Treatment of Anemia in Patients With Heart DiseaseFREE
The benefits of anemia treatment in patients with heart disease are uncertain.
To evaluate the benefits and harms of treatments for anemia in adults with heart disease.
MEDLINE, EMBASE, and Cochrane databases; clinical trial registries; reference lists; and technical advisors.
English-language trials of blood transfusions, iron, or erythropoiesis-stimulating agents in adults with anemia and congestive heart failure or coronary heart disease and observational studies of transfusion.
Data on study design, population characteristics, hemoglobin levels, and health outcomes were extracted. Trials were assessed for quality.
Low-strength evidence from 6 trials and 26 observational studies suggests that liberal transfusion protocols do not improve short-term mortality rates compared with less aggressive protocols (combined relative risk among trials, 0.94 [95% CI, 0.61 to 1.42]; I2 = 16.8%), although decreased mortality rates occurred in a small trial of patients with the acute coronary syndrome (1.8% vs. 13.0%; P = 0.032). Moderate-strength evidence from 3 trials of intravenous iron found improved short-term exercise tolerance and quality of life in patients with heart failure. Moderate- to high-strength evidence from 17 trials of erythropoiesis-stimulating agent therapy found they offered no consistent benefits, but their use may be associated with harms, such as venous thromboembolism.
Few trials have examined transfusions in patients with heart disease, and observational studies are potentially confounded by indication. Data supporting iron use come mainly from 1 large trial, and long-term effects are unknown.
Higher transfusion thresholds do not consistently improve mortality rates, but large trials are needed. Intravenous iron may help to alleviate symptoms in patients with heart failure and iron deficiency and also warrants further study. Erythropoiesis-stimulating agents do not seem to benefit patients with mild to moderate anemia and heart disease and may be associated with serious harms.
Primary Funding Source:
U.S. Department of Veterans Affairs.
Approximately one third of patients with congestive heart failure (CHF) and 10% to 20% of those with coronary heart disease (CHD) also have anemia (1–3). Anemia is associated with more symptoms, a greater hospitalization rate, and increased mortality rates both in patients with CHF (4–6) and CHD (7, 8). It is unclear whether anemia directly leads to these poor outcomes or simply reflects more severe underlying illness. Indeed, many factors probably contribute to the development of anemia in heart disease, including comorbid chronic kidney disease, blunted erythropoietin production, hemodilution, aspirin-induced gastrointestinal blood loss, the use of renin–angiotensin–aldosterone system blockers, cytokine-mediated inflammation, gut malabsorption, and iron deficiency (9, 10).
For many years, the epidemiologic data and biological plausibility supporting a link between anemia and poor outcomes in patients with heart disease prompted many physicians to advocate treatment of anemia with more aggressive use of blood transfusions. Interest in erythropoiesis-stimulating agents (ESAs) and iron supplementation to treat anemia in heart disease has also been growing. An increasing body of literature has recently tested whether these strategies improve health outcomes in patients with heart disease. This review summarizes and updates a report commissioned by the U.S. Department of Veterans Affairs’ Evidence-based Synthesis Program and the Clinical Guidelines Committee of the American College of Physicians, which evaluated the health outcome effects of each of these strategies in adult patients with heart disease (11).
Data Sources and Searches
We conducted a search for literature published in MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from database inception to August 2012. We searched EMBASE through November 2010 because we could not retain our license for this database beyond that time frame. The search strategy included such terms as anemia, congestive heart failure, coronary heart disease, ischemic heart disease, erythropoiesis-stimulating agents, iron, and red blood cell transfusion. The detailed search strategy is provided in Table 1 of the Supplement. We obtained additional articles from systematic reviews; reference lists of pertinent studies, reviews, and editorials; and consulting experts. We also searched for ongoing and recently completed studies on ClinicalTrials.gov and included reports of trials that had been published as of April 2013.
The analytic framework that guided our review and synthesis of the literature is provided in Appendix Figure 1. Eligible articles had English-language abstracts and provided primary data about the effects of ESAs, iron, or blood transfusions in adult populations with anemia (hemoglobin levels <13 g/dL in men and <12 g/dL in women) and symptomatic CHF (with or without decreased systolic function) or CHD (the acute coronary syndrome, the postacute coronary syndrome, and history of myocardial infarction [MI] or angina). We included trials with mixed populations of patients with and without anemia as long as data specific to the anemia subgroup were reported. We considered trials comparing interventions with placebo or those comparing more intensive with less intensive interventions (that is, trials examining different transfusion thresholds or hemoglobin targets). Because few trials of red blood cell transfusion were found, we included observational studies to characterize the evidence on which current transfusion practice is based. Outcomes of interest included mortality, hospitalization, exercise tolerance, cardiovascular events, quality of life, and adverse effects of treatment.
Three investigators reviewed the titles and abstracts of citations identified from literature searches, and 2 reviewers independently assessed the selected full-text articles for inclusion on the basis of the eligibility criteria shown in Table 2 of the Supplement. Disagreements were resolved by consensus.
Data Extraction and Quality Assessment
From each study, we abstracted study design, objectives, setting, population characteristics (including sex, age, left ventricular ejection fraction, baseline New York Heart Association [NYHA] class, and CHD definition), participant eligibility and exclusion criteria, number of participants, years of enrollment, duration of follow-up, the study and comparator interventions, important cointerventions, baseline hemoglobin levels, change in hemoglobin levels, health outcomes, and adverse effects. If only the hematocrit was reported, we used a conversion of 3:1 to approximate the hemoglobin value. To evaluate harms, we collected data on adverse effects from all included trials and specifically gathered data from each ESA trial on hypertension, venous thromboembolic events (including deep venous thrombosis, pulmonary embolism, and vascular access thrombosis), and ischemic cerebrovascular events. In trials examining blood transfusions, we specifically looked for reporting of transfusion reactions.
Two reviewers independently assessed the quality of each trial using a tool developed by the Cochrane Collaboration (12). Disagreements were resolved by discussion. Each study was given an overall summary assessment of low, high, or unclear risk of bias. We assessed the overall quality of evidence for outcomes using a method developed by the Grading of Recommendations Assessment, Development, and Evaluation Working Group (13), which considers the consistency, coherence, and applicability of a body of evidence, as well as the internal validity of individual studies, to classify the grade of evidence across outcomes.
Although there is no widely accepted standard for quality assessment of observational studies, we adapted existing tools (14, 15) relevant to this review and specifically assessed whether each observational blood transfusion study conducted an analysis adjusting for patient propensity to receive a blood transfusion, accounted for bleeding complications (regardless of whether they were procedure-related), and accounted for the timing of transfusion given the potential for survival bias in which patients who died could not have received a transfusion. The detailed assessment of quality for each study is provided in Tables 3 to 6 of the Supplement. We do not report an overall summary assessment for observational studies because there are no validated criteria for doing so.
Data Synthesis and Analysis
We did meta-analyses of study-level data evaluating the effects of liberal compared with restrictive transfusion strategies on short-term mortality rates (defined as death during or within 30 days after the hospital stay) and cardiovascular events (defined as MI, CHF exacerbation, arrhythmia, or cardiac death—we distinguished in-hospital events from those occurring during longer-term follow-up). We abstracted the number of events and total participants from each treatment group and obtained a pooled estimate of relative risk (RR) using a random-effects model (16). We preferentially used 30-day mortality for the analysis, followed by in-hospital and 72-hour mortality. We conducted a sensitivity analysis on the basis of the definition of short-term mortality. If trials included mixed populations of patients with and without heart disease, we contacted authors for subgroup information if it was not available in published reports.
We also did meta-analyses of ESA trials for each of the following outcomes: mean difference in the change in NYHA class, exercise duration during the 6-minute walk test, all-cause mortality, hospitalizations, cardiovascular events, hypertension events, and ischemic cerebrovascular events. Given the variety of assessment tools used, we did not do meta-analyses of quality-of-life outcomes. We ran sensitivity analyses for all outcomes, excluding studies with high or unclear risk of bias.
All analyses were done using Stata 10.0 (StataCorp, College Station, Texas). Statistical heterogeneity among the trials combined in meta-analysis was assessed by the Cochran Q test and I2 statistic (12). Publication bias was not assessed because of the small number of trials that could be combined (17).
We qualitatively synthesized the results of trials of iron therapy because only 3 trials examined the effects of iron, with 1 large trial dominating.
Role of the Funding Source
The U.S. Department of Veterans Affairs Quality Enhancement Research Initiative supported this review but had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
We reviewed 1740 titles and abstracts from the electronic search and identified an additional 79 from reviewing reference lists and doing manual searches for recently published and unpublished or ongoing studies (Appendix Figure 2). After inclusion and exclusion criteria were applied at the abstract level, 404 full-text articles were reviewed. Fifty-five articles comprising 52 primary studies met our inclusion criteria. Detailed results for each intervention are presented in the following sections, and the overall findings are summarized in Table 1.
Six trials compared liberal and restrictive transfusion protocols (18–20, 23–25) (Table 7 of the Supplement). Three of these were conducted in nonoperative settings among critically ill patients or those with the acute coronary syndrome (23, 25, 26). Three studies were conducted in patients with and without known heart disease in perioperative settings (18–20), but only 1 of these studies had CHD-specific subgroup information available (20).
Overall, low-strength evidence from the 6 trials suggests that liberal transfusion protocols do not reduce 30-day mortality rates compared with restrictive transfusion protocols (RR, 0.94 [95% CI, 0.61 to 1.42]; I2 = 16.8%). Exclusion of the 2 studies in which CHD subgroup-specific information was not available (18, 19) yielded similar results (RR, 0.86 [CI, 0.46 to 1.62]; I2 = 50.0%) (Figure 1).
However, more aggressive transfusion protocols may be associated with lower risk for cardiovascular events (5 trials; RR, 0.64 [CI, 0.38 to 1.09]; I2 = 0.0%). As previously described, exclusion of the 2 studies in which CHD subgroup information was not available did not affect the findings (RR, 0.60 [CI, 0.34 to 1.03]; I2 = 0.0%) (Appendix Figure 3).
Aside from cardiovascular events, which we report in a subsequent section, there were no reports of excess adverse effects from more aggressive transfusion in the trials, although harms reporting was sparse and only 1 trial recorded transfusion reactions (23).
Low-strength evidence from 3 trials (23–25) (combined RR, 0.58 [CI, 0.23 to 1.48]; I2 = 29.9%) and 23 observational studies (8, 27–48) suggests that more aggressive transfusion does not decrease mortality rates in patients who are critically ill with heart disease or those with the acute coronary syndrome (Table 1).
Results among studies, however, were conflicting. A recent multicenter, randomized, controlled trial of 110 patients compared transfusion thresholds of 10 and 8 g/dL in patients with the acute coronary syndrome or stable angina having cardiac catheterization (25). The liberal transfusion strategy was associated with a lower 30-day mortality rate (1.8% vs. 13.0%; P = 0.032), but the rates of MI (9.1% vs. 13.0%; P = 0.52) and unscheduled coronary revascularization (0.0% vs. 3.7%; P = 0.24) were similar in both groups. Another trial of patients with acute MI compared similar transfusion thresholds but found that the liberal transfusion group had a greater rate of the primary end point, a composite of in-hospital death, recurrent MI, or new or worsening heart failure (38% vs. 13%; P = 0.046), with most of the difference explained by a greater incidence of new or worsening CHF (23). An older trial of patients without bleeding who were critically ill and had anemia compared transfusion hemoglobin thresholds of 10 and 7 g/dL. The overall trial population included 838 patients with and without heart disease and found no difference in mortality or cardiovascular event outcomes (49). In a post hoc subgroup analysis of the 257 patients with known ischemic heart disease, 30-day mortality rates were also similar between the liberal and restrictive transfusion groups (21.2% vs. 26.1%; RR, 0.81 [CI, 0.52 to 1.26]) (24).
Twenty-three observational studies were done in patients having percutaneous coronary intervention or hospitalized with the acute coronary syndrome, MI, or decompensated heart failure (Table 8 of the Supplement). There was little evidence in nearly all studies that transfusions at hemoglobin levels greater than 8 to 9 g/dL were associated with improved outcomes, although there were 2 exceptions (8, 45). However, many observational studies found that transfusions at hemoglobin levels greater than 9 to 10 g/dL were associated with an increased risk for death. Whether these findings reflect a true effect of transfusion or confounding by indication is unclear.
No studies examined transfusions in stable outpatients with a history of CHD.
Low-strength evidence from 3 trials in hip fracture and vascular surgery patients with heart disease found no short-term mortality benefit from a liberal compared with a conservative transfusion strategy (RR, 1.35 [CI, 0.80 to 2.25]; I2 = 0.0%) (18–20). However, fewer cardiovascular events occurred with more aggressive use of transfusions in patients having surgery. A recent large trial randomly assigned patients who had hip fracture surgery and a history of, or risk factors for, cardiovascular disease to a liberal (hemoglobin level threshold of 10 g/dL) or restrictive transfusion strategy (symptoms of anemia or at the physician's discretion for hemoglobin levels <8 g/dL) (20). As expected, more patients in the liberal transfusion group received 1 or more transfusions than the restrictive group (96.7% vs. 41.0%; P < 0.001). In a post hoc analysis of the subgroup of 796 patients with known CHD, 30-day mortality rates in the 2 groups were similar (RR, 1.44 [CI, 0.81 to 2.54]), but the liberal transfusion strategy was associated with a reduced risk for in-hospital MI that approached statistical significance (RR, 0.52 [CI, 0.27 to 1.01]). When we used a broader definition of cardiovascular disease to include patients with CHF, peripheral vascular disease, or cerebrovascular disease, the reduction in MI reached statistical significance (1267 patients; RR, 0.50 [CI, 0.27 to 0.91]). Of note, among the 748 patients without known cardiovascular disease, the liberal transfusion strategy had no effect on mortality rates (RR, 1.12 [CI, 0.50 to 2.50]) or MI (RR, 1.02 [CI, 0.39 to 2.69]).
In the observational cohorts, transfusion did not seem to offer any protection, and in 1 vascular surgery study, mortality and MI rates were greater overall in the transfusion group (Table 8 of the Supplement) (50–52).
Moderate-strength evidence from 3 trials (53–55) found that intravenous iron improved exercise tolerance, quality of life, and cardiovascular events in patients with heart failure (Tables 1 and 2). Results are dominated by 1 large, multicenter trial that found intravenous ferric carboxymaltose improved 6-month exercise tolerance and quality of life in patients with heart failure (55, 56). Most patients had NYHA class III symptoms and moderate to severe systolic dysfunction. Only one half of the patients had anemia (hemoglobin levels ≤12 g/dL), but most had ferritin levels less than 224.7 pmol/L. Intervention patients were more likely to report they were greatly or moderately improved on the Patient Global Assessment (50% vs. 28%; odds ratio, 2.51 [CI, 1.75 to 3.61]) and showed improvement in NYHA functional class (odds ratio for improvement by 1 class, 2.40 [CI, 1.55 to 3.71]). Results were similar in patients with hemoglobin levels less than and greater than 12 g/dL for the Patient Global Assessment (P value for interaction with hemoglobin level = 0.98), NYHA class (P value for interaction = 0.51), and quality-of-life (P value for interaction = 0.59) outcomes (56). There were fewer cardiac events in the intervention group (27.6% vs. 50.2%; P = 0.01), although this outcome was poorly defined and not prespecified. Mortality rates were similar in both groups (3.4% vs. 5.5%), but the trial was not powered for mortality outcomes. Serious adverse effects were uncommon, although there was a trend toward increased gastrointestinal events in the intervention group (Table 2). The long-term effects of iron treatment are unknown.
Seventeen randomized, controlled trials of ESAs in patients with heart disease were published in 19 reports (Table 9 of the Supplement) (21, 22, 57–73). Twelve trials enrolled patients with CHF, and the mean ejection fraction was 35% or less among 11 trials that reported systolic function. Most patients had comorbid CHD. Two trials included roughly equal proportions of patients with CHD and CHF (22, 59), and only 1 trial focused exclusively on patients with CHD (70). Two trials were primarily designed to assess the comparative effects of ESAs titrated to high or low hemoglobin targets in patients with anemia and chronic kidney disease but included a large proportion of patients with heart disease for whom adequate subgroup data were reported (58, 59).
Overall, there is high-strength evidence that ESA use has no beneficial effects on mortality rates, cardiovascular events, and hospitalizations (Table 1). Moderate-strength evidence suggests that ESAs do not consistently improve quality of life either. Although some studies found that ESA use improved exercise tolerance and duration, no improvement was seen on combining trials with low risk of bias (mean difference in NYHA score change, −0.15 [CI, −0.36 to 0.06]). By contrast, moderately strong evidence in patients with CHF shows that ESA use may be associated with serious harms, such as hypertension and venous thromboembolism, and possibly increased mortality rates (Figure 2). The study characteristics, quality assessment, and meta-analyses of the ESA trials are shown in detail in Tables 6 and 9 of the Supplement and Appendix Figures 4, 5, 6, 7, 8, 9, 10, and 11.
The Reduction of Events With Darbepoetin Alfa in Heart Failure trial, by far the largest trial (to our knowledge) to examine ESA use specifically in patients with CHF, randomly assigned 2278 patients with systolic heart failure and hemoglobin levels of 9 to 12 g/dL to darbepoietin titrated to a target hemoglobin level of 13 g/dL or to placebo (71). There were no differences in any health outcomes, other than a greater rate of thromboembolic events in the intervention group (13.5% vs. 10.0%; P = 0.009) after a median 28-month follow-up.
We found no substantive difference in results when we excluded studies in which the mean baseline hemoglobin levels were less than 11 g/dL or studies in which the mean increase in hemoglobin levels associated with ESA use were less than 2 g/dL. However, these parameters varied little among the trials, which could have made it difficult to detect any true influence of baseline hemoglobin levels or change in hemoglobin levels on outcomes.
Three trials compared ESAs titrated to normal or near-normal targets with those titrated to lower targets (hemoglobin levels, 9 to 11.3 g/dL) (21, 58, 59). None of the trials found a benefit from aggressive ESA use, and in fact, 2 of the trials found a significant increase in venous thromboembolic risk and a near-significant increase in mortality rates (21, 59).
No trials in patients with heart disease have evaluated the effects of more moderate hemoglobin level targets (for example, 10 to 12 g/dL) compared with lower targets.
We examined the effects of 3 strategies for treating anemia in patients with heart disease. Overall, despite the epidemiologic and biologically plausible association of anemia with poor outcomes, we did not find consistent evidence that anemia correction improves outcomes in patients with heart disease, although there were notable exceptions.
The effects of more liberal transfusion protocols on outcomes are mixed. Low-strength evidence suggests that more aggressive use of blood transfusions does not consistently decrease mortality rates. However, we found very limited evidence from a small trial of patients with the acute coronary syndrome that a transfusion threshold of 10 g/dL may decrease mortality rates. Data from a post hoc subgroup analysis of a trial of patients who had hip fracture surgery and heart disease suggest that liberal transfusion strategies may reduce in-hospital MI, although the clinical significance of this finding is unclear in the absence of mortality benefit and in the context of serial troponin measurement (20, 25).
Conflicting biological plausibility arguments have been espoused to support the benefits or harms of transfusions in patients with coronary disease, but surprisingly few trials have tested these biological assumptions (74). The more recent trial data suggesting a potential benefit from more liberal transfusion practices in patients with heart disease urgently need to be confirmed in large-scale trials. In the meantime, the low-strength evidence suggesting a possible benefit needs to be weighed against the well-known potential adverse effects of blood transfusions, which range from relatively common volume overload and febrile reactions to rare infectious and serious hemolytic complications (75). The precise level of harm associated with transfusions in patients with heart disease is unknown because data on adverse effects were inconsistently reported among trials.
We found a large body of observational studies that consistently showed that more aggressive transfusion practices had either neutral or deleterious effects on health outcomes, but the potential for confounding by indication is a limitation (76). The decision to transfuse patients in those studies was based on clinical judgment, which would naturally be influenced by severity of illness, symptoms, and observation of bleeding. Despite very careful propensity adjustment in some studies, the possibility of residual confounding renders this base of evidence fairly tenuous.
Two meta-analyses examining the effects of transfusions were published in 2013, but neither study included CHD-specific subgroup data or more recent data in patients with the acute coronary syndrome (77, 78). One of the meta-analyses focused on a smaller body of 9 observational studies and found that transfusions at greater hemoglobin levels were associated with an increased risk for death in patients with MI, although this risk was not apparent in studies of patients who had ST-segment elevation MI or baseline hemoglobin levels less than 10 g/dL. The other meta-analysis found that restrictive transfusion strategies were associated with a lower risk for death that approached statistical significance (RR, 0.85 [CI, 0.70 to 1.03]), but a broad range of patient populations was examined and applicability to patients with heart disease is low.
There is moderate-strength evidence, mainly from 1 large, multicenter trial, that intravenous iron carboxymaltose improves exercise tolerance, quality of life, and exercise duration in patients with chronic, stable systolic heart failure (55). These results are most applicable to patients with NYHA class III heart failure and low ferritin levels. Biological plausibility and test-of-concept studies suggest that iron replacement could play a role in improving symptoms of heart failure even when iron stores are theoretically adequate, because symptoms may be related to a functional misuse of iron rather than absolute deficiency (10). Nevertheless, although the criteria used to define iron deficiency were fairly broad, most patients enrolled in the Assessment in Patients With Iron Deficiency and Chronic Heart Failure trial had evidence of more advanced iron deficiency and limited iron stores. Although the trial results are encouraging and at least 1 study has supported the cost-effectiveness of iron treatment (79), the long-term health implications are uncertain, and harms have not been more widely assessed in this population. In other populations, iron carboxymaltose has not been associated with an increased risk for serious adverse effects, such as anaphylactic reactions, which were possibly linked with older iron preparations, such as iron sucrose (80, 81).
There is moderate- to high-strength evidence that ESAs do not improve health outcomes and may be associated with serious harms in patients with heart disease. The data are most applicable to patients with CHF and systolic dysfunction. Future studies may be useful to clarify the role of ESAs in patients with preserved systolic function or those with CHD only. The balance of benefits and harms is most straightforward for the use of ESAs titrated to normal or near-normal hemoglobin levels. It is unknown whether more modest hemoglobin targets would be safer and yield a net health outcome benefit, but the lack of any functional or quality-of-life benefits from more aggressive use of ESAs suggests that a potential benefit is unlikely.
Anemia is common in patients with heart disease. Greater transfusion thresholds are not consistently associated with mortality benefit, but there are few trials. Recent data suggest a possible benefit in patients with the acute coronary syndrome, but large trials are needed to better clarify the role of transfusions in these patients. Evidence mostly from 1 large trial suggests that intravenous iron treatment may help to alleviate symptoms over the short term in patients with symptomatic heart failure and iron deficiency. Strong evidence shows that ESAs do not improve symptoms or outcomes in patients with mild to moderate anemia and heart disease and may be associated with serious harms.
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Author, Article, and Disclosure Information
From Portland Veterans Affairs Medical Center and Oregon Health & Science University, Portland, Oregon.
Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government.
Acknowledgment: The authors thank Rose Relevo, MLIS, MS, AHIP, for developing the search strategy and conducting the database searches and Tomiye Akagi, BA, for providing administrative support. They also thank Dr. Jeffrey Carson for his advice and for sharing subgroup data from the Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair study.
Grant Support: From the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative, Evidence-based Synthesis Program (project 05-225).
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0078.
Corresponding Author: Devan Kansagara, MD, MCR, Portland Veterans Affairs Medical Center, Mailcode RD71, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239; e-mail, [email protected].
Current Author Addresses: Dr. Kansagara and Ms. Freeman: Portland Veterans Affairs Medical Center, Mailcode RD71, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239.
Drs. Dyer and Kagen: Portland Veterans Affairs Medical Center, Mailcode P3-MED, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97239.
Dr. Englander: Oregon Health & Science University, BTE 119, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239.
Dr. Fu: Department of Public Health & Preventive Medicine, Oregon Health & Science University, Mailcode CB669, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239.
Author Contributions: Conception and design: D. Kansagara, H. Englander, D. Kagen.
Analysis and interpretation of the data: D. Kansagara, E. Dyer, H. Englander, R. Fu, D. Kagen.
Drafting of the article: D. Kansagara, H. Englander, D. Kagen.
Critical revision of the article for important intellectual content: D. Kansagara, E. Dyer, H. Englander, R. Fu, M. Freeman, D. Kagen.
Final approval of the article: D. Kansagara, H. Englander, R. Fu, D. Kagen.
Statistical expertise: D. Kansagara, R. Fu.
Administrative, technical, or logistic support: M. Freeman.
Collection and assembly of data: D. Kansagara, E. Dyer, H. Englander, M. Freeman, D. Kagen.