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Tice JA, Ross E, Coxson PG, et al. Cost-effectiveness of Vitamin Therapy to Lower Plasma Homocysteine Levels for the Prevention of Coronary Heart Disease: Effect of Grain Fortification and Beyond. JAMA. 2001;286(8):936–943. doi:10.1001/jama.286.8.936
Author Affiliations: Division of General Internal Medicine, Department of Medicine (Dr Tice), Department of Medicine (Drs L. Goldman and Coxson), University of California, San Francisco; Division of Clinical Nutrition (Drs Ross and Rosenberg) and General Internal Medicine (Dr Ross), Tufts University, Boston, Mass; Department of Health Policy and Management (Drs Hunink, Weinstein, Ms Goldman, and Mr Williams), Harvard School of Public Health, Boston, Mass; the Department of Epidemiology and Biostatistics and Department of Radiology, Erasmus Medical Center, Rotterdam, the Netherlands (Dr Hunink).
Context A high homocysteine level has been identified as an independent modifiable
risk factor for coronary heart disease (CHD) events and death. Since January
1998, the US Food and Drug Administration has required that all enriched grain
products contain 140 µg of folic acid per 100 g, a level considered
to decrease homocysteine levels.
Objectives To examine the potential effect of grain fortification with folic acid
on CHD events and to estimate the cost-effectiveness of additional vitamin
supplementation (folic acid and cyanocobalamin) for CHD prevention.
Design and Setting Cost-effectiveness analysis using the Coronary Heart Disease Policy
Model, a validated, state-transition model of CHD events in adults aged 35
through 84 years. Data from the third National Health and Nutrition Examination
Survey (NHANES III) were used to estimate age- and sex-specific differences
in homocysteine levels.
Intervention Hypothetical comparison between a diet that includes enriched grain
products projected to increase folic acid intake by 100 µg/d with the
same diet without folic acid fortification; and a comparison between vitamin
therapy that consists of 1 mg of folic acid and 0.5 mg of cyanocobalamin and
the diet that includes grains fortified with folic acid.
Main Outcome Measures Incidence of myocardial infarction and death from CHD, quality-adjusted
life-years (QALYs) saved, and medical costs.
Results Grain fortification with folic acid was predicted to decrease CHD events
by 8% in women and 13% in men, with comparable reductions in CHD mortality.
The model projected that, compared with grain fortification alone, treating
all patients with known CHD with folic acid and cyanocobalamin over a 10-year
period would result in 310 000 fewer deaths and lower costs. Over the
same 10-year period, providing vitamin supplementation in addition to grain
fortification to all men aged 45 years or older without known CHD was projected
to save more than 300 000 QALYs, to save more than US $2 billion, and
to be the preferred strategy. For women without CHD, the preferred vitamin
supplementation strategy would be to treat all women older than 55 years,
a strategy projected to save more than 140 000 QALYs over 10 years.
Conclusions Folic acid and cyanocobalamin supplementation may be cost-effective
among many population subgroups and could have a major epidemiologic benefit
for primary and secondary prevention of CHD if ongoing clinical trials confirm
that homocysteine-lowering therapy decreases CHD event rates.
In 1969, McCully1 proposed homocysteine
as an etiologic agent in the pathogenesis of vascular disease. Over the past
decade, at least 10 large prospective cohort studies have published data demonstrating
a statistically significant association of basal homocysteine levels with
coronary heart disease (CHD) events and death.2-11
Nygard et al11 reported that patients with
known CHD had a 1.6- to 2.5-fold increase in mortality per each 5-µmol/L
(0.68-mg/L) increase in fasting total homocysteine.
Randomized clinical trials have demonstrated that low-dose B vitamins,
particularly folic acid and cyanocobalamin, significantly lower homocysteine
A recent meta-analysis by the Homocysteine Lowering Trialists' Collaboration40 found that folic acid therapy lowered homocysteine
levels (standardized at 12 µmol/L [1.62 mg/L]) by 25% and that the addition
of cyanocobalamin therapy lowered levels an additional 7%.
Since January 1998, the US Food and Drug Administration (FDA) has required
that all enriched grain products produced in the United States contain 140
µg of folic acid per 100 g.41 Since that
mandate, Framingham cohort data document that homocysteine levels in the general
population have decreased.42 In this study,
we first estimated the epidemiologic impact of grain fortification on CHD
events and then calculated the additional costs and benefits of further homocysteine
lowering using vitamin supplementation. These projections, despite their logic,
should be interpreted in the context of the absence of clinical trial data
that proves the efficacy of reducing homocysteine levels to prevent myocardial
infarction or CHD death.
The Coronary Heart Disease Policy Model is a validated, state-transition
model of CHD events and costs among US residents aged 35 through 84 years.43 The model was recently updated and calibrated using
1980 and 1986 US Vital Statistics to predict CHD mortality within 2% of the
reported age- and sex-specific rates in the 1990 US Vital Statistics.44 We refined the model using data from the third National
Health and Nutrition Examination Survey (NHANES III) to estimate the age-
and sex-specific distribution of homocysteine levels in the US population
Validation analyses confirmed that the model incorporating the homocysteine-level
distribution predicts CHD mortality within 2% of the 1990 US Vital Statistics.
The overall model consists of 3 integrated submodels: the demographic epidemiologic
submodel, the bridge submodel, and the disease history submodel.
The disease epidemiologic submodel uses population risk factor distributions
to predict new CHD events in people with no known CHD. The distributions of
smoking status, diastolic blood pressure, high-density lipoprotein levels,
and total serum cholesterol levels were derived from the NHANES II.46 The 4 risk factor distributions were assumed to be
independent, conditional on age range and sex. The number of US residents
who enter the model each subsequent year was estimated from projections of
the US Bureau of the Census.47
Age- and sex-specific relative risk coefficients for CHD incidence and
all-cause mortality were based on the Framingham Heart Study's 30-year follow-up
results for all risk factors other than homocysteine levels.48
Noncardiac disease mortality was based on US Vital Statistics.49
Coronary heart disease incidence rates for persons aged 35 through 74 years
were based on the Framingham Heart Study, with adjustment for the secular
decline in CHD incidence44 since the beginning
of the study. These rates were extrapolated to persons aged 75 through 84
years, and linear interpolation was used to smooth the age-specific annual
The bridge submodel characterizes events occurring during the first
30 days following a primary CHD event, and the disease history submodel predicts
subsequent events in those who survived the initial CHD event. The bridge
and disease history submodels were based on literature describing the presentation
of CHD as angina, myocardial infarction, or cardiac arrest,50
the incidence and case-fatality rates of recurrent coronary events,43 and the age- and sex-specific risk of noncoronary
death.51 The disease history submodel estimates
the subsequent annual risk of recurrent coronary events and coronary revascularization
procedures based on a patient's prior history of angina, myocardial infarction,
coronary revascularization, or cardiac arrest.
Health related quality-of-life estimates were calculated for people
with angina, congestive heart failure, or both. The health-related quality-of-life
weights were derived by pooling the time–trade-off method based responses
from patients in the Acute Myocardial Infarct Patient Oriented Research Team
and the Beaver Dam Health Outcomes Study.52
Short-term quality of life adjustments were made to account for the dysutility
of cardiac events by assuming a utility of 0 during the average hospital length
of stay for those events. No other effects of vitamin supplementation on quality
of life were modeled.
The age-specific costs of treating CHD including hospital costs, procedure
costs, and annual cost of outpatient care were derived from the Medicare Provider
Analysis and Review files and the Acute Myocardial Infarction (AMI) Patient
Outcome Research Team.52 All costs were inflated
to 1997 dollars using the Medical Care Component of the Consumer Price Index.
We searched MEDLINE from 1966 through February 1999 using the keywords homocysteine, folic acid, vitamin B12, and cardiovascular disease . The reference lists of all review articles and epidemiologic studies
were hand searched for further references. We contacted experts asking for
unpublished trials and abstracts presented at research conferences.
Articles containing data on pretreatment and posttreatment homocysteine
were pooled using analysis of covariance to estimate the posttreatment homocysteine
levels adjusting for baseline values of homocysteine (Table 1 and Table 2).56 We estimated that vitamin therapy consisting of 1
mg of folic acid and 0.5 mg of cyanocobalamin would lower the serum homocysteine
levels of people with pretreatment levels of 12 µmol/L (1.62 mg/L) by
33%. A recent meta-analysis reported no evidence that age or sex affected
the homocysteine-lowering effect of vitamin therapy but that higher pretreatment
levels were associated with greater absolute and relative declines.40 The estimated proportional reduction of a blood homocysteine
level of 12 µmol/L (1.62 mg/L) of folic acid supplementation was 25%,
with the addition of a mean of 0.5-mg cyanocobalamin providing an additional
7% reduction for a 32% total decrease.40 Populations
with higher pretreatment homocysteine levels had a greater percentage and
absolute reduction in homocysteine levels; those with low pretreatment homocysteine
levels had almost no change in homocysteine level with vitamin supplementation
In our model, we assumed 100% compliance with therapy for the primary
simulations. For sensitivity analyses of compliance, we assumed that everyone
would continue to receive homocysteine screening and prescriptions for vitamin
supplementation (thus accruing all costs), but only a reduced percentage would
take the supplements and accrue benefit.
We assumed that the relative risk reduction (RRR) from homocysteine-lowering
therapy was equivalent for both primary and secondary prevention. We derived
summary odds ratios (ORs) for changes in CHD event rates from homocysteine
level modification using a standard random-effects model57
to combine results from studies of homocysteine and CHD.2,3,5,8,10,11,58-70
The summary OR was 0.63 per 5-µmol/L (0.68-mg/L) decrease in total homocysteine
level (95% confidence interval [CI], 0.55-0.71). This did not differ by sex,
and there were no data supporting an interaction of the risk relationship
with age. For the baseline analysis, we used the conservative bound (0.71
per 5 µmol/L [0.68 mg/L], a 29% RRR) as our primary estimate because
cross-sectional studies often overestimate the strength of the risk relationship
compared with prospective studies and clinical trials. For sensitivity analyses,
we used a range from 0.55 to 0.91 (45% to 9% RRR), based on the upper bound
of the 95% CI of the random effects model including only prospective studies
in the meta-analysis2,3,5,8,10,11
and the lower bound of the full random effects model (Table 2). We did not model any adverse effects of vitamin supplementation.
Based on FDA projections, we assumed that fortified cereal grain would
increase the folic acid intake of the average US consumer by 100 µg/d.71 We did not model differential increases in folic
acid consumption by age and sex. The effect of increasing folic acid intake
by 100 µg on total homocysteine level was estimated with the same analysis
of covariance model56 used for modeling vitamin
supplementation above, limited to clinical trials using supplements containing
less than 200 µg of folic acid.26,32
Grain fortification was estimated to decrease a basal homocysteine level of
12 µmol/L (1.62 mg/L) to 10.7 µmol/L (1.45 mg/L), an 11% reduction.
Sensitivity analyses evaluated a reduction as low as 5%. Our estimates virtually
replicated the drop in homocysteine levels in the Framingham cohort: the geometric
mean homocysteine level was 10.1 µmol/L (1.37 mg/L) before grain fortification
was mandated and declined to 9.4 µmol/L (1.27 mg/L) after fortification.42 Our model predicts that the group mean would decrease
from 10.1 to 9.37 µmol/L (1.37-1.27 mg/L). These lower homocysteine
levels were used as the starting point for all subsequent models of primary
and secondary prevention.
Our secondary prevention models assumed that persons with clinically
manifest CHD (the population of the disease history submodel) would take a
daily supplement containing 1 mg of folic acid and 0.5 mg of cyanocabolamin
in addition to cereal grain fortification.
Primary prevention was modeled as an incremental strategy to secondary
prevention. As CHD would become manifest in those untreated, they were assumed
to have started receiving supplements. Two strategies were modeled: treat
everyone with no known CHD with a daily supplement containing 1 mg of folic
acid and 0.5 mg of cyanocobalamin or measure everyone's homocysteine level
and treat only those with a homocysteine level greater than 10 µmol/L
(>1.35 mg/L). These strategies were evaluated separately for men and women.
For each sex, 5 different age cutoffs were modeled beginning with individuals
aged 75 years or older. Younger people were added in 10-year increments. The
strategies for each sex were then compared. We assumed that everyone would
have had an increased folic acid intake at baseline due to grain fortification.
Both primary and secondary prevention strategies were modeled to begin
in the year 2001 and were run through 2010. Flour fortification with folic
acid was assumed to have begun on January 1, 1998. Our projections assumed
that treatment with vitamin therapy, including flour fortification, had a
2-year delay before affecting CHD event rates, analogous to clinical data
used to model cholesterol-lowering therapy in prior studies.72
This approach biases the model against effectiveness in the youngest individuals
because they would miss quality-adjusted life-years (QALYs) that they would
accrue due to the intervention well after the year 2010.
The cost of the vitamin therapy was estimated to be $20.29 per year
based on the median 1997 Red Book average wholesale
price of 1 mg folic acid supplements plus the median value of 0.5 mg cyanocobalamin
supplements.54 A range from $10 to $30 was
used for sensitivity analyses. We did not assume any extra costs for office
visits to implement vitamin therapy since this expense was treated as a routine
part of health care maintenance requiring less than 1 minute of time. The
cost of the homocysteine assay ($26.32) reflected the 1997 Health Care Financing
Administration reimbursement for an amino acid assay (CPT-4 code 8213190)
and blood specimen handling.55
All costs were converted to 1997 dollars using the Medical Care Component
of the Consumer Price Index. The cost effectiveness (CE) ratio was expressed
in 1997 dollars per QALY. A 3% discounting rate for costs and benefits was
used for the primary projections.73 The discounting
rate was varied from 0% to 5% in sensitivity analyses (Table 2). Costs were calculated using a health care perspective.
Patient-time costs, lost productivity, and other non–health care costs
were not considered in these models, but the costs of CHD events, hospitalizations,
revascularization procedures, and outpatient therapy were included. Before
calculating CE ratios, we eliminated strategies that were less effective and
either more expensive (dominated) or have a higher incremental CE ratio (fail
by extended dominance).74
Using baseline estimates, the model predicted that flour fortification
would lead to a 13% reduction in myocardial infarctions in men and an 8% reduction
in women with comparable reductions in CHD mortality (Table 3). Using our most conservative assumptions, the estimated
reductions in annual CHD mortality rates were 1% to 3%.
If, in addition to grain fortification, all patients with known CHD
were treated with 1 mg of folic acid and 0.5 mg of cyanocobalamin as supplements
to lower their homocysteine levels, it was projected that approximately 310 000
fewer CHD deaths would occur over a 10-year period compared with grain fortification
alone (Table 4). The estimated
absolute reduction in deaths would be greatest in the older age groups in
whom mortality from CHD and initial homocysteine levels tend to be higher.
Because the baseline homocysteine levels at all ages are higher in men and
because age-specific CHD mortality is also higher in men, they were expected
to benefit more than women. Treating everyone with known CHD with a vitamin
supplement was predicted to save money as well as lives in all age and sex
In men, the model predicted that each of the 10 primary prevention strategies
would save lives and money compared with men who would consume fortified grain
alone (Figure 1). Screening men
aged 45 years or older with no known CHD and treating those whose homocysteine
levels were higher than 10 µmol/L (1.35 mg/L) was predicted to maximize
cost savings. Providing vitamin supplementation beyond grain fortification
to all men aged 45 years or older was projected to cost $9000/QALY saved compared
with screening for elevated homocysteine levels (screen and treat). Extending
supplementation to men aged 35 through 44 years had an incremental CE ratio
of nearly $100 000/QALY and, thus, generally would not be recommended.
In women aged 75 years or older without CHD, vitamin supplementation
was predicted to have an incremental CE ratio of $1200/QALY vs grain fortification
alone. Screening women aged 65 through 74 years and treating those with elevated
homocysteine levels had an incremental CE ratio of $5500/QALY vs treating
all women aged 75 years or older. Extending treatment to all women aged 65
years or older was predicted to have an incremental CE ratio of $8800/QALY
vs the screen-and-treat strategy. Treating all women aged 55 through 64 years
had an incremental CE ratio of $39 000/QALY, which is in the range of
other commonly recommended therapies. Routine treatment of all women aged
45 years or older ($180 000/QALY) or all women aged 35 years or older
($830 000/QALY) would be too expensive for routine recommendation.
If the RRR of vitamin supplementation is 9% rather than 29%, the primary
prevention strategies of treating everyone without measuring homocysteine
levels would remain attractive at less than $40 000/QALY saved for men
aged 55 years or older and women aged 75 years or older. A 2-way sensitivity
analysis assuming less effective lowering of homocysteine values by vitamin
therapy (26%) and the weaker association between homocysteine and CHD risk
(RRR 9%) demonstrated that the screen-and-treat strategy would cost $29 000/QALY
saved for men aged 45 years or older and $42 000/QALY saved for women
aged 65 years or older. If the cost of the vitamin supplement decreased to
$10 per year in the prior analysis, the screen-and-treat strategy would save
costs and lives in men aged 45 years or older and would cost less than $10 000/QALY
gained for women aged 65 years or older. If compliance with vitamin supplementation
is only 50%, the treat-all strategy's incremental CE ratios remain less than
$50 000/QALY gained for men aged 45 years or older and women aged 65
years or older.
The primary parameter that determines the benefit of homocysteine-lowering
therapy for any person or group is their absolute risk of having a CHD event.
Age is the single strongest predictor of CHD risk75
and is readily available to clinicians when making decisions about whether
to screen for hyperhomocysteinemia or recommend vitamin supplementation for
CHD prevention. Furthermore, homocysteine increases with age in both men and
women. At any given age, both CHD risk and homocysteine levels are lower in
women, so sex differences were also considered.
There is always uncertainty in the assumptions used to project cost
and effectiveness. We performed a systematic literature review to find the
best available data. The risk estimates were based on multivariate analyses
of data from the Framingham Heart Study, a source of data demonstrated to
be accurate.76,77 The model's
simplifying use of categories to summarize risk factors has been shown to
be comparable to what would be obtained by considering each risk factor on
a continuous scale.78 Furthermore, future projections
based on the Coronary Heart Disease Policy Model have been proven consistently
accurate in comparison with subsequent prospective trials. For example, the
model's analyses of the cost-effectiveness of cholesterol reduction in patients
after experiencing myocardial infarction72
are similar to those calculated from the results of randomized trials.79-81 The Coronary Heart
Disease Policy Model also carries the limitation of any state-transition model—the
so-called Markov assumption or limited memory for previous states. This problem
has been addressed primarily by creating states in the model to account for
prior events (myocardial infarction, cardiac arrest, or coronary artery bypass
graft surgery) that influence subsequent CHD event rates. Prior analyses using
the model43,44 suggest that this
is not a significant problem.
The major limitation of our projections is the absence of clinical trial
data on the effect of homocysteine-lowering therapy on disease rates. Data
from a cohort of patients with homocystinuria treated with vitamin therapy
provide evidence for biological plausibility. Compared with historical controls,
up to a 90% reduction in catastrophic cardiovascular events has been reported.82 Our conservative baseline estimate of the association
between change in homocysteine level and risk of CHD events was equivalent
to the lower bound of the 95% CI in the meta-analysis by Boushey et al.53 It was also more conservative (closer to an OR of
1) than the summary odds ratio in a recent meta-analysis of prospective observational
trials.10 Sensitivity analyses assuming one
fourth the effect size of the baseline estimates projected an attractive CE
ratio for men aged 55 years or older and women aged 75 years or older.
We decided not to model benefits for diseases other than CHD despite
evidence that elevated homocysteine levels are associated with increased risk
for stroke and peripheral vascular disease.83-89
Therapy with folic acid and cyanocobalamin may also decrease the incidence
of pernicious anemia, dementia, and other clinical manifestations of deficiency
of these vitamins.
We also did not model any negative consequences of vitamin supplementation.
Both folic acid and cyanocobalamin are water-soluble vitamins with very low
potential for adverse effects. One concern frequently raised when considering
population-based folic acid therapy is the potential to accelerate the neurologic
sequelae of vitamin B12 deficiency.90-92
However, a recent clinical trial demonstrated that oral cyanocobalamin was
as effective as parenteral cyanocobalamin in treating multiple etiologies
of cyanocobalamin deficiency.93
The observational evidence supporting high homocysteine levels as a
risk factor for CHD events is strong.94 Furthermore,
clinical trial data demonstrate that homocysteine levels can be lowered by
inexpensive and safe doses of folic acid and cyanocobalamin. Nevertheless,
recent clinical trials of beta carotene, vitamin E, and hormone replacement
therapy have contradicted strong evidence for benefit demonstrated in multiple
prospective observational studies.95-99
Ultimately, we would recommend homocysteine-lowering therapy routinely only
if ongoing clinical trials demonstrate that vitamin therapy reduces clinically
important CHD events. In the meantime, since combined therapy with folic acid
and cyanocobalamin is well tolerated, it is reasonable to consider routine
therapy in men older than 45 years and women older than 55 years.
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