Evidence review for follow up
Evidence review F
NICE Guideline, No. 239
1. Follow up
1.1. Review question
What is the optimal frequency of follow-up for people with vitamin B12 deficiency, including pernicious anaemia?
1.1.1. Introduction
It is important that people who are diagnosed with vitamin B12 deficiency are followed up to ensure that their treatment is working. There are currently no national guidelines as to the frequency and the components of follow up for people with vitamin B12 deficiency. The most effective frequency and components of follow up are not known. Currently, the frequency and components of follow up are determined by the clinician, considering the reason for the B12 deficiency, treatment offered and a person’s response to treatment.
This review seeks to determine the most effective way of following up people with vitamin B12 deficiency. The most appropriate frequency and components of follow up are expected to differ depending on whether a person receives oral or intramuscular treatment, and the evidence will therefore be stratified according to treatment route.
1.1.2. Summary of the protocol
For full details see the review protocol in Appendix A.
Table 1
PICO characteristics of review question.
1.1.3. Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.
Declarations of interest were recorded according to NICE’s conflicts of interest policy.
1.1.4. Effectiveness evidence
1.1.4.1. Included studies
No relevant clinical studies comparing different frequencies of follow up of people with diagnosed vitamin B12 deficiency were identified.
See also the study selection flow chart in Appendix C.
1.1.4.2. Excluded studies
See the excluded studies list in Appendix J.
1.1.5. Summary of studies included in the effectiveness evidence
No included studies.
1.1.6. Summary of the effectiveness evidence
No evidence identified.
1.1.7. Economic evidence
1.1.7.1. Included studies
No health economic studies were included.
1.1.7.2. Excluded studies
No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.
See also the health economic study selection flow chart in Appendix G.
1.1.8. Summary of included economic evidence
None
1.1.9. Economic model
This area was not prioritised for new cost-effectiveness analysis.
1.2. Review question
What should be included in a follow-up review for people with vitamin B12 deficiency, including pernicious anaemia?
1.2.1. Introduction
See section 1.1.1.
1.2.2. Summary of the protocol
For full details see the review protocol in Appendix A.
Table 2
PICO characteristics of review question.
1.2.3. Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document.
Declarations of interest were recorded according to NICE’s conflicts of interest policy.
1.2.4. Effectiveness evidence
1.2.4.1. Included studies
No relevant clinical studies comparing review of vitamin B12 levels, other haematological values, symptoms, or diet, alone or in combination, with each other, or no follow up were identified.
See also the study selection flow chart in Appendix C.
1.2.4.2. Excluded studies
See the excluded studies list in Appendix J.
1.2.5. Summary of studies included in the effectiveness evidence
No included studies.
1.2.6. Summary of the effectiveness evidence
No evidence identified.
1.2.7. Economic evidence
1.2.7.1. Included studies
No health economic studies were included.
1.2.7.2. Excluded studies
No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.
See also the health economic study selection flow chart in Appendix G.
1.2.8. Summary of included economic evidence
None
1.2.9. Economic model
This area was not prioritised for new cost-effectiveness analysis.
1.2.10. Unit costs
Relevant unit costs are provided below to aid consideration of cost effectiveness.
Table 3
Test costs.
1.3. The committee’s discussion and interpretation of the evidence
The committee discussion of the review on what should be included in a follow up review is included in the discussion of the review on frequency of follow up.
1.3.1. The outcomes that matter most
The committee considered quality of life, patient reported outcomes including symptom scores, haematological values, complications and adverse events, adherence to treatment and education/work absence to be the most important outcomes of follow up. All outcomes were considered equally important for decision making and therefore were all rated as critical.
No evidence was identified for any of the outcomes.
1.3.2. The quality of the evidence
No evidence was identified.
1.3.3. Benefits and harms
The committee discussed the varying definitions of a medicine review that are being used in current practice. For example, some medicine reviews are computerised, based on blood test results, whereas others are with the patient. There is also variation in what is included in the review, such as whether symptoms are reviewed.
In the absence of any evidence, the committee agreed, based on their experience and expertise, that follow up needs are dependent on the type of treatment being received and the clinical presentation of B12 deficiency. For those with more severe symptoms, such as neurological symptoms, haematological abnormalities may require more frequent review until resolved.
From the patient perspective, concerns were expressed that medicines could be stopped when it is still needed if the review is based on test results alone. Blood levels do not always reflect lived experience of the condition, so the person may still be experiencing symptoms despite normal test results. Alternatively, the person may not experience symptoms because the condition is being effectively managed and withdrawing the treatment will cause a relapse in symptoms.
In the absence of any evidence on the optimal frequency or composition of follow up reviews, the committee made consensus recommendations based on their experience and expertise. However, they agreed that research is needed on which components of follow up reviews lead to the best outcomes for people receiving vitamin B12 replacement. In particular, they agreed the value in monitoring different haematological parameters, assessing dietary vitamin B12 intake and assessing symptoms needs to be determined for people receiving oral and intramuscular replacement. Therefore, they made a research recommendation.
The committee agreed for most people, an initial follow-up appointment three months after treatment initiation would give enough time to ensure treatment is working. However they also agreed that it may need to be sooner depending on the severity of symptoms. During pregnancy or breastfeeding, people should be followed up at one month to make sure they are getting the treatment they need to protect both their health and that of their baby.
The committee discussed what should be assessed at the first follow up review. The committee agreed it is important to check that the person is taking their tablets as prescribed and receiving the correct dosage and frequency, as these factors can impact the efficacy of the treatment. The committee cross referred to the recommendations on supporting adherence in the NICE guideline on medicines adherence if there is concern about adherence.
The committee highlighted that although the recommendations on ongoing care and follow up in this guideline provide a guide on when and how often to carry out follow up reviews with people with vitamin B12 deficiency, people should return to their healthcare professional if symptoms are not improving, getting worse or new symptoms develop. The committee agreed it was important not to leave people waiting for their next scheduled follow-up when they could benefit from changes to their treatment. See also the recommendations on information and support for people with vitamin B12 deficiency and signs and symptoms.
The committee agreed that there are differences in the requirements for ongoing care and follow up depending on whether the person is receiving oral or intramuscular replacement. Therefore, separate recommendations were made.
People receiving oral treatment
The committee discussed the appropriate time interval between initiation of treatment and first follow up review. They considered that three months would allow adequate time for enough B12 to be absorbed, and to alleviate symptoms. This would indicate whether the person is able to absorb the vitamin. However, the committee also agreed that some people may need an earlier follow up if they have severe symptoms. Therefore, they agreed that people should be followed up at three months after they started treatment, or earlier depending on severity of symptoms.
The committee agreed that the focus of follow-up appointments should be based on assessing the person’s response to treatment based on the change in their symptoms. They did not recommend retesting because total vitamin B12 or holotranscobalamin markers can be falsely elevated with treatment, leading to false assumptions that a deficiency has been resolved. The committee were aware that some people are retested at their follow up appointment to see if vitamin B12 replacement was being absorbed. Taking this into consideration the committee decided not to recommend repeating initial tests but did not explicitly state they should not be repeated.
Treatment would need to be reviewed and changed if the person’s symptoms have not sufficiently improved so that they are still interfering with their normal daily activities, then the committee agreed treatment should be changed. This could be by either increasing oral vitamin B12 replacement to the maximum licensed dosage, or by switching to intramuscular injections. The committee agreed the person’s preference would need to be taken into account when deciding on any change to treatment.
If the person’s symptoms have worsened or they have new symptoms, then it is important to think about alternative diagnoses in case their symptoms are not linked to a deficiency. Further testing with serum MMA or plasma homocysteine should also be considered provided the person has not already had these tests. Based on their experience and expertise, the committee agreed that serum MMA was the better test in these circumstances. However, they were aware that not everywhere has access to this test and that plasma homocysteine could help support a diagnosis instead. The committee also agreed that treatment would need to be continued until the test result is available to ensure symptoms do not worsen. If further testing suggests a deficiency, or the result is uncertain, then treatment will need to be changed by either increasing oral vitamin B12 replacement to the maximum licensed dosage or by switching to intramuscular injections. A result that suggests deficiency is no longer present should also prompt exploration of an alternative diagnoses. People with a result that indicates there is no longer a deficiency.
If symptoms have resolved or improved to the point that they are no longer affecting normal daily activities, then a decision to continuing with treatment will depend on the cause of the deficiency and whether it has been addressed. If the cause, or suspected cause, has not been addressed – or the cause is unknown – treatment should continue to prevent symptoms getting worse again. If the cause has been addressed, then stopping treatment should be considered because symptoms are unlikely to return. However, people should be advised to return if symptoms reappear, because this may indicate that the deficiency has returned and they may need further treatment.
People receiving intramuscular injections
The committee agreed that for most people receiving intramuscular injections a follow up review at three months would be sufficient. This is in line with the licenced frequency of injections, so the person should be due for their next injection at three months anyway. The committee also considered that by three months, people should have noticed an improvement in their symptoms. However, the committee also agreed that some people may need an earlier follow up. Therefore they recommended an initial follow up appointment at 3 months after they started treatment, or earlier depending on severity of symptoms.
The committee agreed there is little benefit in measuring B12 concentration in a person receiving and adhering to intramuscular treatment, because results will reflect the pharmacological dose of vitamin B12 rather than status at tissue level. Therefore, the committee recommended that B12 should not be retested while the person is receiving intramuscular injections.
The committee highlighted the importance of discussing the person’s signs and symptoms with them, as this will guide decisions about changes to treatment and frequency of follow up. The committee agreed that if symptoms have not improved, or new symptoms of deficiency have developed, it may suggest that more frequent injections are needed to help manage these. If this is decided, then a date for the next follow up should be discussed and agreed with the person. The committee noted the variation in the licensed frequency of administration of two to three months. They agreed that if symptoms return before the person’s next injection, the frequency of injections could be increased to achieve optimal symptom control. The committee agreed that it would also be prudent to think about an alternative diagnosis at the same time to ensure other causes of the symptoms have not been ruled out and to avoid any unnecessary treatment.
The form of ongoing care and follow-up also depends on the cause of the deficiency. The committee agreed that those with an irreversible cause would need to continue with lifelong intramuscular injections. If treatment is working, these groups would not need a regular review. However, people should be advised to return if symptoms reappear, because the dose and frequency of their injections may need to be reassessed.
People with a cause that is potentially reversible would need to continue with treatment until this has been addressed and their symptoms have improved or are no longer present. The same applies to people with an unknown cause of deficiency because until this cause is known and addressed, a stop in treatment may cause symptoms to return or get worse. If the cause, or suspected cause, and the symptoms have been addressed, then further treatment is unlikely to be necessary and could be either stopped, or the frequency of the injections could be reduced. However, people should be advised to return if symptoms reappear, as this may indicate that the deficiency has returned and they may need further treatment.
1.3.4. Cost effectiveness and resource use
Published cost effectiveness evidence
No economic evaluations were identified for this review.
Consideration of cost effectiveness
Unit costs of tests were presented to aid the committee with considerations of cost effectiveness. There was no evidence identified as part of the clinical review. Evidence from the diagnostics review (Evidence Review C) and patient experiences indicate that haematological values may not truly reflect the condition so patients may still have symptoms despite having B12 test results within a normal range. Therefore, for people on oral treatment, the committee noted that it is important to review patient symptoms and not use haematological test values due to concerns that medicine may be inappropriately stopped. By stopping B12 treatment inappropriately, it could potentially result in further primary care appointments and additional costs of investigations or potential referrals to secondary care.
For the diagnosis of vitamin B12 deficiency, a cost-effectiveness analysis showed that serum MMA is likely to be cost-effective for people with an indeterminate serum B12 test result (see Evidence Review C). The committee thought that it is likely that MMA would also be cost-effective for people who are on oral treatment but are still symptomatic at follow-up, to investigate whether there is still B12 deficiency which may be due to inadequate absorption. Plasma homocysteine could be used as an alternative if serum MMA is not available. This could result in the treatment route being changed to parenteral which is thought by the committee to be more effective in resolving symptoms. The cost of parenteral treatment is lower than oral, however this is dependent on the length of treatment and whether there is a loading dose required for parenteral treatment which will influence the costs.
Recommendations
Follow-up was proposed at three months (or sooner depending on the severity of symptoms) after starting oral treatment to check that the medicine was providing a response. If there has been improvement, then consider continuing or stopping treatment and having a patient led follow up. By reviewing the need for the medicine, this will ensure that treatment is appropriate. During this review, it may be advised that treatment be continued or stopped depending on symptom control, potential cause of B12 deficiency and the test results.
For oral treatment, if a person is still symptomatic despite B12 levels improving, consider MMA testing, homocysteine testing where MMA is unavailable, or switching to parenteral treatment. The benefit of further testing or offering parenteral treatment is to potentially identify malabsorption issues which can be overcome by treating with parenteral treatment. This would also reduce the need for further investigations and inappropriate referrals. By confirming that a B12 deficiency is present, it can then be treated appropriately by parenteral treatment which will provide health gains and offset the cost of the MMA test and the potential inappropriate costs of investigations.
For some reversible causes of B12 deficiency, for example diet related, assuming that the person has no symptoms, the committee decided that it would be sensible to stop treatment, provide dietary advice and advise the person to seek medical attention if symptoms reoccur. Offering longer term treatment may not be required when people have no symptoms.
Alternatively, there may be some cases whereby it may be appropriate to consider stopping parenteral treatment if there is a reversible cause of B12 deficiency. However, it is important to ensure it is stopped appropriately as the cost saving of ceasing treatment will be cancelled out if a person’s B12 symptoms worsen, leading to additional costs incurred by primary care appointments, investigations and potential referrals.
For follow up of people on long-term vitamin B12 treatment, the committee thought that in practice patient led follow up would be best. For people that are on parenteral treatment, the committee agreed that there is almost no benefit of testing using total B12, therefore routine testing has not been recommended.
Resource impact
In terms of resource impact, the main change in practice relates to the potential increased use of further testing with serum MMA (or plasma homocysteine if serum MMA is not available) for people on oral B12 treatment who have new or worsened, symptoms related to B12 deficiency. This could potentially have a significant resource impact; however, the committee expressed the view that the benefit of using further testing would outweigh the testing costs. Further testing costs could be at least partially offset by stopping further inappropriate investigations of other causes of symptoms and reducing primary care appointments. The committee also noted that appropriate testing would improve people’s quality of life by improving symptom control and reducing the risk of B12 deficiency complications and hospitalisations. This suggests that testing for monitoring people on oral B12 treatment who have worsening or new symptoms, is likely to be cost-effective. By not offering MMA retesting to people who have previously had an MMA test, it will limit testing and also limit resource impact.
1.3.5. Recommendations supported by this evidence review
This evidence review supports recommendations 1.6.1 to 1.6.14 and the recommendation for research on what should be included in a follow-up review for people with vitamin B12 deficiency, including people with autoimmune gastritis (pernicious anaemia).
1.4. References
- 1.
- National Institute for Health and Care Excellence. Developing NICE guidelines: the manual [updated January 2022]. London. National Institute for Health and Care Excellence, 2014. Available from: http://www
.nice.org.uk /article/PMG20/chapter /1%20Introduction%20and%20overview
Appendices
Appendix A. Review protocols
A.1. Review protocol for frequency of follow up (PDF, 172K)
A.2. Review protocol for what should be included in a follow up review (PDF, 172K)
Health economic review protocol (PDF, 129K)
Appendix B. Literature search strategies
These literature search strategies were used for the following reviews:
- What is the optimal frequency of follow-up for people with vitamin B12 deficiency, including pernicious anaemia?
- What should be included in a follow-up review for people with vitamin B12 deficiency, including pernicious anaemia?
The literature searches for these reviews are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.1
For more information, please see the Methodology review published as part of the accompanying documents for this guideline.
B.1. Clinical search literature search strategy (PDF, 139K)
B.2. Health Economics literature search strategy (PDF, 133K)
Appendix C. Effectiveness evidence study selection
C.1. Frequency of follow up (PDF, 102K)
C.2. What should be included in a follow up review (PDF, 126K)
Appendix D. Effectiveness evidence
D.1. Frequency of follow up
No evidence identified.
D.2. What should be included in a follow up review
No evidence identified.
Appendix E. Forest plots
E.1. Frequency of follow up
No forest plots.
E.2. What should be included in a follow up review
No forest plots.
Appendix F. GRADE and/or GRADE-CERQual tables
F.1. Frequency of follow up
No GRADE tables.
F.2. What should be included in a follow up review
Appendix G. Economic evidence study selection
Download PDF (162K)
Appendix H. Economic evidence tables
H.1. Frequency of follow up
None
H.2. What should be included in a follow up review
None
Appendix I. Health economic model
I.1. Frequency of follow up
No original economic modelling undertaken.
I.2. What should be included in a follow up review
No original economic modelling undertaken.
Appendix J. Excluded studies
J.1. Clinical studies
J.1.1. Frequency of follow up
Table 6
Studies excluded from the clinical review.
J.1.2. What should be included in a follow up review
Table 7
Studies excluded from the clinical review.
J.2. Health Economic studies
None.
Appendix K. Recommendation for research – full details
K.1. Recommendation for research
What should be included in a follow-up review for people with vitamin B12 deficiency, including people with autoimmune gastritis?
K.1.1. Why this is important
It is important that people with diagnosed vitamin B12 deficiency are followed up to ensure that their treatment is working. However, there is variation in follow up and no evidence on the most effective components of follow up reviews was identified. Therefore, research into which components lead to the best outcomes for people with vitamin B12 deficiency is needed.
K.1.2. Rationale for the recommendation for research
Download PDF (92K)
K.1.3. Modified PICO table
Download PDF (114K)
Final
Evidence reviews underpinning recommendations 1.6.1 to 1.6.14 and the recommendation for research in the NICE guideline
Developed by NICE
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.