YEAR IN CARDIOLOGY SERIES
The Year in Epidemiology, Health Services Research, and Outcomes Research
Mark A. Hlatky, MD*, ,* and
Paul A. Heidenreich, MD, MS,
* Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California
Department of Medicine, Stanford University School of Medicine, Stanford, California
Palo Alto Veterans Affairs Medical Center, Palo Alto, California
Manuscript received October 7, 2008;
revised manuscript received January 8, 2009,
accepted January 19, 2009.
* Reprint requests and correspondence: Dr. Mark A. Hlatky, Stanford University School of Medicine, HRP Redwood Building, Room 150, Stanford, California 94305-5405 (Email: hlatky{at}stanford.edu).
Key Words: outcomes • epidemiology • health services
There have been many new developments in the broad fields of epidemiology, health services research (HSR), and outcomes research during the past year, many more than can be discussed in detail in this review. We selected articles published since the last article in this series (1), covering roughly the period April 2007 through March 2008, that examined important issues or advanced research methods in the field.
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Epidemiology
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The focus of genetic epidemiology studies has shifted from testing variations in specific candidate genes that encode proteins suspected of a role in the pathogenesis of atherosclerosis to testing a comprehensive set of markers spaced across the entire genome. This "whole-genome association" approach aims to find all the common genetic variants that are linked to disease, whether or not there is pathophysiologic evidence of their importance. Several large whole-genome association studies have reported that common variants in an interval on chromosome 9 (9p21) are associated with coronary disease (2–4). These associations have been replicated in different populations and appear to predict risk in individuals of either European ancestry or African-American ancestry (5). Although a statistical association has been shown, the mechanism by which 9p21 genetic variants affects risk remain to be elucidated.
The replication of genetic associations in independent studies is important because the screening of multiple markers often leads to "false positives." The importance of replication was underscored by a report based on patients with acute coronary syndrome from 2 Kansas City hospitals (6) in which only 1 of the 85 genetic variants previously reported as significant predictors of coronary disease was replicated independently. This study also underscores the considerable bias toward publication of "positive studies" over "negative studies" in major journals. All well-designed studies attempting to replicate genetic associations should be reported to dispel overoptimism based on single promising results.
For genetic markers to be useful, they will have to inform clinical decisions, change patient management, and ultimately improve patient outcomes. Few new risk markers have been subjected to such rigorous evaluation. Anderson et al. (7) evaluated pharmacogenetic-guided dosing of warfarin in a randomized trial of 206 patients who had been genotyped for variants (CYP 2C9*2, CYP 2C9*3, VKORCI) that had been previously shown to affect response to warfarin. One-half of the patients had warfarin dosing based on a nomogram that included genotype data, and the other one-half had warfarin managed conventionally. Although patients assigned to pharmacogenetically guided therapy had fewer dose adjustments over the 3 months to follow (3.0 vs. 3.6, p < 0.05), they spent no more time in the therapeutic range (69.7% vs. 68.3%, p = 0.85), and were no less likely to experience a serious adverse event (4.0% vs. 5.1%, p = 0.71). This well-designed study suggests that considerable work remains in translating genetic marker data into improved clinical management.
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Risk Assessment
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Estimation of individual patient risk is a key element in decisions about the initiation of drug therapy, and the Framingham risk score has been extensively evaluated as a predictor of future cardiovascular events in asymptomatic individuals. D'Agostino et al. (8) used the original Framingham Heart Study population and the more recently recruited Framingham Offspring Study population to extend the risk score to the prediction of any cardiovascular disease event, including stroke and peripheral artery disease events as well as coronary heart disease and heart failure. This general cardiovascular disease risk score had good discrimination (a c-index of 0.76 in men and 0.79 in women), was well calibrated, and had significant net reclassification improvement measures.
Although the Framingham risk score is widely used, coronary disease is still unpredictable, and there is widespread interest in the development of novel risk markers. Impaired renal function has drawn considerable interest as a potentially overlooked risk factor for coronary disease. Deo et al. (9) from the Health ABC Study showed that serum creatinine and cystatin-C predicted cardiac events in a cohort of 3,044 subjects ages 70 to 79 years at entry, even after adjusting statistically for established risk factors.
The development of numerous biomarkers has raised questions regarding their incremental value in predicting heart disease and death. The Uppsala Longitudinal Study of Adult Men reported that a combination of 4 biomarkers (i.e., troponin I, N-terminal pro-hormone brain natriuretic peptide (NT-proBNP), cystatin C, and high-sensitivity C-reactive protein) improved risk stratification beyond traditional risk cardiovascular risk factors (10), with discrimination based on the c-statistic improving from 0.66 to 0.77. Similar findings were observed in a subset of patients without cardiovascular disease at baseline.
Coronary artery calcification (CAC) also has attracted considerable interest as a potential predictor of coronary artery disease events in asymptomatic populations. In the past year, several large cohort studies reported long-term outcome data in relation to coronary calcium scores (11–13). Budoff et al. (11) followed 25,253 subjects for an average of 6.8 years, during which 510 patients died (2.0%). Unadjusted 10-year mortality ranged in graded fashion from a low of 0.4% in subjects with a CAC score of 0 to a high of 27% in those with a CAC score >1,000, and CAC scores added significantly to a prediction model containing standard risk factors. The MESA (Multi-Ethnic Study of Atherosclerosis) also reported that CAC scores improved the c-index from 0.79 to 0.83 of a predictive model that included standard risk factors (13). The implications of a given CAC score may depend on patient characteristics, however, as African-American subjects had a greater cardiovascular risk at every level of CAC score in studies by Nasir et al. (12) and the MESA investigators (13).
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Risk Reduction
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The substantial reduction in coronary disease mortality in the U.S. and Western Europe has been a major accomplishment. But like all successes, there is a question of where the credit should go; 2 recent studies addressed the cause of this decline in population level mortality (14,15). Ford et al. (14) used the IMPACT model of coronary heart disease outcomes to examine the contribution of various factors to the reduction of coronary deaths in the U.S. between 1980 and 2000. They estimate that 47% of the deaths were averted by treatment for established coronary disease, whereas 44% were averted by changes in risk factor levels (Fig. 1). Hardoon et al. (15) estimated that 46% of the decline in the rate of myocardial infarction (MI) between 1978 and 2003 in the British Regional Heart Study could be attributed to lower risk factor levels, primarily by a fall in cigarette smoking.
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Figure 1 Percentage of Decrease in Deaths From Coronary Disease Due to Treatments for Established Disease and Changes in Risk Factors in Various Studies (Citations in the Original Article)
Note that the same IMPACT model shows more of the decrease in deaths in the U.S. (line 8) are due to treatment compared with Scotland (line 5), England and Wales (line 6), and Finland (line 10). Reprinted, with permission, from Ford et al. (14).
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Economic Evaluation
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Assessment of the economic impact of new diagnostic and therapeutic options has become increasingly important as large health systems attempt to control rising costs. The major question has been whether the greater costs of new technology are justified by much better outcomes.
Ultrasonography for abdominal aortic aneurysm is one of the few cardiovascular screening tests ever evaluated in a randomized trial. Seven-year follow-up of the MASS (Multicentre Aneurysm Screening Study) trial of 67,770 patients (16) showed abdominal aortic aneurysm mortality was reduced 47% by screening, whereas costs were increased only $135 per patient, yielding an attractive cost-effectiveness ratio of $19,500 per life-year added (Fig. 2).
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Figure 2 Cost Acceptability Curve for Abdominal Aortic Aneurysm Screening With Ultrasonography
The vertical axis is the cumulative percentage of simulations in which the cost-effectiveness ratio was below the value shown on the horizontal axis. The best estimate of the cost-effectiveness ratio ($19,500 per life-year added) is in the middle of this curve. Reprinted, with permission, from Kim et al. (16).
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The cost-effectiveness of coronary revascularization compared with medical therapy was assessed in an observational study in the United Kingdom by Griffin et al. (17). Costs were increased more by bypass surgery than by angioplasty, but bypass surgery was cost-effective among appropriate candidates as a result of improved quality of life ($40,400 per quality-adjusted life-year [QALY]). By contrast, angioplasty has a less favorable cost-effectiveness ratio compared with medical therapy, even among appropriate candidates ($86,300 per QALY).
Cardiac resynchronization therapy (CRT) is another costly new technology that has been scrutinized for its cost-effectiveness. A National Institutes of Clinical Effectiveness economic model (18) showed that CRT increased costs by $21,400 per patient, and QALYs by 0.70, yielding a favorable cost-effectiveness ratio ($30,700 per QALY). Adding defibrillation capability to a CRT device increased costs by another $21,500 but did not increase QALYs in proportion (0.29) and consequently had a less favorable cost-effectiveness ratio of $73,800 per QALY.
Heart failure-management programs aim to improve clinical outcomes and reduce long-term costs but require up-front expenditures. Chan et al. (19) used a Markov model to assess the economic impact of heart failure management programs, and found a favorable cost-effectiveness ratio of $9,700 per life-year gained, which was not affected by variation in model assumptions.
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Quality Improvement
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Achieving full use of evidence-based therapies for heart disease in routine clinical practice has proved to be a challenge, so there is great interest in improving systems to deliver greater quality of care. A clinical trial in the Netherlands randomized 38 general practices that were using electronic medical record systems to receive alerts when patients needed to be screened or treated for lipid abnormalities (20). Practices that received alerts were significantly more likely to follow guideline recommendations on screening and treatment than practices that were not reminded. Heidenreich et al. (21) performed a randomized trial of clinical reminders embedded in echocardiography reports about the use for beta-blockers in patients with a depressed ejection fraction ( 40%). Those randomized to the reminder were significantly more likely to receive a prescription for a beta-blocker within the next 9 months (74%) compared with those not receiving the reminder (64%).
Even if physicians prescribe evidence-based therapies, patients may not take them. In Ontario 18% of patients never filled their cardiac medication prescriptions in the year after discharge for an acute MI (22). Patients who filled all of their prescriptions were younger, had lower income levels, and fewer prescriptions before admission, and were more likely to have received pre-discharge counseling. Patients who filled all their prescriptions also had significantly lower mortality in the subsequent years. Adherence to guideline-based therapy may be improved by active interventions. The Michigan Guidelines Applied in Practice program (23) found that patients treated in hospitals that used an explicit "discharge contract" with patients about cardiac medication use had better adherence and lower mortality over the subsequent year of follow-up.
The initial treatment of ST-segment elevation MI requires coordination among first responders, emergency departments, and cardiac catheterization laboratories. A statewide program (RACE [Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments]) in North Carolina to provide rapid access to reperfusion therapy for ST-segment elevation MI patients reduced treatment delays in both percutaneous coronary intervention capable and nonpercutaneous coronary intervention hospitals (24). A new citywide protocol in Ottawa reduced door-to-balloon times for primary angioplasty (25), and patients who had an electrocardiogram performed in the field by paramedics were referred directly to a center capable of performing primary angioplasty and had significantly less delay in all measures of care delivery, including receipt of an electrocardiogram, arrival at a cardiac center, and the initial balloon inflation. A protocol mandating emergency department activation of the catheterization laboratory and immediate patient transfer if the laboratory was not available reduced door-to-balloon time by 38 min (26) and increased treatment within 90 min from 28% to 71%. The rapid activation of treatment systems for acute MI may, however, lead to angiography in some patients who are not having an acute MI. Roughly 10% of 1,335 patients at a regional referral center in Minneapolis went to the catheterization laboratory but had no coronary disease, negative cardiac markers, or both (27).
Hospitals use specialized code teams to respond rapidly to inpatients who experience a cardiac arrest. Two recent studies showed that response to and outcomes of cardiac arrests during nights and weekends were significantly worse than during the day (28,29). In a study of 6,789 patients at 369 hospitals, after-hours defibrillation was significantly delayed (28). In a larger study of 58,593 cases of cardiac arrest in 507 hospitals (29), survival to hospital discharge was significantly lower for cardiac arrests that occurred at night (14.7%) than during the day (19.8%).
Optimal use of tests at the time of initial diagnosis and in subsequent monitoring of patients over the course of their disease has not been established. The value of measuring brain natriuretic peptide (BNP) levels in patients with heart failure was tested in 2 randomized trials (30,31). In the IMPROVE-CHF (Improved Management of Patients With Congestive Heart Failure) study, 500 patients presenting to 1 of 7 emergency departments in Canada were randomized to have NT-proBNP results used to guide management or to be managed conventionally. The patients randomized to NT-proBNP assessment had shorter stays in the emergency department, fewer subsequent rehospitalizations within 60 days, and lower total costs of care (30). In the STARS-BNP (Systolic Heart Failure Treatment Supported by BNP) trial, 220 outpatients with stable heart failure were randomized to BNP monitoring with a goal of lowering plasma levels <100 pg/ml or to conventional clinical monitoring (31). During the subsequent follow-up, the 110 patients randomized to BNP-guided therapy had significantly more medication adjustments, greater drug doses, and were hospitalized for heart failure at one-half the rate of the conventionally managed patients. Serial assessment of the health status of patients with congestive heart failure also provides information on their subsequent risk of death, as a drop of 5 points in the Kansas City Cardiomyopathy Questionnaire was correlated with a 10% increase in subsequent mortality (32).
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Health Policy
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Pay-for-performance (P4P) is a new buzzword that refers to various programs by which payors provide financial incentives to doctors or hospitals based on whether they meet a set of benchmarks in the provision of care. Although the goal of P4P is to improve quality of care, a pilot project did not have a significant impact on evidence-based medication use for acute MI in participating hospitals (33). Another study suggested a hospital P4P program had a modest effect (34). Primary care doctors in the United Kingdom improved the quality of care for diabetes but not for coronary disease after the introduction of P4P (35). Like any intervention, P4P may have unintended consequences. Karve et al. (36) used Medicare data to rank hospitals on care measures for acute MI, heart failure, and pneumonia. They found hospitals that care for more African-American patients were less often eligible for bonuses and more likely to face financial penalties under a P4P plan. Physician P4P in London had less impact on minority patients with diabetes than on white patients (37). These studies suggest that P4P programs will need to be assessed carefully to determine the optimal form of the intervention itself, as well as to assess the clinical outcomes of the intervention on quality of care, access, and health disparities.
Measuring performance accurately is clearly essential for the success of P4P programs, but how should performance be measured? O'Brien et al. (38) showed that the ranking of hospitals on coronary artery bypass surgery was quite different depending on whether performance was assessed using a set of process measures or by outcome measures. Their results suggest that a careful approach to defining performance will be essential.
The affordability of prescription drugs was a major reason for the recent enactment of a pharmacy benefit in Medicare. Choudhry et al. (39) assessed the likely costs and outcomes of full drug coverage for medications prescribed after an acute MI. They project that the drug benefit should increase adherence to evidence-based therapies, which should in turn improve survival and reduce total medical costs by reducing subsequent hospitalization. In a study of changing coverage policies in British Columbia, introduction of either copayments or coinsurance for prescription medications doubled the chance a patient would stop taking statin therapy (40). In a review of published evidence, Goldman et al. (41) report that every 10% increase in cost sharing decreases prescription drug use by 2% to 6%.
The increase in health care costs has been driven by many factors, but the introduction of new medical technology has been identified as a major contributor. Medical imaging has drawn the particular interest of health care policymakers because of its particularly rapid growth. Pearlman et al. (42) showed that echocardiography in Medicare beneficiaries grew an average of 7.7% per year from 1999 to 2004, with a 3-fold variation in per-capita echocardiography use across states.
Public reporting of hospital outcomes has been embraced as a method to improve choice of providers, but criticized for not adjusting fully the severity of illness among patients. Stukenborg et al. (43) showed that risk adjustment for acute MI was improved by the availability of International Classification of Diseases-9th Edition codes that distinguish conditions present on hospital admission from complications that subsequently developed in-hospital. Acute noncardiac conditions present on admission were found to increase in-hospital mortality for acute MI significantly (44). The use of invasive treatment for cardiogenic shock after acute MI was significantly lower in New York State, where operator specific mortality for angioplasty and bypass surgery is publicly reported, than in other states (45), which suggests that physicians in New York State may avoid treating high-risk patients based on concerns about a negative effect on their reported procedural outcomes.
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Outcomes Research
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Observational studies of the outcomes of clinical management decisions can provide important insights into optimal therapies, despite the lack of randomization. One interesting example from the Cleveland Clinic examined whether a longer "shelf-life" of stored red blood cells affected the outcomes of coronary bypass surgery (46). Patients who received blood stored more than 14 days had more complications (26% vs. 22%, p = 0.001) and significantly greater risk-adjusted mortality in-hospital and during the subsequent year. A large registry of patients undergoing bypass surgery (47) reported that preoperative anemia was associated with a 2-fold increase in death, stroke, or renal failure after adjusting for confounding factors. Another, multicenter study found that preoperative anemia increased cardiac events after bypass surgery, primarily in those with comorbidities (48). These studies underscore the difficulties surrounding the management of anemia and transfusions in acutely ill patients.
If anemia is bad and transfusions not good either, perhaps reduction of bleeding during bypass surgery would be a rational approach to improving outcome. The antifibrinolytic agent aprotinin reduces bleeding during cardiac surgery, but observational studies of 9,875 patients in the Bristol Royal Infirmary (49), 10,275 patients at Duke Medical Center (50), and 78,199 patients in the Premier Perspective Cardiovascular Database (51) all showed significantly worse outcomes after aprotinin treatment. These observational results were consistent with the results of the randomized BART (Blood Conservation Using Antifibrinolytics in a Randomized Trial) of 2,331 high-risk patients, in which aprotinin increased mortality by 53% compared with 2 other antifibrinolytic agents (52), despite lower rates of bleeding. On the basis of these data, aprotinin has been withdrawn from the market.
Treatment options for abdominal aortic aneurysm now include open surgical repair and endovascular repair. Small randomized trials suggested endovascular repair had good short-term results, but larger studies with long-term outcomes have been needed. Schermerhorn et al. (53) used Medicare data from 45,660 patients to perform an observational, nonrandomized comparison of these alternatives using the technique of propensity score matching. Open repair had a significantly higher procedural mortality (4.8% vs. 1.2%), but by 4 years of follow-up, the mortality of patients who had either open or endovascular repair was equal, roughly 30%.
Off- versus on-pump coronary artery bypass graft surgery were compared in an observational, nonrandomized study by Hannan et al. (54) using the New York State Cardiac Surgery Registry based on matched pairs of patients with equivalent propensity scores. During 3 years of follow-up, the survival after off-pump surgery (89.4%) was not significantly different from that of on-pump surgery (90.1%), but the rate of repeat revascularization was significantly higher after off-pump (10.1%) than on-pump surgery (6.4%). These investigators also used a propensity score approach to compare patients with multivessel disease treated either with coronary bypass surgery or coronary angioplasty in New York State (55). They found survival over an average 18 month follow-up was better after surgery than angioplasty, both in patients with 3-vessel disease (94.0% vs. 92.7%) and in patients with 2-vessel disease (96.0% vs. 94.6%).
In the absence of randomization, statistical methods must be used to control for differences in patients given alternative therapies. Instrumental variables methods are a less frequently used tool that was developed by economists, and although it has been used less often in medical studies than the propensity score method, it may have advantages. Using data on Medicare patients with an acute MI, Stukel et al. (56) tested the effect of cardiac catheterization on mortality using three alternative statistical methods to adjust for nonrandom assignment of therapy. Although all 3 statistical methods showed lower risk-adjusted mortality with catheterization, the treatment effect was 49% when estimated by standard direct risk adjustment methods, 46% when estimated by propensity score methods, but only 16% when estimated by instrumental variables methods, which was closer to the risk reductions of 8% to 21% reported by randomized trials (56). Pilote et al. (57) also used an instrumental variables method to assess the effect of coronary angiography (and subsequent revascularization) on 1-year mortality after acute MI. They found a significant 11% reduction in mortality related to use of invasive management.
Yet another approach to observational treatment assessment is the time-varying exposure method, which is applicable to interventions applied over time, such as use of prescription drugs. Ho et al. (58) applied this approach to assess the effects of clopidogrel after acute coronary syndromes and found a significantly greater risk of death and MI in the 90 days after stopping clopidogrel. Interestingly, this effect was found in medically treated patients as well as those treated with angioplasty, suggesting there may be "rebound" in platelet aggregation after clopidogrel discontinuation.
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Variations in Care
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Variations in clinical practice according to characteristics of the patient, the doctor, or the hospital have attracted considerable attention because of the concern that they may compromise quality of care and clinical outcomes. Disparities in the use of invasive cardiac procedures according to the patient's race or sex have drawn particular scrutiny. Data from the Cooperative Cardiovascular Project from Medicare patients treated for acute MI showed African-American patients were significantly less likely to receive timely reperfusion, a beta-blocker, coronary angiography, angioplasty, and bypass surgery than white patients, even after adjusting for differences in comorbidity (59). Although African-American patients may not have as ready access to hospitals that perform cardiac procedures, Popescu et al. (60) found the lower invasive procedure use among African Americans was evident both in hospitals with and without invasive procedure capability. Lucas et al. (61) found that stress tests were also less likely to be used in African-American patients and in women. Minority patients may be less willing to travel to referral centers to undergo invasive cardiac procedures, and Sketch et al. (62) showed that outreach with a mobile catheterization laboratory that visited local community hospitals led to significantly higher procedure use in African-American subjects and women.
Disparities in the use of implantable cardioverter-defibrillators (ICDs) also have been demonstrated. Women were less than one-half as likely as men to have an ICD implanted for either primary or secondary prevention of sudden death in an analysis of Medicare data (63). In a registry of patients with heart failure, women eligible for ICD therapy were 40% less likely to receive an ICD compared with white men, and black men were 27% less likely to receive an ICD (64). These differences in ICD use were not explained by clinical measures.
Characteristics of the treating physician may also affect patterns of care. Turchin et al. (65) analyzed the treatment of 8,127 patients with hypertension and diabetes treated by 301 internists (65) and reported that physicians who had been board certified for 10 years or less were significantly more likely to intensify antihypertensive drug treatment in the face of an elevated blood pressure reading. In the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) registry (66), patients with acute coronary syndromes were significantly more likely to receive evidence-based therapies if care was provided on a cardiology specialty service than on other types of services. Patients with acute MI or heart failure treated by hospitalists had shorter lengths of stay with equivalent mortality than patients treated by general internists or family physicians (67).
Hospital and health system characteristics also may affect processes of care. Shah et al. (68) analyzed care in the CRUSADE registry according to the ownership status of the hospital and found generally similar use of evidence-based therapies in for-profit and not-for-profit facilities. Nallamothu et al. (69) evaluated treatment and outcomes for acute MI and heart failure among Medicare beneficiaries treated in one of 16 cardiac specialty hospitals compared with 121 similar general hospitals. Patients seen at the specialty hospitals were younger, had less comorbidity, and had significantly lower 30-day mortality rates. The difference in mortality was attenuated, but not eliminated, by adjustment for potential confounding factors.
Geographic practice variation in the use of cardiac procedures has been documented previously, but the reasons for this variation have been unclear. The possibility that areas with high utilization have more inappropriate procedures was examined by Ko et al. (70) among Medicare beneficiaries after acute MI. They found that catheterization was 36% higher for strong indications (Class I) and 40% greater for equivocal indications (Class II) in regions with greater overall use of angiography, but catheterization was also 34% greater for inappropriate indications (Class III).
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Conclusions
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Epidemiology, HSR, and outcomes research are examples of the value of multidisciplinary research as applied to cardiovascular disease. Research in these fields typically requires investigators from different backgrounds, high-quality data from a variety of sources, statistical methods to analyze observational data, and often can be applied directly to clinical practice.
Thus, population sciences research, only a portion of which we could summarize here, will continue to be important in translating research discoveries into practice and improving the quality and outcomes of care for cardiovascular disease.
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Footnotes
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Dr. Heidenreich is a consultant to Siemens Diagnostics.
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References
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