Association of percentile ranking with citation impact and productivity in a large cohort of de novo NIMH-funded R01 grants.

Previous reports from National Institutes of Health and National Science Foundation have suggested that peer review scores of funded grants bear no association with grant citation impact and productivity. This lack of association, if true, may be particularly concerning during times of increasing competition for increasingly limited funds. We analyzed the citation impact and productivity for 1755 de novo investigator-initiated R01 grants funded for at least 2 years by National Institute of Mental Health between 2000 and 2009. Consistent with previous reports, we found no association between grant percentile ranking and subsequent productivity and citation impact, even after accounting for subject categories, years of publication, duration and amounts of funding, as well as a number of investigator-specific measures. Prior investigator funding and academic productivity were moderately strong predictors of grant citation impact.

Using exercise testing to prognosticate patients with heart failure. Which parameter should we measure?

Peak oxygen consumption, as measured by direct gas exchange analysis during exercise testing, is well established as a powerful and independent predictor of risk for death among patients with chronic, but stable, heart failure. Although there is still some debate about whether peak oxygen consumption should be indexed against a predicted value and what the best cut-off point may be, most authorities agree that peak oxygen consumption is such a powerful predictor of outcome that it routinely should be incorporated into the evaluation of all ambulatory heart transplant candidates. A few recent studies have demonstrated that a hyperventilatory response to exercise, as measured by the VE/VCO2 slope, also may be a powerful and independent predictor of death; however, more large studies, with large numbers of end-points, will be needed before this measure can deservedly take a place alongside peak oxygen consumption as a primary component of the heart failure staging process.

Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis.

BACKGROUND: Recent studies have supported the hypothesis that calcific aortic stenosis is the product of an active inflammatory process, with similarities to atherosclerosis. We sought to determine whether therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) might slow the progression of aortic stenosis. METHODS AND RESULTS: A retrospective study of 174 patients (mean age 68+/-12 years) with mild to moderate calcific aortic stenosis was conducted. Patients required normal left ventricular function, /=2 echocardiograms performed at least 12 months apart. Fifty-seven patients (33%) received treatment with a statin; the remaining 117 (67%) did not. The statin group was older and had a higher prevalence of hypertension, diabetes mellitus, and coronary disease. During a mean follow-up of 21 months, patients treated with statin had a smaller increase in peak and mean gradient and a smaller decrease in aortic valve area. When annualized, the decrease in aortic valve area for the nonstatin group was 0.11+/-0.18 cm(2) compared with 0.06+/-0.16 cm(2) for those treated with a statin (P=0.03). In multivariate analysis, statin usage was a significant independent predictor of a smaller decrease in valve area (P=0.01) and a lesser increase in peak gradient (P=0.02). CONCLUSIONS: Statin-treated patients, despite a higher risk profile for progression, had reduced aortic stenosis progression compared with those not treated with a statin. These data provide justification for a prospective randomized trial to substantiate whether statin therapy slows the progression of aortic stenosis.

Heart rate recovery immediately after treadmill exercise and left ventricular systolic dysfunction as predictors of mortality: the case of stress echocardiography.

BACKGROUND: An attenuated heart rate recovery after exercise has been shown to be predictive of mortality. In prior studies, recovery heart rates were measured while patients were exercising lightly, that is, during a cool-down period. It is not known whether heart rate recovery predicts mortality when measured in the absence of a cool-down period or after accounting for left ventricular systolic function. METHODS AND RESULTS: We followed 5438 consecutive patients without a history of heart failure or valvular disease referred for exercise echocardiography for 3 years. Heart rate recovery was defined as the difference in heart rate between peak exercise and 1 minute later; a value

Exercise electrocardiogram testing and prognosis. Novel markers and predictive instruments.

Ample evidence now exists supporting the use of the exercise test primarily for prognostic, as opposed to diagnostic, purposes. Although limitations must be recognized, the Duke exercise treadmill score, the chronotropic response to exercise, and heart rate recovery appear to function as powerful and independent predictors of risk. With the possible exception of exercise-induced ischemia, as manifested by the ST-segment and angina components of the Duke exercise treadmill score, exercise predictors of risk are not clearly modifiable. Nonetheless, they are clinically quite useful since they may well identify patients who are or are not likely to gain benefit from further testing and aggressive therapies. How so? The "plain old" exercise treadmill test makes it possible to easily, safely, and inexpensively identify a large group of patients who are at low risk for death or major cardiac events. For this reason alone, the predictive instruments described in this article should be routinely incorporated into clinical practice. It makes no sense to perform expensive and potentially risky diagnostic tests, prescribe polypharmacy, or institute invasive therapeutic procedures in patients who are already at low risk. As an example, Weiner and colleagues found that coronary bypass grafting only benefited CASS registry patients who had a high-risk exercise test result. Future research will be needed to further refine risk stratification with the exercise test, and determine how best to use adjunctive imaging studies and to reduce risk among patients with prognostically important findings.

Aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: A propensity analysis.

CONTEXT: Although aspirin has been shown to reduce cardiovascular morbidity and short-term mortality following acute myocardial infarction, the association between its use and long-term all-cause mortality has not been well defined. OBJECTIVES: To determine whether aspirin is associated with a mortality benefit in stable patients with known or suspected coronary disease and to identify patient characteristics that predict the maximum absolute mortality benefit from aspirin. DESIGN AND SETTING: Prospective, nonrandomized, observational cohort study conducted between 1990 and 1998 at an academic medical institution, with a median follow-up of 3.1 years. PATIENTS: Of 6174 consecutive adults undergoing stress echocardiography for evaluation of known or suspected coronary disease, 2310 (37%) were taking aspirin. Patients with significant valvular disease or documented contraindication to aspirin use, including peptic ulcer disease, renal insufficiency, and use of nonsteroidal anti-inflammatory drugs, were excluded. MAIN OUTCOME MEASURE: All-cause mortality according to aspirin use. RESULTS: During 3.1 years of follow-up, 276 patients (4.5%) died. In a simple univariable analysis, there was no association between aspirin use and mortality (4.5% vs 4.5%). However, after adjustment for age, sex, standard cardiovascular risk factors, use of other medications, coronary disease history, ejection fraction, exercise capacity, heart rate recovery, and echocardiographic ischemia, aspirin use was associated with reduced mortality (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.51-0.87; P =.002). In further analysis using matching by propensity score, 1351 patients who were taking aspirin were at lower risk for death than 1351 patients not using aspirin (4% vs 8%, respectively; HR, 0.53; 95% CI, 0.38-0.74; P =.002). After adjusting for the propensity for using aspirin, as well as other possible confounders and interactions, aspirin use remained associated with a lower risk for death (adjusted HR, 0.56; 95% CI, 0.40-0.78; P<.001). The patient characteristics associated with the most aspirin-related reductions in mortality were older age, known coronary artery disease, and impaired exercise capacity. CONCLUSION: Aspirin use among patients undergoing stress echocardiography was independently associated with reduced long-term all-cause mortality, particularly among older patients, those with known coronary artery disease, and those with impaired exercise capacity.

Incremental prognostic value of elevated baseline C-reactive protein among established markers of risk in percutaneous coronary intervention.

BACKGROUND: Established methods of risk assessment in percutaneous coronary intervention have focused on clinical and anatomical lesion characteristics. Emerging evidence indicates the substantial contribution of inflammatory processes to short-term and long-term outcomes in coronary artery disease. METHODS AND RESULTS: Within a single-center registry of contemporary percutaneous coronary revascularization strategies with postprocedural creatine kinase and clinical events routinely recorded, we assessed the association of baseline C-reactive protein with death or myocardial infarction within the first 30 days. Predictive usefulness of baseline C-reactive protein within the context of established clinical and angiographic predictors of risk was also examined. Among 727 consecutive patients, elevated baseline C-reactive protein before percutaneous coronary intervention was associated with progressive increase in death or myocardial infarction at 30 days (lowest quartile, 3.9%, versus highest quartile, 14.2%; P=0.002). Among clinical and procedural characteristics, baseline C-reactive protein remained independently predictive of adverse events, with the highest quartile of C-reactive protein associated with an odds ratio for excess 30-day death or myocardial infarction of 3.68 (95% CI, 1.51 to 8.99; P=0.004). A predictive model that included baseline C-reactive protein quartiles, American College of Cardiology/American Heart Association lesion score, acute coronary syndrome presentation, and coronary stenting appears strongly predictive of 30-day death or myocardial infarction within this population (C-statistic, 0.735) and among individual patients (Brier score, 0.006). CONCLUSIONS: Elevated baseline C-reactive protein portends heightened risk of 30-day death or myocardial infarction after coronary intervention. Coupled anatomic, clinical, and inflammatory risk stratification demonstrates strong predictive utility among patients undergoing percutaneous coronary intervention and may be useful for guiding future strategies.

Using aspirin and ACE inhibitors in combination: why the hullabaloo?

Observational studies indicate that aspirin may counteract the beneficial effect of angiotensin-converting enzyme (ACE) inhibitors, but the data are not yet sufficient for making firm recommendations. We review the available data and offer tentative conclusions.

Independent contribution of myocardial perfusion defects to exercise capacity and heart rate recovery for prediction of all-cause mortality in patients with known or suspected coronary heart disease.

OBJECTIVES: The goal of this study was to determine the value of thallium201 single photon emission computed tomography (SPECT) imaging for prediction of all-cause mortality when considered along with functional capacity and heart rate recovery. BACKGROUND: Myocardial perfusion defects identified by thallium201 SPECT imaging are predictive of cardiac events. Functional capacity and heart rate recovery are exercise measures that also have prognostic implications. METHODS: We followed 7,163 consecutive adults referred for symptom-limited exercise thallium SPECT (mean age 60 +/- 10, 25% women) for 6.7 years. Using information theory, we identified a probable best model relating nuclear findings to outcome to calculate a prognostic nuclear score. RESULTS: There were 855 deaths. Intermediate- and high-risk prognostic nuclear scores were noted in 28% and 10% of patients. Compared with those with low-risk scans, patients with an intermediate-risk score were at increased risk for death (14% vs. 9%, hazard ratio: 1.67, 95% confidence interval [CI]: 1.44 to 1.95, p < 0.0001), while those with high-risk scores were at greater risk (24%, hazard ratio: 2.98, 95% CI: 2.49 to 3.56, p < 0.0001). In multivariable analyses that adjusted for clinical characteristics, functional capacity and heart rate recovery, an intermediate-risk nuclear score remained predictive of death (adjusted hazard ratio: 1.50, 95% CI: 1.28 to 1.76, p < 0.0001), as did a high-risk score (adjusted hazard ratio: 2.76, 95% CI: 2.13 to 2.56, p < 0.0001). Impaired functional capacity and decreased heart rate recovery provided additional prognostic information. CONCLUSIONS: Myocardial perfusion defects detected by thallium SPECT imaging are independently predictive of long-term all-cause death, even after accounting for exercise capacity, heart rate recovery and other potential confounders.

Prediction of coronary artery disease in patients undergoing operations for mitral valve degeneration.

OBJECTIVES: We sought to develop and validate a model that estimates the risk of obstructive coronary artery disease in patients undergoing operations for mitral valve degeneration and to demonstrate its potential clinical utility. METHODS: A total of 722 patients (67% men; age, 61 +/- 12 years) without a history of myocardial infarction, ischemic electrocardiographic changes, or angina who underwent routine coronary angiography before mitral valve prolapse operations between 1989 and 1996 were analyzed. A bootstrap-validated logistic regression model on the basis of clinical risk factors was developed to identify low-risk (< or =5%) patients. Obstructive coronary atherosclerosis was defined as 50% or more luminal narrowing in one or more major epicardial vessels, as determined by means of coronary angiography. RESULTS: One hundred thirty-nine (19%) patients had obstructive coronary atherosclerosis. Independent predictors of coronary artery disease include age, male sex, hypertension, diabetes mellitus,and hyperlipidemia. Two hundred twenty patients were designated as low risk according to the logistic model. Of these patients, only 3 (1.3%) had single-vessel disease, and none had multivessel disease. The model showed good discrimination, with an area under the receiver-operating characteristic curve of 0.84. Cost analysis indicated that application of this model could safely eliminate 30% of coronary angiograms, corresponding to cost savings of $430,000 per 1000 patients without missing any case of high-risk coronary artery disease. CONCLUSION: A model with standard clinical predictors can reliably estimate the prevalence of obstructive coronary atherosclerosis in patients undergoing mitral valve prolapse operations. This model can identify low-risk patients in whom routine preoperative angiography may be safely avoided.

Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study.

BACKGROUND: Lipid-lowering agents are known to reduce long-term mortality in patients with stable coronary disease or significant risk factors. However, the effect of lipid-lowering therapy on short-term mortality immediately after an acute coronary syndrome has not been determined. We did an observational study using data from two randomised trials to investigate this issue. METHODS: We used data from the GUSTO IIb and PURSUIT trials to compare all-cause mortality among patients with acute coronary syndromes who were discharged on lipid-lowering agents (n=3653) with those who were not (n=17,156). A propensity analysis was done to adjust for presumed selection biases in the prescription of lipid-lowering agents. FINDINGS: Lipid-lowering therapy was associated with a smaller proportion of deaths at 30 days (17 [0.5%] vs 179 [1.0%], hazard ratio 0.44 [95% CI 0.27-0.73], p=0.001) and at 6 months (63 [1.7%] vs 605 [3.5%], 0.48 [0.37-0.63], p<0.0001). After adjustment for the propensity to be prescribed lipid-lowering agents and other potential confounders, prescription of a lipid-lowering agent at discharge remained associated with a reduced risk of death at 6 months (0.67 [0.48-0.95], p=0.023). INTERPRETATION: Prescription of a lipid-lowering drug at hospital discharge was independently associated with reduced short-term mortality among patients after an acute coronary syndrome.

A propensity analysis of cigarette smoking and mortality with consideration of the effects of alcohol.

Although it is well established that cigarette smoking causes excess mortality, the extent of the increased risk has been challenged because self-selection biases and confounding factors may not have been adequately accounted for in prior studies. We therefore performed a propensity analysis on a population-based cohort. A logistic regression model was used to generate a propensity score for current smoking in 6,099 adults (mean age 46 years, 54% men, 36% current smokers) participating in the National Heart Lung and Blood Institute's (NHLBI) Lipid Research Clinic Prevalence Study. During 12 years of follow-up, 513 subjects (8%) died. After adjusting for age, current smoking was strongly associated with death (compared with never and former smokers, relative risk [RR] 2.69, 95% confidence interval [CI] 1.98 to 0.64, p <0.0001 and RR 1.79, 95% CI 1.26 to 2.55, p = 0.001, respectively). After adjusting for a propensity score based on 27 covariates and the covariates themselves, current smoking remained strongly and independently predictive of excessive death risk in smokers compared with never and former smokers (adjusted RR 2.96, 95% CI 2.16 to 4.05, p <0.0001 and adjusted RR 1.87, 95% CI 1.31 to 2.67, p = 0.0006, respectively). Although smokers were more likely to also drink alcohol, an interaction was noted, whereby, after adjustment for propensity score and other covariates, current smoking was associated with a moderately strong increase in mortality among drinkers (adjusted RR 2.00, 95% CI 1.42 to 2.82, p <0.0001), but was also associated with a markedly increased death risk among nondrinkers (adjusted RR 4.74, 95% CI 3.24 to 6.92, p <0.0001). The independent association of smoking with death even after a rigorous propensity analysis argues that it is highly unlikely that the link between smoking and mortality is materially biased or confounded.

Prognostic importance of concomitant heparin with eptifibatide in acute coronary syndromes. PURSUIT Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy.

Platelet glycoprotein IIb/IIIa inhibitors have been extensively studied in the treatment of patients with ischemic heart disease. Data regarding the use of these agents in the absence of concomitant intravenous heparin have been conflicting. We sought to determine, using propensity analysis, whether the benefit of eptifibatide, a IIb/IIIa inhibitor, in the treatment of acute coronary syndromes is affected by the concurrent administration of heparin. By trial design, patients were randomized to either eptifibatide or placebo, whereas use of intravenous heparin was left to the discretion of treating physicians. The effect of eptifibatide on the 30-day composite end point of death or myocardial infarction was studied in patients who received heparin and those who did not. Propensity analysis methods were used to control for confounding and presumed selection biases. Among 5,576 patients who were receiving heparin when the bolus dose of the study drug was administered, eptifibatide was associated with a reduced composite end point rate (13%) compared with that of placebo (14.5% vs 16.6%, p = 0.03). In contrast, among 1,441 patients who were not receiving heparin, there was no difference in 30-day event rates with eptifibatide compared with placebo (13.7% vs 13.1%, p > 0.7). After a propensity score for use of heparin was developed, however, use of heparin did not affect the reduced risk associated with eptifibatide (adjusted relative risk [RR] for heparin-eptifibatide interaction term 0.90, 95% confidence interval [CI] 0.61 to 1.32, p > 0.5), but the propensity for heparin use was a strong predictor of events (adjusted RR 1.76, 95% CI 1.42 to 2.17, p < 0.001). The use of eptifibatide independently predicted a lower risk of events (adjusted RR 0.31, 95% CI 0.10 to 0.93, p = 0.04). Thus, the apparent positive impact of heparin on the benefits of eptifibatide therapy was largely due to confounding and bias.

Complete bundle branch block as an independent predictor of all-cause mortality: report of 7,073 patients referred for nuclear exercise testing.

PURPOSE: Complete left bundle branch block is a well-established independent risk factor for mortality, but the prognostic importance of right bundle branch block is unclear. We determined whether left and right bundle branch block was associated with all-cause mortality risk after adjustment for potential confounders, including clinical, exercise, and nuclear scintigraphic variables. SUBJECTS AND METHODS: We studied 7,073 adults who were referred for symptom-limited nuclear exercise testing. Patients with heart failure or pacemakers were excluded. The presence or absence of bundle branch block was determined from resting electrocardiograms. The main outcome measure was all-cause mortality during a mean of 6.7 years of follow-up. RESULTS: One hundred ninety patients (3%) had complete right bundle branch block, and 150 (2%) had complete left bundle branch block. There were 825 deaths (12%). Mortality was greater in patients with complete right bundle branch block (24% [46 of 190]) or left bundle branch block (24% [36 of 150]) than in those without these findings (11% [779 of 6,883 and 789 of 6,923, respectively]; both P <0.0001). After adjustment for potential confounders, right bundle branch block was as strong an independent predictor of mortality (hazard ratio [HR] 1.5; 95% confidence interval [CI]: 1.1 to 2.1; P = 0.007) as left bundle branch block (HR 1.5; 95% CI: 1.0 to 2.0; P = 0.017). Incomplete right bundle branch block was not associated with mortality. CONCLUSION: Complete right and left bundle branch block are independent predictors of all-cause mortality risk even after adjustment for exercise capacity, nuclear perfusion defects, and other risk factors.

Evaluation of the effects of aspirin combined with angiotensin-converting enzyme inhibitors in patients with coronary artery disease.

BACKGROUND: Several studies have suggested that there may be an interaction between angiotensin-converting enzyme (ACE) inhibitors and aspirin in patients with congestive heart failure, such that their benefits are attenuated when used in combination. Whether this interaction exists in patients with coronary artery disease is not known. SUBJECTS AND METHODS: Patients enrolled in two large trials, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) and Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG), were stratified according to use of aspirin and ACE inhibitors on discharge from the hospital. In the EPILOG trial, left ventricular systolic function was assessed by contrast ventriculography. The primary endpoint was all-cause mortality at 1 year. EPILOG patients, all of whom were receiving aspirin, were also examined for the combined endpoint of death or nonfatal myocardial infarction. Stratified and multivariate analyses were used to adjust for baseline differences in patient characteristics. RESULTS: We studied 31,622 patients in the GUSTO-I trial and 2,619 patients in the EPILOG trial. There were 615 deaths among the GUSTO-I patients and 45 deaths among the EPILOG patients at 1 year. Unadjusted mortality was greater among patients treated with both ACE inhibitors and aspirin than among patients treated with aspirin alone (3.3% versus 1.6%, P <0.001 for GUSTO-I; and 3.7% versus 1.2%, P <0.001 for EPILOG). Similarly, the composite endpoint of death or nonfatal myocardial infarction was more frequent among EPILOG patients who were taking ACE inhibitors (6.3% versus 3.3%, P = 0. 001). After adjusting for confounders, combined use of aspirin and ACE inhibitors was associated with increased mortality in GUSTO-I patients (hazard ratio [HR] = 2.2, 95% confidence interval [CI]: 1.1 to 4.3, P = 0.03) compared with aspirin alone. In EPILOG patients, after adjusting for clinical factors and extent of left ventricular dysfunction, the combination of aspirin and ACE inhibitors was associated with an increased risk of death (HR = 2.1, 95% CI: 1.1 to 3.8, P = 0.02) and of death or nonfatal myocardial infarction (HR = 1.5, 95% CI: 1.1 to 2.5, P = 0.02) compared with aspirin alone. CONCLUSION: These observational findings suggest the possibility of an interaction between aspirin and ACE inhibitors among patients with ischemic heart disease. Further study of this issue is warranted.

Heart rate recovery and treadmill exercise score as predictors of mortality in patients referred for exercise ECG.

CONTEXT: Both attenuated heart rate recovery following exercise and the Duke treadmill exercise score have been demonstrated to be independent predictors of mortality, but their prognostic value relative to each other has not been studied. OBJECTIVE: To assess the associations among abnormal heart rate recovery, treadmill exercise score, and death in patients referred specifically for exercise electrocardiography. DESIGN AND SETTING: Prospective cohort study conducted in an academic medical center between September 1990 and December 1997, with a median follow-up of 5.2 years. PATIENTS: A total of 9454 consecutive patients (mean [SD] age, 53 [11] years; 78% male) who underwent symptom-limited exercise electrocardiographic testing. Exclusion criteria included age younger than 30 years, history of heart failure or valvular disease, pacemaker implantation, and uninterpretable electrocardiograms. MAIN OUTCOME MEASURES: All-cause mortality, as predicted by abnormal heart rate recovery, defined as failure of heart rate to decrease by more than 12/min during the first minute after peak exercise, and by treadmill exercise score, defined as (exercise time) - (5 x maximum ST-segment deviation) - (4 x treadmill angina index). RESULTS: Three hundred twelve deaths occurred in the cohort. Abnormal heart rate recovery and intermediate- or high-risk treadmill exercise score were present in 20% (n = 1852) and 21% (n = 1996) of patients, respectively. In univariate analyses, death was predicted by both abnormal heart rate recovery (8% vs 2% in patients with normal heart rate recovery; hazard ratio [HR], 4.16; 95% confidence interval [CI], 3.33-5.19; chi(2) = 158; P<.001) and intermediate- or high-risk treadmill exercise score (8% vs 2% in patients with low-risk scores; HR, 4.28; 95% CI, 3.43-5.35; chi(2) = 164; P<.001). After adjusting for age, sex, standard cardiovascular risk factors, medication use, and other potential confounders, abnormal heart rate recovery remained predictive of death (among the 8549 patients not taking beta-blockers, adjusted HR, 2.13; 95% CI, 1.63-2.78; P<.001), as did intermediate- or high-risk treadmill exercise score (adjusted HR, 1. 49; 95% CI, 1.15-1.92; P =.002). There was no interaction between these 2 predictors. CONCLUSIONS: In this cohort of patients referred specifically for exercise electrocardiography, both abnormal heart rate recovery and treadmill exercise score were independent predictors of mortality. Heart rate recovery appears to provide additional prognostic information to the established treadmill exercise score and should be considered for routine incorporation into exercise test interpretation. JAMA. 2000;284:1392-1398.