Search

A previous report found an association of topic choice with race-based funding disparities among R01 applications submitted to the National Institutes of Health (‘NIH’) between 2011 and 2015. Applications submitted by African American or Black (‘AAB’) Principal Investigators (‘PIs’) skewed toward a small number of topics that were less likely to be funded (or ‘awarded’). It was suggested that lower award rates may be related to topic-related biases of peer reviewers. However, the report did not account for differential funding ecologies among NIH Institutes and Centers (‘ICs’). In a re-analysis, we find that 10% of 148 topics account for 50% of applications submitted by AAB PIs. These applications on ‘AAB Preferred’ topics were funded at lower rates, but peer review outcomes were similar. The lower rate of funding for these topics was primarily due to their assignment to ICs with lower award rates, not to peer-reviewer preferences.

Objective The Patient-Centered Outcomes Research Institute (PCORI) uses a unique approach to Merit Review that includes patients and stakeholders as reviewers with scientists, and includes unique review criteria (patient-centeredness and active engagement of end users in the research). This study assessed the extent to which different reviewer types influence review scores and funding outcomes, the emphasis placed on technical merit compared to other criteria by a multistakeholder panel, and the impact of the in-person discussion on agreement among different reviewer types. Methods Cross-sectional analysis of administrative data from PCORI online and in-person Merit Review (N = 1312 applications from the five funding cycles from November 2013 to August 2015). Linear and logistic regression models were used to analyze the data. Results For all reviewer types, final review scores were associated with at least one review criterion score from each of the three reviewer types. The strongest predictor of final overall scores for all reviewer types was scientists’ prediscussion ratings of technical merit. All reviewers’ prediscussion ratings of the potential to improve health care and outcomes, and scientists’ ratings of technical merit and patient-centeredness, were associated with funding success. For each reviewer type, overall impact scores from the online scoring were changed on at least half of the applications at the in-person panel discussion. Score agreement across reviewer types was greater after panel discussion. Conclusions Scientist, patient, and stakeholder views all contribute to PCORI Merit Review of applications for research funding. Technical merit is critical to funding success but patient and stakeholder ratings of other criteria also influence application disposition.

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

Randomized clinical trials and large-scale, cohort studies continue to have a critical role in generating evidence in cardiovascular medicine; however, the increasing concern is that ballooning costs threaten the clinical trial enterprise. In this Perspectives article, we discuss the changing landscape of clinical research, and clinical trials in particular, focusing on reasons for the increasing costs and inefficiencies. These reasons include excessively complex design, overly restrictive inclusion and exclusion criteria, burdensome regulations, excessive source-data verification, and concerns about the effect of clinical research conduct on workflow. Thought leaders have called on the clinical research community to consider alternative, transformative business models, including those models that focus on simplicity and leveraging of digital resources. We present some examples of innovative approaches by which some investigators have successfully conducted large-scale, clinical trials at relatively low cost. These examples include randomized registry trials, cluster-randomized trials, adaptive trials, and trials that are fully embedded within digital clinical care or administrative platforms.

The recently updated US National Institutes of Health clinical trials policies will apply broadly to studies involving experimental manipulations of humans. These studies will require registration and reporting in ClinicalTrials.gov, grant application submission under a clinical trials funding opportunity announcement, and Good Clinical Practice training for investigators.

At this year’s State of the Union address, the President announced a new $215 million Precision Medicine Initiative in the 2016 budget that will pioneer a new model of patient-empowered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients [1, 2]. Concurrently, Directors of the National Institutes of Health and the National Cancer Institute, Drs. Francis Collins and Harold Varmus, respectively, published an article in the New England Journal of Medicine that describes two main components of this initiative, a near-term focus on cancer therapy and a longer-term effort to generate knowledge applicable to a wide range of health and disease [3]. This longer-term initiative seeks to generate a cohort of one million or more Americans to “enable better assessment of disease risk, understanding of disease mechanisms, and the prediction of optimal therapy for many more diseases, with the goal of expanding the benefits of precision medicine into myriad aspects of health and healthcare” [3]. Matching treatment to the unique biological, behavioral, or environmental characteristics of the individual is nothing new. Matching blood type for transfusions has been common practice for nearly a century [4]. The guidelines for the management of cholesterol have been based on individual patient factors for over a decade [5]. Tailored behavioral interventions have been evaluated for over two decades. Although early treatment matching studies were disappointing [6], tailored behavioral interventions, especially computerized tailored interventions, have generally been found more efficacious than untailored interventions [7, 8]. The concept of precision medicine is not new, but recent advances in genome sequencing, cohort study designs, health informatics, and mobile/wireless technologies make now an opportune time for a large precision medicine cohort initiative.

Imagine a world where we are able to prevent and pre-empt the burden of cardiovascular, lung, and blood diseases, a world where we are able to capture the promise of personalized precision medicine, where each person receives the right treatment, tailored to his or her needs, at the right time. In

Objectives The Patient-Centered Outcomes Research Institute (PCORI) includes patients and stakeholders alongside scientists in reviewing research applications using unique review criteria including patient-centeredness and patient and/or stakeholder engagement. To support extension of this unique collaborative model to other funders, information from the reviewers on the review process is needed to understand how scientists and nonscientists evaluate research proposals together. Thus, this study aimed to describe reviewers' perspectives of the interactions during the in-person review panel; to examine the value and challenges of including scientists, patients, and stakeholders together; and to understand the perceived importance of PCORI's review criteria. Methods This study utilized anonymous, cross-sectional surveys (N = 925 respondents from 5 funding cycles: 470 scientists, 217 patients, 238 stakeholders; survey completion rates by cycle: 70–89%) and group interviews (N = 18). Results Reviewers of all types describe PCORI Merit Review as respectful, balanced, and one of reciprocal influence among different reviewer types. Reviewers indicate strong support and value of input from all reviewer types, receptivity to input from others, and the panel chair's incorporation of all views. Patients and stakeholders provide real-world perspectives on importance to patients, research partnership plans, and study feasibility. Challenges included concerns about a lack of technical expertise of patient/stakeholder reviewers and about scientists dominating conversations. The most important criterion for assigning final review scores was technical merit—either alone or in conjunction with patient-centeredness or patient/ stakeholder engagement. Conclusions PCORI Merit Reviewers' self-reports indicate that the perspectives of different reviewer types are influential in panel discussions and Merit Review outcomes.

Rationale : Funding decisions for cardiovascular R01 grant applications at the National Heart, Lung, and Blood Institute (NHLBI) largely hinge on percentile rankings. It is not known whether this approach enables the highest impact science. Objective : Our aim was to conduct an observational analysis of percentile rankings and bibliometric outcomes for a contemporary set of funded NHLBI cardiovascular R01 grants. Methods and Results : We identified 1492 investigator-initiated de novo R01 grant applications that were funded between 2001 and 2008 and followed their progress for linked publications and citations to those publications. Our coprimary end points were citations received per million dollars of funding, citations obtained Conclusions : In a large cohort of NHLBI-funded cardiovascular R01 grants, we were unable to find a monotonic association between better percentile ranking and higher scientific impact as assessed by citation metrics.

To the editor: The National Heart, Lung, and Blood Institute (NHLBI) community has established a long legacy of research success, resulting in dramatic improvements in longevity and quality of life. To continually advance its mission of research that enhances public health, the NHLBI is embarking

From the Office of Special Projects of the Division of Cardiovascular Sciences (D.G., W.T.-P., A.M.), Office of Science and Technology (M.A.), the Clinical Applications and Prevention Branch of the Division of Cardiovascular Sciences (P.G.K.), and Office of the Director of the Division of Cardiovascular Sciences (M.S.L.) — all at the National Heart, Lung, and Blood Institute, Bethesda, MD. Address reprint requests to Dr. Lauer at 6701 Rockledge Dr., Rm. 8128, Bethesda, MD 20892, or at

Translation of medical evidence into practice has not kept pace with the growth of medical technology and knowledge. We present three case studies – statins, drug eluting stents and bone marrow transplantation for breast cancer – to propose a framework for describing five factors that may influence the rate of adoption. The factors are: validity, reliability and maturity of the science available before widespread adoption; communication of the science; economic drivers; patients’ and physicians’ ability to apply published scientific findings to their specific clinical needs; and incorporation into practice guidelines.

To inform the retirement of NIH-owned chimpanzees, we analyzed the outcomes of 764 NIH-owned chimpanzees that were located at various points in time in at least one of 4 specific locations. All chimpanzees considered were alive and at least 10 years of age on January 1, 2005; transfers to a federal sanctuary began a few months later. During a median follow-up of just over 7 years, there were 314 deaths. In a Cox proportional hazards model that accounted for age, sex, and location (which was treated as a time-dependent covariate), age and sex were strong predictors of mortality, but location was only marginally predictive. Among 273 chimpanzees who were transferred to the federal sanctuary, we found no material increased risk in mortality in the first 30 days after arrival. During a median follow-up at the sanctuary of 3.5 years, age was strongly predictive of mortality, but other variables – sex, season of arrival, and ambient temperature on the day of arrival – were not predictive. We confirmed our regression findings using random survival forests. In summary, in a large cohort of captive chimpanzees, we find no evidence of materially important associations of location of residence or recent transfer with premature mortality.

Comparative effectiveness research (CER) aims to provide decision makers with the evidence needed to evaluate the benefits and harms of alternative clinical management strategies. CER has become a national priority, with considerable new research funding allocated. Cardiovascular disease is a priority area for CER. This workshop report provides an overview of CER methods, with an emphasis on practical clinical trials and observational treatment comparisons. The report also details recommendations to the National Heart, Lung, and Blood Institute for a new framework for evidence development to foster cardiovascular CER, and specific studies to address 8 clinical issues identified by the Institute of Medicine as high priorities for cardiovascular CER.

Comparative effectiveness research (CER) is the study of existing treatments or ways to deliver health care to determine what intervention works best under specific circumstances. CER evaluates evidence from existing studies or generates new evidence, in different populations and under specific conditions in which the treatments are actually used. CER does not embrace one research design over another but compares treatments and variations in practice using methods that are most likely to yield widely generalizable results that are directly relevant to clinical practice. Treatments used in transfusion medicine (TM) are among the most widely used in clinical practice, but are among the least well studied. High-quality evidence is lacking for most transfusion practices, with research efforts hampered by regulatory restrictions and ethical barriers. To begin addressing these issues, the National Heart, Lung, and Blood Institute convened a workshop in June 2011 to address the potential role of CER in the generation of high-quality evidence for TM decision making. Workshop goals were to: 1) evaluate the current landscape of clinical research, 2) review the potential application of CER methods to clinical research, 3) assess potential barriers to the use of CER methodology, 4) determine whether pilot or vanguard studies can be used to facilitate planning of future CER research, and 5) consider the need for and delivery of training in CER methods for researchers.

Over the past 50 years, we have seen dramatic changes in cardiovascular science and clinical care, accompanied by marked declines in the morbidity and mortality. Nonetheless, cardiovascular disease remains the leading cause of death and disability in the world, and its nature is changing as Americans become older, fatter, and ethnically more diverse. Instead of young or middle-aged men with ST-segment elevation myocardial infarction, the “typical” cardiac patient now presents with acute coronary syndrome or with complications related to chronic hypertension or ischemic heart disease, including heart failure, sudden death, and atrial fibrillation. Analogously, structural heart disease is now dominated by degenerative valve or congenital disease, far more common than rheumatic disease. The changing clinical scene presents cardiovascular scientists with a number of opportunities and challenges, including taking advantage of high-throughput technologies to elucidate complex disease mechanisms, accelerating development and implementation of evidence-based strategies, assessing evolving technologies of unclear value, addressing a global epidemic of cardiovascular disease, and maintaining high levels of innovation in a time of budgetary constraint and economic turmoil.

A few weeks ago Alberts et al published a PNAS Perspective with the attention-grabbing title “Rescuing US Biomedical Research From It Systematic Flaws.”(1) The authors noted that we suffer from “a severe imbalance between the dollars available for research and the still growing scientific community in United States.” At the National Institutes of Health (NIH), we are painfully aware of this, as over the past 10 years we have seen a steady decline in purchasing power, while the number of grant applications has increased and success rates have decreased. In 2000, while the NIH-doubling was still underway, 32% of R01 grant applications were funded; in 2013, that proportion had fallen to 17%.(2)

It is essential that the medical profession play a central role in critically evaluating the evidence related to drugs, devices, and procedures for the detection, management, or prevention of disease. Properly applied, rigorous, expert analysis of the available data documenting absolute and relative benefits and risks of these therapies and procedures can improve the effectiveness of care, optimize patient outcomes, and favorably affect the cost of care by focusing resources on the most effective strategies. One important use of such data is the production of clinical practice guidelines that, in turn, can provide a foundation for a variety of other applications, such as performance measures, appropriate use criteria, clinical decision support tools, and quality improvement tools. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) have jointly engaged in the production of guidelines in the area of cardiovascular disease since 1980. The ACCF/AHA Task Force on Practice Guidelines (Task Force) is charged with developing, updating, and revising practice guidelines for cardiovascular diseases and procedures, and the Task Force directs and oversees this effort. Writing committees are charged with assessing the evidence as an independent group of authors to develop, update, or revise recommendations for clinical practice. Experts in the subject under consideration have been selected from both organizations to examine subject-specific data and write guidelines in partnership with representatives from other medical practitioner and specialty groups. Writing committees are specifically charged to perform a formal literature review; weigh the strength of evidence for or against particular tests, treatments, or procedures; and include estimates of expected health outcomes where data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that may influence the choice of tests or therapies are considered. When available, information from studies on cost is considered, but data on efficacy and clinical outcomes constitute …

Alice K. Jacobs, MD, FACC, FAHA, Chair, 2009–2011 Sidney C. Smith, Jr, MD, FACC, FAHA, Immediate Past Chair, 2006–2008 [⁎⁎⁎][1] Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect Nancy Albert, PhD, CCNS, CCRN Christopher E. Buller, MD, FACC[⁎⁎⁎][1] Mark A. Creager, MD, FACC

This document was developed by the American College of Cardiology Foundation (ACCF) Task Force on Clinical Expert Consensus Documents (ECDs) and cosponsored by the American College of Radiology (ACR), American Heart Association (AHA), American Society of Nuclear Cardiology (ASNC), North American

Thanks to the dedicated involvement of the communities it serves, the National Heart, Lung, and Blood Institute (NHLBI) completed development of a scientific working strategic plan in 2007 to guide its activities and initiatives over the next 5 to 10 years.1 The plan outlines a cross-cutting approach that identifies areas in which the NHLBI is well positioned to make major contributions through investigator-initiated research and through programs that enable and supplement investigator-initiated activities. Translational research—both from the bench to the bedside and from the bedside to the community—is strongly and specifically underscored throughout the plan. Here, we summarize NHLBI programs and efforts in translational research. Funding opportunities and early career advice for aspiring researchers have been presented previously in this series.2,3 The ultimate goal of biomedical research is to improve individual and public health by discovering new effective strategies for the maintenance of wellness and for the prevention and treatment of disease. The Institute of Medicine Clinical Research Roundtable identified 2 “translational blocks,” or obstacles, to the realization of tangible health benefits derived from original research.4 The first block, or T1, is “the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans.” The second block, or T2, is “the translation of results from clinical studies into everyday clinical practice and health decision making.” Some authorities divide T2 into 2 components: T2 includes guideline development, meta-analyses, and systematic reviews, whereas T3 includes dissemination and implementation research.5 Some commentators have argued that the National Institutes of Health (NIH) disproportionately funds T1 compared with T2/T3 and that there is a need for increased national commitments to T2/T3 (from this point referred to as T2).5,6 A recent survey of >3000 …

This document details the procedures and recommendations of the Goals and Metrics Committee of the Strategic Planning Task Force of the American Heart Association, which developed the 2020 Impact Goals for the organization. The committee was charged with defining a new concept, cardiovascular health , and determining the metrics needed to monitor it over time. Ideal cardiovascular health, a concept well supported in the literature, is defined by the presence of both ideal health behaviors (nonsmoking, body mass index 2 , physical activity at goal levels, and pursuit of a diet consistent with current guideline recommendations) and ideal health factors (untreated total cholesterol

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.

Background Abnormal microvolt T-wave alternans (MTWA) and low peak oxygen consumption (VO 2 ) both predict poor outcome in heart failure. However, their independent predictive properties have not been assessed in large-scale cohorts. Methods This was an observational prospective cohort study of 303 consecutive patients referred for metabolic stress testing. All had an ejection fraction ≤ 40% and were considered candidates for transplantation. The exercise laboratory did not collect MTWA data from patients with implanted pacemakers or defibrillators. The primary end point was a composite of all-cause death or United Network for Organ Sharing status 1 transplantation. Results During a 2.8-year period, there were 34 deaths and 17 transplantations. Patients with abnormal MTWA had a higher event rate of 23% (31 of 136) vs 12% (20 of 167), with an unadjusted hazard ratio (HR) of 1.90 (95% confidence interval [CI], 1.90–3.33; p = 0.03). The association remained significant after adjustment for 3 clinical variables (HR, 1.89; 95% CI, 1.05–3.39; p = 0.03). After adding peak VO 2 to the model, the association was no longer significant (adjusted HR, 1.18; 95% CI, 0.64–2.17, p = 0.60). After accounting for peak VO 2 and 28 other confounders in a matched propensity analysis, MTWA was not predictive (propensity-matched HR, 0.79; 95% CI, 0.37–1.66; p = 0.53). Conclusions These results confirm the association of abnormal MTWA with poor outcome amongst patients with impaired left ventricular systolic function. However, this association is markedly attenuated after accounting for peak VO 2 .

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.

ObjectivesWe sought to examine the short- and long-term outcomes of blood transfusion in patients presenting with ST-segment elevation myocardial infarction (STEMI).BackgroundThe short- and long-term consequences of blood transfusion in anemic patients with recent STEMI remain controversial.MethodsWe evaluated 30-day, 6-month, and 1-year all-cause mortality among 4,131 STEMI patients enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial. Patients were categorized according to whether they received a blood transfusion during hospitalization. Cox proportional hazards survival models with transfusion as a time-dependent covariate were conducted for the whole and for the propensity-matched groups. Additionally, a series of sensitivity analyses assessed the magnitude of hidden bias that would need to be present to explain the associations actually observed.ResultsDeath at 30 days (13.7% vs. 5.5%), 6 months (19.7% vs. 6.9%), and 1 year (21.8% vs. 8.7%) was significantly higher for transfused patients than for nontransfused patients, respectively. After adjusting for over 25 baseline characteristics, nadir hemoglobin, and propensity score for transfusion, and using transfusion as a time-dependent covariate, transfusion remained significantly associated with increased risk of mortality at 30 days (hazard ratio [HR]: 3.89, 95% confidence interval [CI]: 2.66 to 5.68, p < 0.001), 6 months (HR: 3.63, 95% CI: 2.67 to 4.95, p < 0.001), and 1 year (HR: 3.03, 95% CI: 2.25 to 4.08, p < 0.001). Similar results were observed in the propensity-matched patients.ConclusionsBlood transfusion is associated with increased short- and long-term mortality in the setting of STEMI.

The increasing availability of personal genomic tests has led to discussions about the validity and utility of such tests and the balance of benefits and harms. A multidisciplinary workshop was convened by the National Institutes of Health and the Centers for Disease Control and Prevention to review the scientific foundation for using personal genomics in risk assessment and disease prevention and to develop recommendations for targeted research. The clinical validity and utility of personal genomics is a moving target with rapidly developing discoveries but little translation research to close the gap between discoveries and health impact. Workshop participants made recommendations in five domains: (1) developing and applying scientific standards for assessing personal genomic tests; (2) developing and applying a multidisciplinary research agenda, including observational studies and clinical trials to fill knowledge gaps in clinical validity and utility; (3) enhancing credible knowledge synthesis and information dissemination to clinicians and consumers; (4) linking scientific findings to evidence-based recommendations for use of personal genomics; and (5) assessing how the concept of personal utility can affect health benefits, costs, and risks by developing appropriate metrics for evaluation. To fulfill the promise of personal genomics, a rigorous multidisciplinary research agenda is needed. Genet Med 2009:11(8):559-567.

The International Classification of Diseases, Tenth Revision, defines sudden cardiac death (SCD) as death due to any cardiac disease that occurs out of hospital, in an emergency department, or in an individual reported dead on arrival at a hospital. In addition, death must have occurred within 1

Meta-analyses showed that exercise training decreased mortality in patients after myocardial infarction, but no single adequately powered trial has shown this benefit. The purpose of this study was to evaluate the effect of cardiac rehabilitative exercise training on prognostic variables derived from the exercise tolerance test and whether these changes had an effect on predicted cardiovascular and all-cause mortality using externally validated risk scores. Two hundred ten consecutive patients who completed a 12-week cardiac rehabilitation program were analyzed. Peak MET level, heart rate recovery, chronotropic index, Duke prognostic score, and Cleveland Clinic Foundation risk score obtained at program entry and exit were compared. All prognostic variables and risk score-derived predicted 5-year mortality rates improved significantly after cardiac rehabilitation. Exercise capacity increased by 32% (6.6 +/- 2.7 to 8.7 +/- 2.9 METS; p0.0001), heart rate recovery increased by 20% (15 +/- 9 to 18 +/- 10 beats/min; p0.0001), and chronotropic index increased by 11% (56 +/- 22% to 62 +/- 22%; p0.0001). Duke prognostic score 5-year predicted cardiovascular mortality rate decreased by 33% (6 +/- 4% to 4 +/- 2%; p0.0001), and Cleveland Clinic Foundation risk score 5-year predicted total mortality rate decreased by 40% (5 +/- 7% to 3 +/- 5%; p0.0001). These improvements remained significant in high-risk subgroups. When controlled for age, gender, diabetes, MET level achieved, ejection fraction, and beta-blocker use, changes remained significant (p0.0001) for each outcome measure. In conclusion, exercise training in supervised cardiac rehabilitation programs significantly improved exercise capacity, measures of chronotropic dynamics, and prognostic risk scores. These differences translate into a decrease in predicted mortality.

Recent clinical trials found that, compared with an angiotensin-converting enzyme inhibitor, angiotensin-receptor blocker and neprilysin inhibitor combination therapy decreased cardiovascular morta...

Background— Quantitative ECG measures of left ventricular mass and repolarization predict outcome in population-based cohorts and patients with hypertension. We assessed the prognostic value of preoperative quantitative electrocardiography in patients who underwent isolated coronary artery bypass grafting. Methods and Results— For 6 years we followed 8166 patients who underwent primary isolated coronary artery bypass grafting between 1990 and 2003, all of whom had routine preoperative ECGs. With use of specialized digital software, quantitative measures were recorded on ventricular rate, P duration, PR interval, QRS duration, QT interval, QRS axis, Sokolow-Lyon and Cornell voltages, and ST-segment depression and slope. There were 1516 deaths. After adjustment for age, gender, clinical characteristics, left ventricular ejection fraction, and other confounders, death was independently predicted by ventricular rate (adjusted hazard ratio [AHR] for 90 versus 60 beats per minute, 1.34; 95% confidence interval [CI], 1.21 to 1.50; P P P P P Conclusions— Quantitative ECG measures of left ventricular rate, mass, and repolarization are predictive of mortality among patients who underwent isolated coronary artery bypass grafting. These findings suggest that quantitative electrocardiography may be valuable for risk stratification in patients with severe coronary artery disease.

AIM: To examine the association of left ventricular hypertrophy (LVH) on admission electrocardiography with adverse outcomes in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: A total of 7443 non-ST-elevation ACS patients in Global Utilization of STrategies to Open occluded arteries (GUSTO) IV ACS trial had admission electrocardiograms analysed at a core laboratory. LVH [>or=20 mm Cornell voltage (LV voltage) (women) or >or=28 mm (men) plus strain patterns] was observed in 586 (7.9%) patients, and women accounted for 74%. LVH patients were also older and had more co-morbidities, ST-depression >or= 0.5 mm, elevated C-reactive protein and N-terminal pro-brain naturetic peptide (NT-proBNP), and lower troponin T. Invasive procedures occurred less often in LVH patients (cardiac catheterization: 31 vs. 38%, P = 0.001; percutaneous coronary intervention: 12 vs. 20%, P < 0.001). Mortality was significantly higher in patients with LVH (30 day: 5 vs. 3%, P = 0.046; 1 year: 14 vs. 7%, P < 0.001), whereas 30 day myocardial infarction (MI) and death/MI did not differ. After baseline adjustment including NT-proBNP, LVH remained associated with increased hazard of 1 year mortality in women, but not in men [P-interaction = 0.033; women: adjusted hazard ratio (LVH vs. no LVH): 1.42 (1.04-1.94), P = 0.029]. CONCLUSION: Electrocardiographic-LVH identifies an important subset of ACS patients with a higher risk of long-term mortality, particularly among women. These novel findings highlight opportunities to improve treatment and outcome among similar ACS patients. Udgivelsesdato: 2007-Sep

Although peak oxygen consumption (VO(2)) during exercise is frequently used to help predict optimal timing for heart transplantation, its long-term prognostic value in women is not known. We followed 2,105 adult patients with heart failure (HF) and with impaired left ventricular (LV) systolic function for 5 years, including 525 women (25%) who underwent metabolic stress testing between January 1995 and December 2002. Multivariable proportional hazards modeling related VO(2) to survival with adjustments for30 confounders and with transplantation considered as a time-dependent covariate. During follow-up, 129 women (26%) died, as did 572 men (36%). There were 175 transplants, including 34 women. Women and men were similar in age (54 vs 55 years), but women were less likely to have coronary artery disease (28% vs 58%). Peak VO(2) was strongly predictive of time to death in women (adjusted hazard ratio [HR] for peak VO(2) decreasing from 15 to 14 ml/kg/min, 1.11, 95% confidence interval [CI] 1.05 to 1.18, p0.0001) and in men (adjusted HR 1.12, 95% CI 1.08 to 1.16, p0.0001). There was no gender interaction with peak VO(2) (p = 0.80), but for any given peak VO(2) women were at lower risk (adjusted HR for men compared with women 2.22, 95% CI 1.58 to 3.10, p0.0001). A significant interaction was found between gender and presence of coronary artery disease (p for interaction 0.02); in women, those with ischemic cardiomyopathy had a worse survival for any given peak VO(2). In conclusion, in this large cohort, peak VO(2) predicted survival in women and men whether or not coronary artery disease was present, but an interaction was noted between coronary artery, gender, and survival.

ObjectivesThe aim of this work was to determine whether mitral valve (MV) annuloplasty benefits patients with moderate/severe (3+/4+) functional ischemic mitral regurgitation (MR) who undergo coronary artery bypass grafting (CABG).BackgroundMitral regurgitation is a strong predictor of poor outcomes in patients with ischemic cardiomyopathy; whether correcting it at the time of CABG improves outcomes is less certain.MethodsFrom 1991 to 2003, 390 patients with 3+/4+ ischemic MR had CABG with (n = 290) or without (n = 100) MV annuloplasty. Groups were propensity-matched using demographics, extent of coronary disease, regional wall motion, and quantitative electrocardiography. Survival, echocardiographic severity of MR, and New York Heart Association (NYHA) functional class were compared.ResultsOne-, 5-, and 10-year survival was 88%, 75%, and 47% after CABG alone and 92%, 74%, and 39% after CABG + MV annuloplasty (p = 0.6). Mortality was increased in patients with severe lateral wall motion abnormalities (p = 0.05), ST-segment elevation in lateral leads (p < 0.004), and higher QRS voltage sum (p < 0.0001). Patients undergoing CABG alone were more likely to have 3+/4+ postoperative MR than those undergoing CABG + MV annuloplasty (48% vs. 12% at 1 year, p < 0.0001). The NYHA functional class substantially improved in both groups (p < 0.001) and remained improved; at 5 years, 23% of patients having CABG + mitral annuloplasty and 25% having CABG alone were in NYHA functional class III/IV.ConclusionsAlthough CABG + MV annuloplasty reduces postoperative MR and improves early symptoms compared with CABG alone, it does not improve long-term functional status or survival in patients with severe functional ischemic MR. The MV annuloplasty in this setting, without addressing fundamental ventricular pathology, is insufficient to improve long-term clinical outcomes.

An entity of patients with mixed physiology of constriction and restriction has been reported, however, the characteristics of these patients have not been well documented. We evaluated the clinical features and the outcome of these patients.Study subjects consisted of 38 patients (57+/-14 years, 8 females, 30 males) who were diagnosed as having mixed physiology based on transthoracic and/or transesophageal echocardiography, MRI (or CT), cardiac catheterization, endomyocardial biopsy and/or surgical findings. Prior radiation therapy was the most frequent (50%) cause of mixed physiology followed by coronary artery bypass graft without prior radiation (24%) and heart transplantation (8%). The respiratory variation of peak early diastolic transmitral flow velocity by pulsed Doppler transesophageal echocardiography was 10.7% in patients with sinus rhythm and 18.1% in patients with atrial arrhythmia. Pericardial thickening was noted adjacent to the right-sided chambers in 19 patients, left-sided chambers in 10 patients, or both in 9 patients. All-cause 5-year mortality was 40% and unrelated to age, etiology, left ventricular systolic function and therapeutic course. There was a statistically significant difference (p0.01) between the survival rates in patients with mixed physiology and in patients with pure constriction (n=125).Due to the high mortality in this disease, discrimination of the entity from the patients with pure constriction is mandatory. Transthoracic and transesophageal echocardiography are helpful noninvasive techniques in the diagnosis and the understanding of the physiology of patients with mixed constriction and restriction.

Objectives We examined the safety and efficacy of nonculprit multivessel compared with culprit-only stenting in patients with multivessel disease presenting with unstable angina or non–ST-segment elevation myocardial infarction (non–ST-segment elevation acute coronary syndromes [NSTE-ACS]). Background In patients presenting with NSTE-ACS, multivessel coronary artery disease (CAD) is associated with adverse outcome. Methods Patients with multivessel CAD and NSTE-ACS that underwent percutaneous coronary intervention were included. The culprit lesion was defined by reviewing each patient’s angiographic report, electrocardiogram, echocardiogram and, if available, nuclear stress test. All patients had at least 2 vessels with ≥50% stenosis, and the angiographic severity of CAD was assessed using the Duke Prognostic Angiographic Score. Patients with coronary bypass grafts, chronic total occlusions, and those with uncertain culprit lesions were excluded. Our end point was the composite of death, myocardial infarction, or any target vessel revascularization. Results From January 1995 to June 2005, 1,240 patients with ACS and multivessel CAD underwent percutaneous coronary intervention with bare-metal stenting and met our study criteria. Of these, 479 underwent multivessel and 761 underwent culprit-only stenting. There were 442 events during a median follow-up of 2.3 years. Multivessel intervention was associated with lower death, myocardial infarction, or revascularization after both adjusting for baseline and angiographic characteristics (hazard ratio 0.80; 95% confidence interval 0.64 to 0.99; p = 0.04) and propensity matched analysis (hazard ratio 0.67; 95% confidence interval 0.51 to 0.88; p = 0.004). Conclusions In patients with multivessel CAD presenting with NSTE-ACS, multivessel intervention was significantly associated with a lower revascularization rate, which translated to a lower incidence of the composite end point compared with culprit-only stenting.

Preamble......379 Introduction......380 Consensus Statement Method......380 Introduction to CAC Measurement......381 Role of Risk Assessment in Cardiovascular Medicine......381 Matching Intensity of Intervention With Severity of Risk......382 Current Approaches to Global Risk Assessment and to

Background We previously demonstrated that cardiovascular (CV) trials funded by the National Heart, Lung, and Blood Institute ( NHLBI ) were more likely to be published in a timely manner and receive high raw citation counts if they focused on clinical endpoints. We did not examine the metrics of trial reports, and our citation measures were limited by failure to account for topic‐related citation behaviors. Methods and Results Of 244 CV trials completed between 2000 and 2011, we identified 184 whose main results were published by August 20, 2014. One investigator who was blinded to rapidity of publication and citation data read each publication and characterized it according to modified Delphi criteria. There were 46 trials (25%) that had Delphi scores of 8 or 9 (of a possible 9); these trials published faster (median time from trial completion to publication, 12.6 [interquartile range { IQR }, 6.7 to 23.3] vs. 21.8 [ IQR , 12.1 to 34.9] months; P IQR , 0.64 to 7.83] vs. 8.41 [ IQR , 1.80 to 24.75]; P =0.002). By random forest regression, we found that the 3 most important predictors of normalized citation percentile values were total costs, intention‐to‐treat analyses (as a modified Delphi quality measure), and focus on clinical (not surrogate) endpoints. Conclusions NHLBI CV trials were more likely to publish results quickly and yield higher topic‐normalized citation impact if they reported results according to well‐defined metrics, along with focus on clinical endpoints.

Aims To determine whether the presence and severity of aortic atheroma predict long-term all-cause mortality among patients undergoing cardiac surgery. Methods and results We followed 8581 patients who underwent cardiac surgery and had routine intraoperative transoesophageal echocardiography for 2.8 years (range 0.06–6.0 years). Data regarding multiple potential confounders were prospectively collected and electronically recorded. There were 2878 (34%) patients with no atheroma; 4129 (48%) patients with mild atheroma; 1215 (14%) with moderate atheroma; and 359 (4%) with severe atheroma. There were 1000 deaths. Death rates were increased in patients with moderate [relative risk (RR) 3.29, 95% CI 2.50–4.32, P < 0.0001) and severe atheroma (RR 5.21, 95% CI 3.65–7.41, P < 0.0001). After adjusting for multiple other confounders, severe atheroma remained modestly predictive of risk (adjusted RR 1.46, 95% CI 1.07–2.00, P = 0.02); but moderate atheroma and mild atheroma were not predictive of increased risk. In a propensity analysis that matched patients with comparable range of variables, severe atheroma was no longer predictive of risk (adjusted RR 1.39, 95% CI 0.87–2.23, P = 0.17). Conclusion Our study shows that severe atheroma is associated with increased long-term mortality in patients undergoing cardiac surgery; however, the relationship is weak using propensity analysis, suggesting no causal association.

Exercise testing remains the most widely accessible and relatively inexpensive method for initial evaluation of suspected coronary disease and for evaluation of its severity.1–3 Clinical usefulness has been limited, however, by poor sensitivity of standard ST-segment depression criteria for assessment of anatomic and functional coronary disease severity and for prediction of risk.1,2,4–6 Recent data make it clear that symptomatic obstructive plaques that typically result in exercise-mediated ischemia may be less relevant to infarction and sudden death than less obstructive unstable plaques.7 These limitations mandate a rethinking of the exercise ECG along 2 distinct lines: First, is it possible to improve the diagnostic value of the exercise ECG? Second, separate from its ability to diagnose obstructive coronary artery lesions, can the exercise test be used as a prognostic tool that can encourage effective prevention of premature deaths or coronary events? Both goals take us beyond the ST segment. Reversible ST-segment depression is the characteristic finding associated with exercise-induced, demand-driven ischemia in patients with significant coronary obstruction but no flow limitation at rest. This process differs from the flow-limited acute coronary syndromes because exercise-related ischemia is generally limited to the subendocardium and is proportional to increases in myocardial oxygen demand. Ventricular waveforms of the ECG can be related to the net uncanceled transmural gradients between endocardial and epicardial myocardium, as extrapolated from the work of Holland and Brooks, among others.8–10 Accordingly, isoelectric TQ and ST segments in normal and in nonischemic patients can be related to comparable resting membrane and action potential plateau voltages in endocardial and epicardial action potentials. During exercise, progressive ischemia results in changing endocardial action potentials during both diastole and systole. Less negative endocardial cell resting membrane potential leads to current flow across the ischemic boundary during diastole, leading to elevation of the TQ …

OBJECTIVES The purpose of this study was to develop 30-day and 1-year risk stratification models for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients that incorporate quantitative ST-segment depression and novel biomarkers. BACKGROUND Several novel biomarkers have changed the risk profile of ACS; thus, the reassessment of traditional indicators such as ST-segment depression in this new context is warranted. METHODS Multivariable logistic regression was used to identify significant predictors of 30-day death and death/myocardial infarction (MI) and 1-year mortality in 7,800 NSTE-ACS patients enrolled in the GUSTO-IV (Global Utilization of Strategies to Open Occluded Arteries-IV ACS) trial between 1998 and 2000. RESULTS Among all other predictors, the degree of ST-segment depression had the highest prognostic value for 30-day death, 30-day death/MI, and 1-year death. Troponin T (TnT), creatinine clearance, N-terminal pro-brain natriuretic peptide (NT-proBNP), heart rate, and age were also highly influential on adverse outcomes. Unlike TnT and NT-proBNP, C-reactive protein was only predictive of long-term death. In contrast to mortality, the contribution of TnT to predicting 30-day death/MI increased, whereas NT-proBNP's role was attenuated. The discriminatory power was excellent (c-index [adjusted for over-optimism]: 0.82 [30-day death]; 0.72 [30-day death/MI]; 0.81 [1-year]). CONCLUSIONS In this large contemporary study of NSTE-ACS patients, novel insights into risk stratification were observed-in particular, the utility of quantitative ST-segment depression and multiple biomarkers. Collection of these indicators in future NSTE-ACS populations is recommended to evaluate generalizability and clinical application of these findings.

Objectives: Exercise-induced QT/RR hysteresis exists when, for a given R-R interval, the QT interval duration is shorter during recovery after exercise than during exercise. We sought to assess the association between QT/RR hysteresis and imaging evidence of myocardial ischemia.Background: Because ischemia induces cellular disturbances known to decrease membrane action potential duration, we hypothesized a correlation between QT/RR and myocardial ischemia.Methods: We digitally analyzed 4-second samples of QT duration and R-R–interval duration in 260 patients referred for treadmill exercise stress and rest single photon emission computed tomography myocardial perfusion imaging; a cool-down period was used after exercise. None of the patients were in atrial fibrillation or used digoxin, and none had marked baseline electrocardiographic abnormalities. Stress and rest myocardial perfusion images were analyzed visually and quantitatively to define the extent and severity of stress-induced ischemia. QT/RR hysteresis was calculated using a computerized algorithm.Results: There were 82 patients (32%) who manifested myocardial ischemia by single photon emission computed tomography myocardial perfusion imaging. The likelihood of ischemia increased with increasing QT/RR hysteresis, with prevalence according to quartiles of 20%, 30%, 26%, and 49% (P = .003 for trend). In analyses adjusting for ST-segment changes, exercise capacity, heart rate recovery, and other confounders, QT/RR hysteresis was independently predictive of presence of myocardial ischemia (adjusted odds ratio for 100-point increase of QT/RR hysteresis, 1.61; 95% confidence interval, 1.22-2.12; P = .0008). QT/RR hysteresis was also predictive of severe ischemia.Conclusion: Exercise-induced QT/RR hysteresis is a strong and independent predictor of myocardial ischemia and provides additional information beyond that afforded by standard ST-segment measures.

Background— The clinical value of revascularization and other procedures in patients with severe systolic heart failure is unclear. It has been suggested that assessing ischemia and viability by positron emission tomography (PET) with fluorodeoxyglucose (FDG) imaging may identify patients for whom revascularization may lead to improved survival. We performed a propensity analysis to determine whether there might be a survival advantage from revascularization. Methods and Results— We analyzed the survival of 765 consecutive patients (age 64±11 years, 80% men) with advanced left ventricular systolic dysfunction (ejection fraction ≤35%) and without significant valvular heart disease who underwent PET/FDG study at the Cleveland Clinic between 1997 and 2002. Early intervention was defined as any cardiac intervention (surgical or percutaneous) within the first 6 months of the PET/FDG study. In the entire cohort, 230 patients (30%) underwent early intervention (188 [25%] had open heart surgery, most commonly coronary artery bypass grafting, and 42 [5%] had percutaneous revascularization); 535 (70%) were treated medically. Using 39 demographic, clinical and PET/FDG variables, we were able to propensity-match 153 of the 230 patients with 153 patients who did not undergo early intervention. Among the propensity-matched group, there were 84 deaths during a median of 3 years follow-up. Early intervention was associated with a markedly lower risk of death (3-year mortality rate of 15% versus 35%, propensity adjusted hazard ratio 0.52, 95% CI 0.33 to 0.81, P =0.0004). Conclusions— Among systolic heart failure patients referred for PET/FDG, early intervention may be associated with improved survival irrespective of the degree of viability.

Chronotropic incompetence, or an inability to increase heart rate during exercise, independently predicts death in patients not taking beta blockers. Whether it predicts death in patients taking beta blockers is not known. Consecutive patients (n = 3,736; mean age 58 +/- 11 years; 68% men), who were taking either metoprolol tartrate or atenolol and were referred for symptom-limited exercise testing from 1990 to 2002 at a major academic medical center, formed the prospective study cohort. None had heart failure, pacemakers, atrial fibrillation, or any electrocardiographic abnormalities. Patients were followed for a median of 4.5 years for all-cause mortality. Chronotropic response was defined as the percentage of heart rate reserve used. A value ofor =62%, which was noted in 813 patients (22%), was considered abnormal, meaning that chronotropic incompetence was present. There were 173 deaths. After adjusting for age, gender, heart rate at rest, standard risk factors, other medications, Duke treadmill score, and heart rate recovery, chronotropic incompetence predicted death (adjusted hazard ratio 1.94, 95% confidence interval 1.43 to 2.64, p0.0001). The association of chronotropic incompetence with death was present, irrespective of which drug was taken or the number of half-lives that had elapsed since the last dose. In conclusion, in patients taking beta blockers, chronotropic incompetence is independently predictive of death.

Along with coronary artery calcium scanning, ankle-brachial index measurement, and carotid artery ultrasound, exercise electrocardiography has been proposed as a screening tool for asymptomatic subjects thought to be at intermediate risk for developing clinical coronary disease. A wealth of data indicate that exercise testing can be used to assess and refine prognosis, particularly when emphasis is placed on nonelectrocardiographic measures such as exercise capacity, chronotropic response, heart rate recovery, and ventricular ectopy. Nevertheless, randomized trial data on the clinical value of screening exercise testing are absent; that is, it is not known whether a strategy of routine screening exercise testing in selected subjects reduces the risk for premature mortality or major cardiac morbidity. The writing group believes that a large-scale randomized trial of such a strategy should be performed.