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n clinical n
with diabetes and/or cardiovascular disease. In patients with diabetes,
coronary artery disease (CAD), or other occlusive arterial disease, sim-
vastatin 40 mg/day reduces by about one-quarter the risk of myocardial
infarction (MI), stroke, revascularization procedures, and coronary
deaths.1,2 Among individuals with known vascular disease or diabetes
and another risk factor, ACeIs reduce the rate of MIs by 18% and the
rate of stroke by 23%.3,4
More recently, researchers have investigated the impact of combina-
tion pharmacotherapy. In a very small study, the vascular and metabolic
effects of combined therapy with simvastatin and ramipril in patients
with type 2 diabetes were more beneficial than those of either drug
alone.5 In patients with diabetes, evidence-based pharmacotherapy
combined with dietary and exercise interventions reduced the risk of
cardiovascular events by approximately 50%.6 In a pilot study of pa-
tients undergoing peripheral vascular interventions, evidence-based
use of statins, ACeIs, beta-blockers, and antiplatelet therapy reduced
death, MI, and stroke at 6 months; in a later study of patients with
acute coronary syndrome, this evidence-based drug therapy was associ-
ated with a greatly reduced risk of death at 6 months.7,8 In adults with-
out known cardiovascular disease, a “polypill” containing low doses of
thiazide, atenolol, ramipril, simva statin, and aspirin reduced blood pres-
sure, low-density lipoprotein cholesterol (LDL-C), and urinary 11-de-
hydrothromboxane b2 levels.9
Individual drug trials and subsequent studies raised 2 questions. First,
could a simple process be developed to deliver combination pharmaco-
therapy to large numbers of people with diabetes or CAD in realistic set-
tings across an entire delivery system? Second, how would implementing
such a process affect hospitalizations for cardiovascular events?
In 2002, Kaiser Permanente used the Archimedes Model to project
the effects of combined pharmacotherapy and to develop a simple, inex-
pensive method for delivering it.10-12 The Archimedes Model realistically
simulates the pathophysiology,
treat ments, and outcomes of dis-
ease and its complications at the
level of individuals and aggregates
the results to project population-
eminal clinical trials established that statins and angiotensin-
converting enzyme inhibitors (ACeIs) individually reduce the
rate of fatal and nonfatal cardiovascular events among people
In this article
Take-Away Points / e89
Published as a Web exclusive
Preventing Myocardial Infarction and Stroke
With a Simplified bundle of Cardioprotective Medications
R. James Dudl, MD; Margaret C. Wang, PhD, MPH; Michelle Wong, MPH, MPP;
and Jim Bellows, PhD
Objective: To assess the effect of promoting a
bundle of fixed doses of a generic statin and
angiotensin-converting enzyme inhibitor/angio-
tensin receptor blocker (ACEI/ARB), delivered
with minimal outpatient visits, laboratory testing,
and dosage titration, to people with diabetes,
coronary artery disease (CAD), or both in a large
integrated healthcare system.
Study Design: Three-year observational study of
170,024 Kaiser Permanente members with diabe-
tes, CAD, or both.
Methods: Using instrumental variable analysis,
we assessed the impact of promoting the cardio-
protective bundle on hospitalization rates for
stroke and myocardial infarction (MI).
Results: In 2004 and 2005, 47,268 of 170,024
individuals received “low exposure” (medication
possession on 1 to 365 days). Their risk of hospi-
talization for MI or stroke in 2006 was lowered by
15 events per 1000 person-years (95% confidence
interval [CI] = 1, 30), preventing events in 726
people. Furthermore, 21,292 of 170,024 individuals
received “high exposure” (medication possession
on 366 to 730 days). Their risk of hospitalization
for MI or stroke was reduced by 26 events per
1000 person-years (95% CI = 17, 34), preventing
events in 545 people.
Conclusion: A simplified method for bundling
fixed doses of a generic statin and an ACEI/ARB
was successfully implemented in a large, diverse
population in an integrated healthcare delivery
system, reducing the risk of hospitalization for MI
(Am J Manag Care. 2009;15(10):e88-e94)
For author information and disclosures,
see end of text.
VOL. 15, NO. 10
n THe AMerICAN JOUrNAL OF MANAGeD CAre n?
Simplified Bundle of cardioprotective Medications
level effects that correlate well with
clinical trial results.13 Using evi-
dence from available clinical trials,
the model forecasted that a “bun-
dle” of a statin and an ACeI would,
beginning in the first year, reduce
by 71% the risk of MI and stroke in
a high-risk population of individu-
als with diabetes. Subsequent tri-
als and meta-analyses enriched our
understanding of the benefits of these medications, but were
not available at the time of modeling.14,15
The modeling also determined that using generic formula-
tions and offering a fixed dose to every person, regardless of base-
line blood pressure or LDL-C level, would achieve these results
with the most efficient use of clinical resources. The model
also predicted that population-level clinical benefits could be
achieved without patient-by-patient titration to physiologic
target, which has since been confirmed elsewhere.16
As a result, Kaiser Permanente’s clinical leaders launched
an initiative to make bundled cardioprotective therapy rap-
idly and widely available to all Kaiser Permanente members
with diabetes over the age of 55 years and all members with
CAD. Individuals were offered a medication bundle consist-
ing of a statin (typically lovastatin 40 mg/day) and an ACeI
(typically lisinopril 20 mg/day). Physicians were advised to
use a single initiation visit to rule out contraindications,
eliminate patients at high risk for complications (eg, those
with serum creatinine >1.5 mg/dL, underlying liver disease,
or prior rhabdomyolysis or angioedema), and adjust down-
ward the lisinopril dosage in hypotension-prone patients.
Physicians exercised clinical judgment about whether it was
appropriate to titrate the dosage for safety purposes or to meet
a target. An angiotensin II receptor blocker was substituted
for the ACeI when clinically indicated; for convenience, we
refer to both here as ACeIs. Laboratory tests consisting of
total cholesterol and LDL-C, triglycerides, high-density lipo-
protein cholesterol, serum creatinine, potassium, and alanine
aminotransferase were advised before starting therapy and at
3 weeks to 3 months. The medication bundle also included
low-dose aspirin, but aspirin was not part of our study because
we could not consistently measure its use.
A variety of programwide strategies supported rapid imple-
mentation. each Kaiser Permanente region determined how
best to meet the guidelines of the initiative under local condi-
tions, but key elements across all regions included extensive
use of clinical champions, patient education, outreach strate-
gies, and point-of-service reminders. In addition, electronic
clinical decision support tools at the point of care identified
members in the target population who were not yet receiv-
ing statins and ACeIs. As the initiative rolled out across
the regions, a national network of clinical champions tele-
conferenced quarterly to share regional performance reports
on bundle use and learnings about how to facilitate rapid
bundle use grew rapidly. between 2002 and 2005, the per-
centage of eligible members in the regions we studied who
consistently used the medication bundle increased from 33%
to 52% of the target population. We report here the clinical
impact of the initiative.
Setting, Subjects, and Data Sources
Kaiser Permanente is the largest not-for-profit integrated
health delivery system in the United States, serving 8.7 mil-
lion members in 8 regions spanning 9 states and the District
of Columbia. Kaiser Permanente provides and coordinates
the entire scope of members’ care, including preventive care,
well-baby and prenatal care, immunizations, emergency care,
hospital and medical services, and ancillary services such as
pharmacy, laboratory, and radiology.
We studied the bundle’s impact in Kaiser Permanente’s
2 largest regions: Northern and Southern California. Our
study population consisted of 170,024 members who were
(1) diagnosed with CAD and/or over the age of 55 years and
diagnosed with diabetes, (2) not already taking both bundle
medications as of 2003, and (3) continuously enrolled be-
tween January 1, 2001, and December 31, 2006. Members
were included in the study if they received either statins or
ACeIs in 2003 but were excluded if they received both. The
study population was part of the much larger, programwide
Kaiser Permanente population receiving the medication
We obtained baseline characteristics for the study popula-
tion dating from 2001. Widespread use of the medication bun-
dle rose most rapidly during 2003. We measured bundle use in
2004 and 2005 and adverse events in 2006. Data on diagnoses,
medication use, and event rates before and after the initiative
were derived from inpatient and outpatient encounter records
Statins and angiotensin-converting enzyme inhibitors individually reduce cardiovascular
events, but their combined effectiveness in large populations is undocumented.
n We promoted the use of a cardioprotective bundle delivered via a simplified regimen—fixed
doses of generic medications and minimal outpatient visits, laboratory testing, and dosage
titration—to a high-risk population.
n Exposure to the bundle over 2 years reduced the risk of hospitalization for myocardial infarc-
tion or stroke in the following year.
n Our approach can be applied in many settings to reduce cardiovascular events in popula-
tions at risk.
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n clinical n
Instrumental variable analysis can effectively address pa-
tient-level selection biases caused by unmeasured confound-
ing variables.19-21 It does so by introducing into the analytic
model 1 or more variables, the “instruments,” that are cor-
related with the treatment but not causally related to out-
comes except through the treatment (Figure). Instrumental
variable analysis yields unbiased estimates of individual-level
treatment effectiveness if the underlying assumption about
absent causal relationships between instruments and outcome
We used facility-level use rates as instruments, making use
of variations across facilities in promoting bundle use. Facil-
ity-level use rates make good instrumental variables for this
purpose because they are strongly associated with individual
bundle exposure; by definition, patients at high-use facili-
ties are more likely to have statins and ACeIs dispensed. We
reasoned that facility-level use rates would be related to the
outcomes only through individual exposure. The reasoning
underlying our use of instrumental variable analysis is that pa-
tients can be viewed as randomly assigned to high- or low-use
facilities. The resulting estimate of treatment effectiveness is
based on patients who would have been treated at high-use
facilities but not treated at low-use facilities.
Instrumental Variable. A total of 58 facilities, with 74
to 11,600 members of the study population per facility, were
included; for each, we calculated the percentage of members
of the target population who had any exposure to the bundle.
Facility-level use rates ranged from 32.2% in the lowest-using
quintile of facilities to 49.1% in the highest-using quintile.
Unadjusted annual rates of hospitalization for MI or stroke
in 2006 ranged from 22.8 per 1000 members in the lowest-
using quintile of facilities to 17.7 per 1000 in the highest-
Covariates. We adjusted for covariates for which we were
able to obtain reliable and consistent observational data:
age, sex, comorbidities (diabetes, heart failure, depression,
CAD), and geographic region. We also adjusted for glyce-
mic control in 2003; the number of previous hospitalizations
due to MI, stroke, and all other causes in 2001-2004; and
the number of previous coronary artery bypass graft and per-
cutaneous transluminal coronary angioplasty procedures in
2001-2004. We also adjusted for history of hyperlipidemia
through 2003, using a proxy variable based on documented
LDL-C control and use of lipid-lowering medications during
Risk Estimation. We examined patterns of bundle use
across patient risk categories by first estimating a model of pa-
tients’ risk of MI or stroke in 2006 using all the covariates list-
ed above except bundle use and the instrumental variable. We
then categorized patients according to their underlying risk of
and pharmacy and laboratory databases. Data on hospitalization
rates for MI and stroke were extracted from hospital discharge
and billing claims databases. The appropriate institutional re-
view boards approved the evaluation protocol.
To measure exposure to the medication bundle, we first
examined statins and ACeIs independently. We calculated
exposure as the total number of days for which each drug was
dispensed between January 1, 2004, and December 31, 2005
(“dispensed days”). We assumed that exposure to the medi-
cation bundle (“bundle days”) was equal to the lower of the
dispensed days for individual medications.
We classified members with zero bundle days dispensed
during 2004 and 2005 as “no exposure,” those with 1 to
365 bundle days dispensed as “low exposure,” and members
with 366 to 730 bundle days dispensed as “high exposure.”
The main outcome measure was hospitalization due to MI or
stroke between January 1 and December 31, 2006.
As is commonly the case when estimating clinical effects
from observational studies, patient selection represented a sig-
nificant source of potential bias.17 Patients at highest risk may
be more apt to take prescribed medications, and clinicians
may be more likely to prescribe cardioprotective medications
for patients at highest risk, although some evidence suggests
a paradoxical risk-treatment relationship.18 The possibility of
selection bias is most acute when the analysis cannot incor-
porate some risk factors, as was the case in our study because
we could not consistently obtain data on factors such as body
mass index or smoking status.
n Figure. Instrumental Variables Analysis
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Simplified Bundle of cardioprotective Medications
MI or stroke and calculated the bundle use rate by quintile of
individual risk and by facility use rate.
We performed analyses with Stata version 10 (StataCorp
LP, College Station, TX) and considered a 2-sided P value
of less than .05 to be significant. We calculated the num-
ber of avoided events by multiplying the rate reduction per
1000 members by the number of individuals in each exposure
Medication Bundle Exposure
The study population consisted of 170,024 individuals
without prior bundle exposure, 77.8% of whom had diabetes
with or without CAD and 31.7% of whom had CAD (Table
1). Of the study population, 47,268 (27.8%) had low exposure
in 2004 and 2005 with a median exposure duration of 157 days;
21,292 (12.5%) had high exposure with a median exposure du-
ration of 500 days; and 101,464 (59.7%) had no exposure.
We noted an unplanned pattern of bundle use involving
facility-level use rates and patients’ underlying risk of MI
or stroke. At low-use facilities, bundle exposure was greater
among members with the lowest underlying risk than among
higher-risk members. The pattern was reversed at high-use fa-
cilities, where high-risk patients had greater bundle exposure.
The risk of MI or stroke, irrespective of medication exposure
or facility-level use rates, ranged from 5 to 9 events per 1000
individuals per year in the lowest-risk quintile to 27 to 38
events per 1000 in the highest-risk quintile.
Adverse Event Rates
In 2006, the rate of hospitalization for MI and stroke in the
entire study population was 21 per 1000 members, reflecting
3570 adverse cardiovascular events. Among members with
low 2-year bundle exposure, the hospitalization rate for MI
and stroke was lower by 15 per 1000 members in the following
year compared with members who had no exposure. Among
members with high 2-year bundle exposure, the MI and stroke
hospitalization rate in the following year was lower by 26 per
1000 members compared with members who had no exposure
Although our goal was to study decreased incidence of MI
and stroke, we also assessed the relationship between bundle
exposure and all-cause mortality, neither expecting nor find-
ing any statistically significant differences. We also examined
the rate of coronary artery bypass graft and percutaneous
transluminal coronary angioplasty procedures. Among mem-
bers with low bundle exposure, where MI hospitalization rates
were not significantly reduced, the rate of percutaneous trans-
luminal coronary angioplasty was lower by 15 per 1000 mem-
bers (95% confidence interval [CI] = 6, 24) compared with
members who had no exposure. The procedure rate remained
unchanged among members with high exposure, where we ob-
served a reduction in MIs.
After querying the Kaiser Permanente risk management
database for the years 2004-2006, we found 5 reports of events
potentially related to exposure to the bundle medications.
Four resulted from drug–drug interactions, and all events were
A bundle consisting of fixed doses of generic statins and
ACeIs reduced the MI and stroke hospitalization rate in a
high-risk population. Higher exposure was associated with
a greater reduction. Our finding is consistent with the well-
documented cardioprotective effects of these medications and
demonstrates that they can be obtained on a large scale with
a simplified regimen, allowing for rapid implementation in
populations at risk.
Strengths of our study include a large heterogeneous
population treated in dozens of natural clinical settings and
an analytical model that minimized the impact of selection
bias. Limitations of our study include our inability to test the
assumption that facility use rates were not causally related
n Table 1. Characteristics of the Study Population
(N = 170,024)
Median age, y
Male 93,629 (55.1)
Diabetes132,286 (77 .8)
Cardiovascular disease 53,883 (31.7)
Heart failure11,584 (6.8)
2003 use of lipid-lowering medicationa
57 ,084 (33.6)
2003 use of ACEI medication 43,556 (25.6)
>1 hospitalization due to MI263 (0.2)
>1 hospitalization due to stroke106 (0.1)
>1 hospitalization due to any cause17 ,167 (10.1)
ACEI indicates angiotensin-converting enzyme inhibitor;
MI, myocardial infarction.
aLipid-lowering medication includes statin, cholestyramine,
fibric acid, derivative, and niacin.
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to outcomes and to measure a few potentially confounding
variables, such as ejection fraction and serum creatinine.
Although using facility-level use rates as the instrumental
variable addressed the risk of individual-level confounding,
it raised the possibility of facility-level confounding.
Facility use rates may be associated with unmeasured
confounding variables such as high use rates for other medi-
cations. In a separate survey, we found that 75% of Kaiser Per-
manente members in the target population also were taking
aspirin (r. J. Dudl, MD, unpublished data, October 2008).
Thus, a conservative interpretation of the observed decreases
in MI and stroke is that they also include any cardioprotec-
tive effects of aspirin, although these effects are uncertain
among patients with diabetes but without cardiovascular dis-
ease or symptomatic peripheral arterial disease.22,23 We found
that beta-blocker use was weakly and negatively correlated
with facility-level bundle use, suggesting it was not respon-
sible for the observed effects. We did not measure use rates for
other cardioprotective medications such as calcium channel
blockers and aldosterone antagonists.
behavioral interventions, such as smoking cessation or
weight management, also could have affected our findings.
Kaiser Permanente has long advocated lifestyle changes, but
neither region engaged in enhanced promotion of behavioral
interventions during the study period.
We observed the effect of the medication bundle on MI
and stroke hospitalization rates in 1 calendar year. based on
results of the Archimedes Model, we anticipate that contin-
ued bundle use would result in ongoing reductions. Further
study would confirm this. Our results do imply reductions in
the rate of MI and stroke consistent with those predicted by
the Archimedes Model; compared with no exposure, the low-
exposure group experienced a 60% (95% CI = 1%, 96%) re-
duction in hospitalizations for MI and stroke.
We note that the estimated rate reduction in the high-
exposure group, 26 events per 1000 members, exceeds the
overall rate of 21 events per 1000 in the study population as
a whole. This finding likely arises from the instrumental vari-
able analysis estimates being inherently based on individuals
who would have been treated in high-use facilities but not in
low-use facilities; they include a disproportionate share of in-
dividuals with the highest underlying risk at 27 to 38 adverse
events per 1000 members.
Although we did not observe a reduction in mortality in
this study, longer-term follow-up may accentuate the bene-
fits. An important direction for future research is to quantify
3- to 5-year outcomes, including both cardiovascular and all-
The scale of the initiative and competition for scarce orga-
nizational resources and constrained clinician time impeded
the speed of implementation. Use of the bundle in the 2 re-
gions continued to rise after the observation period; by 2008,
approximately 65% of patients with CAD or with diabetes and
over the age of 55 years were taking the medication bundle.
Although we lack data on population characteristics
needed to precisely estimate the impact of widely implement-
ing the A.L.L. (aspirin, lisinopril, lipid lowering therapy)
bundle across the US healthcare delivery system, extrapolat-
ing from our results provides insight into its potential mag-
nitude. Conservatively assuming that 20% of the 5.8 million
Americans over the age of 65 years who are predicted to have
diabetes by the year 2010 are exposed to the bundle for 1 to
365 days over 24 months, more than 17,000 MIs and strokes
would be avoided the following year.24 More boldly, assuming
an additional 10% of this population has 366 to 720 days
of exposure to the bundle over 2 years, a total of more than
32,000 MIs and strokes would be avoided in the following
single calendar year.
n Table 2. Impact of 2-Year Exposure to a Cardioprotective Medication Bundle on Rates of MI and Stroke,
Compared With No Exposure
Change in No. of Events per
1000 Members (95% CI)
Change in No. of
Events (95% CI)
MI 1 (−13, 15) 60 (−607 , 726)
−15 (−25, −6)a
−727 (292, 1162)a
MI and stroke
−15 (−30, −1)a
−726 (38, 1414)a
−10 (−19, −1)a
−209 (21, 397)a
−14 (−20, −9)a
−305 (181, 428)a
MI and stroke
−26 (−34, −17)a
−545 (361, 728)a
CI indicates confidence interval; MI, myocardial infarction.
VOL. 15, NO. 10
n THe AMerICAN JOUrNAL OF MANAGeD CAre n?
Simplified Bundle of cardioprotective Medications
Preventing adverse cardiovascular events among popula-
tions at risk is a pressing, ongoing need, and developing next-
generation statins and ACeIs consumes substantial resources.
However, improving treatment rates with generic formula-
tions of older medications may yield improvements that ex-
ceed those of pursuing new medications with relatively small
increases in efficacy. Forgoing the development of rosuva-
statin and instead improving performance of and compliance
with older, generic statins have been estimated to potentially
save 7 times as many lives over 5 years.25
The initiative we describe is broadly applicable to other
health plans and delivery systems. It already has been applied
in community health centers in an underserved population
with varying levels of health literacy, where the number
of patients taking the bundle increased fourfold within a
Translating evidence from clinical trials into practices re-
sulting in large-scale benefits requires attention to scalability
and efficiency. We designed, implemented, and evaluated a
simplified formulation and process for delivering generic car-
dioprotective medications with minimal titration, testing,
and outpatient visits. The strategy we describe here can be
replicated in a wide variety of additional settings.
We thank the leadership team of the Care Management Institute for their
support; all the Kaiser Permanente senior leaders, staff, and clinicians who
were instrumental in implementing A.L.L. (aspirin, lisinoporil, lipid low-
ering therapy) programwide; and our colleagues at the Division of research
for manuscript review. Thanks also go to David eddy, MD, PhD, and Len
Schlessinger, PhD, for their help with the Archimedes calculations and for
manuscript review; to Joel Handler, MD, for supporting the institutional re-
view board process; to Paul Wallace, MD, for manuscript review; and to Jenni
Green, MS, for writing and editing assistance, which was funded by the Care
Author Affiliations: From Care Management Institute (rJD, MCW,
MW, Jb), Kaiser Permanente, Oakland, CA.
Funding Source: None reported.
Author Disclosure: The authors (rJD, MCW, MW, Jb) report no re-
lationship or financial interest with any entity that would pose a conflict of
interest with the subject matter of this article.
Authorship Information: Concept and design (rJD, MW, Jb); acquisi-
tion of data (rJD, MCW); analysis and interpretation of data (MCW, MW, Jb);
drafting of the manuscript (rJD, MCW, MW, Jb); critical revision of the manu-
script for important intellectual content (MCW, MW, Jb); statistical analysis
(MCW, Jb); provision of study materials or patients (rJD); administrative,
technical, or logistic support (MCW, MW, Jb); and supervision (rJD, Jb).
Address correspondence to: r. James Dudl, MD, Care Management In-
stitute, Kaiser Permanente, One Kaiser Plz, 16th Fl, Oakland, CA 94612.
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