Dr  Josep  Vidal-Alaball Department of General Practice www.cardiff.ac.uk/medicine/general_practice
Medicine’s Best Kept secret  (Lederle 1991)
Oral Vitamin B 12  for the treatment of Vitamin B 12  deficiency: A Systematic Review Vidal-Alaball J , Butler CC, Hood K,...
Background <ul><li>Vitamin B 12  is necessary for the development of red blood cells, growth and nervous system maintenanc...
<ul><li>Vitamin B 12  (cobalamin) deficiency is  common , especially amongst elderly: true prevalence 1.5 to 15 %  (van Wa...
<ul><li>This is probably because: following binding to intrinsic factor, free Vitamin B 12  can be absorbed passively as w...
<ul><li>Despite availability, oral Vitamin B 12  is rarely prescribed, other than in  Sweden   (and Canada)  where in 2000...
Patients on oral high-dose cyanocobalamin in Sweden 1990-2000 Norberg B. Oral high-dose cyanocobalamin – a contagious conc...
Why change to oral Vit B 12  ? <ul><li>Intramuscular injections are a &quot;considerable source of work&quot; for health c...
Cost implications   <ul><li>More appropriate prescribing of parenteral Vit B 12  among 492 patients could free up between ...
<ul><li>A Canadian study  (van Walraven 2001)  estimated that converting patients over 65 years from parenteral to oral vi...
Is oral Vitamin B 12  as good as parenteral Vitamin B 12 Looking at the evidence
Search Strategies <ul><li>Types of studies examining the use of oral or parenteral Vitamin B 12  to treat Vitamin B 12  de...
<ul><li>Types of participants </li></ul><ul><ul><li>Demonstrated  Vit B 12  deficiency  and who met the criteria for B 12 ...
<ul><li>Outcome measures </li></ul><ul><ul><li>Equivalence of both routes of administration using biochemical markers </li...
Results <ul><li>Number of papers: </li></ul><ul><ul><li>Case Reports/Series  (before and after studies) : 15 </li></ul></u...
Case Reports/Series <ul><li>15 Studies  (1948-2001 but mostly 50’s and 60’s)  </li></ul><ul><li>n ranged from 9 to 94 </li...
Randomised Controlled Trials
RCTs <ul><li>745  abstracts or titles scrutinised. </li></ul><ul><li>57  papers pre-selected and checked for inclusion and...
<ul><li>A total of 174 participants were included in the four trials and the length of follow up ranged from 1 to 6 months...
<ul><li>Lower doses ( 50  µ cg ) daily produce haematological response when compared to placebo but do not produce statist...
<ul><li>Evidence derived from RCTs long term effectiveness not identified.   </li></ul><ul><li>Small number of studies (4)...
Final thoughts <ul><li>If oral Vitamin B 12  at high doses seems to be as effective as parenteral, why do Doctors not pres...
Future <ul><li>If the truth is out there, do we need to do more RCTs? </li></ul><ul><li>BUT… No pragmatic trial of changin...
<ul><li>Dr Josep Vidal-Alaball National Public Health Service Wales  </li></ul><ul><li>Mid and West Wales Region - Swansea...
References <ul><li>Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 withou...
 
 
Bolaman Z, et al. Oral Versus Intramuscular Cobalamin Treatment in Megaloblastic Anemia: A Single-Center, Prospective, Ran...
 
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Oral Vitamin B12 for the treatment of Vitamin B12 deficiency: A Systematic Review

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If oral Vitamin B12 at high doses seems to be as effective as parenteral, why do Doctors not prescribe it?

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    I used Pure Vegan B12 spray.There is also a cheaper version that does not advertise vegan but says so on the label called Pure Advantage B12. The ingredients are identical.

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Oral Vitamin B12 for the treatment of Vitamin B12 deficiency: A Systematic Review

  1. 1. Dr Josep Vidal-Alaball Department of General Practice www.cardiff.ac.uk/medicine/general_practice
  2. 2. Medicine’s Best Kept secret (Lederle 1991)
  3. 3. Oral Vitamin B 12 for the treatment of Vitamin B 12 deficiency: A Systematic Review Vidal-Alaball J , Butler CC, Hood K, Cannings R, McCaddon A, Papaioannou, A Cochrane Metabolic and Endocrine Disorders Group Orlando, October 2004
  4. 4. Background <ul><li>Vitamin B 12 is necessary for the development of red blood cells, growth and nervous system maintenance </li></ul><ul><li>The only dietary sources of vitamin B 12 are animal products, such as eggs, fish and meats. </li></ul><ul><li>Daily requirements are age-related; recommended dietary amounts for adults and infants are 1.5 and 0.4 µ cg respectively </li></ul>
  5. 5. <ul><li>Vitamin B 12 (cobalamin) deficiency is common , especially amongst elderly: true prevalence 1.5 to 15 % (van Walraven 1999 ). </li></ul><ul><li>Vitamin B 12 isolated in 1948 (Rickes 1948, Smith 1948) , now widely used for vitamin B 12 replacement. </li></ul><ul><li>Initially intramuscular although several studies have since demonstrated equal efficacy of oral route (Spies 1949, Ross 1954, Chalmers 1958) . </li></ul>
  6. 6. <ul><li>This is probably because: following binding to intrinsic factor, free Vitamin B 12 can be absorbed passively as well as actively in the terminal ileum. </li></ul><ul><li>Passive diffusion accounts for 1.2% of total absorption: unaffected by pernicious anaemia or gastro-duodenal surgical resection (Berlin 1968, Berlin 1978) . </li></ul><ul><li>High doses of Vitamin B 12 (1,000 µ cg ) may be acceptable and safe alternative to parenteral route. </li></ul>
  7. 7. <ul><li>Despite availability, oral Vitamin B 12 is rarely prescribed, other than in Sweden (and Canada) where in 2000, 73% of the total Vitamin B 12 prescribed was oral (Norberg 2001) . </li></ul><ul><li>Doctors may be unaware of this route or concerned about its unpredictable absorption (Lederle 1991, Lederle 1998) . </li></ul><ul><li>In the UK, oral Vitamin B 12 is not currently available in high doses. </li></ul>
  8. 8. Patients on oral high-dose cyanocobalamin in Sweden 1990-2000 Norberg B. Oral high-dose cyanocobalamin – a contagious concept (editorial). Rondel 2001; 8. URL:http://www.rondellen.net
  9. 9. Why change to oral Vit B 12 ? <ul><li>Intramuscular injections are a &quot;considerable source of work&quot; for health care professionals (Middleton 1985). </li></ul><ul><li>Parenteral administration often involves a special trip to a clinic or a home visit by a health professional (Lederle 1991). </li></ul>
  10. 10. Cost implications <ul><li>More appropriate prescribing of parenteral Vit B 12 among 492 patients could free up between 600 and 1470 health professional hours (Middleton 1985). </li></ul><ul><li>It takes around 15 to 30 minutes of nurse time to give a patient a Vit B 12 injection. </li></ul>
  11. 11. <ul><li>A Canadian study (van Walraven 2001) estimated that converting patients over 65 years from parenteral to oral vitamin B 12 could save between $2.9 and $17.6 million over 5 years just in Ontario alone. </li></ul>
  12. 12. Is oral Vitamin B 12 as good as parenteral Vitamin B 12 Looking at the evidence
  13. 13. Search Strategies <ul><li>Types of studies examining the use of oral or parenteral Vitamin B 12 to treat Vitamin B 12 deficiency: </li></ul><ul><ul><li>Case Reports/Series </li></ul></ul><ul><ul><li>Controlled Clinical Trials </li></ul></ul><ul><ul><li>Randomised Controlled Trials </li></ul></ul>
  14. 14. <ul><li>Types of participants </li></ul><ul><ul><li>Demonstrated Vit B 12 deficiency and who met the criteria for B 12 replacement therapy. We used a threshold level of Vitamin B 12 to consider deficiency. </li></ul></ul><ul><ul><li>Newly diagnosed and patients on longstanding treatment entered into trials. </li></ul></ul><ul><li>  Excluded studies: </li></ul><ul><ul><li>Vitamin B 12 for preventing cardio-vascular diseases </li></ul></ul><ul><ul><li>Primary folate deficiency (as the concomitant use of folate can mask results) </li></ul></ul><ul><ul><li>End-stage renal disease haemodialysis   </li></ul></ul>
  15. 15. <ul><li>Outcome measures </li></ul><ul><ul><li>Equivalence of both routes of administration using biochemical markers </li></ul></ul><ul><ul><ul><li>Serum levels of Vitamin B 12 </li></ul></ul></ul><ul><ul><ul><li>Total homocysteine levels and serum methylmalonic acid (two metabolic indicators of Vitamin B 12 deficiency) </li></ul></ul></ul><ul><ul><li>Clinical signs and symptoms of Vitamin B 12 deficiency after treatment with either route of administration </li></ul></ul>
  16. 16. Results <ul><li>Number of papers: </li></ul><ul><ul><li>Case Reports/Series (before and after studies) : 15 </li></ul></ul><ul><ul><li>Controlled Clinical Trials: 1 </li></ul></ul><ul><ul><li>Randomised Controlled Trials: 4 </li></ul></ul>
  17. 17. Case Reports/Series <ul><li>15 Studies (1948-2001 but mostly 50’s and 60’s) </li></ul><ul><li>n ranged from 9 to 94 </li></ul><ul><li>Outcomes: all found oral route effective. ?Selection bias. </li></ul>Controlled Clinical Trials <ul><li>1 Study looked at time taken to develop Vitamin B 12 deficiency after gastrectomy. Some patients started on oral and some on i.m. Vit B 12 . No difference found (Adachi 2000). </li></ul>
  18. 18. Randomised Controlled Trials
  19. 19. RCTs <ul><li>745 abstracts or titles scrutinised. </li></ul><ul><li>57 papers pre-selected and checked for inclusion and exclusion criteria. </li></ul><ul><li>Disagreements resolved by consensus </li></ul><ul><li>4 studies met the inclusion criteria. </li></ul><ul><li>Meta analysis not possible due to heterogeneity of dosages and subjects. </li></ul>
  20. 20. <ul><li>A total of 174 participants were included in the four trials and the length of follow up ranged from 1 to 6 months </li></ul><ul><li>High doses of oral vitamin B 12 (1,000 mcg and 2,000 mcg) are as effective as intramuscular vitamin B 12 administration in achieving satisfactory short term haematological and neurological responses (Kuzminski 1998, Bolaman 2003) . </li></ul>Results
  21. 21. <ul><li>Lower doses ( 50 µ cg ) daily produce haematological response when compared to placebo but do not produce statistically significant neurological response </li></ul><ul><li>Very low doses ( 10 µ cg ) daily do not produce statistically significant haematological or neurological response compared to placebo </li></ul>
  22. 22. <ul><li>Evidence derived from RCTs long term effectiveness not identified. </li></ul><ul><li>Small number of studies (4), relatively short follow up periods (1 to 6 months), small number of participants (174). </li></ul><ul><li>None of the studies conducted in Primary Care. </li></ul>Limitations
  23. 23. Final thoughts <ul><li>If oral Vitamin B 12 at high doses seems to be as effective as parenteral, why do Doctors not prescribe it? </li></ul><ul><li>What do we need to change 50 years of practice? </li></ul><ul><ul><li>Is more than 30 years of experience using oral vitamin B 12 in Sweden not enough? </li></ul></ul><ul><ul><li>Is more than a dozen of case series since the earlier fifties showing equivalence of both routes of administration not enough </li></ul></ul><ul><ul><li>Are 2 RCTs showing that oral Vit B 12 is as effective as intramuscular or even more not enough? </li></ul></ul>
  24. 24. Future <ul><li>If the truth is out there, do we need to do more RCTs? </li></ul><ul><li>BUT… No pragmatic trial of changing people from parenteral to oral Vit B 12 done. </li></ul><ul><li>? Explore reasons why some patients and some clinicians are reluctant to change from intra muscular to oral treatment (? Psychotropic/social benefits) </li></ul>
  25. 25. <ul><li>Dr Josep Vidal-Alaball National Public Health Service Wales </li></ul><ul><li>Mid and West Wales Region - Swansea Office </li></ul><ul><li>36 Orchard Street </li></ul><ul><li>Swansea </li></ul><ul><li>SA1 5AQ </li></ul><ul><li>U.K. </li></ul><ul><li>Tel. + 44 (0) 1792 607411 </li></ul><ul><li>Fax. + 44 (0) 1792 470743 </li></ul><ul><li>FOR MORE INFORMATION: </li></ul><ul><li>[email_address] </li></ul>
  26. 26. References <ul><li>Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Medica Scandinavica 1968;184(4):247-58. </li></ul><ul><li>Berlin R, Berlin H, Brante G, Pilbrant A. Vitamin B12 body stores during oral and parenteral treatment of pernicious anaemia. Acta Medica Scandinavica 1978;204(1-2):81-4. </li></ul><ul><li>Chalmers JNM, Shinton NK. Absorption of orally administered vitamin B12 in pernicious anemia. Lancet 1958; 2:1298-302 </li></ul><ul><li>Lederle FA. Oral cobalamin for pernicious anemia. Medicine's best kept secret? Journal of the American Medical Association 1991;265(1):94-95. </li></ul><ul><li>Lederle FA. Oral Cobalamin for Pernicious Anemia: Back from the Verge of Extinction. Journal of the American Geriatrics Society 1998; 46: 1125-27 </li></ul><ul><li>Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. American Journal of Clinical Nutrition 1994;60(1):2-11 </li></ul><ul><li>Middleton J, Wells W. Vitamin B12 injections: considerable source of work for the district nurse. British Medical Journal Clinical Research Ed. 1985;290(6477):1254-5. </li></ul><ul><li>Norberg B. Oral high-dose cyanocobalamin - a contagious cocept. Rondel 2001; 8: URL: http://www.rondellen.net </li></ul><ul><li>Pennypacker LC, Allen RH, Kelly JP, Matthews LM, Grigsby J et al </li></ul><ul><li>TI:High prevalence of cobalamin deficiency in elderly outpatients. Journal of the American Geriatrics Society 1992; 40:1197-204 </li></ul><ul><li>Rickes EL, Brink NG, Koniuszy FR, Wood TR, Folkers K. Crystalline vitamin B12. Science 1948; 107: 396 </li></ul><ul><li>Ross GIM, Mollin DL, Cox EV, Ungley CC. Hematologic responses and concentration of vitamin B12 in serum and urine following oral administration of vitamin B12 without intrinsic factor. Blood 1954; 9: 473-88 </li></ul><ul><li>Spies TD, Stone RE, Lopez GG, Milanes F, Toca RL, Aramburu T. Vitamin B12 by mouth in pernicious and nutritional macrocytic anaemia and sprue. Lancet 1949; 2:454-6 </li></ul><ul><li>van Walraven C, Austin P, Naylor CD. Vitamin B12 injections versus oral supplements. How much money could be saved by switching from injections to pills? Canadian Family Physician 2001;47:79-86. </li></ul><ul><li>Bolaman Z, et al. Oral Versus Intramuscular Cobalamin Treatment in Megaloblastic Anemia: A Single-Center, Prospective, Randomized, Open-Label Study. Clinical Therapeutics 2003; 25 (12) : 3124-34. </li></ul>
  27. 29. Bolaman Z, et al. Oral Versus Intramuscular Cobalamin Treatment in Megaloblastic Anemia: A Single-Center, Prospective, Randomized, Open-Label Study. Clinical Therapeutics 2003; 25 (12) : 3124-34.

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