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Use of the Statins in Patients After Acute Myocardial Infarction
Does Evidence Change Practice?
Cynthia A. Jackevicius, BScPhm, MSc;
Geoffrey M. Anderson, MD, PhD;
Lawrence Leiter, MD;
Jack V. Tu, MD, PhD
Arch Intern Med. 2001;161:183-188.
ABSTRACT
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Objective To compare the use of lipid-lowering agents in 42 628 elderly patients
(aged  65 years) after acute myocardial infarction, before and after the
publication of the Scandinavian Simvastatin Survival Study (4S), using the
Ontario Myocardial Infarction Database.
Methods Multivariate regression models were created to estimate changes in the
rate of statin use over time in monthly cohorts of elderly patients after
acute myocardial infarction in Ontario from April 1, 1992, to March 31, 1997.
Changes in the rate of statin use over time were estimated using patient and
prescriber characteristics.
Results We found a 3.6-fold significant increase in the monthly rate of statin
use after the publication of 4S compared with before the publication of 4S
(P<.001); specifically, the rate of increase in
simvastatin and pravastatin sodium use was higher after the publication of
4S (P<.001 for each). Before the publication of
4S, the rate of increase in statin use in younger patients (aged 65-74 years)
was 2.7 times higher than in older patients (aged 75 years) (P = .02), while after the publication of 4S, the rate of increase in
statin use was only 1.8-fold higher in the younger group (P<.001). After the publication of 4S, there was a 1.6-fold higher
rate of increase in statin use in male compared with female patients (P = .006). Also after the publication of 4S, specialists
(cardiologists and internists) had a 2-fold higher rate of increased use of
the statins than did generalists (P<.001).
Conclusion It is possible to shift practice if the evidence of benefit is strong,
the intervention is easy to implement, and the intervention is marketed aggressively.
INTRODUCTION
THE SCANDINAVIAN Simvastatin Survival Study (4S),1
published in 1994, was the first large, randomized, clinical trial to demonstrate
that lipid lowering with simvastatin resulted in a clear and substantial decrease
in total mortality and in fewer coronary heart disease events and less cardiovascular
mortality when used in patients with coronary heart disease (history of angina
or myocardial infarction) who also had high low-density lipoprotein cholesterol
levels. Subsequent trials2, 3 have
reaffirmed these initial findings.
New research evidence, even evidence from landmark clinical trials,
often has a delayed or minimal impact on practice.4
For example, although aspirin (formerly acetylsalicylic acid) and ß-blockers
have been shown to increase survival in patients with acute myocardial infarction
(AMI) since the 1980s, uptake (use of an innovation or intervention in practice)
of these interventions has been suboptimal.5, 6
The diffusion (or uptake) of innovations in medical care is a complex process
that is driven by the features of the innovation and the explicit efforts
to change physician behavior.4, 7
The uptake of drugs that are easy to use and are not costly (eg, ß-blockers
and aspirin) may be related to behavior change efforts. Randomized trials8 have shown that it is possible to increase the use
of ß-blockers and aspirin using interventions based on marketing techniques
(opinion leaders using small-group discussions), and the failure of these
agents to be used more commonly in everyday practice may be in part the result
of a lack of a systematic effort to promote their use. Aspirin and most ß-blockers
are available in generic forms, and proprietary firms have little to gain
by marketing their use. It is also possible that there are barriers that make
practice change related to AMI care difficult, no matter how simple and effective
the intervention. The use of statins in patients after AMI represents a proven
innovation that is not complex to use, that has been endorsed by professional
societies and practice guidelines, and that has been aggressively marketed
by drug manufacturers.9, 10 Analysis
of the use of statins may provide us with information on the extent to which
it is possible to change prescribing behavior in a large population when strong
clinical evidence and practice guidelines are combined with aggressive marketing.
PATIENTS AND METHODS
A time series design and regression techniques were applied to administrative
data that identified patients with AMI and their subsequent prescription drug
use, and were used to study the association between the release of results
from 4S and the proportion of patients after AMI who filled a prescription
for a statin within 6 months of hospital discharge.
The Ontario Myocardial Infarction Database was created by using the
unique scrambled health insurance number to link data on hospital discharges
to data on prescription drugs in a comprehensive cohort of elderly Canadian
patients with AMI from April 1, 1992, to March 31, 1997.11
The Ontario Myocardial Infarction Database has been described in detail previously.12, 13 Briefly, all Ontario residents have
universal publicly funded health insurance for hospital care, and each discharge
from an acute care hospital results in the production of a discharge abstract
that is submitted to the provincial government, containing patient demographics
and diagnoses and the specialty of the physician most responsible for the
care of the patient during the hospital stay. The most responsible
physician for a hospital admission is defined as "the attending physician
most responsible for the care of the patient and/or for the longest length
of stay." Specialists were defined as cardiologists
and internists, with all other physician types being classified as nonspecialists.
All Ontario residents 65 years or older are covered under a comprehensive
drug benefit plan. Each time a prescription is filled, a claim is submitted
to the provincial government that contains the patient health insurance number
and a unique drug identifier. The Ontario Myocardial Infarction Database provides
data on all elderly patients treated for AMI in any Ontario hospital and records
any prescriptions filled after hospital discharge. A patient was identified
as having a statin prescription if the patient had been dispensed at least
one prescription for a statin in the 6-month period after discharge for AMI
treatment. This would allow enough time for clinicians to properly test patients'
cholesterol levels and give a trial of dietary therapy as appropriate before
initiating drug therapy.
Sixty monthly cohorts of elderly patients with AMI were used for the
analysis during the study: 32 before the publication of 4S (April 1, 1992,
to November 30, 1994, inclusive) and 28 after the publication of 4S (December
1, 1994, to March 31, 1997, inclusive). The monthly rate of statin use was
calculated for each cohort, with the total number of elderly patients with
AMI per cohort as the denominator.
The baseline clinical characteristics for 12-month periods during the
study were compared by using a t test for continuous,
normally distributed variables; the Kruskal-Wallis test for nonnormally distributed
continuous variables; and a  2 test for categorical variables.
The main analysis compared the primary end point of statin use within 6 months
post-AMI before and after the publication of 4S by linear regression. Additional
analyses investigated subgroup effects based on prescriber and patient characteristics.14, 15 The regression model used 3 time
variables as independent variables to model the time-related effects: a variable
that indicated the monthly rate of statin use during the entire period (ie,
monthly intervals 1, 2, 3, . . . , 60); a variable that indicated the monthly
rate of statin use after the publication of 4S, starting on December 1, 1994,
and continuing until March 31, 1997; and a dummy variable indicating whether
the period was either before or after the publication of 4S, with the change
point at December 1, 1994.
All variables were entered into the model simultaneously without the
use of stepwise or conditional procedures. All models were evaluated for appropriateness
of fit using standard graphical and statistical methods, including use of
the Durbin-Watson statistic for autocorrelation.14
Models using interaction terms were constructed for physician specialty, age,
and sex with the same independent variables as in the base model. The purpose
of the interaction models was to allow estimates of differences in the effects
of different subgroups. Determining separate estimates for subgroups allowed
for assessment of nonparallel effects over time, before and after the publication
of 4S. By convention, all P values were 2-tailed,
and were considered significant at the .05 level, without correction for multiple
comparisons. Adjusting for age and sex distribution of the cohort over time
did not change the results; therefore, all results are presented as unadjusted
analyses.14, 15
Statistical analyses were performed using SAS statistical software,
version 6.12 (SAS Institute Inc, Cary, NC).
RESULTS
The study sample consisted of 42 628 patients aged 65 years or
older who experienced an AMI as the primary reason for a hospital admission
between April 1, 1992, and March 31, 1997. Baseline characteristics of the
subjects by year are summarized in Table
1. During the 5-year period, substantial changes included a higher
proportion of patients admitted by specialists, more prior use of statins,
and more overall and individual statin use. Substantial increases in the level
of statin use were apparent between fiscal years 1994-1995 and 1995-1996,
the period in which 4S was published, with the exception of lovastatin, for
which the use levels appeared to peak in fiscal year 1995-1996 and decline
thereafter. Subjects treated by specialists were younger, were more likely
to be men, were more frequently treated at teaching hospitals, had fewer strokes,
had more prior statin use, and had a greater level of use of any statin post-AMI
(Table 2).
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Table 1. Characteristics of an Elderly Acute Myocardial Infarction
(AMI) Survivor Cohort in Ontario*
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Table 2. Characteristics of Patients in the Cohort by Physician Specialty*
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As shown in Figure 1, the
rates of change in the use of all statins as a group and those of simvastatin
and pravastatin sodium increased substantially following the publication of
4S (P<.001). Before the publication of 4S, the
rate of increase in all statin use was 0.14% per month, which increased 3.6-fold
to 0.51% per month after the publication of 4S. Simvastatin and pravastatin
also showed significant increases in the rates of use before and after the
publication of 4S. After the publication of 4S, there was a 6.6-fold (95%
confidence interval, 2.0- to 8.6-fold) increase in the rate of pravastatin
use and a 3.7-fold (95% confidence interval, 3.3- to 4.5-fold) increase in
the rate of simvastatin use compared with before the publication of 4S. There
was no statistically significant change in the rate of use of lovastatin or
fluvastatin sodium.
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Figure 1. Use of each statin and overall
statin use 6 months after myocardial infarction. For all statins, before the
publication of 4S, ß = .14 (P<.001); and after the publication
of 4S, ß = .51 (P<.001). For the all statins model, F
= 562.41 (P<.001), R2 = 0.97, and
the Durbin-Watson statistic = 1.89. 4S indicates Scandinavian Simvastatin
Survival Study.
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Figure 2 illustrates that
it was only after the publication of 4S that patients admitted to the hospital
under the primary care of a specialist were more often dispensed statins compared
with those admitted under the care of a nonspecialist. A regression model
constructed to assess for differential rates of use based on physician specialty
found that the overall rate of increase in statin use was significantly greater
for specialists (0.60% per month) than for nonspecialists (0.29% per month)
during the post-4S period (P<.001).
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Figure 2. Use of statins 6 months after
myocardial infarction in patients admitted by a specialist (cardiologist or
internist) vs a nonspecialist physician. Before the publication of 4S, ß
= .13 vs .15 (P= .58); and after the publication of 4S, ß
= .29 vs .60 (P<.001). For the model, F = 320.07 (P<.001), R2 = 0.95, Durbin-Watson statistic
= 1.99.
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Since patients admitted by specialist physicians were generally younger
and more likely to be men, it was possible that the specialist effect we found
was actually due to increased statin use in the younger, male patients, who
are more likely to be treated by specialist physicians. Regression models
were constructed to assess the specialist effect separately in 4 patient groups:
men, women, patients aged 65 to 74 years, and patients aged 75 years and older.
In each of these 4 groups, patients admitted to the hospital by specialists
had a statistically significant greater rate of increase in statin use after
the publication of 4S than did those admitted by nonspecialist physicians
(P<.05). The results of these models confirm an
independent effect of physician specialty that cannot be attributed to sex
or age differences of patients admitted by specialist physicians. In addition,
further regression analyses demonstrate a significant specialist effect in
teaching and nonteaching hospitals when analyzed separately.
There was a significantly higher rate of overall statin use before (P = .02) and more substantially after (P<.001) the publication of 4S in younger (aged 65-74 years) compared
with older (aged 75 years) patients (Figure 3). A small but statistically significant 1.6-fold greater
rate of statin use was found for men compared with women only after 4S was
published (P = .006).
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Figure 3. Use of statins 6 months after
myocardial infarction by age category. Before the publication of 4S, ß
= .20 vs .08 (P= .02); and after the publication of 4S, ß
= .68 vs .38 (P<.001). For the model, F = 465.77 (P<.001), R2 = 0.97, Durbin-Watson statistic
= 2.12. 4S indicates Scandinavian Simvastatin Survival Study.
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COMMENT
We found that there was a steady increase in the overall rate of statin
use before the publication of 4S, but that the rate increased significantly
after publication. Interestingly, the rate of use of simvastatin and pravastatin
increased after the publication of 4S, even though simvastatin was the drug
used in 4S. The publication of the West of Scotland Coronary Prevention Study
in 1995,16 although it was a primary prevention
trial, may have had an impact on prescribers, and some may have believed that
the 4S trial indicated a drug class effect rather than a drug-specific effect.
However, if there was a class effect, it did not seem to extend to lovastatin
as the use of this drug continued to decline.
The present study confirms and expands on previous work on the prescribing
of lipid-lowering agents.17, 18
The time trend analysis of Baxter et al18 of
changes in the prescribing of lipid-lowering drugs in the general population
of southeast Thames, England, found an exponential increase from 1990 to 1996,
with great regional variation in the uptake of the change in practice. The
study by Lemaitre et al17 of a general population
cohort of patients aged 65 years and older also found a significant 4-fold
increase from June 1989 to May 1996, with an apparent significant undertreatment
of many patients. We not only found a substantial rate of increase in statin
use over similar periods but also uncovered differential use related to prescriber
and patient characteristics.
Although there was no statistically significant difference in the rate
of uptake in the use of statins between specialists and nonspecialists before
the publication of 4S, there was a significant consistent effect of specialty
after the study's publication. This suggests that specialists take up new
information from clinical trials at a greater rate and speed than nonspecialists.
These results are congruent with those of previous studies,19, 20, 21, 22, 23
in which specialists' prescribing practice was nearer to clinical trial evidence
than was nonspecialists' prescribing practice. Specifically, Whyte et al20 found that patients followed up by cardiologists
were more than twice as likely to receive drug therapy for a low-density lipoprotein
cholesterol level above the accepted target level than were patients treated
by generalists. Most of these studies were conducted in the United States,
where the nonspecialists used for comparison were internists who are often
primary care physicians in the American health care system, similar to family
physicians or general practitioners in the Canadian health care system. In
Canada, the licensing body did not mandate formal continuing education for
either generalists or specialists during the period of interest for our study.
While generalist physicians have a broader area of knowledge to maintain,
specialist physicians are able to read literature on a narrower range of topics
pertinent to their specialty and to attend scientific specialty meetings where
late-breaking results of clinical trials are first presented and discussed.
Not only do specialist physicians inherently have a quicker uptake of new
information, they also are often the first to be targeted for marketing of
new drugs by pharmaceutical companies.
Based on reports of the range of serum cholesterol levels in patients
with coronary heart disease and the target cholesterol level of 5.5 to 8.0
mmol/L (213-309 mg/dL) of patients in 4S, a conservative estimate of a potentially
desirable target rate of statin use in a post-AMI population would be approximately
50% to 60%.1, 24 Previous surveys25, 26 demonstrated that approximately 65%
to 69% of older patients after AMI have an elevated total cholesterol (>5.5
mmol/L [>213 mg/dL]) or an elevated low-density lipoprotein cholesterol (>3.2
mmol/L [>124 mg/dL]) level, typically requiring therapy. If we assumed that
the rates of increase in statin use were to continue at the rate estimated
in this study and if we assumed an overall level of 60% of patients receiving
statins at 6 months was a marker of appropriate uptake, we estimate that it
would take until September 2000 for specialists and until November 2008 for
nonspecialists to reach this level of prescribing. In other words, specialists
would reach the "target" rates 6 years after the trial was published and nonspecialists
would reach this level in 14 years. While the specialists had better rates
of incorporating the 4S results into their prescribing practices, their rates
were still far from optimal. Antman et al27
have shown that even clinical experts have difficulty keeping up with and
summarizing the latest evidence in a timely fashion.
Although we found an increase in the rate of statin use in elderly patients,
the rate of increase was much higher in the younger patients. Since patients
in 4S were 70 years or younger at enrollment, lower rates of use in the very
elderly (>75 years old) may be appropriate. In contrast to the significantly
lower observed rates of use of ß-blockers and aspirin in women in previous
studies,1, 5, 6 we
found a negligible sex difference in our study, despite the fact that in 4S
women represented only 18% of the study population and in subgroup analysis
they did not achieve a statistically significant mortality benefit. Marketing
efforts of the statins after the publication of 4S may not have differentiated
between the effects due to sex and likely influenced the achievement of similar
rates of statin use in men and women.
It is impossible to separate the effects of the publication of 4S, the
subsequent continuing education efforts, and the effects of marketing by the
pharmaceutical industry. Therefore, the results of this study show the effects
of the combined efforts among many different parties to promote appropriate
medication prescribing with lipid-lowering therapy in patients after AMI.
The impact of marketing by the pharmaceutical industry must not be unexpected
or underestimated. Surveys28, 29, 30
demonstrate that physicians often do rely on pharmaceutical representatives
as a main source of their continuing medical education. Potential effects
of the pharmaceutical industry that were demonstrated in this study include
the continual decline in the use of lovastatin, possibly due to the genericization
of this preparation in Canada and subsequent decreased promotion, and the
transient decline in the rates of use of pravastatin shortly after the publication
of 4S. The key questions are related to how marketing should be used to promote
high-quality, evidence-based care. Who should market low-cost effective therapies
that are not patented, such as ß-blockers? Why has the use of ß-blockers
continually remained well below target levels despite solid evidence of benefit?31, 32 Can marketing of some agents have
unexpected negative results? For example, previous research33
with ß-blockers and calcium channel blockers has demonstrated that properly
targeted marketing can inhibit the use of well-proven therapies with the substitution
of less well-proven therapies in patients after AMI.
Our study has some limitations. Use of statin therapy was available
solely for patients 65 years and older. It is possible that even higher rates
of uptake of statin use would have been found with a younger post-AMI population
given the existing age bias in post-AMI prescribing. Our database did not
have access to actual cholesterol profiles for the patients in our cohort,
which limits our ability to determine, based on post-AMI guidelines, which
individual patients should have received cholesterol-lowering therapy. However,
since our study relied on a large, population-based database, our results
are likely quite generalizable to many post-AMI populations. Our study did
not assess the adherence of patients to their statin prescriptions. It has
been reported34 that up to half of the patients
prescribed a lipid-lowering agent discontinue the medication within 1 year.
Since the benefits of lipid lowering with simvastatin on mortality started
after 1 to 2 years of therapy, nonadherence represents a lost opportunity
for prevention of cardiovascular disease events.
This study has demonstrated that one large randomized clinical trial,
4S, was associated with a significant change in the prescribing of lipid-lowering
agents in patients 65 years and older after AMI. Differential prescribing
was associated with age and physician specialty status. While rates of statin
use significantly increased during the period of interest, additional efforts
need to be put into place to sufficiently increase the prescribing rates to
target levels. This study suggests that it is possible to shift practice if
the evidence of benefit is strong, the intervention is easy to implement,
and the intervention is marketed aggressively.
AUTHOR INFORMATION
Accepted for publication July 13, 2000.
This study was funded by an operating grant from the Medical Research
Council of Canada, Ottawa, Ontario, and in part by a Medical Research Council
Scholar award (Dr Tu).
Presented at the Canadian Cardiovascular Society Meeting, Quebec City,
Quebec, October 20, 1999.
We thank Peter Austin, PhD, for his consultation on statistical issues.
From the Pharmacy Department, University Health Network–Toronto
General Hospital (Ms Jackevicius), the Departments of Health Administration
(Ms Jackevicius and Drs Anderson and Tu), Medicine (Drs Leiter and Tu), Nutritional
Sciences (Dr Leiter), and Public Health Sciences (Dr Tu), University of Toronto,
the Institute for Clinical Evaluative Sciences (Drs Anderson and Tu), St Michael's
Hospital (Dr Leiter), and the Division of General Internal Medicine, Sunnybrook
and Women's College Health Science Centre (Dr Tu), Toronto, Ontario. Dr Leiter
has received research funding from and has been a speaker for Merck Canada,
Montreal, Quebec, the manufacturer of simvastatin.
Corresponding author and reprints: Cynthia A. Jackevicius, BScPhm,
MSc, Pharmacy Department, University Health Network–Toronto General
Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4 (e-mail: cynthia.jackevicius{at}uhn.on.ca).
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