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The American Journal of Managed Care October 2009
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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

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

Bundled cardioprotective medications with simplified delivery reduced the risk of hospitalization for myocardial infarction or stroke among patients at high risk.

Risk Estimation. We examined patterns of bundle use across patient risk categories by first estimating a model of patients’ risk of MI or stroke in 2006 using all the covariates listed above except bundle use and the instrumental variable. We then categorized patients according to their underlying risk of 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 number of avoided events by multiplying the rate reduction per 1000 members by the number of individuals in each exposure group.


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 duration 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 facilities, 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 (Table 2).

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 finding any statistically significant differences. We also examined the rate of coronary artery bypass graft and percutaneous transluminal coronary angioplasty procedures. Among members with low bundle exposure, where MI hospitalization rates were not significantly reduced, the rate of percutaneous transluminal coronary angioplasty was lower by 15 per 1000 members (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 observed 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 resolved.


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 welldocumented 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 relatedto 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 medications. In a separate survey, we found that 75% of Kaiser Permanente 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 cardioprotective effects of aspirin, although these effects are uncertain among patients with diabetes but without cardiovascular disease 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 responsible 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 continued 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 lowexposure group experienced a 60% (95% CI = 1%, 96%) reduction in hospitalizations for MI and stroke.

We note that the estimated rate reduction in the highexposure 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 variable 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 individuals 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 benefits. An important direction for future research is to quantify 3- to 5-year outcomes, including both cardiovascular and all-cause mortality.

The scale of the initiative and competition for scarce organizational resources and constrained clinician time impeded the speed of implementation. Use of the bundle in the 2 regions 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 implementing the A.L.L. (aspirin, lisinopril, lipid lowering therapy) bundle across the US healthcare delivery system, extrapolating from our results provides insight into its potential magnitude. 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.

Preventing adverse cardiovascular events among populations at risk is a pressing, ongoing need, and developing nextgeneration statins and ACEIs consumes substantial resources. However, improving treatment rates with generic formulations of older medications may yield improvements that exceed those of pursuing new medications with relatively small increases in efficacy. Forgoing the development of rosuvastatin 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 12-month period.26

Translating evidence from clinical trials into practices resulting in large-scale benefits requires attention to scalability and efficiency. We designed, implemented, and evaluated a simplified formulation and process for delivering generic cardioprotective 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 lowering 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 review 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 Management Institute.

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 relationship 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); acquisition of data (RJD, MCW); analysis and interpretation of data (MCW, MW, JB); drafting of the manuscript (RJD, MCW, MW, JB); critical revision of the manuscript 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 Institute, Kaiser Permanente, One Kaiser Plz, 16th Fl, Oakland, CA 94612. E-mail:

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