Identifying Favorable-Value Cardiovascular Health Services

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The American Journal of Managed Care, June 2011, Volume 17, Issue 6

Health improvements are usually expensive. If healthcare does not encourage high-value care and discourage low-value care, insurance premiums will continue to outpace inflation.

Objective:

To identify cardiovascular health services with a high level of evidence to suggest that they deliver favorable value.

Study Design:

Evidence synthesis using the Cost-Effectiveness Analysis Registry.

Methods:

We queried the registry to identify published cost-effectiveness analyses of cardiovascular health services in the United States. In addition to searching the registry, we performed supplementary searches of published literature for cost-effectiveness studies of cardiovascular interventions that were endorsed by guidelines of national medical and scientific societies. We defined favorable value as an incremental costeffectiveness ratio of $100,000 or less per qualityadjusted life-year.

Results:

Our initial review of cardiovascular health services in the United States revealed 174 separate peer-reviewed studies. Of those, 157 studies did not meet our inclusion criteria, leaving 17 studies for further evaluation that covered the following services with potentially high value: statins to prevent myocardial infarction (for primary and secondary prevention), screening for and treatment of high blood pressure (diuretics or ß-blockers and angiotensin-converting enzyme inhibitors in the case of diabetes) to prevent myocardial infarction and stroke, warfarin sodium and low-molecular-weight heparin to prevent pulmonary emboli, implantable cardiac defibrillators for patients at high risk of sudden death, antiplatelet drugs (aspirin and clopidogrel bisulfate) to prevent future myocardial infarction, ß-blockers for patients who have had myocardial infarction, warfarin to prevent future stroke in persons with nonvalvular atrial fibrillation, and percutaneous procedures to relieve claudication symptoms.

Conclusion:

We describe a new way of synthesizing cost-effectiveness evidence for use by consumers, payers, and other decision makers.

(Am J Manag Care. 2011;17(6):431-438)

Our study identifies cardiovascular health services with a high level of evidence to suggest that they deliver favorable value. This information has many potential uses for consumers, payers, and other decision makers.

  • The data show how health improvements are usually expensive even when we focus on those with the highest value.

  • If the healthcare system does not produce systematic ways to encourage high-value care and discourage low-value care, health insurance premiums will continue to outpace inflation, causing multiple economic problems for consumers.

  • Because few cardiovascular services have been demonstrated to have a favorable value, it is important to support funding of comparative effectiveness research.

A consensus is building to increase “value” as a guiding principle for US health reform1; indeed, value is used repeatedly throughout the health reform law as a unifying principle and as a descriptor for various new incentives that will be applied to providers and clinicians. At the same time, there is a complementary emphasis on the emerging role of consumers as active participants in their care, who engage in shared decision making with their clinicians and health organizations.1 As a result, it may be argued that health reform can be advanced by incentivizing and increasing consumer knowledge about high-value health services or health systems that deliver favorable value. In addition, emphasizing value rather than cost control may reduce the likelihood of rationing decisions that harm health by restricting high-value services.2

Although there is no consensus on how to define and measure value, the health reform law consistently juxtaposes the use of the word value with statements about the importance of improving quality or lowering cost.1 One published definition of value that is notably close to that embedded in the health reform law is the ratio of incremental benefits to incremental costs.3 In lay terms, this definition corresponds to the notion of “bang for the buck,” and in technical terms, this definition corresponds to the inverse of the incremental cost-effectiveness ratio.

The Cost-Effectiveness Analysis Registry4 summarizes and reviews published original English-language analyses that estimate incremental cost-effectiveness ratios using various methods (eg, mathematical modeling and primary data analysis). In principle, this registry should be an essential tool for informing the measurement of value and facilitating its use in US health reform. However, there are several important barriers to the use of this registry for policy decisions. First, the quality of analyses in the registry is not measured using a reproducible and validated approach, and the strength of evidence underlying particular analyses is sometimes questionable. This is a particularly important consideration because of the lack of transparency underlying assumptions in mathematical models of cost-effectiveness and because there sometimes is little high-quality evidence to inform model results.5 Second, analyses do not have expiration dates; therefore, an included analysis might concern a treatment that is obsolete or might involve a comparison that is no longer relevant. Third, analyses may often reach differing conclusions, rendering it difficult to know how to use conflicting analyses to inform policy. Fourth, some payers might argue that industry-funded analyses may present important conflicts of interest, which make their results hard to interpret because of the importance of subjective judgments in constructing the models that underlie their results. Fifth, analyses in the registry often include a wide range of healthcare settings and patient characteristics, and decision makers may want to base their decisions only on those analyses with similar settings and patients.

Herein, we describe an approach using the Cost-Effectiveness Analysis Registry that helps address these challenges. We used this registry to identify a subset of cardiovascular health services with a high level of evidence to suggest that they deliver favorable value. Identifying high-value services has many benefits for consumers in that they can be encouraged to use them when clinically appropriate, can engage in more informed health discussions with their clinicians, and can seek health plans that offer these services without barriers, such as copayments, deductibles, or burdensome administrative procedures.

This work was performed at the request of Consumers Union, publisher of Consumer Reports. The study objective was to provide comparisons and ratings of heart and vascular disease services that Consumers Union is pursuing.

METHODS

We first describe how we identified cardiovascular health services with known value; second, how we applied quality-ofevidence standards together with nonobsolescence standards; third, how we applied consistency of evidence standards for high value; and fourth, how we applied additional inclusion criteria to ensure relevance to consumers. Through these stepwise filters, we identified a list of cardiovascular health services with particularly robust evidence to suggest high value and high relevance to consumers.

We adopted stringent standards for evidence. In other words, we sought to identify a limited number of health services that we are confident represent favorable value rather than seeking to identify a broader number of health services with less certain value estimations. We defined services broadly, including prevention, diagnosis, treatment, and management.

Identifying a Pool of Cardiovascular Health Services With Known Value

To identify a pool of cardiovascular health services potentially meeting high-value criteria, we queried the Cost- Effectiveness Analysis Registry4 to identify all published cost-effectiveness analyses of cardiovascular health services in the United States. The registry summarizes and reviews original English-language cost-utility analysis articles and can be searched by type of health services, such as cardiovascular, and by country of analysis, such as the United States. The articles undergo a screening and review process before being included in the registry. A MEDLINE search is performed using the keywords QALYs, quality, and cost-utility analysis, and then the Cost-Effectiveness Analysis Registry team screens the article abstracts to determine if the articles contain an original cost-utility estimate. Studies are excluded if they are reviews, editorials, or methodological articles, as well as cost-effectiveness analyses that do not measure health effects in quality-adjusted life-years (QALYs). These methods are described in more detail at the Cost-Effectiveness Analysis Registry Web site (http://www.cearegistry.org).

When synthesizing evidence, it is often necessary to supplement algorithm-based database searches with manual searches of journals that are likely to publish relevant articles and of bibliographies from select review articles. Accordingly, we supplemented our algorithm-based search of the Cost-Effectiveness Analysis Registry with manual searches of select national medical and scientific guidelines (eg, US Preventive Services Task Force, American Heart Association, and American College of Physicians), focusing our attention on those that were published in peer-reviewed scientific journals and that used explicit and standardized evidence syntheses. In addition, we searched select review articles for cost-effectiveness studies.3,6 We reviewed the titles or abstracts of all studies, and we obtained the source publications to evaluate quality-ofevidence standards and inclusion criteria. Finally, we searched other disease fields of the registry that might overlap with cardiovascular health services (endocrine for diabetes and lipids and smoking and tobacco for smoking).

Although value has many plausible alternative definitions and perspectives, we defined value for the purposes herein as the ratio of additional benefits to additional costs or, equivalently, as the inverse of the incremental cost-effectiveness ratio. We chose this definition because it is consistent with the scientific literature3 and because it corresponds to lay concepts (bang for the buck and best buy).

Published work suggests that the acceptable threshold for healthcare value in the United States is unlikely to be lower (eg, more restrictive) than the value of modern healthcare in aggregate (approximately $100,000 per quality-adjusted life-year or per life-year, in 2003 US dollars)7 and may be substantially higher (up to $265,000 per quality-adjusted life-year).8 Consequentially, we conservatively use $100,000 per quality-adjusted life-year or per life-year as our criterion threshold for high value in this proposal. However, because some prior published cost-effectiveness analyses have used an even more restrictive threshold of $50,000 per qualityadjusted life-year to demarcate high value, we performed sensitivity analyses incorporating this alternative threshold.9

A quality-adjusted life-year is a unit that simultaneously measures quality and quantity of life and reflects the idea that individuals often are willing to trade off some quantity of life if they can substantially improve their quality of life. Therefore, a year of life in high-quality health should “count for” more than a year of life in poor-quality health. Quality-adjusted life-years enable value to be compared across different healthcare interventions and represent an attempt to integrate all the benefits, harms, and burdens of interventions other than cost into a single number.

Quality of Evidence and Nonobsolescence Standards

We reviewed articles for quality of evidence by applying the Quality of Health Economic Studies, a validated instrument for measuring the quality of cost-effectiveness analyses.10 Scores vary from 0 to 100, and 75 is a commonly used cutoff for high quality.11 Each study was reviewed by at least 1 author, and studies were considered only if their Quality of Health Economic Studies score met this cutoff (in a comparison scoring of 20 randomly selected articles, our k value was .68).

We reviewed studies for robustness of clinical effectiveness and for nonobsolescence by verifying that services with favorable value were also favored or by using the most up-to-date clinical guidelines of a medical or scientific society. Because clinical guidelines are proliferating rapidly and are of varying quality, evidentiary basis, and health effect, we considered only those clinical guidelines that were published in peer-reviewed journals and used explicit evidence rating scales for level of endorsement and underlying evidence. (While it may be argued that peer review does not itself guarantee quality, we regarded peer review as a reasonable first step given the absence of standard quality metrics for clinical guidelines.) To meet criteria for robustness of clinical effectiveness, services had to receive the highest grade of supporting evidence (eg, level A in the case of American Heart Association guidelines) and the strongest recommendation in favor (eg, level 1 in the case of American Heart Association guidelines). To identify clinical guidelines meeting these criteria, we used the search tools of the National Guideline Clearinghouse,12 a repository of clinical guidelines from a wide variety of sources (eg, health plans and government, professional, and specialty organizations) that is supported by the Agency for Healthcare Research and Quality.

Consistency of Evidence Standards

We sought to include only services that were supported by consistent evidence. The following 2 criteria were used: (1) there should not be conflicting results if more than 1 high-quality published study addresses the same question and (2) the results of each study should be robust with regard to alternative but plausible assumptions.

Consistency was assessed by asking whether there was a different implication for decision making rather than asking whether a particular number was different outside the realm of chance. For example, 2 studies analyzing the same cardiovascular health service with results of $40,000 per life-year and $70,000 per life-year would be regarded as consistent because they were on the same side of the relevant decision threshold (<$100,000 per life-year denotes high value) and would yield the same inference for decision making (the service is high value and should be encouraged). In contrast, 2 studies with results of $40,000 per life-year and $140,000 per life-year would not be regarded as consistent because they were on opposite sides of the decision threshold and yielded inconsistent inferences for decision making (one suggesting high value and encouragement, with the other suggesting low value and an alternative decision).

Similarly, robustness of results was assessed based on whether varying assumptions across plausible ranges would cause the results to cross a decision threshold and produce a different implication for decision making. For example, if varying one assumption in a study caused the result to vary between $40,000 and $70,000 per life-year, that result would be interpreted as robust because any number in this range has the same implication for decision making (the service is high value and should be encouraged). In contrast, if varying one assumption in a study caused the result to vary between $40,000 and $140,000, that result would be interpreted as not being robust because numbers within this range may have different implications for decision making. When necessary, we inflation-adjusted incremental cost-effectiveness ratios so that their cost measurements were consistent across studies based on the Consumer Price Index for All Urban Consumers (http://www.bls.gov/news.release/cpi.t01.htm).

Relevance to Consumers

To maximize the relevance of our study to health consumers interested in cardiovascular care, we required that studies address health services that were likely to have substantial health effect, as judged by meaningful influence on quality or quantity of life. We required that studies address health problems that were not rare and address health services that could be standardized across different health settings (eg, a particular medication or procedure). We required that studies address decisions in which consumer preferences may be reasonably expected to influence decision making; therefore, we excluded studies that addressed health services in which the decision would need to be made immediately or was of sufficiently technical nature that it would be an unlikely candidate for shared decision making between patient and clinician (eg, different types of stents for angioplasties). Finally, we required that studies analyze services that are applicable to adults and would be considered within the cardiovascular domain by lay and professional audiences.

Sensitivity Analyses

Because some payers and consumer groups do not regard applying quality ratings as a sufficiently sensitive screen for excluding conflict-of-interest bias, our base-case analysis excluded from consideration all studies that were partially or completely industry funded or that did not explicitly state their funding source. However, it can be argued that this is an arbitrary criterion, as industry-funded studies may be of high quality and without commercial bias. For this reason, we performed a sensitivity analysis in which we included industry-funded studies on services that were favored by high-grade evidence in the most up-to-date clinical guidelines (grade A) of the US Preventive Services Task Force.

RESULTS

Figure 1

Our initial review of cardiovascular health services in the United States revealed 174 separate peer-reviewed studies of their value (). Of those, 157 studies did not meet our inclusion criteria for quality of evidence, consistency of evidence, relevance to consumers, and low potential for commercial bias, leaving 17 studies for further evaluation that covered the following 10 services with potentially high value13-38: (1) statins to prevent myocardial infarction (for primary and secondary prevention), (2) screening for and treatment of high blood pressure (diuretics or b-blockers and angiotensinconverting enzyme inhibitors in the case of diabetes) to prevent myocardial infarction and stroke, (3) warfarin sodium to prevent pulmonary emboli, (4) low-molecular-weight heparin to prevent pulmonary emboli, (5) implantable cardiac defibrillators for patients at high risk of sudden death, (6) aspirin to prevent future myocardial infarction, (7) clopidogrel bisulfate to prevent future myocardial infarction, (8) ß-blockers for patients who have had myocardial infarction, (9) warfarin to prevent future stroke in persons with nonvalvular atrial fibrillation, and (10) percutaneous procedures to relieve claudication symptoms.

Figure 2

We performed a sensitivity analysis in which we also considered industry-funded studies on services that were favored by high-grade evidence in the most up-to-date clinical guidelines of a medical or scientific society. Of 100 industry-funded studies, 10 were candidates for inclusion in this analysis (). Of those, 4 studies were excluded because they did not meet our criteria for quality or consistency of evidence, leaving 6 studies for consideration that covered 4 services with potentially high value39-45: (1) smoking cessation counseling and therapy (including nicotine and drug therapies), (2) clopidogrel to prevent future stroke in patients who have had stroke or transient ischemic attack, (3) aspirin to prevent future stroke in patients who have had stroke or transient ischemic attack, and (4) aspirin to prevent myocardial infarction in middle-aged men who have a moderate or higher risk of myocardial infarction (>5% over the next 10 years) and who do not have an unusually high risk of bleeding.

Table 1

Table 2

Finally, we performed sensitivity analyses in which we used $50,000 per quality-adjusted lifeyear as a threshold for high value rather than $100,000 per quality-adjusted life-year, as in our base-case analysis. We found that 8 of 10 services identified from non—industry-funded studies continued to satisfy criteria for high value () and that 3 of 4 services identified from industry-funded studies continued to satisfy criteria for high value ().

DISCUSSION

When using stringent standards for quality of evidence, consistency of evidence, and relevance to consumers, several cardiovascular health services met our criteria for demonstrated high value. Identifying these services has practical importance because consumers can be encouraged to use them when clinically appropriate, can engage in more informed health discussions with their clinicians, and can seek health plans that offer these services without barriers, such as copayments, deductibles, or burdensome administrative procedures.2 Indeed, because there are many alternative health system approaches for encouraging the use of high-value services, whether financial (eg, eliminating copayments and deductibles) or nonfinancial (eg, integration with other services and administrative streamlining), future work is needed to compare which approaches are most effective and lead to better patient outcomes.

It is important to note that our study does not evaluate an exhaustive list of high-value cardiovascular health services, as few services have been studied in all relevant patient groups. Indeed, the sparse results highlight the importance of expanding comparative effectiveness research46 that asks which health services work in which patients at which times and assesses the comparative benefits and costs of a wider range of services in a wider range of patient populations.

The Cost-Effectiveness Analysis Registry4 has potential as a resource that can inform decision making by consumers, clinicians, health plans, and policy experts. It is a searchable repository of cost-effectiveness results that include a wide range of interventions, delivery system innovations, and public health measures. However, some decision makers may find this registry difficult to use because its quality ratings for included studies are subjective rather than objective, it does not indicate whether included studies are based on robust and high-quality evidence, and it does not indicate when analyses have become obsolete. Our study describes a strategy for using the registry to inform decision making that may mitigate these limitations. However, other limitations of the registry are unaffected by our strategy, namely, the possibility of publication bias and restriction to studies reporting a particular outcome (quality-adjusted life-years) in a particular database (MEDLINE).

Our study provides a sobering account of how health improvements are usually expensive (and drive up health insurance premiums) even when we restrict our attention to health improvements with the highest value. If the healthcare system does not produce systematic ways to encourage highvalue care and discourage low-value care, health insurance premiums will continue to outpace inflation, causing multiple economic problems for consumers. More optimistically, this review underscores the numerous ways in which cardiovascular care can prevent myocardial infarction and stroke, which is an important reason why deaths from these 2 occurrences have decreased dramatically in the United States over the last few decades. Greater attention to healthcare value has the potential to accelerate these benefits, while effectively controlling rising healthcare costs and premiums.

Author Affiliations: From the Section of Value and Comparative Effectiveness (RSB, SMM), Division of General Internal Medicine, NYU School of Medicine, New York, NY.

Funding Source: This work was funded by Consumers Union (consultant support to Dr Braithwaite).

Author Disclosures: The authors (RSB, SMM) 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 (RSB); acquisition of data (RSB, SMM); analysis and interpretation of data (RSB, SMM); drafting of the manuscript (RSB, SMM); critical revision of the manuscript for important intellectual content (RSB, SMM); statistical analysis (RSB, SMM); obtaining funding (RSB); and administrative, technical, or logistic support (SMM).

Address correspondence to: R. Scott Braithwaite, MD, MS, Section of Value and Comparative Effectiveness, Division of General Internal Medicine, NYU School of Medicine, 423 E 23rd St, 15th Floor, New York, NY 10010. E-mail: scott.braithwaite@nyumc.org.

1. Patient Protection and Affordable Care Act. Pub L No. 111-148, 124 Stat 119.

2. Braithwaite RS, Omokaro C, Justice AC, Nucifora K, Roberts MS. Can broader diffusion of value-based insurance design increase benefits from US health care without increasing costs? evidence from a computer simulation model. PLoS Med. 2010;7(2):e1000234.

3. Braithwaite RS, Rosen AB. Linking cost sharing to value: an unrivaled yet unrealized public health opportunity. Ann Intern Med. 2007;146(8):602-605.

4. Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center. Cost- Effectiveness Analysis Registry. http://www.cearegistry.org. Accessed February 10, 2010.

5. Braithwaite RS, Roberts MS, Chang CC, et al. Influence of alternative thresholds for initiating HIV treatment on quality-adjusted life expectancy: a decision model. Ann Intern Med. 2008;148(3):178-185.

6. Neumann PJ, Rosen AB, Weinstein MC. Medicare and cost-effectiveness analysis. N Engl J Med. 2005;353(14):1516-1522.

7. Braithwaite RS, Meltzer DO, King JT Jr, Leslie D, Roberts MS. What does the value of modern medicine say about the $50,000 per qualityadjusted life-year decision rule? Med Care. 2008;46(4):349-356.

8. Ubel PA, Hirth RA, Chernew ME, Fendrick AM. What is the price of life and why doesn’t it increase at the rate of inflation? Arch Intern Med. 2003;163(14):1637-1641.

9. Neumann PJ, Sandberg EA, Bell CM, Stone PW, Chapman RH. Are pharmaceuticals cost-effective? a- review of the evidence. Health Aff (Millwood). 2000;19:92-109.

10. Ofman JJ, Sullivan SD, Neumann PJ, et al. Examining the value and quality of health economic analyses: implications of utilizing the QHES. J Manag Care Pharm. 2003;9(1):53-61.

11. Spiegel BM, Targownik LE, Kanwal F, et al. The quality of published health economic analyses in digestive diseases: a systematic review and quantitative appraisal. Gastroenterology. 2004;127(2):403-411.

12. National Guideline Clearinghouse. http://www.guideline.gov/. Accessed February 10, 2010.

13. Prosser LA, Stinnett AA, Goldman PA, et al. Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics. Ann Intern Med. 2000;132(10):769-779.

14. Ganz DA, Kuntz KM, Jacobson GA, Avorn J. Cost-effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy in older patients with myocardial infarction [published correction appears in Ann Intern Med. 2002;136(8):635]. Ann Intern Med. 2000;132(10):780-787.

15. Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid-lowering. Ann Intern Med. 2009;150(4):243-254.

16. CDC Diabetes Cost-Effectiveness Group. Cost-effectiveness of intensive glycemic control, intensified hypertension control, and serum cholesterol level reduction for type 2 diabetes. JAMA. 2002;287(19): 2542-2551.

17. Edelson JT, Weinstein MC, Tosteson AN, Williams L, Lee TH, Goldman L. Long-term cost-effectiveness of various initial monotherapies for mild to moderate hypertension. JAMA. 1990;263(3):407-413.

18. Pignone M, Earnshaw S, Tice JA, Pletcher MJ. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease in men: a cost-utility analysis. Ann Intern Med. 2006;144(5):326-336.

19. Heidenreich PA, Davis BR, Cutler JA, et al. Cost-effectiveness of chlorthalidone, amlodipine, and lisinopril as first-step treatment for patients with hypertension: an analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Gen Intern Med. 2008;23(5):509-516.

20. Littenberg B. A practice guideline revisited: screening for hypertension. Ann Intern Med. 1995;122(12):937-939.

21. Aujesky D, Smith KJ, Roberts MS. Oral anticoagulation strategies after a first idiopathic venous thromboembolic event. Am J Med. 2005;118(6):625-635.

22. Gould MK, Dembitzer AD, Sanders GD, Garber AM. Low-molecularweightheparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a cost-effectiveness analysis. Ann Intern Med. 1999;130(10):789-799.

23. Chan PS, Nallamothu BK, Gurm HS, Hayward RA, Vijan S. Incremental benefit and cost-effectiveness of high-dose statin therapy in highrisk patients with coronary artery disease. Circulation. 2007;115(18): 2398-2409.

24. Sanders GD, Hlatky MA, Every NR, et al. Potential cost-effectiveness of prophylactic use of the implantable cardioverter defibrillator or amiodarone after myocardial infarction. Ann Intern Med. 2001;135(10): 870-883.

25. Owens DK, Sanders GD, Heidenreich PA, McDonald KM, Hlatky MA. Effect of risk stratification on cost-effectiveness of the implantable cardioverter defibrillator. Am Heart J. 2002;144(3):440-448.

26. Gaspoz JM, Coxson PG, Goldman PA, et al. Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N Engl J Med. 2002;346(23):1800-1806.

27. Schleinitz MD, Weiss JP, Owens DK. Clopidogrel versus aspirin for secondary prophylaxis of vascular events: a cost-effectiveness analysis. Am J Med. 2004;116(12):797-806.

28. Phillips KA, Shlipak MG, Coxson P, et al. Health and economic benefits of increased b-blocker use following myocardial infarction. JAMA. 2000;284(21):2748-2754.

29. Gage BF, Cardinalli AB, Albers GW, Owens DK. Cost-effectiveness of warfarin and aspirin for prophylaxis of stroke in patients with nonvalvular atrial fibrillation. JAMA. 1995;274(23):1839-1845.

30. Bosch JL, Haaring C, Meyerovitz MF, Cullen KA, Hunink MG. Costeffectiveness of percutaneous treatment of iliac artery occlusive disease in the United States. AJR Am J Roentgenol. 2000;175(2):517-521.

31. Hunink MG, Goldman L, Tosteson AN, et al. The recent decline in mortality from coronary heart disease, 1980-1990: the effect of secular trends in risk factors and treatment. JAMA. 1997;277(7):535-542.

32. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.

33. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290(2):197]. JAMA. 2003; 289(19):2560-2572.

34. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Ed.) [published correction appears in Chest. 2008;134(4):892]. Chest. 2008;133(6)(suppl):454S-545S.

35. Epstein AE, DiMarco JP, Ellenbogen KA, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices); American Association for Thoracic Surgery; Society of Thoracic Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers an Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons [published corrections appear in J Am Coll Cardiol. 2009;53(16):1473 and 2009;53(1):147]. J Am Coll Cardiol. 2008;51(21):e1-e62.

36. Smith SC Jr, Allen J, Blair SN, et al; AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute [published correction appears in Circulation. 2006;113(22): e847]. Circulation. 2006;113(19):2363-2372.

37. Hirsch AT, Haskal ZJ, Hertzer NR, et al; American Association for Vascular Surgery; Society for Vascular Surgery; Society for Cardiovascular Angiography and Interventions; Society for Vascular Medicine and Biology; Society of Interventional Radiology; ACC/AHA Task Force on Practice Guidelines; American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; Vascular Disease Foundation. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/ Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol. 2006;47(6):1239-1312.

38. European Heart Rhythm Association; Heart Rhythm Society, Zipes DP, Camm AJ, Borggrefe M, et al; American College of Cardiology; American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol. 2006;48(5):e247-e346.

39. Eddy DM, Peskin B, Shcheprov A, Pawlson G, Shih S, Schaaf D. Effect of smoking cessation advice on cardiovascular disease. Am J Med Qual. 2009;24(3):241-249.

40. Fiscella K, Franks P. Cost-effectiveness of the transdermal nicotine patch as an adjunct to physicians’ smoking cessation counseling. JAMA. 1996;275(16):1247-1251.

41. Howard P, Knight C, Boler A, Baker C. Cost-utility analysis of varenicline versus existing smoking cessation strategies using the BENESCO simulation model: application to a population of US adult smokers. Pharmacoeconomics. 2008;26(6):497-511.

42. Smith MY, Cromwell J, DePue J, Spring B, Redd W, Unrod M. Determining the cost-effectiveness of a computer-based smoking cessation intervention in primary care. Manag Care. 2007;16(7):48-55.

43. Matchar DB, Samsa GP, Liu S. Cost-effectiveness of antiplatelet agents in secondary stroke prevention: the limits of certainty. Value Health. 2005;8(5):572-580.

44. US Preventive Services Task Force. The Guide to Clinical Preventive Services. Rockville, MD: Agency for Healthcare Research and Quality, US Dept of Health and Human Services; August 2009. AHRQ publication 09-IP006.

45. Sacco RL, Adams R, Albers G, et al; American Heart Association; American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(2):577-617.

46. Institute of Medicine of the National Academies. Initial national priorities for comparative effectiveness research. http://www.iom.edu/ Reports/2009/ComparativeEffectivenessResearchPriorities.aspx. Accessed February 10, 2010.