Comparing costs of intramuscular and oral administration of vitamin B12 in Primary Care in Wales: a cost minimisation analysis

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  • 1. Comparing costs of intramuscular and oral administration of vitamin B12 in Primary Care in Wales: a cost minimisation analysis Dr. Josep Vidal-Alaball A dissertation submitted in partial fulfilment for the degree of Masters of Public Health 2002-2004 December 04 Wales College of Medicine Cardiff University
  • 2. Dr. Josep Vidal-Alaball Declaration This work has not been previously been accepted in substance for any degree and is not being concurrently submitted in candidature for any degree. Signed ………………………………… Date …………………………………... STATEMENT 1 This dissertation is being submitted in partial fulfilment of the requirements for the degree of MPH. Signed ………………………………… Date …………………………………... STATEMENT 2 This dissertation is the result of my own independent work/investigation, except where otherwise stated. Other sources are acknowledged giving explicit references. A bibliography is appended. Signed ………………………………… Date …………………………………... STATEMENT 3 I hereby give consent for my dissertation, if accepted, to be available for photocopying and for inter- library loan, and for the title and summary to be made available to outside organizations. Signed ………………………………… Date …………………………………... Signature of Supervisor …………………………. Date ……………………………………………... 2
  • 3. Dr. Josep Vidal-Alaball Oh, que cansat estic de la meva covarda, vella, tan salvatge terra, i com m'agradaria d'allunyar-me'n, nord enllà, on diuen que la gent és neta i noble, culta, rica, lliure, desvetllada i feliç! (…) Però no he de seguir mai el meu somni i em quedaré aquí fins a la mort. Car sóc també molt covard i salvatge i estimo a més amb un desesperat dolor aquesta meva pobra, bruta, trista, dissortada pàtria. Assaig de Càntic en el Temple. Salvador Espriu (1913 - 1985) Voldria dedicar aquest treball a la meva esposa Gemma, sempre al meu costat animant-me a millorar. Moltes Gràcies! To my wife, Gemma 3
  • 4. Dr. Josep Vidal-Alaball Acknowledgements I wish to thank Christopher Potter, my supervisor, for guiding me throughout this dissertation. With his advice, he has been always supportive and has encouraged me to think critically. Despite his commitments, he has been always available. I am grateful to Prof. David Cohen and Mirella Longo from the Health Economics Research Unit at the University of Glamorgan. Mirella Longo provided me with relevant and valuable references. Prof. Cohen gave me initial advice about the best method of economic evaluation for my study and reviewed my dissertation research plan project. I am thankful to Prof. Christopher Butler, my line manager when I was working at the Department of General Practice, UWCM. He had the original idea of conducting a systematic review comparing intramuscular and oral vitamin B12 and he guided me during the early phase of this dissertation. A special thank to Dr. Sara Hayes, my actual line manager at the National Public Health Service for Wales, for providing me with the time I needed to finish this dissertation. A special thank you to Dr. Siân Griffiths for her help in proof-reading this dissertation. 4
  • 5. Dr. Josep Vidal-Alaball Ethical issues I did not seek ethical approval, as the study did not raise ethical issues. This study has not involved direct contact with patients and has not used patient’s personal medical information. 5
  • 6. Dr. Josep Vidal-Alaball Word Count Summary 229 words Dissertation 11,870 words (excluding bibliography) 6
  • 7. Dr. Josep Vidal-Alaball Summary Background Vitamin B12 (cobalamin) has been widely used for the treatment of vitamin B12 deficiency. Most vitamin B12 deficient individuals have been managed with intramuscular vitamin B12 , despite several case control and case series studies which demonstrate equal efficacy of the oral route. Intramuscular injections are a considerable source of work for health care professionals. Apart from being as safe and effective as intramuscular vitamin B12 , oral treatment could save considerable Health Service resources. Objectives To determine using a NHS perspective whether any saving could be made by switching patients from intramuscular to high doses of oral vitamin B12 . Methods I used methods of health economic analysis. I performed a cost minimisation analysis. Results I have calculated the cost of the resources used to treat patients with vitamin B12 deficiency with intramuscular vitamin B12 to be between £55.99 and £99.99 per year. The cost of treating patients with high doses of oral vitamin B12 during the first year is between £125.55 and £248.55. However, once they have been converted, or in new patients, the cost is £35.55 per year. One variable, home visits, has a high impact on the calculations. Conclusion Switching patients with vitamin B12 deficiency from intramuscular to oral therapy could save resources to the NHS in the medium and long term and in newly diagnosed patients. Savings would come particularly in the form of nursing time. 7
  • 8. Dr. Josep Vidal-Alaball Table of Contents 1. Introduction 11 1.1. Context of the study 11 1.2. Aims and objectives 12 1.3. Literature Review. Search strategy 12 2. Background 14 2.1. Context of the project 14 2.2. Welsh perspective 17 2.3. Health Economics 17 3. Methods 21 3.1. Effectiveness estimation 21 3.2. Identification of resources 21 3.3. Measurements of resource use 22 3.4. Cost valuation 23 3.5. Resources excluded 26 3.6. Sensitivity analysis 28 8
  • 9. Dr. Josep Vidal-Alaball 3.7. Time horizon 29 3.8. Discounting costs 30 4. Results 31 4.1. Cost minimisation analysis 31 4.2. Costs of resources used in intramuscular treatment compared with oral treatment 34 4.3. Sensitivity analysis 35 4.4. Discounting costs 37 5. Discussion 39 5.1. Summary of results 39 5.2. Prevalence of vitamin B12 deficiency in Wales 5.3. Limitations of the study 41 5.4. How this fits in with other work 46 5.5. Implications for service delivery 47 6. Conclusions 48 9
  • 10. Dr. Josep Vidal-Alaball 7. Appendix 49 7.1. Prices of oral vitamin B12 on the Internet 49 7.2. Personal Social Services Research Unit 50 8. Bibliography 52 10
  • 11. Dr. Josep Vidal-Alaball 1. Introduction 1.1. Context of the study I have conducted a systematic review on the use of oral vitamin B12 for the treatment of vitamin B12 deficiency, leading and coordinating a group working for the Metabolic and Endocrine Disorders Group of the Cochrane Collaboration. We have published the protocol (Vidal-Alaball et al., 2004) and the full systematic review is pending peer review and publication. In writing up the background for this dissertation, I have incorporated some parts of my own work done for the systematic review and published in the protocol. This has been appropriately quoted. In our systematic review, we found two randomized controlled trials (Kuzminski et al., 1998, Bolaman et al., 2003) and several non-randomized studies (Reisner et al., 1955, Unglaub and Goldsmith, 1955, McIntyre PA, 1960, Berlin et al., 1968, Kondo, 1998, Andres et al., 2001, Nyholm et al., 2003) comparing oral and intramuscular vitamin B12 for the treatment of vitamin B12 deficiency. These studies suggest that high oral doses of B12 (1,000 mcg and 2,000 mc g) could be as effective as intramuscular administration in achieving haematological and neurological responses. During my extensive literature search, I found evidence that changing patients from intramuscular to high doses of oral vitamin B12 could save money to the NHS and I decided to conduct an economic evaluation to explore it. The skills obtained during the first year of the MPH, mainly in Health Economics and Health Policy, have been an invaluable start for this project. However, I needed expansion of my knowledge on health economics and I decided to undertake a module in health economics (Introduction to Health Economics) at the University of Glamorgan. Vitamin B12 is mainly prescribed in primary care health settings and skills gained as a practising General Practitioner have allowed me to conduct the study from the primary care point of view needed. 11
  • 12. Dr. Josep Vidal-Alaball 1.2. Aims and Objectives 1.2.1 Research questions • What are the costs of the intramuscular vitamin B12 administered in primary care in Wales? • What cost implications arise when changing patients who receive intramuscular vitamin B12 to high doses of oral vitamin B12 ? 1.2.2. Aim of the research To establish whether savings could be make by changing patients from intramuscular to high doses of oral vitamin B12 in primary care in Wales without compromising their wellbeing. 1.2.3. Objectives of the research • To analyse how resources are used in the treatment of vitamin B12 deficiency with intramuscular vitamin B12 in primary care in Wales. • To establish how resources would be affected by switching to high doses of oral vitamin B12 . • To quantify the cost of converting patients on intramuscular vitamin B12 to high doses of oral vitamin B12 . • To determine whether any saving could be made by converting people from intramuscular to high doses of oral vitamin B12 . • To gain experience in methods of health economic evaluation. 1.2.4. Hypothesis Switching patients from intramuscular to oral vitamin B12 in primary care in Wales could save Health Service resources. 12
  • 13. Dr. Josep Vidal-Alaball 1.3. Literature Review. Search strategy For the literature review, I adapted the one I used for my systematic review and published in the protocol (Vidal-Alaball et al., 2004). I used several sources of information: 1.3.1. Electronic databases For the electronic search, I used the following key words to identify relevant trials and reviews: vitamin B12 , cost, cost benefit, cost minimisation, cost effectiveness, oral therapy. I used OVID to scan the following databases: • The Cochrane Library (2004, Issue 1) • MEDLINE (1966 to March 2004) • EMBASE (1980 to 2004 week 14) • ACP Journal Club (1991 to March 2004) 1.3.2. Handsearching I searched the bibliographies of all relevant papers selected with this strategy. An important number of articles about the use of oral vitamin B12 date from the early 50’s and 60’s, and these articles could only be identified though handsearching. 1.3.3. Other search strategies I tried to contact authors of relevant identified studies and clinical experts on the use of vitamin B12 to enquire about other published or unpublished studies, ongoing trials and to obtain additional references. Some authors replied and suggested further references. I searched www.google.com. 13
  • 14. Dr. Josep Vidal-Alaball 2. Background 2.1. Context of the project ‘Vitamins are a group of substances required for effective human metabolism. Under normal circumstances, it is essential that they are present in a person's diet because, with few exceptions, the human body is unable to manufacture them’ (Vidal-Alaball et al., 2004). ‘Vitamin B12 , also known as cobalamin is necessary for the development of red blood cells, growth, and nervous system maintenance’ (Vidal-Alaball et al., 2004). Plant foods contain no detectable vitamin B12 and the only dietary sources of vitamin B12 are animal products, such as milk, eggs, fish and meats. (Basu and Dickerson, 1996, Herbert, 2002). Daily requirements of vitamin B12 are age-related; the recommended dietary amounts for adults and infants are 1.5 micrograms and 0.4 micrograms respectively (FAO and WHO, 1988, DH, 1991). The most common cause of vitamin B12 deficiency is autoimmune pernicious anaemia where its absorption in the terminal ileum is impaired due to Intrinsic Factor (IF) deficiency. ‘Other causes of IF deficiency include gastrectomy, total ileal resection, chronic gastritis and other ileal malabsorption syndromes such as Crohn's disease, tropical sprue and coeliac disease’ (Vidal-Alaball et al., 2004). Nutritional deficiency is rare and usually occurs only in strict vegetarians (eating no food of animal origin, including eggs and dairy products) after a period of many years (Swain, 1995). Vitamin B12 deficiency commonly causes megaloblastic anaemia, chronic tiredness, loss of appetite, unsteadiness, poor muscular coordination, impaired memory and mood disturbance. The initial clinical manifestations of vitamin B12 deficiency may be subtle but if left untreated, serious and some times irreversible neurological and neuropsychiatric complications occur. Neurological sequelae include peripheral neuropathy, paresthesias and demyelination of the corticospiral tract and dorsal columns (Oh and Brown, 2003). Neuropsychiatric symptoms include psychosis, dementia, paranoia, hallucinations and depression (Delva, 1997). Vitamin B12 14
  • 15. Dr. Josep Vidal-Alaball deficiency has also been linked with an increased risk of myocardial infarction and stroke (Stabler, 1995, Nygard et al., 1997, Penix, 1998). ‘Vitamin B12 (cobalamin) was first isolated in 1948 (Rickes et al., 1948, Smith, 1948) and has since then been widely used for the treatment of vitamin B deficiency’ 12 (Vidal- Alaball et al., 2004). During the last half century, most vitamin B12 deficient individuals in the UK and other countries have been managed with intramuscular vitamin B12 , despite several case control and case series studies have since demonstrated equal efficacy of the oral route (Spies et al., 1949, Ungley, 1950, Reisner et al., 1955, Unglaub and Goldsmith, 1955, McIntyre PA, 1960, Berlin et al., 1968). The normal absorption of B12 starts when the stomach facilitates the breakdown of vitamin B12 bound to food. IF, secreted by parietal cells in the stomach, binds to vitamin B12 in the duodenum and the complex B12 -IF is actively absorbed in the terminal ileum (Basu and Dickerson, 1996). In addition to this mechanism of absorption, there is evidence that another mechanism independent of IF allows free vitamin B12 to be absorbed passively in the terminal ileum (Ross et al., 1954, Metz, 1999, Oh and Brown, 2003). Passive diffusion accounts for 1.2% of total absorption and is unaffected in patients with pernicious anaemia or gastro-duodenal surgical resection (Berlin et al., 1968, Berlin et al., 1978). This pathway is very important in relation to oral vitamin B replacement because daily high doses of oral cobalamin 12 (1,000 micrograms) could be an acceptable and safe alternative to the intramuscular route in most patients. If 1.2% of 1,000 micrograms were absorbed orally, this would represent 12 micrograms absorbed, which is 8 times more than the daily requirement for an adult. Oral therapy it is rarely prescribed in this form, other than in Sweden where in the year 2000 it accounted for 73% of the total vitamin B12 prescribed (Norberg, 2001). In the USA, oral vitamin B12 ceased to be available in the late 1950s but became available again in the early 1970s (Lederle, 1991). In the UK, oral vitamin B12 is not currently available in the NHS. Why oral vitamin B12 is so rarely used is a question for debate. Some authors have suggested that this might be because doctors are generally unaware of this route or because concerns are expressed in some medical 15
  • 16. Dr. Josep Vidal-Alaball text-books regarding its unpredictable absorption, patient compliance and costs (Lederle, 1998, Paauw, 1999). In 1989 a survey amongst 245 physicians in Minneapolis, 91% believed that vitamin B could not be absorbed without IF and 12 94% were not aware of the existence of the oral therapy (Lederle, 1991). The same author repeated the survey 7 years later and found that 19% of the physicians had started using oral vitamin B12 to treat pernicious anaemia but still just 29% of the participants were aware of the existence of the oral therapy (Lederle, 1998). The true prevalence of vitamin B12 deficiency in the general population is unknown but the condition is common, especially amongst the elderly as its incidence appears to increase with age (Herbert, 2002). Depending on the diagnostic criteria used to define vitamin B12 deficiency, studies have reported a prevalence in the elderly between 1.5 and 15% (Pennypacker et al., 1992, van Walraven and Naylor, 1999, Rajan et al., 2002, Figlin et al., 2003, Clarke et al., 2004). As well as with age, the prevalence also varies with sex and ethnic group; elderly men are more likely to have low vitamin B12 levels than elderly women and the prevalence of vitamin B12 deficiency is higher in Europe than in USA (Pennypacker et al., 1992, Lindenbaum et al., 1994). Intramuscular injections are a ‘considerable source of work’ for health care professionals (Middleton and Wells, 1985). Intramuscular administration ‘often involves a special trip to a health facility or a home visit by a health professional with the associated costs that this entails (Lederle, 1991). Archie Cochrane, working in South Wales, was one of the first to identify that substantial financial savings could be made from more evidence-based prescribing of vitamin B12 . His focus was on excessive prescription of intramuscular vitamin B12 ’(Cochrane and Moore, 1971, Vidal-Alaball et al., 2004). More recently, a Canadian study estimated that converting patients aged over 65 years from intramuscular vitamin B12 to an oral form could save between $2.9 (£1.26) and $17.6 (£7.65) million over 5 years just in Ontario alone (van Walraven et al., 2001). All these facts support my hypothesis that apart from being as safe and effective as intramuscular vitamin B12 , oral treatment could save considerable Health Service resources. 16
  • 17. Dr. Josep Vidal-Alaball 2.2. Welsh perspective The UK in general has a problem of excessive prescribing of medication. This problem is particularly acute in Wales, where research has showed that GPs issue more prescriptions items per head of population than in the other UK countries. The cost of primary care prescribing in Wales has also been consistently 20% higher than in England (Routledge, 2002). About 46 million prescriptions were dispensed in Wales in year 2000, this was equivalent to 15.9 prescriptions per person per year and represented a cost of £456 million (Routledge and Fitzgerald, 2002). In Wales, the cost of the prescribed vitamin B12 , including intramuscular and oral preparations, was estimated to be around £335,120 in 2001 (NHS-Wales, 2001). The vast proportion of this money was spent on intramuscular vitamin B12 but a small proportion was spent on low doses of oral vitamin B12 (50 micrograms). It is difficult to explain clinically why low doses of vitamin B12 are prescribed in the NHS (personal communication, N John, 2004) when it is clear that they will not treat vitamin B12 deficiency. I can just speculate that they have been used as vitamin supplements, in which case they should not be prescribed though the NHS. Oral vitamin B12 in high doses is not available on prescription in the NHS. 2.3. Health Economics The simplest way to describe health economics is by saying that it is the economics applied to health. However, it is not just this, health economics is also a ‘way of thinking’ (Mooney, 2003). As with general economics, health economics is based on the principle that resources are scarce relative to the demands made on them. All health systems in the world, and the NHS is not an exception, have the problem of how best to allocate limited resources (Klein, 1995). Choices of how to allocate resources are inescapable. Health economics tries to minimize the problem by firstly increasing awareness that choices have to be made and then by providing tools to help take rational decisions on how to allocate scarce resources. 17
  • 18. Dr. Josep Vidal-Alaball Resources are things that contribute to the production of an output. In healthcare the principal output is ‘health’, which it is a difficult output to define (Salek, 1999). One of the more important concepts in health economics is the concept of opportunity cost. Opportunity cost is the ‘benefit foregone’ when taking actions (Jefferson et al., 1996). Because the resources are scarce, when we use these resources in a particular way we have to be aware that there is an opportunity foregone to obtain benefits if using the resources in another different way (Mooney et al., 1980, Salek, 1999). As Mooney states: ‘opportunity costs entails sacrifice’ (Mooney, 2003). Another important concept is efficiency which Salek defined as ‘maximising the benefits from available resources’ (Salek, 1999). In health, economics efficiency means obtaining as much health as possible from the resources available. 2.2.1. Methods of Economic Evaluation There are four main methods of economic evaluation: cost effectiveness analysis, cost benefit analysis, cost utility analysis and cost minimisation analysis (Jefferson et al., 1996, Drummond et al., 1997, Mooney, 2003): 2.2.1.1. Cost benefit analysis (CBA) This economic analysis intends to determine the value of interventions that have different therapeutic outcomes by assigning monetary value to costs and therapeutic benefits. The CBA deals with the question of ‘whether’ and ‘how much’ and this is why it can assist decision- makers. When doing this economic analysis all costs and benefits related with a particular project are counted and measured in money terms. Two basic principles are used: do only things where benefits exceed costs and do not do things where costs exc eed benefits (Mooney, 2003). The CBA has the difficulty of trying to give monetary va lue to benefits and health consequences, which makes this study restrictive in the questions it can address. 18
  • 19. Dr. Josep Vidal-Alaball CBA can also be used to compare an intervention against a do-nothing option. For example, with a CBA we could assess the benefit of a programme of water fluoridation compared with do-nothing. In this case, we would have to give monetary values to the health gains expected and compare them with the direct and indirect costs of the action. 2.2.1.2. Cost effectiveness analysis (CEA) This economic ana lysis is used to compare interventions that are similar, have similar outcomes and therefore can be measured in identical units. The different interventions are compared in terms of cost per unit. Once it has been decided to do an intervention or project, the CEA tries to address the question of ‘how’ to achieve an objective at the lowest cost or which is the most effective way to achieve an objective. In CEA the effectiveness data can be obtained through the existing medical literature but can also be obtained by conducting the CEA alongside randomised controlled trials (Jefferson et al., 1996). It has the advantage over CBA of being able to measure different outcomes but the CEA is not very useful when the consequences of the interventions are very different. An example of a situation where a CEA has been used is when comparing which is the most cost effective way (considering mortality and post operative infection as outcomes) to perform hysterectomies; using laparoscopy or using the conventional technique (vaginal or abdominal). In 2004, Sculpher et al. conducted a RCT and a CEA comparing both techniques. They concluded that laparoscopic hysterectomy was not cost effective compared to vaginal hysterectomy (Sculpher et al., 2004). 2.2.1.3. Cost minimisation analysis (CMA) In this economic analysis, the interventions compared are considered to have the same consequences and only the inputs are taken into consideration. It is absolutely necessary that the CMA is based on existing medical evidence of effectiveness and that all dimensions have been considered (physical, psychical and social). Some authors maintain that a cost minimisation analysis is really a special form of CEA (Drummond et al., 1997). 19
  • 20. Dr. Josep Vidal-Alaball I found an example of CMA in the study done by Coast et al. comparing the costs associated with early discharge to a hospital at home scheme with the costs associated with acute hospital care (Coast et al., 1998). They randomised patients either to hospital at home or to routine hospital care and because they obtained very similar results in terms of effectiveness and acceptability, they decided to perform a CMA. After the economic analysis, they concluded that the hospital at home programme was less costly than the acute hospital care. 2.2.1.4. Cost utility analysis (CUA) This sophisticated economic analysis is used to compare interventions that produce different consequences in terms of quantity and quality of life (Jefferson et al., 1996). It is a variation of the CEA but takes into consideration patient choices and preferences for the effects of an intervention. CEA and CUA are identical on the cost side, but are different on the outcome side (Drummond et al., 1997). It uses a multidimensional measure of health called QALY (quality-adjusted- life-year) as unit to measure quality and quantity of life. This unit allows comparison of interventions with different outputs. It is a sophisticated economic analysis because it tries to compare the different consequences of different interventions in different problems. However, the CUA has some problems; the main one is that assumes that health is just about health maximisation, ignoring that there are other issues like equity. The QALY league tables, which put different interventions in terms of cost-per-QALY order, are known for being inequitable to the elderly (Jefferson et al., 1996). CUA has been used widely in situations in which quality of life is a very important outcome and in situations where we want to know whether the effect of a new intervention justifies the costs of its implementation. An example of the later is the CUA conducted by Forbes and colleagues in 1999 when they evalua ted the cost utility of interferon beta-1b in secondary progressive multiple sclerosis. They calculated the cost per QALY gained with the new medication and concluded that the high cost per QALY gained (over £1 million) did not justify the availability of the medication though the NHS. The authors also indicated that money could be better spent on other ways of improving quality of life in patients with secondary progressive multiple sclerosis (Forbes et al., 1999). 20
  • 21. Dr. Josep Vidal-Alaball 3. Methods I used methods of health economic analysis to identify, measure and value the resources used with the current treatment of vitamin B12 deficiency with intramuscular vitamin B12 . I looked at how those resources would change if we use high doses of oral vitamin B12 , establishing if savings could be made by switching to the oral regime (CCOHTA, 1996). I excluded several methods of economic evaluation; I excluded CBA because this method is used to decide whether an intervention is worth pursuing and in this case, it is well known that vitamin B12 replacement is a beneficial therapy for vitamin B12 deficiency. I excluded CUA because I did not have data about quality of life of people on vitamin B12 replacement. CEA could have been an appropriate method to use if the effectiveness of both interventions were different, but in this case, I have robust evidence that the effectiveness of both intramuscular and oral vitamin B12 treatments is the same and they have the same consequences (Vidal-Alaball et al., 2004). Therefore, I performed a cost minimisation analysis. With a CMA, I want to find which is the cheapest way to treat vitamin B12 deficiency. 3.1. Effectiveness estimation In the systematic review I have conducted with other colleagues, we concluded that high doses of oral vitamin B12 are as effective as intramuscular vitamin B12 in treating vitamin B12 deficiency (Vidal- Alaball et al., 2004). Another requisite before performing a CMA is to be sure that the adverse effects and compliance are the same between interventions. Through our extensive literature research as part of the systematic review we have found several research studies supporting the fact that oral and intramuscular vitamin B12 have the same adverse effects and the same compliance (Hathcock and Troendle, 1991, Nyholm et al., 2003, Bolaman et al., 2003, Andres et al., 2003). 21
  • 22. Dr. Josep Vidal-Alaball 3.2. Identification of resources I had to identify all the resources attributable to intramuscular vitamin B12 . I identified two types of resources: direct and indirect. 3.2.1. Direct resources These are the resources directly involved in the administration of intramuscular vitamin B12 . They include the cost of the drug and the costs of drug administration. The costs of the drug include the costs of the medication, the costs of laboratory monitoring and the costs of the syringe, needle and needle disposal. The costs of administration are mainly the costs of nursing time, which in many cases will involve a home visit. 3.2.2. Indirect resources They are resources not directly attributable to the administration of intramuscular vitamin B12 . These resources include building maintenance, computer maintenance, gas-electricity, telephone and medical insurance. They may also incorporate patients’ experience. Other indirect resources more difficult to evaluate are the costs of productivity and production losses incurred by the patient and the society, including time lost from work and lost wages, loss of leisure time and time lost in travelling to the surgery. Table 1. Resources identified Directs resources Indirect resources Medication Room/room maintenance Syringe and needle Gas-electricity Needle disposal Building maintenance Nursing/GP time Computer maintenance Home visits Telephone charges Laboratory monitoring Medical insurance 22
  • 23. Dr. Josep Vidal-Alaball 3.3. Measurements of resource use Most economic analyses are conducted as part of bigger trials with the economic data being collected alongside the running of the trial. This allows researchers to use primary data specifically collected during the study, reflecting the context in which the intervention is delivered. When this is not possible, researchers can also use other sources for data gathering. In this study, I determined the quantity of resources required in the treatment with intramuscular vitamin B12 using secondary data obtained from databases, experts and the literature available. 3.4. Cost valuation For this study I have used pound sterling (£) to put prices to the resources identified. I have used UK prices from the primary care perspective of the National Health Service (NHS). When possible, I have taken into account resource variation in Wales. By taking a NHS perspective I am aware I am taking a pragmatic approach and I am not taking into consideration patient borne costs and cost for society, the reason for this is that these would be very difficult to quantify though secondary data. Ideally, these costs should be collected by questionnaire or direct interview, but this was not possible due to the limitations of my resources. 3.4.1 Costs of medication 3.4.1.1. Intramuscular vitamin B12 Intramuscular vitamin B12 can be administered in two forms: hydroxocobalamin and cyanocobalamin. Cyanocobalamin has a lower bioavailability (it is excreted more quickly by the system) than hydroxocobalamin and needs to be given every month; by contrast hydroxocobalamin can be given every 3 months (BNF, 2004). In UK, the most commonly used form is hydroxocobalamin. The price of Hydroxocobalamin injection was extracted from the British National Formulary. 23
  • 24. Dr. Josep Vidal-Alaball 3.4.1.2. Oral vitamin B12 Oral vitamin B12 in high doses (1,000 mcg) is not available through NHS prescription but is widely available in Health Shops and on the Internet. I conducted an Internet search and found several sites selling vitamin B12 . I used the cheapest price in my calculations. Experts in the field indicate that it is very likely that in the future, oral vitamin B12 therapy will be available at high doses on NHS prescription as there is an international drug company planning to produce high dose oral vitamin B12 in the future (personal communication, E Nyholm, 2004). In this study, I assumed that the cost of the oral medicatio n for the NHS would be the same as the current cost of oral vitamin B12 on the Internet. 3.4.2. Costs of syringes and needles The administration of intramuscular vitamin B requires the use of a 2 mL syringe 12 and a blue needle. To estimate the prices of the syringes and needles used for the administration of intramuscular vitamin B12 I contacted Bridgend Stores, a company providing medical supplies in the south of Wales. 3.4.3. Costs of consultations In my study, I looked at the opportunity costs (that reflect the benefit foregone) of General Practitioners’, practice nurses’ and district nurses’ time. It is quite challenging to try to establish the costs of consultations in primary care and there is not an established method to do this. The main problem is that it is difficult to make an accurate estimate of the length of the consultation and to take into account all GP’s overheads and ancillary staff costs (Hughes, 1991). Hughes recommends using income as a proxy for the value of GP’s time, wages as proxy for the value of ancillary staff time and market values as a proxy for costs of overheads. Given the complexity of calculating the costs of the consultations specifically associated with the treatment of vitamin B12 deficiency, I decided to use data from the 24
  • 25. Dr. Josep Vidal-Alaball Personal Social Services Research Unit, a prestigious unit supported by the Department of Health (Netten and Curtis, 2003). This Unit provides estimates of costs in health and social care. These cover Great Britain and apply discount rates of 3.5% (see example in appendix 7.2). 3.4.3.1. District nurse During my experience as General Practitioner I have seen that district nurses are the ones that administer intramuscular medication when patients can not attend to the surgery, the only exception for this could be the case in what a GP administers the injection when doing a visit for another medical reason. In this study, I have assumed that district nurses do all home visits to administer intramuscular vitamin B12 therapy. The Personal Social Services Research Unit used a national average salary for a mid- point G grade district nurse on the April 2002. It did not include any allowances but it included the costs of training, overheads and travel. It considered 20 minutes as the average of time spent in a home visit. 3.4.3.2. Practice nurse I have assumed that when intramuscular vitamin B12 is administered in the practice, a practice nurse does this. The only exception for this will be when GPs administer the injection during another clinical contact. The Personal Social Services Research Unit used a national average salary for a mid-point F grade district nurse in April 2002. It reflected the proportion of nurses receiving a London allowance and it included the costs of training, overheads and travel. 3.4.3.3. General Practitioner For this study, I have assumed that GPs do not administer intramuscular vitamin B12 unless this is opportunistic (e.g. during another clinical contact). The Personal Social Services Research Unit used an average net income for 2002/2003 for a whole time equivalent GP. The data is quite robust as it takes in account several aspects such as: 25
  • 26. Dr. Josep Vidal-Alaball a) Practice expenses: direct care staff and travel (including costs of owing and running a car). b) Working time, allowing time spent per year on annual leave, sick leave and study leave. c) Expenditure not associated with GP activity such as trainees, associates, locums and assistants whose activity results in separate outputs. d) Capital costs: premises and equipment (including medical and computer equipment). e) Overheads such as administration, transfers of medical records, registration of patients, practice premises, staff, IT and personnel development. f) Prescription costs. 3.4.4. Cost of home visits Home visits may be necessary as many patients being treated with vitamin B12 are elderly and may have difficulties attending the practice. I have included the costs of home visits as part of the costs of consultations (GP and nursing time). Home visits are likely to be done by district nurses. I predicted that the cost of the home visits was going to have a big impact in the overall costs of both oral and intramuscular treatments. To try to analyze this I have calculated the overall cost of the administration of vitamin B12 according to two scenarios; one if a home visit is necessary to administer the medication and the other when the patient is able to go to the surgery to receive the treatment. 3.4.5. Conversion costs I had to take into account the initial extra costs likely to be incurred in converting patients from the intramuscular to the oral regime during the first year. This will be a one off spending that will involve physician visits (home visits when necessary) and laboratory tests: full blood count (FBC) and serum vitamin B12 levels. I have taken a cautious approach and I have assumed that three extra GP visits and laboratory tests will be needed during the conversion period. Extra training for physicians may be required. 26
  • 27. Dr. Josep Vidal-Alaball 3.5. Resources excluded For the purposes of this study and due to my limited resources, it I had to exclude small resources associated with the administration of intramuscular vitamin B12 . These resources are very difficult to disentangle from the overall costs of the normal running of a practice in primary care and will be very similar if patients take oral vitamin B12 . For example, I excluded direct costs such as needle disposal and indirect costs such as room and room maintenance, gas-electricity, building maintenance, computer maintenance, telephone charges, medical insurance and administrative time for tracking recalls. I excluded resources that I have no reason to presume would differ between both modes of administering vitamin B12 . This includes laboratory monitoring, as once established, the conversion from intramuscular to oral administration patients will require the same laboratory monitoring. As I mentioned previously I had to exclude the costs for the patients and society. Such excluded costs are travel to the surgery, time lost from work, loss of productivity, loss of leisure time, costs of non-waged time (people not in employment or retired) and intangible costs such as discomfort of the injection and costs associated with anxiety related to the therapy. I also excluded the cost of managing adverse events and side effects, the cost of non- compliance with tablets or injections, and the cost of incomplete medical treatment, as the literature shows that those are rare in both intramuscular and oral administration of vitamin B12 therapy. 27
  • 28. Dr. Josep Vidal-Alaball Table 2. Resources excluded and reason for exclusion Resource Reason for exclusion Needle disposal Part of overall costs of practice Room maintenance Part of overall costs of practice Electricity, heating Part of overall costs of practice Laboratory monitoring Required in oral and intramuscular administration Costs for the patient Very difficult to quantify though secondary data Costs for the society Very difficult to quantify though secondary data Costs of managing adverse effects Rare in oral and intramuscular administration Costs of non compliance Rare in oral and intramuscular administration 3.6. Sensitivity analysis Any economic analysis requires assumptions about the cost of the resources used. These assumptions lead to a degree of uncertainty. When an economic analysis is conducted alongside a clinical trial uncertainty can be handled by using statistical analysis and confidence intervals can be calculated. However, when as in this case, the economic evaluation is not parallel to a clinical trial, statistical methods may be difficult to use and when used, may not be able to totally remove uncertainty. In these cases it is advised that sensitivity analysis is used to see how much the results of the economic analysis could change if we modify the assumptions we have made. 3.6.1. Types of sensitivity analysis Some authors have distinguish three types of sensitivity analysis (Jefferson et al., 1996, Briggs, 1999, Briggs and Gray, 1999) 28
  • 29. Dr. Josep Vidal-Alaball 3.6.1.1. One -way analysis. This technique consists in analysing the impact that each variable has in the study by holding one variable constant and varying the other variables. 3.6.1.2. Extreme scenario analysis This technique consists in generating a best or worse case scenario taking the most optimistic or pessimistic values of the different variables being analysed. 3.6.1.3. Probabilistic sensitivity analysis Briggs says that this approach may produce a more realistic approach to uncertainty (Briggs, 1999, Briggs and Gray, 1999). The technique consists in allowing each different variable to vary simultaneously and analysing the effects that this has on the results of the economic evaluation. In this study, I have used a combination of one-way sensitivity analysis and the extreme scenario analysis to test the robustness of the results. I have analysed the variable I thought had the biggest impact in the study generating the best and worse scenario. I decided not to use probabilistic sensitivity analysis because it was too complex given the context of this study. 3.6.2. Frequency of injections One of the factors that could be affecting the sensibility of this study is the assumption that people will receive four injections of vitamin B12 every year. General Practitioners commonly report that patients receiving intramuscular vitamin B12 want to get the injections more often than the recommended three month period, despite having serum vitamin B12 levels several times the normal range. In order to try to validate this point I used the PCA Wales Prescribing Data (NHS- Wales, 2001), which has data on the total expenditure on vitamin B12 in a year in Wales. I divided these costs by four and I obtained the number of people in Wales that 29
  • 30. Dr. Josep Vidal-Alaball receive vitamin B12 intramuscularly assuming that they receive the injection every three months. I extrapolated this figure to the total Wales population to obtain a theoretical prevalence of vitamin B12 deficiency. In doing this I have to assume that everybody on vitamin B12 treatment are really vitamin B12 deficient. I have also calculated what would happen if patients receive injections five or six times a year and how this would affect the theoretical prevalence. 3.7. Time horizon Due to the long half- life of vitamin B12 in the body, estimated to be more than 480 days (Basu and Dickerson, 1996), a two years follow up is reasonable and this study has used a time horizon of two years. Moreover, the main costs of switching patients to oral vitamin B12 are likely to occur during these two years of monitoring. I have calculated the costs in years one and two to give a better indication of the economic consequences of switching patients to oral vitamin B12 . In my calculations, I have used a discount rate of 3.5%. 3.8. Discounting costs Discount rates are used to reflect the fact that costs and benefits in the future are valued less to us than if they were incurred now (Jefferson et al., 1996). With the discount rates, we adjust the costs and benefits that will occur in the future so we can compare them with the values we have in the present. Choosing the correct discount rate is not easy but it is important, as can have big repercussions when taking decisions that will have an impact in the future. Lower discount rates will lead to more projects presenting a positive result if applied at the present. Although in the international literature authors have used different discount rates, in UK most economists rely on Netten and Curtis that use 3.5%. This is also the minimum rate of return that the Treasure recommends should be used in the current edition of the ‘Green Book’ (HMTreasury, 2003). In this study, I have used this recommended discount rate. 30
  • 31. Dr. Josep Vidal-Alaball 4. Results 4.1. Cost minimisation analysis 4.1.1. Cost of medication 4.1.1.1. Intramuscular vitamin B12 In the UK, intramuscular vitamin B12 is given in the hydroxocobalamin form. In other countries like the US, intramuscular vitamin B12 is given as cyanocobalamin. The reason why hydroxocobalamin is the preferred choice in UK is because this is excreted more slowly than cyanocobalamin and therefore can be administered in longer intervals. In June 2004, the cost of hydroxocobalamin injection was £2.46 per ampoule (BNF, 2004). Assuming that each patient receives four injections a year as recommended by the British National Formulary the costs to the NHS for a year of treatment is £9.84 (£2.46 x 4 = £9.84). 4.1.1.2. High doses of oral vitamin B12 My Internet research identified several sites selling oral vitamin B12 in high dosages (500 and 1,000 mcg), the prices ranged from £7 per 100 tablets to £14 per 120 tablets. The cheapest price available on the Internet was at www.goldshield.co.uk (see appendix 7.1). In August 2004, the cost of oral vitamin B12 1,000 mcg was £7 for 100 tablets (Goldshield, 2004). Assuming that each patient takes one tablet a day, the theoretical cost to the NHS for a year of treatment would be £25.55 (£7 / 100 = £0.07. £0.07 x 365 = £25.55). 4.1.2. Costs of syringes and needles The costs of the 2 mL syringes used to administer intramuscular vitamin B12 is £3.29 for 140 syringes, this represents a unit cost of £0.023 and an annual cost of £0.09 if four injections are administered per year. The cost of the needles used is £1.53 for 100 needles, this represents a cost of £0.015 per unit, hence a cost of £0.06 per year of 31
  • 32. Dr. Josep Vidal-Alaball treatment. The added total cost for syringes and needles is £0.15 a year ((£0.023 x 4) + (£0.015 x 4) = £0.15). 4.1.3. Costs of consultations. 4.1.3.1. District nurse The cost of a district nurse spending on average 20 minutes in a home visit is estimated to be around £20 (Netten and Curtis, 2003). These costs include wages (mid-point for a G grade district nurse), qualifications (pre and post-registration education), overheads, travel and London allowance (not applicable in this study). Assuming that each patient receives four injections a year, this represents a cost for the NHS of £80 a year (£20 x 4 = £80). 4.1.3.2. Practice nurse The cost of a practice nurse performing a procedure such as administering a intramuscular injection in the premises of a primary care practice is estimated to be around £9 per procedure (Netten and Curtis, 2003). These costs include wages (mid- point for a F grade nurse), qualifications (pre and post-registration education), overheads, travel and London allowance. Assuming that each patient receives four injections a year, this represents a cost for the NHS of £36 a year. 4.1.3.3. General Practitioner The cost of a General Practitioner spending on average 9.36 minutes in a consultation with a patient in the practice premises is estimated to be around £20 (Netten and Curtis, 2003). These costs include wages (net remuneration of £67,911 per annum), qualifications (pre, post-registration education and on- going training), overheads, practice expenses (direct care staff and capital costs of premises and equipment), and travel (costs of owning and running a car). 32
  • 33. Dr. Josep Vidal-Alaball 4.1.4. Costs of home visits As mentioned previously the cost of a district nurse spending on average 20 minutes in a home visit is estimated to be around £20 (Netten and Curtis, 2003). The cost of a General Practitioner doing a home visit lasting on average 13.2 minutes (plus 12 minute travel time) is £61 (Netten and Curtis, 2003). However, GPs are unlikely to do home visits to administer intramuscular vitamin B12 unless this is part of another clinical contact. 4.1.5. Conversion costs 4.1.5.1. Laboratory costs The laboratory costs of monitoring patients on high doses of oral vitamin B12 are the same costs as monitoring people on the intramuscular regime. The NHS laboratory costs of the tests needed for this is £3 for a full blood count (FBC) and £7 for measuring vitamin B12 levels (personal communication, T Gorvett, 2004). These tests are usually requested once a year. When converting patients from intramuscular to oral vitamin B12 the same tests will be necessary but during the first year, a closer monitoring will be required to ensure compliance and response to the treatment. Assuming that three extra blood extractions will be necessary during the first year, the laboratory costs of converting people will be £30 in the first year ((£3 + £7) x 3 = £30). 4.1.5.2. Physician visits The conversion costs will also include the costs of physician visits, which have been mentioned previously. The visits necessary in order to convert patients from intramuscular to high doses of oral vitamin B12 will be carried out by GPs who will need to see these patients an extra three times a year, this will mean a cost of £60 a year if no home visits are involved (£20 x 3 = £60) and £183 if home visits are required (£61 x 3 = £183). 33
  • 34. Dr. Josep Vidal-Alaball 4.1.5.3. Extra training The costs of the extra training that may be required for GPs involved in changing people from intramuscular to the oral regime has been included in the costs of GP consultations as these costs already include a sum for ongoing training. The total conversion costs will range from a minimum of £90 a year if no home visits are required to a maximum of £213 if three home visits are necessary. Conversion costs = laboratory costs x 3 + physician visits x 3 No home visit required. Conversion costs = £30 + £60 = £90 Home visit required. Conversion costs = £30 + £183 = £213 4.2. Cost of resources used in intramuscular treatment compared with oral treatment 4.2.1. Costs during the first year During the first year of conversion from intramuscular to high doses of oral vitamin B12 , the oral regime is remarkably more expensive. This is caused mainly by the initial conversion costs required during this period. Table 3. Cost vitamin B12 replacement. First year Cost per year in £ Intramuscular Oral Medication 9.84 25.55 GP / nursing time 36 to 80 included in conversion costs Syringe and needle 0.15 ------- Conversion costs ------- 90 to 213 (first year) Laboratory monitoring 10 10 TOTAL 55.99 to 99.99 125.55 to 248.55 34
  • 35. Dr. Josep Vidal-Alaball 4.2.2. Costs during the second year During the second year, once the conversion period has ended, the oral regime is cheaper than the intramuscular. This is mainly due to the decreased need for nursing and GP’s time. These calculations are also valid for newly diagnosed patients with B12 deficiency who have been started on oral vitamin B12 , as no conversion will be required. Table 4. Cost vitamin B12 replacement. Second year Cost per year in £ Intramuscular Oral Medication 9.84 25.55 GP / nursing time 36 to 80 ------- Syringe and needle 0.15 ------- Laboratory monitoring 10 10 TOTAL 55.99 to 99.99 35.55 4.2.3. Added costs during the first two years At two years, the cost of both treatments is more similar and in 3-4 years, the oral therapy would be cheaper than the intramuscular regime. Table 5. Added costs vitamin B12 replacement. First two years Cost in £ Intramuscular Oral First year 55.99 to 99.99 125.55 to 248.55 Second year 55.99 to 99.99 35.55 TOTAL 111.98 to 199.98 161.1 to 284.1 35
  • 36. Dr. Josep Vidal-Alaball 4.3. Sensitivity analysis 4.3.1. One -way and extreme scenario analysis. Looking at the numbers, it is clear that the variable home visits is the one that has a bigger impact on the calculations. If we assume all intramuscular injections are administered by a practice nurse in the primary care premises the cost in terms of nursing time is £36 a year. If home visits are required by district nurses the costs increases to £80 a year. In the oral treatment, home visits have also a big impact but these are centred around the conversion period. If home visits are not required during the conversion period the total cost per patient using oral vitamin B12 in the first year is £125.55, however if home visits are required this cost increases to £248.55. It has to be emphasized again that this cost will only be incurred during the initial conversion year. 4.3.2. Costs of intramuscular and oral vitamin B12 in the first year depending on whether home visits are required The following table illustrates the impact that home visits, would have in the costs of intramuscular and oral vitamin B12 during the first year. This impact is particularly important in the oral regime because more visits would be required during the conversion period. In the scenario where no home visits are required, converting people from intramuscular to oral vitamin B12 would incur an extra cost of £69.56. If home visits were required, this would represent an extra cost of £148.56 per person. £ Intramuscular vitamin B12 Oral vitamin B12 Difference No home visit 55.99 125.55 69.56 Home visit 99.99 248.55 148.56 36
  • 37. Dr. Josep Vidal-Alaball 4.3.3. Costs of intramuscular and oral vitamin B12 in the second year and in newly diagnosed patients related to home visits After the initial conversion period and in newly diagnosed patients the picture is very different. The variable ho me visits has its higher impact on the intramuscular treatment. The reason for this is that no home visits would be required with oral vitamin B12 . £ Intramuscular vitamin B12 Oral vitamin B12 Difference No home visit 55.99 35.55 - 20.44 Home visit 99.99 35.55 - 64.44 4.3.4. Frequency of injections and prevalence of vitamin B12 deficiency PCA Wales Prescribing Data shows that in 2001 the costs of prescribed intramuscular vitamin B12 in Wales was £335,120 (NHS-Wales, 2001). Of this, £317,350 corresponded to the cost of intramuscular vitamin B12 (hydroxocobalamin). This cost divided by four (four injections a year) and the cost of the Hydroxocobalamin injection (£2.46 per ampoule) give us 32,251 patients in Wales who were receiving intramuscular vitamin B12 . In 2001 the total population of Wales was 2,903,085 (Census-Wales, 2001). Taking into account this population, the number of people on intramuscular vitamin B12 would represent 1.11% of the population of Wales. If injections were administered five times a year, the number of people on intramuscular vitamin B12 would represent 0.89% of the population of Wales. If injections were administered six times a year, the number of people on intramuscular vitamin B12 would represent 0.74% of the population of Wales. 37
  • 38. Dr. Josep Vidal-Alaball 4.4. Discounting costs In some studies, when for example different treatments were lasting different periods of time, discount rates will be very important. However, in my study, the costs of oral and intramuscular vitamin B treatments have been calculated in both cases at one 12 and two years, making no difference when analysing the results. Although in this particularly study applying a discount rate was not going to change the outcome of my conclusion, I decided to calculate them as an exercise and to produce a more accurate value for the costs of both treatments. The calculation is performed in the following way (Drummond et al., 1997): P = ? Fn (1+r)-n = F 1 / (1+r) + F 2 / (1+r)2 P = present value Fn = future costs at year n r = annual discount rate In this case: P= 55.99/(1.035) + 55.99/(1.035) 2 = 106.38 P= 99.99/(1.035) + 99.99/(1.035) 2 = 189.97 P= 125.55/(1.035) + 35.55/(1.035) 2 = 154.49 P= 248.55/(1.035) + 35.55/(1.035) 2 = 273.33 Costs of intramuscular and oral vitamin B12 at two years applying discount rates Cost in £ Intramuscular Oral TOTAL 106.38 to 189.97 154.49 to 273.33 38
  • 39. Dr. Josep Vidal-Alaball 5. Discussion Two randomized controlled trials and several non-randomized studies suggest that high oral doses of B12 are as effective as intramuscular administration in achieving haematological and neurological responses in the treatment of vitamin B12 deficiency. This cost minimisation stud y has examined the total cost of the resources associated with the treatment of vitamin B12 deficiency with intramuscular vitamin B12 in Wales and has compared them with the cost of treating the same condition with high doses of oral vitamin B12 . The study has tried to establish whether savings could be made by changing patients from intramuscular to oral therapy. I have used Wales as a geographical boundary for my calculations. However, there is no reason to think that the results I have presented here are not easy to extrapolate to other areas in the UK. 5.1. Summary of results This cost minimisation analysis suggests that changing patients with vitamin B12 deficiency from intramuscular to oral treatment could save resources to the NHS. These savings would come mainly in the form of nursing time. The nursing time that could be freed by using the oral regime could be used in providing other services. Initial conversion costs increase considerably the cost of switching patients to high dose oral vitamin B12 . These costs are estimated to be between £90 and £213 but they are just applicable during the first year and are not necessary in patients starting new treatment after being diagnosed with vitamin B12 deficiency. The savings obtained by changing patients from intramuscular to oral vitamin B12 would be obtained in the medium to long term. In the short term (2-3 years) and because the high conversion costs, oral vitamin B12 would be more expensive than the intramuscular regime. 39
  • 40. Dr. Josep Vidal-Alaball For newly diagnosed patients with vitamin B12 deficiency it would be considerable cheaper to use high doses of oral vitamin B12 rather than intramuscular vitamin B12 . I have calculated the cost of the resources used to treat patients with vitamin B12 deficiency with intramuscular vitamin B12 to be between £55.99 and £99.99 per year. The cost of treating patients with high doses of oral vitamin B12 once they have been converted or in new patients is £35.55 per year. Sensitivity analysis shows that the results of my analysis are robust. The variable ‘home visit’ has a higher impact in the oral regime because the initial conversion period required to switch patients from intramuscular to oral vitamin B12 . After the initial conversion period, home visits only have an impact on the intramuscular regime. In this last scenario, even when we remove the costs of the home visits that could be associated with the intramuscular treatment, the oral treatment is still cheaper than the intramuscular (£35.55 versus £59.99) because there is less need for nursing time. I have assumed that three extra blood test and visits will be necessary during the first year to monitor conversion to oral vitamin B12 but it can be argued that the efficacy of the oral regime has already been established and the conversion from intramuscular to high doses of oral vitamin B12 does not need this extra monitoring. I have taken a cautious approach but if fewer blood tests and visits, particularly home visits, were required, this would considerably reduce the costs of the oral treatment during the first year, making an even clearer case for the use of oral vitamin B12 . Another reason why I think this study probably underestimates the cost savings of high doses of oral vitamin B12 is because it is reasonable to expect that during the conversion period, some GPs will discuss switching to the oral regime during consultations for other medical problems and the blood test necessary may be scheduled as part of routine blood testing for other conditions. However, it can be also argued that many intramuscular injections of vitamin B12 may likewise be given at the same time as another clinical contact with a GP, practice nurse or district nurse occurs. 40
  • 41. Dr. Josep Vidal-Alaball 5.2. Prevalence of vitamin B12 deficiency in Wales Although this was not initially part of my study, I could not resist the temptation of speculating about the prevalence of vitamin B12 deficiency in Wales. Several figures for prevalence of vitamin B12 deficiency have been given in different studies and I tried to calculate the prevalence in Wales taking into account the numbers of prescriptions of intramuscular vitamin B12 issued in Wales in 2001 (NHS-Wales, 2001). Assuming that people on vitamin B12 are really vitamin B12 deficient and that they receive four injections a year, I obtained a prevalence of 1.17%. Prevalence between 1.5 and 15% has been reported in the elderly but it is though to be lower amongst the whole population. In 1971, Archie Cochrane (using data from 1966) compared the expected amount of intramuscular vitamin B12 which should be expected to be prescribed on the basis of good clinical practice, with the amount actually prescribed and reported a prevalence of pernicious anaemia (principal cause of vitamin B12 deficienc y) of 0.153% in Wales (Cochrane and Moore, 1971). Therefore, a prevalence of 1.17% in Wales appears to be excessive. This excess in prevalence could have two explanations; patients may receive intramuscular vitamin B12 more often than the recommended period of three months, or some patients receiving vitamin B12 treatment are not really vitamin B12 deficient. It is also possible that Cochrane and Moore underestimated the prevalence of vitamin B12 deficiency. GPs have reported that patients on intramuscular vitamin B12 therapy want to receive the injections more often than the recommended three month period, despite having normal serum vitamin B12 levels. Some patients report that they feel better following an injection of the drug (Jennings, 1996). Several studies have showed that many patients receive more vitamin B12 injections than the recommend fo ur a year (Cochrane and Moore, 1971, Middleton and Wells, 1985, Fraser et al., 1995, van Walraven and Naylor, 1999, Dempsey, 2003). In the context of this study if injections are given more often than the three month period I have used, this will increase the resources needed in the treatment with intramuscular vitamin B12 , making even a stronger case for the oral treatment. The reason why some patients request and receive vitamin B12 injections even when they are not necessary is not clear. Some authors 41
  • 42. Dr. Josep Vidal-Alaball have suggested that intramuscular B12 may carry additional psychotropic effects for patients (personal communication, CC Butler, 2004), which exceed those normally associated with normalisation of vitamin B12 serum levels (Newbold, 1989). Possible psychotropic effects are important because it may make GPs and patients reluctant to implement oral therapy for B12 deficiency, despite this being as effective and probably cheaper than intramuscular treatment. I am aware this is a very rudimentary calculation and that I would need more elements to calculate the real prevalence of vitamin B12 deficiency in Wales. This however would be part of a different research study. 5.3. Limitations of the study I have attempted to minimise the limitations of my study by performing a sensitivity analysis. However, a number of limitations in the study need to be taken into considerations when evaluating the results: 5.3.1. Effectiveness estimation Despite having apparently robust evidence though a systematic review and several case control studies that the effectiveness of both intramuscular and oral vitamin B12 treatments is the same, the systematic review included just two randomized controlled trials (Kuzminski et al., 1998, Bolaman et al., 2003). These two randomized control trials have some limitations themselves; they have relatively short follow up periods (1 to 4 months) and relatively small number of participants (93 participants). None of the studies was conducted in primary care where most of the patients with vitamin B12 deficiencies are treated; this makes the generalisation of the results more difficult. 5.3.2. Adverse reactions and compliance As I mentioned previously, another of the pre-requisites when conducting this study was that any risks and adverse reactions to either the intramuscular or the oral route 42
  • 43. Dr. Josep Vidal-Alaball were the same. Whilst I am convinced this is the case in the treatment of vitamin B12 deficiency, I think this issue has enough relevance to require further explanation: Vitamin B12 is generally considered to have very low toxicity. A report from the Committee on Medical Aspects of Food Policy stated that ‘vitamin B12 has extremely low toxicity; it is toxic at only g/kg intakes in experimental animals, and no toxic effects have been encountered in man’ (DH, 1991). Intramuscular injections of vitamin B12 have been used for the treatment of vitamin B12 deficiency since the early fifties and serious adverse reactions such as anaphylaxis are very rare. However, injections can be dangerous in anticoagulated patients and could cause pain in very thin patients (Elia, 1998). Oral vitamin B12 has few toxic effects in animals and there are no reported cases of toxicity in humans (Miller and Hayes, 1982). The dose of 1,000 micrograms I have used provides an important margin of safety (Hathcock and Troendle, 1991). In my literature review, I did not find any study reporting adverse reactions from high doses of oral vitamin B12 and some of the studies specifically reported that there were not treatment-related adverse effects (Berlin et al., 1968, Bolaman et al., 2003, Andres et al., 2003). The compliance between both routes intramuscular and oral has to be very similar in order to be able to conduct this CMA and this point can be open for discussion. It can be argued that with intramuscular injections it is easier to ensure compliance because nurses will give the injections. With the oral treatment, the compliance can decrease, as it is well known that many patients do not take the tablets prescribed by their doctors. However, similarly, patients may not go to the surgery to receive the injection or they may receive the injection more often than required. Studies of oral vitamin B12 have reported good compliance with the treatment, very similar to the intramuscular regime (Reisner et al., 1955, Berlin et al., 1968). 5.3.3. Identification of resources I have estimated the resources using my experience in clinical practice, data obtained from experts in the field of vitamin B12 deficiency and the findings of the literature review I performed when conducting the systematic review. 43
  • 44. Dr. Josep Vidal-Alaball As I have mentioned previously, in this study the utilization of resources required in the treatment with intramuscular vitamin B12 has not been estimated from a pharmacoeconomic clinical trial and therefore I have not been able to apply statistical methods used in health economics such as Bootstrapping (a method that obtains an estimate of the error by resampling). 5.3.4. Resources excluded In any economic analysis, the more controversial aspect is the decision about excluding resources. I have excluded resources that are part of the overall costs of the practice and resources that are not different in the intramuscular or oral administration of vitamin B12 . I have also excluded the costs of managing side effects, costs of non-compliance and costs for patients and society. I have justified my decisions in the methods section. 5.3.5. Costs for the patient In this study, the resources have been calculated using a NHS perspective without taking into consideration patient borne costs and cost for society. It could be argued that by switching to oral medication what we are doing is shifting the costs to the patients. What it is cheaper for the NHS may not be cheaper for the patient or the society. For example, it may be cheaper for the NHS to have patients attending a clinic in a hospital but for the patient this could represent a long journey by car and for the society this may cause time lost at work. Some authors have indicated that costs to the patient are too often overlooked and should not be excluded in the economic analysis. Including these costs could lead to a higher estimate of the costs of the consultations. Kernick and colleagues counted the indirect costs that 510 adults incurred by visiting their GP surgery and estimated that the average costs were £4.84 if aged over 65 years and £5.45 for patients under 65 44
  • 45. Dr. Josep Vidal-Alaball years. This included work time loss (average of £8.71 per hour), non-waged time (£4.57 per hour) and car costs (39.8p per mile). They concluded that including these patient costs would raise the cost of a GP consultation by one-quarter, approximately £5 (Kernick et al., 2000). In this study, not using a patient perspective has lead to an underestimation of the costs savings made by using high doses of oral vitamin B12 because after the initial conversion period, fewer visits to the nurse (and therefore less travel and time) will be required with oral therapy. On the other hand, the time needed to collect prescriptions for oral vitamin B12 , likely to be less than a surgery visit, may also need consideration. 5.3.6. Opportunity costs This economic study, like many health economic evaluations, tacitly assumes that resources that are freed up will be redeployed efficiently. In this case, I have assumed that resources freed up by changing from intramuscular to high doses of oral vitamin B12 , mainly nursing time, will be efficiently used to provide other services to other patients. If the time freed up is not used in this way no savings will be made. I could have explored this in more detail by looking at fixed, variable and marginal costs, but I decided to use a pure health economic approach. 5.3.7. Cost of vitamin B12 in high doses I have assumed that the price of high doses of vitamin B12 (1,000 micrograms) would be the actual price found on the Internet. If, as expected, an international drug company starts producing oral vitamin B12 , the prices will probably decrease, making the oral regime cheaper for the NHS. 5.3.8. Prescription Charges At the moment in Wales, patients pay a prescription fee for their medication. When vitamin B12 is given intramuscularly, patients pay four prescriptions a year. However, if given orally patients would have to pay twelve prescription charges a year, making the oral regime more expensive for patients. In Wales, this is going to change in 2007 45
  • 46. Dr. Josep Vidal-Alaball when all prescription charges will be abolished, but it has more relevance in other parts of the country where prescriptions charges will be still in place. However, the fact that vitamin B12 affects mainly an elderly population makes prescription charges less relevant because those over 60 years of age are exempt from paying for their prescriptions. 5.4. How this fits in with other work Very few studies have looked at the cost of vitamin B12 replacement. Some studies have reported that saving could be make by switching to oral vitamin B12 treatment (Nyholm et al., 2003) but I found only three studies that provided data about it. In 1985, Middleton and Wells specifically looked at resources used in treatment with intramuscular vitamin B12 administered by district nurses in home visits in the UK. They studied 492 patients and, apart from reporting that 78% of the patients were receiving injections more often than required, they concluded that changes in vitamin B12 prescribing could make between 600 and 1470 nursing hours available for other patients needs. The y gave a monetary value to the extra injections unnecessarily administered of £640 a year for the drug and £600 for syringes and needles. They also calculated that the extra time required by district nurses represented £4,500 a year. Finally, they reported that the cost of vitamin B12 administered intramuscularly was £42 a year per patient (Middleton and Wells, 1985). Although it is difficult to compare as the study was done nearly 20 years ago, the results are similar to those of my study; I have reported that intramuscular vitamin B12 administered at home by district nurses represents a cost of £99.99 a year per patient in the year 2004. More recently, Bolaman and colleagues reported that the cost of treatment with vitamin B12 for the participants in their study conducted in Turkey was $80 (£41) per person in the oral group and $220 (£113) per person in the intramuscular group (drug and injection) (Bolaman et al., 2003). I could not compare these results with the ones in my study as the authors did not provide any information about how they calculated the costs. 46
  • 47. Dr. Josep Vidal-Alaball The only study I found comparing oral and intramuscular treatment with vitamin B12 was the one conducted by Van Walraven and colleagues in Ontario (Canada). The study estimated the savings that could be made if all elderly patients receiving vitamin B12 injections were switched to high-dose oral therapy. The authors specifically considered the costs of drugs, injections, pharmacists’ fees, physician visits and the costs incurred from conversion. They concluded that the cost of vitamin B12 therapy averaged $145.88 (£63) per person per year if administered intramuscularly and $92.6 (£40) if given orally, including conversion costs (van Walraven et al., 2001). Costs for intramuscular therapy are similar to the ones found in my study but it is remarkable that costs of the oral treatment are much lower even considering the initial conversion costs. This is possibly because the authors have considered that just two extra visits to the GP and one extra blood test will be necessary during the conversion period. I have taken a more cautious approach considering that three extra visits and blood tests will be required. The authors have also found cheaper vitamin B12 tablets and have considered that a visit to a GP cost $16.25 (£7). 5.5. Implications for service delivery The finding of my study could have implications for service delivery as switching patients to oral vitamin B12 could save the NHS money. However, it is essential that the change in route of administration is accepted by the patients receiving the treatment if we want this to be successful. Ultimately, the patient should decide whether oral or intramuscular vitamin B12 is used. I have looked at studies where patients’ choice was reported. In USA, Lederle reported that 50% of patients asked preferred injections of vitamin B12 and 44% a daily pill (Lederle, 1991). However, in a recent study conducted by Nyhold and colleagues in the UK, most patients (83%) preferred the tablet to the injection and 87% of patients found the tablets highly acceptable (Nyholm et al., 2003). It is significant that only half of the patients agreed to participate in the study. The author’s conclusions that patients much prefer oral medication could be therefore disproportionate. Possible psychotropic effects of the intramuscular treatment mentioned previously could make patients reluctant to change to oral therapy. 47
  • 48. Dr. Josep Vidal-Alaball 6. Conclusions According to the results of this study, changing patients with vitamin B12 deficiency from intramuscular to oral treatment could save resources to the NHS in the medium and long term. Intramuscular vitamin B12 injections take up resources, mainly nursing time that could be used for other services, perhaps with better returns. At the present time, with acute shortages of nurses in the NHS and the need to employ nurses from other countries, savings in the form of nursing time should not be underestimated. In the short term (2-3 years) and because the high conversion costs, oral vitamin B12 will be more expensive than the intramuscular regime. For newly diagnosed patients with vitamin B12 deficiency it could be considerably cheaper to use high dose oral vitamin B12 instead of intramuscular vitamin B12 . A rudimentary calculation of the prevalence of vitamin B12 deficienc y in Wales based on the costs of the prescriptions issued in 2001 seems to indicate a higher prevalence than expected (1.17%.). This could be explained by excessive prescription or administration. More research is needed to try to understand why some patients receive vitamin B12 injections when there is no clear clinical indication for it, why some patients receive injections more frequently than the adequate interval and why some patients may be reluctant to switch to oral vitamin B12 therapy. 48
  • 49. Dr. Josep Vidal-Alaball 7. Appendix 7.1. Prices of oral vitamin B12 (1,000 mcg) on the Internet. 26/08/04 Price (£) Cost per year (£) Goldshield 7.00 (100 tablets) 25.55 www.egoldshield.com Holland and Barrett 7.19 (100 tablets) 26.24 www.hollandandbarrett.com Solgar Store 8.89 (100 tablets) 32.45 www.solgar.co.uk The Garden Pharmacy 8.95 (100 tablets) 32.30 www.garden.co.uk Natures Concept 8.96 (100 tablets) 32.70 www.discountvitaminsandherbs.com HEALTH AID 10.99 (100 tablets) 40.11 www.auravita.com The Health Leads shop 9.90 (90 tablets) 40.15 www.blueriver-aromatherapy.co.uk Lamberts 6.70 (60 tablets) 40.76 www.auravita.com The World Wide Shopping Mall 11.99 (100 tablets) 43.76 www.worldwideshoppingmall.co.uk Vega Nutritionals 14.99 (120 tablets) 45.59 www.auravita.com 49
  • 50. Dr. Josep Vidal-Alaball 7.2. Personal Social Services Research Unit Example of calculation of unit costs for District Nurses (Netten and Curtis, 2003). UNIT COSTS OF HEALTH AND SOCIAL CARE 2003 Schema 9.1 District nurse Costs and unit 2002/2003 Notes estimation value A. Wages/salary £25,015 per National average salary, based on the April 2002 year scale mid-point for a G grade district nurse. The sum does not include any lump sum allowances or pay enhancements for unsocial hours worked. B. Salary oncosts £2,672 per Employers’ national insurance plus 4 per cent of year salary for employers’ contribution to superannuation. C. Qualifications £5,027 per The equivalent annual cost of pre-registration and year post-registration education after the total investment cost has been annuitised over the expected working life.1 See schema 7.5 for mo re information on training costs of health professionals D. Overheads £5,150 per Comprises £2,381 for indirect overheads and 10 per year cent of salary costs for direct revenue overheads. E. Capital overheads £1,713 per Based on the new build and land requirements of year community health facilities,2/3 but adjusted to reflect shared used of both treatment and nontreatment space. Capital costs have been annuitised over sixty years at a discount rate of 3.5 per cent. See editorial. At 6 per cent, the cost would be £2,643. F. Travel £1.17 per Taken from Netten4 and inflated using the retail visit price index. Working time 42 wks p.a., Nursing and midwifery staffs negotiating council 37.5 hrs p.w. conditions of service and rates of pay. Includes 25 days annual leave and 10 statutory leave days. Assumes 5 study/training days, and 10 days sickness leave. 50
  • 51. Dr. Josep Vidal-Alaball Ratio of direct to indirect time 1:1.08 Dunnell and Dobbs5 estimated that the proportion of on: face-to-face contacts 1:0.58 working time spent in different locations/activities clinic contacts home visits 1:1.21 was as follows: patient’s own home 38 per cent; clinics 6 per cent; hospitals 2 per cent; other face- to-face settings 2 per cent; travel 24 per cent; non- clinical activity 28 per cent. Patient direct to indirect contact ratios allocate all non-contact time to all contact time. Clinic and home visit multipliers allocate travel time just to home visits. Length of contact 20 mins Per home visit. Based on discussions with a group of NHS Trusts. London multiplier 1.13 x (A to Allows for the higher costs associated with London D) compared to the national average cost.6 1.27 x E Non-London multiplier 0.93 x (A to Allows for the lower costs associated with working D) outside London compared to the national average 0.97 x E cost. Building Cost Information Service and Department of the Environment, Transport and the Regions. Unit costs available 2002/2003 (costs including qualifications given in brackets) £22 (£25) per hour; £46 (£52) per hour spent with a patient; £35 (£40) per hour in clinic; £49 (£56) per hour spent on home visits (includes A to E); £17 (£20) per home visit (includes A to F). 1 Netten, A., Knight, J., Dennett, J., Cooley, R. & Slight, A. (1998) Development of a Ready Reckoner for Staff Costs in the NHS, Vols 1 & 2, Personal Social Services Research Unit, University of Kent, Canterbury. 2 Building Cost Information Service (2003) Surveys of Tender Prices, February, BCIS, London. 3 Department of the Environment, Transport and the Regions (2003) Housing and Construction Statistics 1991-2001, The Stationery Office, London. The appropriate inflator is provided by the DETR on request. 4 Netten, A. (1992) Some cost implications of Caring for People: interim report, Discussion Paper 809/4, Personal Social Services Research Unit, University of Kent. 5 Dunnell, K. & Dobbs, J. (1982) Nurses Working in the Community, OPCS, HMSO. 6 Department of Health (1997) Labour Market Forces Factor, Department of Health, London. 51
  • 52. Dr. Josep Vidal-Alaball 8. Bibliography Andres, E., Kaltenbach, G., Noel, E., Noblet-Dick, M., Perrin, A. E., Vogel, T., Schlienger, J. L., Berthel, M. and Blickle, J. F. (2003) 'Efficacy of short-term oral cobalamin therapy for the treatment of cobalamin deficiencies related to food-cobalamin malabsorption: A study of 30 patients', Clin. Lab. Haem, 25, 161-66. Andres, E., Kurtz, J. E., Perrin, A. E., Maloisel, F., Demangeat, C., Goichot, B. and Schlienger, J. L. (2001) 'Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption', American Journal of Medicine., 111, 126-9. Basu, T. K. and Dickerson, J. W. T. (1996) Vitamins in human health and disease, CAB International, Wallingford. 106-24. Berlin, H., Berlin, R. and Brante, G. (1968) 'Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor', Acta Medica Scandinavica, 184, 247-58. Berlin, R., Berlin, H., Brante, G. and Pilbrant, A. (1978) 'Vitamin B12 body stores during oral and parenteral treatment of pernicious anaemia', Acta Medica Scandinavica, 204, 81-4. BNF (2004) British National Formulary 47, British Medical Association and Royal Pharmaceutical Society of Great Britain, London. 441-2. Bolaman, Z., Kadikoylu, G., Yukselen, V., Yavasoglu, I., Barutca, S. and Senturk, T. (2003) 'Oral Versus Intramuscular Cobalamin Treatment in Megaloblastic Anemia: A Single-Center, Prospective, Randomized, Open-Label Study', Clinical Therapeutics, 25, 3124-34. Briggs, A. (1999) 'Economics notes: Handling uncertainty in economic evaluation', BMJ, 319, 120. Briggs, A. H. and Gray, A. M. (1999) 'Methods in health service research: Handling uncertainty in economic evaluations of healthcare interventions', BMJ, 319, 635-638. CCOHTA (1996) A Guidance Document for the Costing Process, Canadian Coordinating Office for Health Technology Assessment, Ottawa. Census-Wales (2001) Census of Population, Office for National Statistics, London. 52
  • 53. Dr. Josep Vidal-Alaball Clarke, R., Grimley Evans, J., Schneede, J., Nexo, E., Bates, C., Fletcher, A., Prentice, A., Johnston, C., Ueland, P. M., Refsum, H., Sherliker, P., Birks, J., Whitlock, G., Breeze, E. and Scott, J. M. (2004) 'Vitamin B12 and folate deficiency in later life', Age Ageing, 33, 34-41. Coast, J., Richards, S. H., Peters, T. J., Gunnell, D. J., Darlow, M.-A. and Pounsford, J. (1998) 'Hospital at home or acute hospital care? A cost minimisation analysis', BMJ, 316, 1802-1806. Cochrane, A. and Moore, F. (1971) 'Expected and observed values for the prescription of Vitamin B12 in England and Wales', British Journal of Preventative and Social Medicine, 25, 147-151. Delva, M. D. (1997) 'Vitamin B12 replacement. To B12 or not to B12?' Canadian Family Physician, 43, 917-922. Dempsey, O. (2003) 'How many patients may be on parenteral lifelong vitamin B12 therapy unnecessary?' Unpublished, 1-25. DH (1991) Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Report of the Panel on Dietary Reference Values of the Committee on Medical Aspects of Food Policy, Department of Health, London. Drummond, M. F., O'Brien, B., Stoddart, G. L. and Torrance, G. W. (1997) Methods for the economic evaluation of health care programmes, Oxford University Press, Oxford. 6-52. Elia, M. (1998) 'Oral or parenteral therapy for B12 deficiency', Lancet, 352, 1721-2. FAO and WHO (1988) Requirements of vitamin A, iron, folate and vitamin B12. Report of a Joint FAO/WHO Expert Consultation, Food and Agriculture Organization, Rome. Figlin, E., Chetrit, A., Shahar, A., Shpilberg, O., Zivelin, A., Rosenberg, N., Brok- Simoni, F., Gadoth, N., Sela, B.-A. and Seligsohn, U. (2003) 'High prevalences of vitamin B12 and folic acid deficiency in elderly subjects in Israel', British Journal of Haematology, 123, 696-701. Forbes, R. B., Lees, A., Waugh, N. and Swingler, R. J. (1999) 'Population based cost utility study of interferon beta-1b in secondary progressive multiple sclerosis', BMJ, 319, 1529-1533. Fraser, R. C., Farooqi, A. and Sorrie, R. (1995) 'Use of vitamin B-12 in Leicestershire practices: a single topic audit led by a medical audit advisory group', BMJ, 311, 28-30. 53
  • 54. Dr. Josep Vidal-Alaball Goldshield (2004) http://www.egoldshield.com/csp/gsh/egoldshield/index.csp, Accessed: 26/08/04. Hathcock, J. N. and Troendle, G. J. (1991) 'Oral cobalamin for treatment of pernicious anemia?' Journal of the American Medical Association, 265, 96-97. Herbert, V. (2002) Vitamin B12 deficiency, Royal Society of Medicine Press Ltd, London. 1-52. HMTreasury (2003) The Green Book, The Stationery Office, Lo ndon. Hughes, D. (1991) 'Costing Consultations in General Practice: Towards a Standardized Method', Family Practice, 388-393. Jefferson, T., Demicheli, V. and Mugford, M. (1996) Elementary Economic Evaluation in Health Care, BMJ Books, London. 1-83. Jennings, M. (1996) 'A survey of prescribing variation in general practice', British Journal of Medical Economics, 10, 79-82. Kernick, D. P., Reinhold, D. M. and Netten, A. (2000) 'What does it cost the patient to see the doctor?' British Journal of General Practice, 50, 401-403. Klein, R. (1995) 'Priorities and rationing: pragmatism or principles?' BMJ, 311, 761- 762. Kondo, H. (1998) 'Haematological effects of oral cobalamin preparations on patients with megaloblastic anaemia', Acta Haematologica, 99, 200-205. Kuzminski, A. M., Del Giacco, E. J., Allen, R. H., Stabler, S. P. and Lindenbaum, J. (1998) 'Effective treatment of cobalamin deficiency with oral cobalamin', Blood., 92, 1191-8. Lederle, F. A. (1991) 'Oral cobalamin for pernicious anemia. Medicine's best kept secret?' Journal of the American Medical Association, 265, 94-95. Lederle, F. A. (1998) 'Oral Cobalamin for Pernicious Anemia: Back from the Verge of Extinction', Journal of the American Geriatrics Society, 46, 1125-27. Lindenbaum, J., Rosenberg, I. H., Wilson, P. W., Stabler, S. P. and Allen, R. H. (1994) 'Prevalence of cobalamin deficiency in the Framingham elderly population', American Journal of Clinical Nutrition, 60, 2-11. McIntyre PA, H. R., Masters JM, Krevans JR (1960) 'Treatment of pernicious anemia with orally administered cyanocobalamin (vitamin B12).' Arch Intern Med, 106, 280-92. Metz, J. (1999) 'What's the true of oral vitamin B12?' Medical Journal of Australia, 170, 407-8. 54
  • 55. Dr. Josep Vidal-Alaball Middleton, J. and Wells, W. (1985) 'Vitamin B12 injections: considerable source of work for the district nurse', British Medical Journal Clinical Research Ed., 290, 1254-5. Miller, D. R. and Hayes, K. C. (1982) In Nutritional Toxicology, Vol. 1 (Ed, Hathcock, J. N.) Academic Press Inc, Orlando. 81-133. Mooney, G. H. (2003) Economics, Medicine and Health Care, Prentice Hall Europe, Hemel Hempstead. 4-16. Mooney, G. H., Russell, E. M. and Weir, R. D. (1980) Choices for health care, Macmillan, London. Netten, A. and Curtis, L. (2003) Unit Costs of Health and Social Care 2003, Personal Social Services Research Unit, Kent. Newbold, H. L. (1989) 'Vitamin B-12: Placebo or Neglected Therapeutic Tool?' Medical Hypotheses, 28, 155-64. NHS-Wales (2001) PCA Wales Prescribing Data 2001, Health of Wales Information Services, Cardiff. Norberg, B. (2001) Oral high-dose cyanocobalamin - a contagious concept, Rondel. http://www.rondellen.net, Accessed: 03/03/04. Nygard, O., Nordrehaug, J. E., Refsum, H., Ueland, P. M., Farstad, M. and Vollset, S. E. (1997) 'Plasma homocysteine levels and mortality in patients with coronary artery disease', N Engl J Med, 337, 230-6. Nyholm, E., Turpin, P., Swain, D., Cunningham, B., Daly, S., Nightingale, P. and Fegan, C. (2003) 'Oral vitamin B12 can change our practice', Postgraduate Medical Journal, 79, 218-9. Oh, R. C. and Brown, D. L. (2003) 'Vitamin B12 Deficiency', American Family Physician, 67, 979-86. Paauw, D. S. (1999) 'Did we learn evidence-based medicine in medical school? Some common medical mythology', Journal of the American Board of Family Practice, 12, 143-149. Penix, L. P. (1998) 'Ischaemic strokes secondary to vitamin B12 deficiency induced hyperhomocysteinaemia', Neurology, 51, 622-4. Pennypacker, L. C., Allen, R. H., Kelly, J. P., Matthews, L. M., Grigsby, J. and Kaye, K. (1992) 'High prevalence of cobalamin deficiency in elderly outpatients', Journal of the American Geriatrics Society, 40, 1197-204. 55
  • 56. Dr. Josep Vidal-Alaball Rajan, S., Wallace, J. I., Beresford, S. A., Brodkin, K. I., Allen, R. A. and Stabler, S. P. (2002) 'Screening for cobalamin deficiency in geriatric outpatients: prevalence and influence of synthetic cobalamin intake', Journal of the American Geriatrics Society, 50, 624-30. Reisner, E., Weiner, L., Schittone, M. and Henck, E. (1955) 'Oral treatment of pernicious anemia with vitamin B12 without intrinsic factor', The New England Journal of Medicine, 12, 502-6. Rickes, E., Brink, N., Koniuszy, F., Wood, T. and Folkers, K. (1948) 'Crystalline vitamin B12', Science, 107, 396. Ross, G., Mollin, D., Cox, E. and Ungley, C. (1954) 'Hematologic responses and concentration of vitamin B12 in serum and urine following oral administration of vitamin B12 without intrinsic factor', Blood, 9, 473-88. Routledge, P. A. (2002) Report on Prescribing in Wales (Paper A), Welsh Medicines Resource Centre (WeMeReC), Penarth. Routledge, P. A. and Fitzgerald, K. (2002) Update on Prescribing in Wales, Welsh Medicines Resource Centre (WeMeReC), Penarth. Salek, S. (1999) Pharmacoeconomics and outcome assessment: a global issue, Euromed Communications Limited, Surrey. 1-17. Sculpher, M., Manca, A., Abbott, J., Fountain, J., Mason, S. and Garry, R. (2004) 'Cost effectiveness analysis of laparoscopic hysterectomy compared with standard hysterectomy: results from a randomised trial', BMJ, 328, 134-0. Smith, E. (1948) 'Purification of anti-pernicious anaemia factor from liver', Nature, 161, 638. Spies, T., Stone, R., Lopez, G., Milanes, F., Toca, R. and Aramburu, T. (1949) 'Vitamin B12 by mouth in pernicious and nutritional macrocytic anaemia and sprue', Lancet, 2, 454-6. Stabler, S. P. (1995) 'Screening the older population for cobalamin (vitamin B12) deficiency', Journal of the American Geriatrics Society, 43, 1290-7. Swain, R. (1995) 'An Update of Vitamin B12 Metabolism and Deficiency States', Journal of Family Practice, 41, 595-600. Unglaub, W. G. and Goldsmith, G. (1955) 'Oral Vitamin B12 in the Treatment of Macrocytic Anemias', Southern Medical Journal, 48, 261-9. 56
  • 57. Dr. Josep Vidal-Alaball Ungley, C. (1950) 'Absorption of vitamin B12 in pernicious anaemia. I.Oral administration without source of intrinsic factor', British Medical Journal, 2, 905-908. van Walraven, C., Austin, P. and Naylor, C. D. (2001) 'Vitamin B12 injections versus oral supplements. How much money could be saved by switching from injections to pills?' Canadian Family Physician, 47, 79-86. van Walraven, C. and Naylor, C. (1999) 'Use of vitamin B12 injections among elderly patients by primary care practitioners in Ontario', Canadian Medical Association Journal, 161, 146-9. Vidal-Alaball, J., Butler, C., Hood, K., Cannings, R., McCaddon, A. and Papaioannau, A. (2004) Oral vitamin B12 versus parenteral vitamin B12 for vitamin B12 deficiency. (Protocol for a Cochrane Review), John Wiley & Sons, Ltd., Chichester, UK. 57