In 1991, Frank A. Lederle identified highdose oral vitamin B12 (cobalamin) treatment for pernicious anemia as “medicine’s best kept secret.” Lederle noted that only mg of cobalamin is required for daily metabolic functions. Because 2.0% of oral vitamin B12 is absorbed by small bowel mucosa independent of intrinsic factor or the terminal ileum, a daily 1000-mg dose of oral cobalamin provides more than enough vitamin to patients with pernicious anemia as well as patients whose B12 deficiency is caused by atrophic gastritis or decreased intake.

Clinical studies with extensive follow up have found that B12 levels in patients with pernicious anemia remain normal with high-dose oral therapy. A recently published randomized trial found that oral B12 supplementation was superior to parenteral therapy for correcting serum B12, methylmalonic acid, and homocysteine levels. published clinical studies have not found high-dose oral B12 to be unsuccessful in treating patients.

Little is known in North America, however, about the effectiveness of oral B12 therapy. Several review articles regarding treatment of B12 deficiency have acknowledged oral B12 therapy or have supported its use. Three clinical studies favouring high-dose oral B12 therapy have also been published. Regardless, oral therapy is seldom used in North America despite being widely accepted elsewhere. Informal discussion with family physicians, who treat nearly all B12 deficiency in Canada, revealed that few use high-dose oral instead of parenteral B12 for replacement therapy.
Oral B12 therapy is advantageous for patients because it avoids repeated physician visits and painful injections. It can also save money. None of the articles retrieved from a MEDLINE search between 1966 and 1999 using the MeSH heading “vitamin B12″ and the text word “oral” explicitly compared the costs of parenteral and oral B12 supplementation. With this study, we sought to determine the costs and potential savings of switching all elderly Ontarians from parenteral B12 to high-dose oral therapy.

Dr van Walraven is an Assistant Professor of medicine at the University of Ottawa, Principal Investigator at the Loeb Health Research Institute, and a scientist at the Institute for Clinical Evaluative Sciences (ICES) in Ontario. Dr Austin is an Associate Scientist at ICES. Dr Naylor is a Professor of Medicine at the University of Toronto and is Adjunct Senior Scientist at ICES.

METHODS

Patients and databases

All Ontarians between 65 and 100 years old who were prescribed parenteral vitamin B12 between July 1995 and June 1996 were identified in the Ontario Drug Benefit (ODB) database. The ODB database records the drug and the prescription date for each claim.

Resources used for parenteral and oral regimens

To measure resources used to administer parenteral B12 to these patients, we identified all physician claims for an intramuscular injection (fee codes G372 and G373) recorded in the Ontario Health Insurance program (OHIp) database for the year following the B12 prescription. The Ontario Health Insurance Plan (and its database records) covers almost all physician services. To avoid including injections for other reasons (eg, allergy testing by clinical immunologists), only those performed by family physicians and internists (as identified by the Registered Physicians Database) were included. Because vaccinations are claimed using a separate code, intramuscular injections for patients prescribed B12 should almost exclusively represent B12 injections, although we are unable to determine whether injections were provided for other indications. Only visits claimed by the injecting physician for that patient on the day of the injection were counted.

We estimated the resources necessary to switch all patients from parenteral B12 to high-dose oral B12 regimens. We assumed that physicians would meet each patient to explain the advantages of oral therapy and provide instructions for its use. As has been recommended, we also assumed that each patient would have follow-up monitoring where laboratory tests (including hemoglobin, white blood cell count, and a vitamin B12 measurement) would be performed. We assumed that physicians would bill an intermediate assessment (fee code A007) for both these visits and that all patients would switch to and stay on oral B12 therapy.

Costs of parenteral and oral regimens

We used a third-party payer perspective to calculate costs because of the data available to us, and this perspective is the least susceptible to error and uncertainty. Drug costs were abstracted from the ODB formulary. We identified the least expensive wholesale price for oral high-dose B12 preparations by contacting each manufacturer. Although high-dose B12 is not now covered by ODB, we assumed for this study that the plan would pay for the medication. As per usual ODB practice, a pharmacist fee of 10% was added to the wholesale price of the vitamin. The pharmacist’s dispensing fee (a maximum of $6.11) was not included as a cost because this is paid by patients. The OHIP fee schedule determined costs for injections, physician visits, and laboratory investigations.

To calculate the annual costs of parenteral B12 therapy, we determined, for each person, the total number of injections and injection visits and multiplied each by their unit costs. We assumed that one parenteral B12 prescription would last 1 year for each patient. Annual costs were multiplied to calculate 5-year costs. This estimate is conser vative because it assumes that the total number of elderly persons receiving B12 injections will remain static, whereas the proportion of elderly in the population is growing.

For 5-year costs of high-dose oral B12 therapy, we assumed that conversion costs (ie, extra physician visits and investigations incurred by switching patients to oral therapy) were one-time costs only. Thereafter, all newly diagnosed patients with B12 deficiency would be started on oral B12 therapy and therefore avoid the conversion costs. Again we assumed that the total number of elderly receiving therapy for B12 deficiency remained static.

Other direct and indirect costs, including nursing time, syringes, needles, alcohol swabs, and patient travel, were not considered because they are not specifically paid for by the provincial plan. Because these costs are part of parenteral therapy alone, their exclusion ensures a consistent bias against oral therapy as the proposed alternative. Such consistent biasing of assumptions in favour of usual or conventional care, and against any new alternative under consideration, is recommended for economic evaluations by Sonnenberg et al.19 All costs are expressed in Canadian dollars.

Cost savings

We calculated savings associated with switching to oral therapy under two scenarios. In the first scenario, costs were calculated assuming that all injection-associated visits would be avoided by switching to oral therapy.

In the second, more conservative, scenario, we calculated savings based on the number of physician visits avoided by switching to oral B12. To do this, we predicted the annual number of physician visits required for each B12 patient as a function of five markers of illness. To derive a model that predicts the annual number of physician visits, we identified all elderly Ontarians not receiving B12 injections and their annual number of physician visits from the OHIP database. We chose covariates for the model that should correlate with overall patient illness. This included age and sex (from the Registered Persons Database), number of medications chronically used (from the ODB database), annual number of emergency room visits (from the OHIP database), and the annual number of hospitalizations (from the Hospital Discharge Abstract Database). This last database records all hospitalizations in Ontario.

We used Poisson regression to model the annual number of physician visits as a function of these covariates (Table 1). Poisson regression is the most appropriate method for modeling count data for two reasons. Poisson regression, as opposed to ordinary least squares regression, constrains the predicted response to be non-negative. Second, Poisson regression allows the variance of the predicted count to increase as the predicted count increases, an occurrence often seen with count data.

Table 1. Poisson regression model predicting annual number of outpatient physician visits for the elderly: The model was derived using all elderly Ontarians not taking B12 injections and was used to predict the annual number of outpatient physician visits expected based on age, sex, total number of medication groups, annual number of emergency room visits, and annual number of hospital admissions. The annual number of outpatient visits increased for parameters whose coefficient was positive. In the model, age-c represents the centred value for age and equaled age-74.3. Sex was 1 if a patient was male, and 0 otherwise. All coefficients in the model differed significantly from 1.0 (P < .0001 for all parameters). Xindicates an interaction term. The deviance-based generalized R2 for the model is 0.12.

Log (annual number of visits)

=1.3394 + 0.0294*age-c

+ 0.0008*age-c² + 0.0502*sex

+ 0.3697*total number of drug

groups

+ 0.0001*annual number of emergency room visits

+ 0.0622*annual number of hospital admissions

-0.0029*age-c X sex

-0.0008*age-c² X sex

For each B12 patient, values for these covariates were determined from the databases and substituted into this model to predict the number of physician visits if patients were not receiving B12 therapy. We used the difference between the observed number of physician visits (including those for injections) and the expected number of physician visits as the maximum number of injection visits avoided by oral therapy. If this difference was less than zero, no visits would be avoided by switching to oral therapy. If this difference exceeded zero as well as the number of injection visits, all injection visits would be avoided by switching to oral therapy. If this difference exceeded zero but was less than the number of injection visits, we randomly selected those avoided by switching to oral therapy. Costs were then recalculated using only avoided visits.

Sensitivity analysis

The cost of parenteral B12 therapy is heavily influenced by the proportion of injection-associated physician visits that would be avoided by switching patients to oral therapy. We therefore conducted a sensitivity analysis by randomly selecting, for each patient, a varying proportion of injection visits that were avoided by switching the patient to oral therapy. This identified the proportion of injection visits that needed to be avoided for oral B12 therapy to save money.

Table 2. Cost of parenteral B12 therapy for 1 and 5 years: Annual costs were determined for 34 264 seniors in Ontario who received a parenteral B12 prescription between July 1, 1995, and June 30, 1996. Annual costs were used to determine 5-year costs.

Rubramin is the trade name for a cyanocobalamin preparation. Visits costing more than $30 were arbitrarily classified as “high cost.” All costs are presented in Canadian dollars and were not adjusted for inflation. * Includes 10%pharmacist’s fee.

RESULTS

Between July 1995 and June 1996, 34 462 seniors had a prescription for parenteral vitamin B12 filled. We excluded 198 (0.6%) patients because their age or sex was not recorded. The mean age of the remaining 34 264 patients was 78.5 years (standard deviation [SD] 7.4); 22 809 (66.6%) were women.

More than three quarters (26 227) of patients receiving parenteral B12 had one or more injections claimed in the year following the B12 prescription (total 237 951, mean 6.9, SD 7.0). For 176 601 (74.2%) of these injections, a visit was identified. On average, patients received injections every 41.8 days (SD 27.6).

Costs for parenteral B12 therapy

The annual and 5-year cost of parenteral B12 is summarized in Table 2. Physician visits were the most expensive component of parenteral B12 therapy (mean $123.16 [SD 141.11] per person yearly). If all injection-associated visits were avoided by switching to oral therapy, we estimate that parenteral B12 therapy costs almost $5 million yearly (mean $145.88 per person yearly) or $25 million over 5 years (Table 2). If injection visits were avoided only if the total number of physician visits (including injection and noninjection visits) exceeded the expected number of physician visits (Table 1), we estimate parenteral B12 therapy to cost $2.04 million yearly or $10.3 million over 5 years.

The annual and 5-year cost of high-dose oral B12 therapy is summarized in Table 3. We estimated the total cost of switching all 34 264 people to oral therapy and treating them for 5 years at $7.4 million. Therefore, if all injection visits were avoided, $17.6 million would be saved over 5 years by switching all seniors from parenteral to oral B12 therapy. If injection visits were avoided only when the total number of physician visits (including injection and noninjection visits) exceeded the expected number of physician visits, $2.9 million would be saved over 5 years by switching to oral therapy.

Table 3. Cost of oral vitamin B12 therapy for 1 and 5 years: Costs of converting 34 264 elderly patients to oral B12 therapy and treating them for 5 years were estimated. Conversion costs apply only to those who are actually switched to oral therapy and are therefore not repeated each year.

Sensitivity analysis
Because the physician visit is the most expensive component of parenteral B12 therapy (Table 2), this study is sensitive to injection-associated physician visits avoided when patients are switched to oral therapy. Our sensitivity analysis showed that switching all patients to oral therapy would decrease costs as long as 16.3% of injection visits were avoided when oral therapy was used (Figure 1).

Figure 1. Sensitivity analysis determining the effect on savings of varying the proportion of injection visits avoided by switching to oral B12 therapy: As the proportion of injection-associated visits avoid ed by switching to oral B12 supplementation increases, the money saved by converting to oral therapy also increases.

DISCUSSION

The cost of administering parenteral vitamin B12 for 1 year is considerable, and the potential savings from switching all patients to oral cobalamin therapy are substantial. Cost savings from oral therapy result primarily from decreased number of physician visits associated with injections. Costs are saved as long as 16.3% of injection-associated visits are avoided by switching to high-dose oral B12.

Compared with the Ontario annual health care budget of $18.5 billion, the savings associated with oral B12 therapy are small. Considering alternative uses of these funds, however, gives the savings a new meaning. For example, the institutional cost in Ontario for uncomplicated coronary artery bypass surgery in elderly patients is $16 500. Switching all elderly Ontarians from parenteral to oral B12 therapy could therefore “purchase” between 175 and 1067 coronary artery bypass surgeries over 5 years.

We believe that our study underestimates savings from oral therapy. First, we excluded patients younger than 65 years. Second, if claims for B12 injections were not recorded because physicians did not submit a claim or because of coding errors, the cost of both the injection and the physician visit associated with the injection were not considered. This could explain why 23.5% of patients who received a prescription for an injectable B12 formulation had no injections claimed, and why 25.8% of injections had no visit claimed. It is also possible that some patients received B12 injections from home care nurses or family members, costs of which were not considered in the parenteral group.

Third, conversion costs were liberal. We believe that most physicians would discuss switching to oral therapy during a regularly scheduled appointment, thereby reducing some costs of conversion for physician visits (Table 3). Also, laboratory costs of monitoring patients were considered for only oral and not parenteral patients.

Finally, other direct and indirect costs of parenteral B12 administration, such as nursing and patient time, were not considered. Therefore, the strict third-party payer perspective used in this study probably underestimates the true savings associated with switching to oral therapy.

Oral B12 supplementation has other advantages. It avoids patient discomfort and inconvenience. Decreasing low-yield patient visits decreases the burden for many overworked family physicians. Compared with parenteral therapy, oral B12 supplementation could be a rare example of a medical technology that is both better and cheaper than previous methods.

Several factors should be considered when interpreting our results. First, some patients could be unwilling to switch to oral therapy, even given its obvious advantages. Second, patient noncompliance could cause complications and therefore increase the cost of oral therapy. We are unsure whether noncompliance with daily pills would exceed that of injections or whether patients previously compliant with injections would not be so with oral therapy. While patients could occasionally miss their daily oral dose of vitamin B12 without consequences, this point highlights that physicians must consider patient compliance before switching from directly observed parenteral therapy to oral supplements.

Third, some physicians might monitor patients who have recently been switched to oral therapy more closely than we allowed for. It is possible, however, that such physicians also monitor patients closely while continuing parenteral therapy, costs not considered in our study. Fourth, frequent repeat visits by patients for B12 injections can facilitate patient-physician communication, permitting early detection and treatment of serious disease. Although switching to oral B12 therapy might decrease the frequency of which patients see their family physicians, we do not believe that this would prevent patients from visiting their family physicians as needed.

Fifth, the oral group did not consider costs resulting from patients currently taking oral B12 supplements having their vitamin paid by ODB. Because the number of these people is small and the cost of B12 pills is low, this would likely have a limited effect on our estimates. Sixth, our cost analysis applies to Ontario only. We suspect, however, that substituting parenteral B12 with high-dose therapy would save costs elsewhere.
Finally, and most worrisome, switching to oral therapy represents a form of “cost-shifting” to patients. Ontario Drug Benefit mandates that chronic medications are dispensed no more frequently than every 3 months. Because patients pay up to $6.11 each time they obtain a prescription, direct costs for patients are greater for oral B12 (four prescriptions annually) than parenteral therapy (one prescription annually). Other patient costs, however, such as travel and time, are avoided by switching to oral therapy.

Editor’s key points

- High-dose oral vitamin B12 is rarely used to treat pernicious anemia in North America, despite its proven efficacy and acceptance in Europe.

- If family physicians switched to oral vitamin B12 treatment, substantial savings in financial costs, physician time, and patient inconvenience would result.

Points de repere du redacteur

- L’administration de vitamine B12 a forte dose par voie orale est rarement utilisee pour le traitement de l’anemie pernicieuse en Amerique du Nord, en depit de son efficacite eprouvee et de son accepta¬tion en Europe.

- Si les medecins de famille optaient plutot pour un traitement a la vitamine B12 par voie orale, il pourrait en resulter des economies substantielles en termes de couts, de temps pour les medecins et d’inconvenients pour les patients.

CONCLUSION

We believe that switching patients from parenteral to high-dose oral B12 supplements is advantageous for
both patients and the health care system. High-dose oral B12 formulations should be made readily available to physicians and their patients and active measures taken to promote this safe and cost-saving
alternative to B12 injections.

Source:Can Fam Physician. 2001 January; 47: 79–86.