using The Health Improvement Network (THIN) and Prescription Cost Analysis databases indicated that George’s publication [R2] influenced prescribing practices for sodium-containing medications in the UK [E1]. Interrupted time series analysis of THIN data showed that the monthly prescribing rate of sodium-containing formulations was stable between 2009 and 2013; however, following publication of [ R2] the slope reduced significantly by 0.26 per month (95% confidence interval -0.45 to -0.07; p=0.009). The slope for non-sodium standard formulations did not change.

Regulatory and labelling changes

George’s work triggered action on salt in effervescent medications at both UK and EU level; according to the Director of Vigilance and Risk Management of Medicines, MHRA [E2]:

The paper was evaluated and discussed at several of the Agency’s Commission on Human Medicines (CHM) Expert Advisory Groups (EAGs) in 2013/2014…There was agreement that the labelling of sodium in product information at the time of the paper, did not provide meaningful information to guide clinicians, pharmacists or patients and help them choose appropriate medicines in terms of sodium content.

All Expert Groups advised that the high levels of sodium in some medicines, particularly those that dissolve, should be highlighted in the product information of all medicines containing different levels of total sodium.

The UK presented the issue and its expert advice to several European bodies in 2014/2015 including the Pharmacovigilance Risk Assessment Committee (PRAC), the Excipients Drafting Group (ExcpDG), the European Medicines Agency’s Paediatric Committee (EMA’s PDCO) and the Co-ordination Group for Mutual Recognition and Decentralised Procedures (CMDh).

George’s results were also highlighted in a report presented to the UK Parliament in 2015 by the Commission on Human Medicines and the British Pharmacopoeia Commission [E3].

Responding to George’s findings, the EMA commissioned a Europe-wide signal detection programme to assess the impact of sodium-containing medications on cardiovascular health. In 2015 the PRAC published new guidance for sodium labelling and recommended an update to the EMA Excipient Guidelines [E4, E5].

In October 2017 the European Commission updated its Excipient Guideline to require all Marketing Authorisation Holders to submit Variation Documentation within 12 months. The labelling of medicines manufactured, sold or consumed in Europe now features warnings about the effects of sodium loading with prolonged use. For medications exceeding 17 mmol/tablet the Summary of Product Characteristics and Patient Information Leaflet must both state how much sodium they contain.

Impacts on professionals – doctors, prescribers, pharmacists and dispensers

George’s work and the consequent change in labelling regulations have triggered changes in prescribing advice which have been promulgated internationally via websites aimed at prescribing professionals (e.g. [ **E6]**) and influenced recent updates to NICE Guidance; for example, the August 2020 update to NICE guidance on “Analgesia - mild-to-moderate pain” [E7] contains a scenario on paracetamol which advises:

Avoid effervescent preparations of paracetamol where possible, particularly in people with hypertension, heart failure, and renal failure — if oral paracetamol is required in a person with swallowing difficulty, use paracetamol suspension in place of effervescent preparations (which contains up to 6 g salt in a 4 g per 24 hours dose).

[text removed for publication]

Impacts on consumers/patients

Educating clinicians about the risks of consuming high-salt containing medications helps to protect patients receiving them by prescription; however, many over-the-counter effervescent medications also contain high salt concentrations. Package labelling and inserts must now provide consumers of over-the-counter products with the information they need in order to make an informed decision about their use (e.g. **[E9]**).

Influence on the wider debate on dietary sodium intake

In 2014 George was invited to join Consensus Action on Salt and Health (CASH, now called Action on Salt **[E10]**). This group of 25 internationally recognised scientific experts has persuaded the Department of Health (England) to mandate a further 10% reduction in salt thresholds from its 2012 targets with the aim of saving 6000 lives each year.

The Director of Vigilance and Risk Management of Medicines at the MHRA confirms that George’s study “raised an important potential public health issue” [E2]. European Medicines Labelling Legislation changed as a result, thus reducing the prescribing of potentially harmful high-sodium medications, ensuring the provision of better information to consumers of over-the-counter medications and contributing to efforts to reduce dietary sodium intake worldwide.

Bronchiectasis is described by the President of the European Respiratory Society (2018-19) as a “neglected disease with a high morbidity and mortality” [E1]. Historically, poor awareness of the condition and a lack of research meant there was uncertainty about the underlying causes of bronchiectasis and the effectiveness of treatments, further compounded by poorly developed services.

Chalmers’ work has provided much-needed evidence for the investigation and management of bronchiectasis, shifting the clinical approach from reactive symptom control to proactive management based on an understanding of disease aetiology. His work has informed the first international guidelines for the management of bronchiectasis, raised global awareness of the disease and supported the establishment of a patient registry and patient-focussed approaches.

Development of international guidelines

Prior to 2017 there were no international treatment guidelines for bronchiectasis; management of the condition focused primarily on alleviating symptoms. Chalmers (with co-chair Polverino) directed the development of the 2017 European Respiratory Society (ERS) guidelines [E2]. The guidelines draw on Chalmers’ work, prioritising the prevention of exacerbations using mucoactive medications and antibiotics [R2]. According to the President of the ERS, the guidelines:

have been instrumental, as the first international guidelines published for this condition, in driving improvements in care including increased use of diagnostic testing [E1].

Following publication of the ERS guidelines, adoption of evidence-based interventions has increased. A comparison of three-year periods immediately before and after September 2017 reveals, among patients in the registry, increases in appropriate diagnostic testing from 44.7% to 51.8% (p<0.0001), airway clearance use from 47.0% to 57.4% (p<0.0001) and use of prophylactic antibiotic treatment from 28.6% to 32.2% (p=0.009) [E3].

Chalmers was also part of the British Thoracic Society Bronchiectasis in Adults Guideline Development Group [E4]. The resulting (2019) guideline recommends use of the BSI [R2] at baseline/diagnosis in all patients for evaluation and to support treatment planning.

Improving disease management and raising awareness worldwide

The impact of the research is evident beyond Europe. EMBARC (co-chaired by Chalmers) has driven improvements to bronchiectasis services across Europe as well as in Israel and India [E5].

In 2014, EMBARC partnered with the Respiratory Research Network of India to establish the Indian Bronchiectasis Registry. The Registry operates across 31 centres in India; it was the first prospective multicentre bronchiectasis registry established in a lower middle-income country [E6] and according to the Chair of the Respiratory Research Network of India, “by far the largest study into this orphan disease in an Asian country” [E7].

The research identified key differences with European studies including a distinct aetiology (the commonest underlying cause was tuberculosis) and characterisation (typified by early onset, extensive lung damage and severe symptomatology). The findings enabled physicians to identify how management of the condition could be improved, leading to an increased use of diagnostic testing for bronchiectasis patients and improved guideline adherence [E7]. Additionally the registry provided evidence of the underutilisation of macrolide antibiotics for frequently exacerbating patients, thus informing the development of evidence-based consensus recommendations aimed at increasing the use of macrolide antibiotics in bronchiectasis and other respiratory conditions (submitted January 2019, accepted September 2020; final publication March 2021 was delayed due to COVID) [E8].

The work of EMBARC is credited with raising awareness of the condition worldwide, leading to greater public and professional awareness of the disease and ensuring that the disease is now firmly established as a regular core topic at major international meetings [E1] [E7]:

Prior to 2015 there were no specific European meetings on bronchiectasis and the topic was rarely discussed at international society events… Bronchiectasis has now become a core topic, addressed at all international meetings such as the ERS and the American Thoracic Society annual meetings… [E1]

Promoting evidence-based interventions

Until recently, no licensed therapies for bronchiectasis were available and clinical trial findings were inconsistent, possibly because specific treatment-responsive endotypes of bronchiectasis had not yet been identified [E5]. The BSI [R2] is now used to characterise patients for randomised clinical trials and has been used in 12 clinical trials between its publication in March 2014 and the end of 2020. It was, for example, used in a 24-week Phase 2 trial led by Chalmers which tested the effectiveness of Brensocatib, a selective, orally active inhibitor of dipeptidyl peptidase I. This enzyme activates elastase during neutrophil maturation [E9]. The overall risk of exacerbation during the treatment period was 40% less than with placebo, demonstrating the benefits of an evidence-based approach to treatment. Brensocatib entered Phase 3 trials in December 2020, led by Chalmers (NCT04594369).

Championing a patient-focussed approach

Before the establishment of EMBARC, there was no formal patient organisation, charity or advocacy group for bronchiectasis. From the outset, EMBARC has been patient-focussed and, where appropriate, patient-led.

The EMBARC Roadmap Study Group including Chalmers and four “expert patients” set out to identify the challenges faced by bronchiectasis patients, their families and friends. A questionnaire asking what changes would most improve quality of life for people with bronchiectasis was published online in 12 languages, eliciting 1086 responses from 22 countries. The results were used to set priorities and develop an EMBARC consensus statement [E10].

Three members of the Patient Advisory Group established as a result of these efforts participated in the EMBARC steering group and were full members of the 2017 Guidelines Task Force [E11], the first-time patients had played such a role “….the patients’ perspective often differed from those of guideline panellists….[they]….made an important contribution in modifying the ultimate guideline recommendations” [E11].

Patients also led the development of the comprehensive “Patient Priorities: Bronchiectasis” online resources. The website holds a range of resources including factsheets in 21 languages, alongside videos and lay summaries of guidelines in multiple languages to support patients to understand and self-manage their bronchiectasis [E12]. In summary, according to the President of the European Respiratory Society 2018-19 [E1]:

There is no doubt that EMBARC and the collaborative European research that Professor Chalmers has led has been a major contributor.…It is no exaggeration to say that this research has transformed this previously neglected disease and is improving the lives of patients worldwide.

Lang’s work has influenced guideline development and changed prescribing practice in both aortic stenosis and Type II diabetics with heart failure. His analysis of EHRs has been cited in professional body guidelines and scientific statements, leading to changes in prescribing practice. It also provided support for post-hoc analysis of clinical trials which identified potential benefits of RAS inhibitors in reducing hospital readmissions (thus benefitting patients and relieving pressure on health services) and mortality following transcatheter aortic valve implantation (TAVI) for aortic stenosis; this contributed to the design of the first study to prospectively explore the impact of RAS modulation in ventricular remodelling following TAVI.

Changing guidelines and practice and widening treatment options in Aortic Stenosis

By demonstrating that the use of RAS blockers in aortic stenosis is both safe and effective [R1], Lang influenced the development of American College of Cardiology (ACC) and American Heart Association (AHA) guidelines for the management of valvular heart disease; R1 is one of three studies cited in the 2014 Guidelines [E1] as underpinning evidence for the use of RAS blockers as anti-hypertensives in patients with aortic stenosis (Class 1, Level of Evidence: B). It also contributed to the development of advice on target blood pressure in aortic stenosis patients [E2]. The Guidelines Writing Committee Co-Chair writes [E3]:

… the evidence provided by Professor Lang’s research was used to support the recommendations for management of adults with aortic stenosis in both the 2014 and 2020 American College of Cardiology/American Heart Association Valvular Heart Disease Clinical Practice Guidelines.

R1 has also been cited in support of post-hoc analyses of large randomised controlled trials (e.g. PARTNER-2) [E4] and nationwide registry data [E5] investigating the benefit of RAS blockade in aortic stenosis patients undergoing TAVI. In both scenarios, treatment with RAS blockers was associated with reduced mortality 1-3 years post-procedure. In the case of treatment at discharge there was also a reduction in readmission to hospital due to heart failure [E5]. This secondary analysis contributed to the latest ACC/AHA guidelines on the use of RAS in TAVI, which state that “In patients who have undergone TAVI, RAS blockers may be considered to reduce the long-term risk of all-cause mortality” [E2]. R1 also helped to underpin the RASTAVI trial (NCT03201185) [E6], a randomised open label study examining the impact of RAS blockers on clinical outcomes and ventricular remodelling after TAVI. This work has directly influenced clinical practice guidelines on the treatment of hypertension in patients with aortic stenosis and indirectly contributed to the provision of additional medication options for aortic stenosis patients undergoing TAVI.

Changing guidelines and practice and widening treatment options in Type II diabetes with concomitant heart failure

In 2016, the FDA lifted its warning on the use of metformin in certain patients with reduced kidney function, acknowledging Lang’s evidence [R3] that metformin could safely be used in clinical practice outwith the then-current labelling indications [E7]. Prescribing practice has also changed in the UK: the BNF now advocates ‘caution’ when using metformin in patients with chronic stable heart failure rather than listing heart failure as a contraindication for metformin.

At around the same time the AHA issued a Scientific Consensus Statement [E8] which recognised Lang’s work demonstrating the safe use of metformin to achieve glycaemic control in patients suffering from Type II diabetes with concomitant heart failure. In 2019 the AHA and the Heart Failure Society of America (HFSA) issued a joint Scientific Statement [E9] identifying metformin as a treatment option in this group. This noted Lang’s evidence that metformin has a more acceptable safety profile than sulphonylureas and meant that patients with Type II diabetes and heart failure could be given metformin, which had previously been contraindicated in this group, thus changing clinical practice guidelines and widening treatment options.

Metformin can therefore be used to help achieve glycaemic control and HbA_1c targets as recommended by contemporary clinical practice guidelines. The underpinning evidence of Lang’s team [R5] and others has influenced the development of advice on glycaemic control in patients with Type II diabetes and heart failure [E9]; the Co-Chair of Authors of the 2019 AHA/HFSA Scientific Statement writes [E10]:

… the Dundee group’s research on metformin use has also been impactful… showing that metformin is safe and may be beneficial in patients with HF. In the 2019 Scientific Statement, we considered use of metformin in patients with DM at risk of or with established HF to be reasonable.

Based on the above, I recognize the influence of Professor Lang’s group in guiding doctors on how to treat patients with DM and HF and wholeheartedly support his research agenda.

The Co-Chairs of Authors of the AHA/HFSA Scientific Statement [E9] and the ACC/AHA Valve Disease Guidelines [E2] both confirm Lang’s work influence on approaches to treatment across the world; indeed, the latter states [E3]:

Professor Lang’s research on RAS blockers in aortic valvular heart disease is a major therapeutic advance that has significant clinical impact and provides the foundation for evidence-based guidelines.