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Nilsson M. Advice for assessors – how to read context and content of the Nyholm paper [editorial]. Rondel 2009; 29. URL: http://www.rondellen.net

Advice for assessors
How to read context and content of the Nyholm paper

Summary

The paper written by Nyholm et al (1) examines the swapping of patients with vitamin B12 deficiency treated with three monthly 1000mcg hydroxocobalamin injection therapy to oral replacement therapy with daily tablets containing 1000 mcg of cyanocobalamin. The study was conducted in Birmingham, UK, in a primary health care centre. The combined practice population comprised 19,000 patients, out of whom 108 patients were deemed eligible for conversion from injection therapy to oral therapy. From this group, 39 patients performed the first three months of oral maintenance treatment with vitamin B12. Starting at the chosen trough value of the preceding injection therapy, the serum vitamin B12 rose steeply to a plateau level close to the upper limit of the reference range. Thus, British citizens respond to oral vitamin B12 therapy in the same manner as Swedes, Norwegians, Americans, Canadians, Turks, and Dutchmen.

 
Background

We have found that neither injection or oral therapy for vitamin B12 deficiency have been properly examined for efficacy according to the principles of randomised controlled trials (RCT); both regimens were launched by historical comparison with crude preparations from liver or yeast (2). The randomised trials of Kuzminski (3,4) and of Bolaman (5,6) failed to provide the patients of the injection arm and of the oral arm with equal doses (3-6).

Indeed, it might be difficult to design fair comparisons (RCTs) between injection therapy and oral therapy for vitamin B12 deficiency due to the pharmacokinetics of vitamin B12 (1-10).

There are at present three case series of swapping patients from injection therapy to oral maintenance therapy for vitamin B12 deficiency (1,7,9). The aim of the present analysis is to set the British trial into its proper perspective (1).


Material and Methods 

The primary health care centre in Birmingham, UK, served 19,000 patients. 108 patients from this populationwere deemed eligible for conversion from injection therapy to oral therapy, 1000 mcg daily, for vitamin B12 deficiency of various aetiology and pathogenesis. Of these patients, 58 were excluded from the study due to refusal, mental impairment, or acute illnesses. Thus, 17 men and 33 women entered the study, age range 31-90. 

Five of the patients were withdrawn from the study during the standardised loading with 1000 mcg vitamin B12 i.m. – three for social reasons and two did not sink to the chosen trough level of serum vitamin B12, 418 pg/ml. During the oral phase of the trial, two patients died, one left the area, and two were excluded due to protocol violation.


Results and interpretation 

The study ran between July 1998 and October 2000, ending on a fixed date. Thus, patients were on oral treatment for periods of different length. 39 patients participated for the first three months. During this period, serum vitamin B12 levels rose to a plateau level close to the upper limit of the reference range, demonstrating  that all remaining participants responded to oral treatment as expected from other studies in other countries (3-14).

 It should be emphasised that studies of the Nyholm type tend to compare trough values of injection treatment with peak values of oral treatment (10). If this basic feature is taken into account, the differences in dispersion of serum vitamin B12 values in injection therapy and in oral therapy becomes intelligible (12).

It is noteworthy that there was no tendency for serum vitamin B12 values to decline from the plateau level among the patients who remained in the oral stage during the first 12 months (Fig 1). Furthermore, the homocysteine values remained low during the study. This observation also excludes folate deficiency as a confounder in the British study (cf 3,4).

In conclusion, the Nyholm study showed that it was possible to convert about 30% of patients eligible from injection therapy to oral therapy for vitamin B12 deficiency in the British context (1). The results were similar in two other studies in societies without previous traditions of oral treatment for vitamin B12 deficiency (3,9).


Impact of the Nyholm paper on British practice

The Nyholm study reflected a wish among some British physicians to convert a fraction of their patients from injection therapy to oral therapy for vitamin B12 deficiency in order to save work, costs  and meet patient preferences for an oral therapy (1). The prototype is Sweden, where physicians started to convert their patients, when they payments for injection therapy was removed in 1970 (15,16).

Present British practice of vitamin B12 therapy was recently subject to an interesting evaluation by the independent and impartial Drugs and Therapeutics Bulletin, a journal within the BMJ group (17). Oral cyanocobalamin, 1000 mcg, is still unlicensed in UK. However, most physicians are able to obtain such tablets for approximately 25£ a year, although the preparations may not be of pharmaceutical grade – just as the preparations of recent trials (1,3,9).

The grade of oral vitamin B12 preparations may not be crucial, since it is an obligation of the responsible physician to check patient compliance and the effective absorption of the medication regularly after conversion to tablets by means of serum vitamin B12 level monitoring.

It is suggested that such a follow-up should be performed 6 and 12 months after conversion. Then patients suitable for permanent oral therapy should be monitored by annual examination of haemoglobin, mean corpuscular volume, and serum vitamin B12.

Some official dose recommendations have been out of date for more than 30 years (cf 17). Those recommendations provide a relic from times when the hidden agenda of remission treatment was to drain the patient of as much money as possible (cf 2,15). Weekly injections of hydroxocobalamin, 1000 mcg, are optimal (13).


Conclusions

The Nyholm trial showed that approximately 30% of the patients could be successfully switched from injection therapy for vitamin B12 deficiency to oral therapy, 1000 mcg daily, in a British context (1). The finding is in agreement with American experience (3,4) and Canadian experience (9,10). It is reasonable to assume that some patients may fare better with tablets, others with injections (cf 16). UK primary care physicians are responsible for monitoring replacement drug therapy with levothyroxine, lithium and other treatments – surely oral vitamin B12 falls into the same category.It is suggested that the choice between tablets or injections should rest with the patient and his or her doctor.

Mats Nilsson, PhD
County Council Hospital of Ryhov
Futurum Academy for Health and Care, Building B4
SE-551 85 Jönköping, Sweden
E-mail: mats.p.nilsson@lj.se
 

References

  1. Nyholm E, Turpin P, Swain D, Cunningham B, Daly S, Nightinggale P, Fegan C. Oral vitamin B12 can change our practice. Postgrad Med J 2003; 79:218:209

  2.  Lee GR, Bitchell TC, Forster J, Athens JW, Lukens JN, eds. Wintrobe´s Clinical Hematology, Ed 9. Philadelphia : Lea & Febiger. 1993; 158-94, 777-80

  3. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency sith oral cobalamin. Blood 1998; 92:1191-8

  4. Nilsson M. Advice for assessors – how to read context and content of the Kuzminski paper [evaluation]. Rondel 2008; 28. URL: http://www.rondellen.net/evaluation28_eng.htm

  5. Bolaman Z, Kadikoylu G, Yukselen V, Yavasoglu I, Barultca S, Senturk T. Oral versus intramuscular cobalamin treatment in megaloblastic anemia: A single-center, prospective, randomized, open-label study. Clin Ther 2003; 25:3124-34

  6. Lökk J. Advice for assessors – how to read context and content of the Bolaman paper [debate]. Rondel 2008; 28. URL: http://www.rondellen.net/debate28_eng.htm

  7. Roth M, Orija I. Oral vitamin B12 therapy in vitamin B12 deficiency Amer J Med 2004; 116:358

  8. Björkegren K. Advice for assessors - how to read context and content of the Roth-Orija paper [evaluation]. Rondel 2009; 29. URL: http://www.rondellen.net/evaluation29_eng.htm

  9. Kwong JC, Carr D Dhalla IA, Tom-Kun D, Upshur REG. Oral vitamin B12 therapy in the primary care setting: a qualitative and quantitative study of patient perspectives. BMC Family Practice 2005; 6:8, http: //www.biomedcentral.com/1471-2296/6/8

  10. Schneede J. Oral B12 treatment – putting the results of the Kwong paper into a broader context [debate]. Rondel 2009; 29. URL: http://www.rondellen.net/debate29_eng.htm

  11. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand 1968; 184:247-58

  12. Berlin R, Berlin H, Brante G, Pilbrant Å. Vitamin B12 body stores during oral and parenteral treatment of pernicious anemia Acta Med Scand 1978; 204:81-4

  13. Magnus EM. Cobalamin and unsaturated cobalamin values in pernicious anaemia: Relation to treatment. Scand J Haematol 1986; 36:457-65

  14. Eussen SJPM, Groot LCPG, Clarke R, Schneede J, Ueland PM, Hoefnagels WHL, Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency. A dose-finding trial. Arch Intern Med 2005; 165:1167-72

  15. Nilsson M. Cobalamin communication in Sweden 1990-2000. Views, knowledge, and practice among Swedish physicians, p 12. Dissertation, Umeå University 2005 (http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-416)

  16. Norberg B. Deficiency of vitamin B12 and folate – the branded generic for optimal oral therapy [editorial]. Rondel 2008; 28. URL: http://www.rondellen.net/publisher28_eng.htm

  17. Drugs and Therapeutics Bulletin. Oral or intramuscular vitamin B12? DTB 2009; 47(2):19-21 (http://dtb.bmj.com/cgi/content/abstract/47/2/19)

Published March 29, 2009