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Background Jehovah's Witness patients (Witnesses) who undergo cardiac surgery provide a unique natural experiment in severe blood conservation because anemia, transfusion, erythropoietin, and antifibrinolytics have attendant risks. Our objective was to compare morbidity and long-term survival of Witnesses undergoing cardiac surgery with a similarly matched group of patients who received transfusions. Methods A total of 322 Witnesses and 87 453 non-Witnesses underwent cardiac surgery at our center from January 1, 1983, to January 1, 2011. All Witnesses prospectively refused blood transfusions. Among non-Witnesses, 38 467 did not receive blood transfusions and 48 986 did. We used propensity methods to match patient groups and parametric multiphase hazard methods to assess long-term survival. Our main outcome measures were postoperative morbidity complications, in-hospital mortality, and long-term survival. Results Witnesses had fewer acute complications and shorter length of stay than matched patients who received transfusions: myocardial infarction, 0.31% vs 2.8% (P = . 01); additional operation for bleeding, 3.7% vs 7.1% (P = . 03); prolonged ventilation, 6% vs 16% (P Conclusions Witnesses do not appear to be at increased risk for surgical complications or long-term mortality when comparisons are properly made by transfusion status. Thus, current extreme blood management strategies do not appear to place patients at heightened risk for reduced long-term survival.

Following the first convincing trials in humans on the benefits of cholesterol lowering for preventionof atheroscleroticrelated events, in 1985, then-Director of the National Heart, Lung, and Blood Institute Robert Levyasserted that the cholesterol“question”wasno longer whether to treat high cholesterol levels, but rather when, inwhom,andhow.1For 30years, it hasbeenwell known that lowering blood cholesterol concentrations by a variety of drugs and other approaches reduces cardiovascular disease (CVD) risk.2Withmore trials in patient groupswith lower risk, including thosewith relatively low levels of low-density lipoprotein cholesterol (LDL-C),3 it has become clear that atherosclerotic cardiovascular disease (ASCVD) canbeprevented by loweringLDL-C levels, especiallywith statindrugs,2,3 in broad segments of the general population. However, the critical questions—when, in whom, and how to lower cholesterol— still remain. This Editorial, with new evidence from 2 reports in this issueof JAMA, addresses 2 of thesequestions: inwhom and how to treat cholesterol levels in 2015. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guidelines2 recommended consideration of statin treatment for 4 clinical scenarios: (1) patients with clinical ASCVD including those with myocardial infarction, angina, or previous coronary revascularization; (2) patients without clinical ASCVD but with an LDL-C level higher than 190 mg/dL and without secondary cause; (3) patients aged 40 through 75 years without clinical ASCVD but with diabetes mellitus and LDL-C levels from 70 through 189mg/dL; and (4) patients aged 40 through 75 years without clinical ASCVD and diabetes, but with an LDL-C level of 70 through 189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher. For the first 3 clinical scenarios there was almost universal acceptance with general agreement that the new recommendations were based on strong and consistent data.4 However, nearly immediately after release of the guidelines therewas considerable scrutiny and controversy regarding the fourth clinical scenario: primary prevention in adults without diabetes butwith an estimated 10-yearASCVD risk of 7.5% or higher. One group reported a set of analyses suggesting that the new ACC/AHA Pooled Cohort Equation overestimated risk in various populations,5 whereas others reported that, in properly selected cohorts, the new equation performedmore accurately thanpreviouslyused risk equations.6 Uncertainties about the accuracy of the risk calculator raised concerns about the wisdom of the newly lowered treatment threshold.Would the new guidelines lead tomassive and unjustified overtreatment ofmillions of people? Thequestionof in whom to use statins lingered. Basedonevidence frommultipleclinical trials, statindrugs havebeenshownto lowerCVDrisk forprimarypreventioneven among relatively low-risk people and even among thosewith relatively low LDL-C concentrations.3 Although a 10-year ASCVD risk threshold of 7.5%orhighermight initially seem to be a low threshold, many, indeed most, CVD events occur among the low-riskmembers of thepopulation.7Rose first described theseemingparadox8 that relatively fewASCVDevents occur in high-risk individuals simply because there are so few high-risk people in the population. The vast majority ofASCVDeventsoccuramong lower-riskpersonsbecause they comprise the greatest portion of the population.9 To prevent manymoreASCVDevents, it is reasonable to considerwhether statin drugs should be used in lower-risk individuals, and whether risk assessment by the new Pooled Cohort Equation leads to a reasonable level of treatment of at-risk people and a rational use of medical resources, even if potentially billions of people worldwide would be recommended for statin drugs.10 In this issue of JAMA, 2 reports suggest that the new risk threshold is likely to be reasonable and cost-effective; it may not even go far enough. If true, even a risk calculator that overestimates risk might be reasonable to use in the clinical setting. In the first report, using FraminghamOffspring Study data, Pursnani et al11 sought to determine whether the 2013 ACC/AHA guidelines improved identification of individuals who developed incident ASCVD, had evidence of coronary artery calcium, or had both compared with the National Cholesterol Education Program’s 2004 Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines. As expected, among 2435 statin-naive people, the new Pooled Cohort Equation led to many more people being eligible for statin therapy (39% for ACC/AHA guidelines vs 14% for ATP III guidelines). However, the newly statin-eligible people were at markedly increased risk for experiencing clinical events, for having elevated levels of coronary calcium, or for having both. These findings offer assurance that the 2013 Pooled Cohort Equation can efficiently and appropriately identify those destined to develop a major ASCVD event in the near future. However, identifying those at risk with reasonable accuracy is only part of the decision-making process. An imporRelated articles pages 134 and 142 Opinion

Randomized clinical trials remain the most reliable means of identifying the drugs, devices, and treatment strategies that will improve human health. There is increasing interest in the possibility that “personalized” medicine can be evaluated in much smaller trials because the average treatment effect is expected to be larger in highly selected cohorts. Smaller, biomarkerdriven trials can provide major insights into whom to treat and may be sufficient for selected disease states in which considerable treatment effects may be observed. However, a precise biological understanding of most chronic illnesses and biomarkers that might predict response has eluded investigators. Moreover, treatment effect sizes in chronic conditions are expected to be modest in most cases. As a result, determining the long-term balance of risk and benefit, particularly in comparative effectiveness trials, often requires large numbers of clinical events in representative populations. The conduct of large trials by government agencies, industry sponsors, academicians, and advocacy groups is limited by complexity and cost. As a result, many trials are too small to provide reliable estimates of the risk-benefit balance. Without adequate trials, clinicians will have insufficient guidance on how to meaningfully affect individual and population health. Achieving the “triple aim” (improving patient experience of care, improving health of populations, and reducing per

Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient-centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes.

Verification bias occurs when test findings influence the decision to perform a gold standard test. It adversely influences diagnostic test accuracy by inflating sensitivity and deflating specificity. We studied the impact of verification bias on the estimated accuracy of a test commonly used in suspected lung cancer.We studied 534 consecutive patients referred for [(18)F]fluorodeoxyglucose uptake by positron emission tomography (PET). Primary outcomes were tissue diagnoses of cancer and of mediastinal lymph node metastases. A secondary outcome was 3-year mortality. We accounted for verification bias using 2 validated methods.The gold standard test, namely tissue acquisition, was performed in 419 patients (78%); mediastinal lymph node sampling occurred in 301 (56%). While the 410 patients with PET-diagnosed stage I cancer or higher were more likely than patients with negative PET scan findings to undergo tissue diagnosis testing (92% vs 34%) (P.001), there was no association between PET findings and performance of mediastinal sampling. Without accounting for verification bias, the sensitivity and specificity of PET for diagnosis of cancer were 0.95 (95% confidence interval [CI], 0.92-0.97) and 0.31 (95% CI, 0.21-0.42), respectively. After adjustment, sensitivity fell to 0.85 (95% CI, 0.81-0.89), while specificity increased to 0.51 (95% CI, 0.40-0.60). For diagnosis of mediastinal disease, verification bias had slight effects on test accuracy. There were 224 deaths, with a strong gradient between PET stage and death (P.001).The diagnostic accuracy of PET for assessment of suspected lung cancer is substantially affected by verification bias.

ContextLower socioeconomic status (SES) confers heightened cardiovascular risk and mortality, although the mediating pathways are unclear.ObjectiveTo evaluate the extent to which exercise physiologic characteristics account for the association between lower SES and mortality.Design, Setting, and ParticipantsProspective cohort study of 30 043 consecutive patients living in 7 counties in northeast Ohio referred between 1990 and 2002 for symptom-limited stress testing for evaluation of known or suspected coronary artery disease. Follow-up for mortality continued through February 2004.Main Outcome MeasuresEstimated functional capacity in metabolic equivalents and heart rate recovery, physiologic characteristics that are determined directly from exercise; testing and all-cause mortality during a median follow-up of 6.5 years.ResultsMultivariable models adjusting for demographics, insurance status, smoking status, and clinical confounders demonstrated a strong association between a composite SES score based on census block data and functional capacity (adjusted odds ratio comparing 25th with 75th percentile values, 1.72; 95% confidence interval [CI], 1.56-1.89; P

More than 1100 articles now appear annually investigating "independent risk factors" or "independent predictors" for various clinical outcomes. In medical research, independence is generally defined in a statistical sense: a variable is called an independent risk factor if it has a significant contribution to an outcome in a statistical model that includes established risk factors. As such, independence is based on a specific statistical model and depends on the set of established risk factors included in that model. Even when strong statistical evidence indicates that a variable is an independent risk factor for an outcome, this does not necessarily indicate that the risk factor causally contributes to the outcome. The opposite is also true: risk factors that have causal relationships with the outcome will not necessarily prove to be independent risk factors. These are basic statistical principles that are too often given short shrift in medical research. Herein, we discuss the clinical implications conferred by the above definition of independence, primarily using examples from recent cardiovascular literature. A glossary and schema are provided to help clinicians and researchers understand and discuss these matters effectively.

Despite multiple randomized trials demonstrating their efficacy for the secondary prevention of coronary disease, lipid-lowering agents remain underused. Few studies have examined the relationship between predischarge initiation of lipid-lowering therapy and long-term use.Using data from patients at 69 centers from the United States and Canada enrolled in the Evaluation in PTCA to Improve Long-term Outcome With Abciximab GP IIb/IIIa Blockade (EPILOG) trial, we performed a retrospective propensity-analyzed cohort study. Patients underwent percutaneous coronary intervention for stable or recently unstable coronary disease and were older than 21 years, were not taking lipid-lowering therapy at the time of admission, and survived to hospital discharge; 175 were discharged taking lipid-lowering therapy and 1951 were not.After 6 months, 77% of patients who started taking lipid-lowering agents before hospital discharge continued taking therapy, compared with only 25% of those discharged without these agents (relative risk, 3.17; 95% confidence interval, 2.88-3.41; P.001). After restricting the analysis to propensity-matched patients (n = 477) and adjusting for other potential confounders, initiation of a lipid-lowering agent during hospitalization was the strongest independent predictor of use at 6 months (relative risk, 2.50; 95% confidence interval, 2.29-2.65; P.001).Inpatient initiation of lipid-lowering therapy is a strong and independent positive predictor of subsequent use, with patients who start taking lipid-lowering therapy before hospital discharge nearly 3 times as likely to be taking these agents 6 months later. Inpatient initiation of lipid-lowering therapy appears to be an effective strategy for bridging the gap between current medical knowledge and practice.

DURING THE PAST DECADE, THERE HAS BEEN TREMENdous progress in identifying novel risk factors and precisely delineating the role of traditional risk factors associated with coronary heart disease (CHD), with substantial research advances related to the role of lipoproteinsandlipidmetabolism.Observationalstudieshaveestablished the relationship of serum cholesterol and other lipoproteins with CHD in specific subgroups. Clinical trials have demonstrated convincing benefits of cholesterol lowering for reducing death and myocardial infarction among patients with CHD as well as beneficial effects of cholesterol lowering for decreasing the incidence of cardiac events in patients without established coronary disease. Accurately synthesizing and appropriatelyapplying this rapidlyaccumulatingevidence into clinicalpractice isessential for reducingthemorbidityandmortality associated with coronary disease. Thus, the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel (Adult Treatment Panel III [ATP III]) published in this issue of THE JOURNAL is most welcome. The NCEP expert panel, a multidisciplinary group that includes leading clinicians and researchers, provides a detailed summary of updated clinical guidelines for the detection, evaluation, and management of high blood cholesterol in adults. The Executive Summary is based on the comprehensive ATP III document, a more than 200-page detailed report that includes numerous tables and over 800 references, and in which the NCEP panel thoroughly evaluates current scientific information on cholesterol, applies a rigorous evidencebased framework, and carefully outlines the clinical and scientific rationale for the guidelines and recommendations. The marked increase in new information on lipoproteins thathasbecomeavailablesincepublicationofAdultTreatment Panel II in1993 has resulted inmanynewand important features in ATP III. Although the authors summarize some of the new features of the updated guidelines (in their Table 1), several aspects of the ATP III Report deserve special mention. First, among patients without clinical coronary disease, emphasis is placed on prospectively estimating absolute risk. Most clinical research literature reports relative risks with statements such as, “Patients with finding X were Y times more likely to have an event than patients without finding X.” Although this information is helpful, it is an important step away from actual clinical practice. Real physicians caring for real patients care about real, that is, absolute, risk. The important clinical question is, “What is this patient’s actual likelihood for developing disease?” In ATP III, patients with an absolute 10-year risk of .20% for developing clinical coronary disease are considered candidates for very aggressive therapy. This includes a lowdensity lipoprotein (LDL) cholesterol treatment goal of ,100 mg/dL and a recommendation to initiate drug therapy at an LDL level of .130 mg/dL. Patients with diabetes are also considered candidates for aggressive therapy, whether or not clinical coronary disease is present, because their absolute risk for major events is also very high. For patients with an estimated absolute risk of 10%-20%, somewhat less aggressive therapy is recommended, although the guidelines do suggest pharmacotherapy if needed to keep LDL levels ,130 mg/dL. To calculate absolute risk for developing new coronary disease, the ATP III Report presents a modification of the Framingham Risk Prediction Score. The scheme presented is slightly, but importantly, different from a previously published version in that it does not include diabetes, because diabetes is now considered a CHD equivalent rather than a risk factor. The scheme takes into account important interactions of age with smoking, age with total cholesterol, and systolic blood pressure with treatment. Despite the sophistication of the sex-specific models, these risk prediction–scoring instruments should be easy to incorporate into clinical practice. A second important feature of the ATP III Executive Summary is the inclusion of lipid abnormalities that go beyond elevated LDL cholesterol. The metabolic syndrome is a recently recognized constellation of findings thought to arise from insulin resistance and includes hypertension, abdominal obesity, hyperglycemia, elevated triglyceride levels, and low levels of high-density lipoprotein (HDL) cholesterol. Specific recommendations for treatment include weight control, physical activity, and a seemingly paradoxi

Objective. —To determine the relationship of varying degrees of obesity with left ventricular mass and geometry. Design. —Survey. Setting. —Population-based epidemiologic study. Participants and Methods. —M-mode echocardiograms, which were adequate for estimation of left ventricular mass, were obtained in 3922 healthy participants of the Framingham Heart Study. Measured height and weight were used to calculate body-mass index, a measure of obesity. Results. —Body-mass index was strongly correlated with left ventricular mass. After adjusting for age and blood pressure, body-mass index remained a strong independent predictor of left ventricular mass, left ventricular wall thickness, and left ventricular internal dimension ( P 2 . Conclusions. —Obesity is significantly correlated with left ventricular mass, even after controlling for age and blood pressure. The increase in left ventricular mass associated with increasing adiposity reflects increases in both left ventricular wall thickness and left ventricular internal dimension. ( JAMA . 1991;266:231-236)