Problem

Harmful or fatal errors related to accidental overdose of methotrexate tablets are well documented.1–3 In England, the coprescription of 2.5 mg and 10 mg methotrexate tablets is not recommended, because both tablets look similar, and may be confused with each other, leading to a potential overdose of methotrexate.1 4 A recent retrospective cohort study identified that while 97% of patients in England were prescribed only 2.5 mg methotrexate tablets, the prescribing of 10 mg tablets or combinations of 2.5 mg and 10 mg tablets was still common practice in a small number of geographical areas across the country.5

The aim of this quality improvement (QI) project was to reduce national variation in the prescription and supply of oral methotrexate 10 mg tablets, for non-cancer treatment, by November 2021.

Background

With more than 1.7 million items issued in England during 2020/2021,6 methotrexate is a commonly prescribed medicine for rheumatoid arthritis, Crohn’s disease, severe psoriasis and some cancers. It is also a high-risk drug, with the combination of a narrow therapeutic index and an unusual weekly dosing regimen predisposing patients to an increased risk of harm from accidental overdose. In 2004, the National Patient Safety Agency (NPSA) issued a national safety alert after 25 patients died and 26 were seriously harmed following accidental overdose of methotrexate tablets during a 10-year period.1 Further cases of accidental overdose prompted a further national safety alert,2 the inclusion of overdose of methotrexate for non-cancer treatment as a national never event7 and more recently updated regulatory measures.8

A range of strategies are in place in England to reduce the risk of accidental overdose that include targeting the manufacture, prescribing and dispensing of methotrexate tablets. When the coprescription of methotrexate 2.5 mg and 10 mg tablets is considered, the British National Formulary states4:

To avoid error with low-dose methotrexate, it is recommended that only one strength of methotrexate tablet (usually 2.5mg) is prescribed and dispensed.

Beyond this and other national prescribing guidance,9 there are no nationally led interventions to reduce the prescribing of 10 mg tablets or combinations of 2.5 mg and 10 mg tablets. Instead, a series of independent local safety initiatives10–13 shared care guidelines dissuading methotrexate 10 mg tablet prescribing14–17 and standard operating procedures18 are in place across some areas of England.

MacKenna et al 5 highlighted the prescribing of both 2.5 mg and 10 mg tablets was common practice with 1689 out of 7349 General Practitioner Surgeries breaching national guidance. Substantial geographical variation existed, with a small number of clinical commissioning groups (CCGs) responsible for high levels of coprescription.

Design

Centrally led five-stage QI intervention focused on providing coaching support to a cohort of high prescribing ICSs in England to reduce variation in methotrexate 10 mg prescribing. This work was led by the English Medication Safety Improvement Programme (MedSIP) team, a team of three pharmacists with training in QI methodology, based at National Health Service (NHS) England.

During the intervention, local oversight of methotrexate prescribing was undertaken by 42 integrated care systems (ICS) each covering an average population size of 1.2 million people. Previously known as Sustainability and Transformation Partnerships (STPs), each ICS was composed of between 2 and 3 CCGs, responsible for commissioning most of the hospital and community NHS services in their local areas. Within each ICS, local prescribing support teams were in place, and the MedSIP team supported these teams during the QI intervention.

The intervention was designed to align with the improvement approach, with five consecutive stages moving from understanding the problem, to testing and implementing change, to focusing on quality control and learning lessons. The five stages are sequentially reported in the strategy and measurement section, including how ICS staff were engaged and supported at each of these points.

Patients and the public were not involved in the design of this QI intervention. This was because the prescription of 2.5 mg methotrexate tablets for non-cancer treatment was already standard national practice, with 98.5% of patients during the time of the QI intervention using only 2.5 mg tablets. Patient engagement instead took place on a patient/clinician basis through clinical consultations with collective feedback collected by participating ICSs. This feedback forms part of the design of this intervention and is incorporated in the balance measures for this QI report.

Strategy and measurement

Lessons and limitations

The aim of this QI intervention was to reduce national variation in the prescription of oral methotrexate 10 mg tablets, for non-cancer treatment, by November 2021. Longitudinal data comparing the high prescribing cohort with all other ICSs/CCGs showed that before the QI intervention took place prescribing was already declining with both groups reducing at a similar pace. However, during the action period, the reduction for the high prescribing cohort (54%) exceeded that of the remaining ICSs/CCGs (23%). This increases our degree of belief that some of the reduction seen by the high prescribing cohort was because of the intervention shared in this QI report and not just because of any background reductions that were also taking place.

In the absence of any centrally led interventions to reduce methotrexate 10 mg tablet prescribing since the publication of the NPSA patient safety alerts in 2004 and 2006,1 2 the background reduction in methotrexate prescribing can be attributed to the cumulative impact of national prescribing guidance and local safety initiatives described in the background of this report.4 8–18 Nevertheless, as highlighted in the Pareto analysis, prescribing levels of methotrexate 10 mg tablets varied substantially across England. Ten ICSs were responsible for 76% of prescribing during the baseline period, painting a similar picture to that identified by MacKenna et al.5 A targeted approach, focusing on reducing variation, was the best use of resources, minimising opportunity costs for most ICSs.

For the eight high prescribing ICSs/CCGs participating in this initiative, the intervention was well received, with positive feedback from those involved. ICS prescribing support teams reported the centrally delivered nature of the intervention enabled the creation of a burning platform, where this had previously been lacking. This together with a data focused, systematic, network-based approach helped create a context that made this work thrive.

During the action period, seven of the eight ICSs saw special cause variation with reductions in methotrexate 10 mg prescribing ranging from 41% to 75%. The timing of reductions varied between the ICSs, with four (ICS 1–5) seeing reductions starting earlier during the QI intervention and three (ICS 6–8) seeing reductions later. We believe that the reason for these differences can be attributed to two causes. The first relates to the sequencing of engagement between the MedSIP team and high prescribing ICSs, with some receiving support before others. ICSs 1–5 were the first to connect with the MedSIP team and start working on this issue, with ICSs 2, 4 and 5 receiving coaching sessions first. ICSs 6–8 did not start working on this issue until approximately 1.5 months after ICS 1–5. A second cause related to the ICS’s pre-existing knowledge of this issue. As the highest prescribers of methotrexate 10 mg tablets in England, we found ICSs 1–5 already had a high level of understanding about the issue and were able to develop and enact their strategies quickly. In the case of ICSs 6–8, they needed longer to understand the problem before they could proceed into action. ICS 9 did not see change during the action period, and this may have been because they had already seen substantial reductions during the baseline period and there was a reluctance to restart this work again owing to change fatigue.

While no patient safety incidents resulting in harm were reported via the NRLS, the MedSIP team was made aware of one near hit and two incidents where patients took a suboptimal dose. In the case of the two incidents, the cause appeared to be ineffective counselling. Information about all three incidents was promptly shared with all participating ICSs, and prescribing teams were encouraged to follow-up patients that had a change in tablet strength. In general, the QI intervention was well received by patients, although several ICSs did identify small populations of patients that were unwilling to change from 10 mg to 2.5 mg tablets owing to increased pill burden. Financial analysis indicated that the QI intervention had no impact on methotrexate expenditure.

A substantial part of this QI intervention focused on quality control by introducing changes to local systems so that improvement was sustained. A variety of changes were implemented that in most cases responded to the local causes of methotrexate 10 mg prescribing. The ICSs shared the networking sessions provided by the MedSIP team were a particularly useful way to share these change ideas. In several instances, ICSs adopted other ICSs ideas and implemented them locally. Such instances of sharing, testing and implementing improvement ideas are a key part of national campaigns.

There are four limitations associated with this report that merit further discussion. First, while we used nationally recognised longitudinal data to understand the impact of the QI intervention, we did not use statistical techniques to control for confounding factors. These could have included the National Pharmacy Association’s Methotrexate Standard Operating Procedure, published February 2021, that may have influenced pharmacies during the intervention period18 and the impact of COVID-19 on methotrexate prescribing and on mortality among those on methotrexate. While an inability to control background confounding factors is a common weakness in QI projects, we increased our degree of belief around the QI intervention through observing similar results across seven of the eight ICSs/CCGs participating in this initiative, listening to feedback from those involved in the change and seeing a greater reduction in methotrexate prescribing in the high prescribing cohort compared with all other ICSs/CCGs.

A second limitation relates to the lack of outcome measures looking at harm to patients from methotrexate 2.5 mg and 10 mg misadministration. While there are a range of national safety alerts, prescribing guidance and standard operating procedures in place to reduce accidental overdose of methotrexate tablets, the NHS does not reliably measure the prevalence of methotrexate overdose on admission into its hospital systems. This forced us to use prescribing levels as a surrogate measure for harm. We did, however, include patient safety incidents reported via the NRLS and ICSs as a balance measure. Those considering future work on this topic may also consider obtaining data from the National Poisons Information Service.

A third limitation relates to our dependence on voluntary reporting rather than systematic identification for three of the five balance measures. In the case of ICS reported patient safety incidents, we attempted to mitigate for this by using nationally collated and managed NRLS data. However, in the case of patients and staff experience, we could have considered more systematic surveys and questionnaires for those affected.

A final limitation relates to this QI report’s generalisability. While there clearly may be other opportunities to replicate this style of approach, there may only be a limited number of national opportunities where there is considerable variation, a manageable patient population affected by the change and a discrete and simple intervention that could easily be replicated with a low impact on NHS resources.