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Cost-effectiveness of Gemfibrozil for Coronary Heart Disease Patients With Low Levels of High-Density Lipoprotein Cholesterol
The Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial
John A. Nyman, PhD;
Melissa S. Martinson, PhD;
David Nelson, PhD;
Sean Nugent, BA;
Dorothea Collins, ScD;
Janet Wittes, PhD;
Carol L. Fye, RPh;
Timothy J. Wilt, MD, MPH;
Sander J. Robins, MD;
Hanna Bloomfield Rubins, MD, MPH;
for the VA-HIT Study Group
Arch Intern Med. 2002;162:177-182.
ABSTRACT
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Background Although numerous clinical trials and economic analyses have established
the efficacy and cost-effectiveness of lowering cholesterol for the prevention
of coronary heart disease, there are few data on the role of raising high-density
lipoprotein cholesterol (HDL-C) levels and lowering triglyceride levels. The
US Department of Veterans Affairs (VA) Cooperative Studies Program HDL-C Intervention
Trial (VA-HIT) was a multicenter, randomized trial of gemfibrozil, an agent
that raised HDL-C levels and lowered triglyceride levels, yet had no effect
on low-density lipoprotein cholesterol (LDL-C) levels. The study showed that
gemfibrozil therapy significantly reduced major cardiovascular events (cardiovascular
death, myocardial infarction, and stroke) in patients with coronary heart
disease, low HDL-C levels, and low LDL-C levels.
Objective To report the results of a cost-effectiveness study based on the results
of the VA-HIT.
Methods The cost per year of life gained with gemfibrozil therapy was calculated.
Hazard functions were estimated, and the resulting probabilities were used
in a Markov model simulation to estimate the effect of gemfibrozil on life
expectancy and costs over a simulated lifetime. Sensitivity analyses were
used to account for uncertainty.
Results Using the prices of gemfibrozil that were negotiated by the VA, gemfibrozil
was cost saving. Using drug prices found outside the VA, a quality-adjusted
life-year saved by gemfibrozil therapy cost between $6300 and $17 100.
Conclusions Gemfibrozil reduces major cardiovascular events in male coronary heart
disease patients with low levels of HDL-C and low levels of LDL-C and would
result in cost saving at annual drug costs of $100 or less in 1998 dollars.
Even at the higher drug prices represented by the average wholesale price
in the United States, the cost of a life-year saved is well below the threshold
that would be deemed cost-effective. To our knowledge, this is the first economic
analysis based on clinical trial data to assess the cost-effectiveness of
raising HDL-C levels and lowering triglyceride levels in a setting in which
LDL-C levels were not lowered.
INTRODUCTION
LOW-DENSITY lipoprotein cholesterol (LDL-C) is a risk factor for coronary
heart disease (CHD), and numerous trials have shown that drugs that lower
elevated LDL-C levels reduce major cardiovascular events, such as CHD death,
myocardial infarction, and stroke.1-3
Approximately 40% of patients with CHD, however, do not have elevated LDL-C
levels. Many of these patients instead exhibit low levels of high-density
lipoprotein cholesterol (HDL-C). Because no clinical trials had determined
the efficacy of lipid therapy in these patients, the US Department of Veterans
Affairs (VA) conducted a multicenter randomized controlled clinical trial
(the VA Cooperative Studies Program HDL-C Intervention Trial [VA-HIT]) to
determine whether therapy aimed at increasing HDL-C levels and decreasing
triglyceride levels would reduce major cardiovascular end points in CHD patients
whose primary lipid abnormality is low HDL-C levels.4
The VA-HIT study compared gemfibrozil (1200 mg/d) with placebo in 2531
men (average ± SD age, 64 ± 7 years) who had CHD, low HDL-C
levels (mean, 32 mg/dL [0.83 mmol/L]), and low LDL-C levels (mean, 111 mg/dL
[2.87 mmol/L]). The median follow-up period was 5.1 years. At 1 year, participants
who underwent gemfibrozil therapy had mean HDL-C levels 6% higher, mean triglyceride
levels 31% lower, and mean total cholesterol levels 4% lower than the placebo
group. (The levels of LDL-C during the trial did not differ significantly
between treatment arms.) At the end of the trial, those in the treatment group
had a 22% reduction in relative risk (a 4.4% absolute risk reduction) for
the primary end point of nonfatal myocardial infarction and CHD death. For
the expanded end points of nonfatal myocardial infarction, CHD death, and
stroke, the relative risk reduction with drug therapy was 24% (a 5.6% absolute
reduction).4
Although the VA-HIT study showed that gemfibrozil was associated with
a reduction in major cardiovascular events in CHD patients whose primary lipid
abnormality was a low level of HDL-C, in an era of concern over rapidly growing
health care expenditures, it is also necessary to investigate the economic
consequences of this therapeutic approach. In the present study, we analyze
the cost-effectiveness of gemfibrozil for the treatment of CHD patients with
this lipid profile. To our knowledge, this is the first economic analysis
based on clinical trial data to assess the cost-effectiveness of raising HDL-C
levels and lowering triglyceride levels in a setting in which LDL-C levels
were not lowered.
METHODS
DATA
The data for this cost-effectiveness study come from the VA-HIT study.
Participants in that study were men younger than 74 years at enrollment, with
a history of CHD, an HDL-C level of 40 mg/dL (1.03 mmol/L) or less, and an
LDL-C level of 140 mg/dL (3.6 mmol/L) or less. Patients with clinically evident
chronic heart failure or other major medical problems likely to result in
mortality within 5 years were excluded. Patients with long-term stable conditions,
such as diabetes and hypertension, were included. The details of the study
and data can be found elsewhere.5
PERSPECTIVE
Costs in this analysis were defined as the direct costs of gemfibrozil
therapy minus any cost savings due to the reduction in downstream medical
treatment costs attributable to the therapy. Effects were defined as the number
of life-years gained with gemfibrozil therapy.
The VA-HIT study was performed from the perspective of a health care
organization such as the VA; thus, it omitted indirect costs (eg, travel costs
and productivity costs stemming from absence from work). Omitting indirect
costs would produce conservative cost-effectiveness results, if the study
were performed from the perspective of society. This is because it is unlikely
that indirect costs would be a substantial portion of the cost of a pharmacologic
intervention such as gemfibrozil. Moreover, because gemfibrozil is associated
with fewer cardiovascular events, the omission of indirect costs in the downstream
costs leads to an underestimate of the cost savings associated with gemfibrozil.
Therefore, the cost-effectiveness ratios from the perspective of the health
plan would represent conservative estimates of the cost-effectiveness of gemfibrozil
from the perspective of society.
ESTIMATES OF EFFECTS
To promote standardization and facilitate comparisons across similar
studies, the analysis was modeled after the cost-effectiveness analysis from
the Scandinavian Simvastatin Survival Study.6
Accordingly, a Markov model was developed to estimate the effects of gemfibrozil
on future years of life.
In the Markov model, a cohort of individuals with age characteristics
of the study participants was followed from their current age to age 110 years,
which was deemed to be the longest possible survival time. In each year, the
men could experience a cardiovascular event or die of a noncardiovascular
cause. Cardiovascular events were either fatal or nonfatal, as described in
detail elsewhere.5 Nonfatal events included
myocardial infarction or stroke. If the person experienced a nonfatal event,
it was assumed that he would remain in a temporary state of disease during
the subsequent year, during which time he was assumed to have an increased
risk of death. If the patient survived this year, he would enter a period
of chronic disease, during which time the risk of death was higher than normal
but lower than during the first year following an event. At the end of every
period in the chronic disease state, patients had a probability of dying or
surviving for another year in that state.
Hazard functions were estimated from the VA-HIT data and used to determine
the probabilities of transitioning from one state to another in the Markov
model. Four probabilities were estimated separately from the VA-HIT data:
(1) the annual risk of a CHD patient dying from a non–CHD-related cause,
(2) the annual risk of a CHD patient experiencing a cardiovascular event,
(3) the annual risk of a patient dying in the first year after a nonfatal
event, and (4) the annual risk of a patient dying in the chronic state, that
is, in a year subsequent to the first year after a nonfatal event. The hazard
functions were estimated from exponential survival models, and each included
a variable that represented whether the patient was in the gemfibrozil group
or not. This variable was only significant in the function estimating the
annual risk of a CHD patient experiencing a cardiovascular event. Thus, the
differential treatment and control probabilities used to generate the life
expectancy effects due to gemfibrozil therapy in the discrete Markov model
were based on this factor alone.
The hazard functions included age as a risk factor but not sex because
all the participants were male. The age variable allowed for the estimation
of effectiveness and costs of gemfibrozil in treating patients of varied ages.
The proportion of cardiovascular events that were fatal, however, was remarkably
similar across age groups. Although there were more events for patients aged
65 to 74 years, the percentage of events that were fatal in both the 65- to
74-year and 55- to 64-year age groups was 28%, using data from both arms of
the trial (Table 1).
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Table 1. Event Rates for Participants 55 to 64 Years Old and 65 to
74 Years Old*
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The differential risks of a cardiovascular event attributable to gemfibrozil
therapy were applied to the Markov model using a Monte Carlo simulation. After
5 years of gemfibrozil treatment, it was assumed that the treatment would
stop and the risk of cardiovascular events for those in the treatment group
would revert to the level found in the control group. Although the effectiveness
of continued gemfibrozil treatment would likely extend beyond 5 years, the
Markov model did not extrapolate effectiveness beyond the period observed
and documented by the VA-HIT. Also, the reduction in risk was assumed to apply
only to the first event and not to any subsequent event. This assumption is
also conservative because the occurrence of an event increases the absolute
risk of further events, and thus any reduction of events would have downstream
effects on risk rates not captured in the analysis.
ESTIMATES OF COSTS
The annual cost of gemfibrozil at two 600-mg tablets per day (Lopid,
Parke-Davis, New York, NY) using the price negotiated by the VA is $46.75.
The annual cost of gemfibrozil based on the 1998 average wholesale price in
the United States (Medi-Span Inc, San Bruno, Calif) is $956.96. The VA vs
wholesale prices were used in an alternative analyses.
The cost of one additional fasting lipid profile per year was also included
as part of the direct treatment costs. Although the number of lipid profiles
ordered is largely a matter of physician practice style, it was thought that
patients undergoing gemfibrozil therapy may receive one additional lipid test
each year, compared with those not receiving a lipid medication. The 1998
price of a lipid panel (Current Procedural Terminology code 80061) was assumed
to be $10.16, based on a sample of this procedure's cost at 5 VA medical centers.
It was assumed that the therapy would cease with the cardiovascular event,
so the drug and monitoring costs were incurred by patients only until the
period in which they transitioned to a cardiovascular event or death.
The direct medical care costs are represented by hospital costs attributable
to treatment of fatal and nonfatal cardiovascular events. A list of diagnosis
related groups (DRGs) that are associated with the treatment of cardiovascular
events was identified (Table 2). For any participant experiencing an event in the VA-HIT study, the DRG treatment
costs incurred by the participant during the subsequent year were summed to
determine the annual cost of an event. The annual cost per participant with
an event was averaged, based on the experience of participants in both arms
of the study. In the Markov model, for any subject who was simulated to have
experienced an event, this average cost was applied. Separate average cost
figures were calculated for the year following a nonfatal event, for a year
subsequent to that year, and for fatal events. Thus, for any person who was
simulated to have experienced a nonfatal coronary event, their annual hospital
costs were estimated to be $10 152 during the first year after an event
and $1600 during a subsequent year. For any person who was simulated to experience
a fatal event, their cost was estimated to be $3430 for the year of that event.
All drug and medical care use was evaluated at 1998 prices.
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Table 2. Cardiovascular DRGs and Their Relative Weights*
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SENSITIVITY ANALYSIS AND THE REFERENCE CASE
Separate cost-effectiveness ratios were calculated for men aged 55,
65, and 75 years, consistent with the range of ages of the men in the VA-HIT
study. In a sensitivity analysis, costs and life-years were calculated with
discount rates of 0%, 3%, and 5%, consistent with recommendations from the
Panel on Cost-effectiveness in Health and Medicine.7
The expected life-years of CHD patients were also adjusted for quality of
life. Because quality of life data were not collected in the VA-HIT study,
a measure was obtained from the literature.8
Accordingly, it was assumed that a life-year with CHD could either take on
a weight of 1.00 or 0.88, the latter reflecting the concept that the quality
of a year of life with CHD was worth 0.88 times a year of life in perfect
health. Finally, we replicated the entire analysis, replacing our original
exponential hazard function with log normal and Weibull functions.
Although the sensitivity analysis calculated cost-effectiveness ratios
for all these potential cases, the case of the 65-year-old man, undiscounted
and unadjusted for quality of life, was considered the reference case.
RESULTS
For the 65-year-old reference case, the life expectancy is estimated
at 17.45 years without gemfibrozil therapy and 18.07 years with the therapy,
for an increase in survival of 0.62 years. The estimated costs using VA prices
are $10 462 without gemfibrozil and $10 352 with gemfibrozil, for
a net lifetime cost savings with gemfibrozil of $110 per patient. The estimated
cost with gemfibrozil using national wholesale drug prices is $14 431,
for a net cost with gemfibrozil of $3969. Therefore, for drug therapy applied
in settings in which gemfibrozil is purchased at prices that reflect the average
national wholesale price, the incremental cost-effectiveness ratio (ICER)
is $6403 in costs per life-year saved. For comparison, the corresponding estimates
for all 3 age levels (ages 55, 65, and 75 years) are presented in Table 3.
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Table 3. Cost-effectiveness Ratios for Individuals Aged 55, 65, and
75 Years*
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Sensitivity analyses were performed for the 3 age levels, using the
3 discount rates (0%, 3%, and 5%) and with effectiveness measured by 2 quality-adjusted
life-year (QALY) weights (1.00 and 0.88).8
The results (Table 4) indicate
a robustness of the cost-saving result using the low drug prices negotiated
by large health plans such as the VA and a range in ICERs from $6305 to $17 075
using national average drug prices. In general, ICERs were found to decrease
with age and increase with the discount rate.
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Table 4. Sensitivity Analysis*
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In addition, break-even annual drug costs were calculated for the 3
age levels (Table 5). These results
suggest that, as a general rule, if the annual cost of gemfibrozil therapy
is $100 or less, the use of the drug would result in a lifetime cost saving.
The average age at first event was also calculated for the 3 age levels. Gemfibrozil
therapy resulted in the greatest delay in the occurrence of the first event
for those in the 65-year-old group (Table
5).
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Table 5. Break-even Costs and Average Age at First Event
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Finally, the analysis was replicated using lognormal and Weibull hazard
functions. The ICERs calculated using probabilities from these hazards showed
a larger range in results; that is, the costs per QALY were greater for the
positive ICERs and the savings per QALY were greater for the negative (cost
saving) ICERs, compared with the original exponential hazard function results,
but were generally consistent with those results. Specifically, for the reference
case at average wholesale prices, the exponential, lognormal, and Weibull
hazards resulted in ICERs of $6403, $9721, and $12 379, respectively.
In all cases, gemfibrozil was cost saving at the prices that the VA paid for
the drug.
COMMENT
This analysis suggests that gemfibrozil therapy will result in a lifetime
cost savings for CHD patients with low HDL-C levels as their primary lipid
abnormality if the drug can be purchased for less than $100 per year (in 1998
prices). Drug prices negotiated by the VA Health Care System and possibly
by other large health care organizations place gemfibrozil therapy in this
price range. This is an important finding because only a handful of health
care interventions have shown to be cost saving (ie, improve clinical outcomes
and save money). Even allowing for higher gemfibrozil prices, this intervention
would still be considered cost-effective (ie, improve outcomes and cost money),
with a range of cost-effectiveness ratios from $6300 to $17 100 per year
of life saved.9-12
Indeed, cost-effectiveness ratios of $100 000 or more per life saved
have been deemed to be cost-effective, based on estimates of the value of
year of life from consumers' revealed preferences for work-related risk.13-14 To our knowledge, this is the first
economic analysis based on clinical trial data to assess the cost-effectiveness
of raising HDL-C levels and lowering triglyceride levels in a setting in which
LDL-C levels were not lowered.
These findings have potentially widespread implications. It is estimated
that among the approximately 13 million patients with established CHD in the
United States roughly 20% to 25%, or 2 million to 3 million people, have low
HDL-C levels in the absence of high LDL-C levels.15
Among the 3 million patients cared for in the VA Health Care System, it is
estimated that approximately 25% have CHD.16-17
Therefore, approximately 175 000 veterans have CHD and low HDL-C levels
in the absence of high LDL-C levels. At an undiscounted lifetime cost saving
of $110 per patient treated, about $19 million could be saved by the VA from
treatment of the existing cohort of CHD patients. Large savings could also
be realized in other health care system settings with sufficient market power
to command similarly low drug prices. These results, however, should not be
extrapolated to patients without established CHD in whom the efficacy and
the cost-effectiveness of gemfibrozil have not been evaluated.
We chose to compare gemfibrozil to the alternative strategy of no lipid
therapy because gemfibrozil is the only lipid intervention that reduces clinical
events in a large-scale randomized trial in CHD patients whose primary lipid
abnormality is low HDL-C levels. Other medications, such as statins, have
never been tested in a similar population. The cost-effectiveness, however,
of statins for treatment of CHD patients with a different lipid profile (ie,
high total or LDL-C levels) has been reported. In the Scandinavian Simvastatin
Survival Study's cost-effectiveness analysis, which used methods similar to
ours, the use of simvastatin for CHD patients with high LDL-C levels was deemed
to be cost-effective based on cost-effectiveness ratios of $3800 to $27 400
in 1995 dollars.5 Other cost-effectiveness
estimates for cholesterol-lowering treatments have varied widely and have
in general suggested that less potent cholesterol-lowering agents applied
to the lowest-risk populations yield the highest costs per year of life saved.18
This analysis, like others, has strengths and limitations. One strength
is that it is based on data collected prospectively in a randomized clinical
trial, thus allowing the analysis to rely on fewer assumptions than if the
analysis were based on epidemiologic data. Analyses based on epidemiologic
data must make assumptions about the treatment efficacy based on presumed
benefits that would accrue from a given change in a risk factor. In contrast,
analyses based on clinical trial data are more robust because the estimates
of effectiveness are based on data from a population that was actually treated
with the intervention.
Even economic analyses that are based on clinical trial data, however,
must resort to some assumptions. Still, another strength of our study is that
conservative assumptions were chosen where possible. For example, in the Markov
analysis, it was assumed that the treatment would be discontinued after 5
years, the period of follow-up in the actual study. However, based on the
evidence of the effectiveness of treatment in 75-year-old patients, it is
likely that if treatment were continued beyond 5 years in the 55- and 65-year-old
cohorts, it would be similarly cost-effective or cost saving. Also, the reduction
in the probability of initial events was assumed not to have any effect on
the probability of subsequent events, when in fact the probability of subsequent
events would be expected to increase following an initial event. Thus, the
analysis underestimates the reduction of future events caused by the treatment.
The results of the study held up well in the sensitivity analysis. Adjusting
for higher drug prices than were paid by the VA, discounting future cost savings
at discount rates greater than 0, and adjusting the value of a life saved
for the quality of life all increased the cost-effectiveness ratios, but these
increases resulted in ICERs that were still within acceptable ranges.
One limitation of our study may have been the lack of data on indirect
costs. Indirect costs would include the costs of traveling to a health care
facility for care following an event and the wages lost in time spent traveling
to and receiving the care. The omission of indirect costs, however, results
in an underestimate of the cost savings from downstream procedures avoided,
so including these costs would result in even lower cost-effectiveness ratios.
This limitation, therefore, also creates a likely conservative bias, if the
study is interpreted as reflecting a societal perspective, and is even more
supportive of the conclusion that gemfibrozil therapy is cost-effective in
this population. Another limitation is that our estimates of efficacy were
based on the results of a clinical trial that, because of the selection of
patients and the intensive follow-up, may overestimate the efficacy that would
be observed in a routine clinical setting. Finally, it should be recognized
that, although there are numerous trials that show efficacy and cost-effectiveness
of statins for patients with elevated LDL-C levels, to date there is just
a single trial that demonstrates efficacy and cost-effectiveness for gemfibrozil
in CHD patients with low HDL-C levels.1-3,6
In conclusion, the VA-HIT demonstrated that gemfibrozil is a safe and
well-tolerated therapy that significantly reduces major cardiovascular events,
including myocardial infarction, cardiovascular death, and stroke, in patients
with established CHD who have low levels of HDL-C and low-risk LDL-C levels.4 This study presents evidence that gemfibrozil therapy
is also highly cost-effective, if not cost saving, thus providing a strong
rationale for incorporating the therapy into practice. These results also
suggest that raising HDL-C levels and lowering triglyceride levels, independent
of changes in LDL-C levels, represent efficacious and cost-effective approaches
for the secondary prevention of CHD.
AUTHOR INFORMATION
Accepted for publication May 8, 2001.
The VA-HIT was supported by the Cooperative Studies Program of the Department
of Veterans Affairs Office of Research and Development, Washington, DC, and
by a supplemental grant from Parke-Davis.
The views expressed in this article do not necessarily represent the
views of the Department of Veterans Affairs.
Corresponding author and reprints: John A. Nyman, PhD, Division of
Health Services Research and Policy, University of Minnesota, 420 Delaware
St SE, Mail Route 729, Minneapolis, MN 55455-0392 (e-mail: nyman001{at}tc.umn.edu).
From the School of Public Health, Division of Health Services Research
and Policy, University of Minnesota (Drs Nyman and Martinson), and Center
for Chronic Disease Outcomes Research, Department of Veterans Affairs Medical
Center, Minneapolis, Minn (Drs Nelson, Wilt, and Rubins and Mr Nugent); Department
of Veterans Affairs Cooperative Studies Program Coordinating Center, West
Haven, Conn (Dr Collins); Statistics Collaborative, Washington, DC (Dr Wittes);
Department of Veterans Affairs Clinical Research Pharmacy Coordinating Center,
Albuquerque, NM (Ms Fye); and Department of Medicine, Boston University School
of Medicine, Boston, Mass (Dr Robins). A list of the members of the VA-HIT
study group was published previously (N Engl J Med.
1999;341:410-418).
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