COMPLETED: Medicines optimisation
Principal Investigator: Dr Simon Fraser
Team members: Dr Simon Fraser (Associate Professor of Public Health. School of Primary Care and Population Sciences, Faculty of Medicine, Southampton General Hospital), Professor Chris Edwards (Professor of Rheumatology, Southampton and Associate Director of the NIHR Clinical Research Facility) Dr Chris Holroyd (Consultant Rheumatologist, University Hospital Southampton NHS Foundation Trust), Dr Kinda Ibrahim (Senior Research Fellow, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust), Dr Ravina Barrett (Pharmacist, University of Portsmouth), Dr Clare Howard (Chief Pharmacist, Medicines Optimisation, Wessex AHSN), Dr Mary O’Brien (NHS England, NHS Rightcare), Dr David Culliford (Senior Medical Statistician, Health Sciences, University of Southampton), Professor Paul Roderick (Professor of Public Health, Primary Care and Population Sciences, University of Southampton), Professor James Batchelor (Director Clinical Informatics Research Unit, Faculty of Medicine, University of Southampton), Dr Matthew Stammers (Senior Endoscopy Fellow, University Hospital Southampton and Clinical Informatics Research Fellow at Clinical Informatics Research Unit)
Start: 1 October 2019
Ends: 30 September 2024
Project Partners: University Hospital Southampton NHS Foundation Trust, NHS England (NHS Rightcare), University of Portsmouth, University of Southampton, Academic Health Sciences Network (AHSN) Wessex.
Lay summary
Painful conditions associated with age (such as arthritis) are common in the UK and safe pain relief options for older people are limited. Anti-inflammatory drugs such as ibuprofen are widely used – both bought from the pharmacy and prescribed by doctors, but they have significant risks, such as bleeding from the stomach and kidney damage. Older people and those with certain long-term medical conditions are at higher risk of experiencing bad effects from these drugs.
Another issue concerns people who are taking one of a group of medications call ‘disease-modifying anti-rheumatic drugs’ (DMARDs). These drugs are often used for rheumatoid arthritis and work by slowing its progression, reducing the likelihood of severe joint damage and other related health problems. They are also used for inflammatory bowel diseases, such as Crohn’s disease. Methotrexate is one of the most commonly used DMARD in arthritis and azathioprine is one of the most commonly used in inflammatory bowel disease. Anti-TNF drugs are an important group of so called ‘biological agents’ – another type of DMARD.
DMARDs are powerful drugs that require regular blood tests to check for adverse effects, such as liver problems, and guidelines advise how often these tests should be done. However, for most people, these blood tests are almost never abnormal, and could potentially be safely done less frequently. In addition, some people with inflammatory arthritis have an excellent response to DMARDs. Stopping DMARDs can lead to flare ups of disease, but the amount of therapy used may be tapered successfully to reduce dose-dependent adverse events and costs.
This project involved two studies
The first study showed that non-steroidal anti-inflammatory drugs (NSAIDs) are still sometimes prescribed for high-risk patients, such as older adults and those with chronic kidney disease. NSAIDs can cause acute kidney injury (AKI), leading to serious complications. This study developed a risk tool for practices to identify those who should not be prescribed NSAIDs.
The second explored the frequency of blood testing for patients on Disease-Modifying Anti-Rheumatic Drugs (DMARDs) like methotrexate, commonly used for rheumatoid arthritis. Guidelines recommend 3-monthly blood tests due to potential liver issues. The research found that many tests were seldom abnormal, suggesting that low-risk patients might safely have less frequent tests if further research is done on the safety of risk-stratifying people.
What did we learn?
In the two different parts of the project we found that:
About half of people taking the ‘disease modifying’ drugs (‘DMARDs’) methotrexate for rheumatoid arthritis or azathioprine for inflammatory bowel disease experienced no blood test abnormality over two years despite having to have blood tests every three months. Reducing testing frequency may therefore be safe for younger people and those without other long-term conditions.
Among people taking non-steroidal anti-inflammatory drugs (‘NSAIDs’ like ibuprofen) the risk of kidney damage was highest among older people with combinations of long-term conditions including chronic kidney disease, diabetes, heart disease and heart failure, and high blood pressure. These people should avoid taking NSAIDs and we provided a way for GPs to identify them in their databases.
What difference will this new knowledge make?
DMARDs: Further investigation is needed on the safety and acceptability of reduced blood testing frequency testing for some people taking DMARDs but this could potentially result in reduced unnecessary patient anxiety and burden, fewer referrals to hospital and reduce resource use for the NHS.
If testing could be reduced this would mean reduced treatment burden for patients and reduced cost and admin work for the NHS
NSAIDs: GP practices can be provided with a search tool that helps identify those at highest risk of kidney damage from NSAIDs. Using this information they can review and stop NSAIDs to reduce the risk.
If prescribing was stopped for some people at risk, this would reduce risk of acute kidney injury which can have lasting consequences or even be fatal
What was the impact?
Non-steroidal anti-inflammatory drugs (NSAIDs)
As part of the medicines optimisation project we explored the risks of acute kidney injury (AKI) associated with taking non-steroidal anti-inflammatory drugs like ibuprofen and naproxen. There was a news article here about it:
https://www.arc-wx.nihr.ac.uk/post/southampton-led-study-shows-need-for-painkiller-caution-to-prevent-kidney-damage and a publication here: https://bjgpopen.org/content/6/1/BJGPO.2021.0208
We developed a risk score that can help GP practices identify those patients at highest risk of NSAID-associated kidney injury. We have run this risk tool in the Dorset Intelligence and Insight Service (a database covering over 70 Dorset GP practices - more than 800,000 people) and along with colleagues from the AHSN we are running a masterclass with many of the GP practices involved to present the findings and to promote best practice in NSAID prescribing. The aim is to reduce NSAID prescribing in those at high risk of adverse outcomes like AKI.
Rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) are prevalent inflammatory conditions, affecting 0.8% and 0.7% of the population, respectively. Disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate for RA and azathioprine for IBD, are commonly used to control disease activity. These drugs require regular safety blood-test monitoring for liver function abnormalities, kidney function, and bone marrow toxicity.
Monitoring is frequent at initiation and less frequent once a maintenance dose is established. In the UK, initiation usually occurs in secondary care, with ongoing monitoring in primary care as recommended by NICE. Regular blood-test monitoring has been linked with anxiety and depression for some patients, incurs substantial costs for healthcare providers, and increases the workload for clinicians and laboratory staff. Despite guidelines, the optimal monitoring frequency has not been established, and the extent to which patients experience prolonged periods with no abnormal tests is unclear.
This study aimed to assess the extent of persistently normal blood-test results among people with RA and IBD, and to describe the frequency of blood testing to indicate health-service and patient workload. Targeted monitoring of higher-risk individuals and reduced monitoring for lower-risk patients may improve efficiency and reduce patient workload.
Our large, 2-year retrospective cohort study (over 700,000 people) assessed persistently normal blood tests among people with rheumatoid arthritis (RA) taking methotrexate and those with inflammatory bowel disease (IBD) taking azathioprine. Approximately half of the patients experienced no blood-test abnormalities using NICE-recommended tests. In the RA/methotrexate cohort, abnormalities were more common in older people with reduced renal function.
For the IBD/azathioprine cohort, abnormalities were less common and mainly involved reduced renal function in older people with comorbidities. The absolute risk of persistently normal blood tests was lowest among older people and those with comorbidities.
Since the study, a piece of work led by Nottingham cited our work (https://www.bmj.com/content/381/bmj-2022-074678) and created a model to risk stratify patients taking methotrexate. This is quite likely to change clinical practice when NICE reviews its guidance on DMARDs in due course.
This work was supported by representatives of the ‘Getting It Right First Time’ programme, who also linked this issue to sustainability:
‘Saving the planet with reduced routine DMARD blood monitoring frequency BMJ 2023; 382 doi: https://doi.org/10.1136/bmj.p1645’
