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1.  Duration of eptifibatide infusion after percutaneous coronary intervention and outcomes among high-risk patients with non-ST-segment elevation acute coronary syndrome: insights from EARLY ACS 
Background and Objectives:
Eptifibatide is indicated during percutaneous coronary intervention (PCI) with continuation for 18–24 hours post procedure but is associated with bleeding. We examined the efficacy and safety of shorter post-PCI eptifibatide infusions in high-risk non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients.
EARLY ACS patients treated with PCI and eptifibatide were grouped by post-procedure infusion duration: <10, 10–13, 13–17, and 17–25 (per protocol) hours. Adjusted estimated event rates for 96-hour death/myocardial infarction (MI)/recurrent ischaemia requiring urgent revascularization (RIUR), 30-day death/MI, post-PCI packed red blood cell (PRBC) transfusion, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate/severe bleeding were obtained using inverse-propensity weighting to account for informative censoring of infusions.
Among 3271 eptifibatide-treated PCI patients, there were 66 96-hour death/MI/RIUR events, 94 30-day death/MI events, 127 PRBC transfusions, and 115 GUSTO moderate/severe bleeds. Compared with per protocol, patients receiving post-PCI infusions <10 hours had similar adjusted estimated rates of 96-hour death/MI/RIUR (absolute difference 0.021 higher; 0.040 vs. 0.019, 95% CI −0.023 to 0.064; p=0.35) and 30-day death/MI (0.020 higher; 0.046 vs. 0.026, 95% CI −0.021 to 0.062; p=0.34). There were also no differences in ischaemic outcomes between infusions of 10–17 hours and per-protocol infusions. Adjusted estimated rates of PRBC transfusion were higher for the <10-hour infusion group compared with per protocol (0.048 higher; 0.079 vs. 0.031, 95% CI 0.005 to 0.091, p=0.03) but were similar for other groups. Adjusted GUSTO moderate/severe bleeding rates were similar to per-protocol rates for all groups.
In high-risk NSTE ACS patients, post-PCI eptifibatide infusions <18 hours were not associated with worse ischaemic outcomes. Shorter eptifibatide infusions in this population may be feasible.
PMCID: PMC3821813  PMID: 24222836
Acute coronary syndrome; glycoprotein IIb/IIIa inhibitor; percutaneous coronary intervention
2.  The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study Community Registry and Biorepository 
Current understanding of chronic diseases is based on crude clinical characterization, imaging studies, and laboratory testing that has evolved over decades. The Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study is a multi-tiered, longitudinal study designed to enable classification of chronic diseases using clinically annotated biospecimen collections, -omic technologies, electronic health records, and standard epidemiological methods. We expect that detailed molecular classification will improve mechanistic understanding of chronic diseases, augmenting discovery and testing of new treatments, and allowing refined selection of prevention and treatment strategies. The MURDOCK Study Community Registry and Biorepository will serve as a bridge for validation of initial exploratory studies, a platform for future prospective studies in targeted populations, and a resource of both data (analytical and clinical) and samples for cross-registry meta-analyses and comparative population studies. Participation of local health care providers and the Cabarrus County/Kannapolis, NC, community will facilitate future medical research and provide the opportunity to educate and inform the public about genomic research, actively engaging them in shaping the future of medical discovery and treatment of chronic diseases. We present the rationale and study design for the MURDOCK Community Registry and Biorepository and baseline characteristics of the first 6000 participants.
PMCID: PMC3493022  PMID: 23145214
Disease reclassification; community registry; biorepository
3.  Prognostic Biomarkers in Individuals with Prevalent Coronary Heart Disease 
Disease markers  2009;26(5-6):265-271.
Coronary disease is the leading killer of individuals worldwide and a leading cause of healthcare expenditure. On a global scale, ischemic heart disease kills over 6 million individuals each year and is projected by the World Health Organization to be the greatest single-disease cause of death worldwide by an increasing margin into 2030. Nearly 17 million Americans (7.6% of the population) have prevalent coronary heart disease, 8 million of whom have had a prior myocardial infarction. It is estimated that in 2009, 550,000 will die from coronary heart disease in the United States and that the direct and indirect costs from treating coronary heart disease will exceed $165 billion. Although patients with known coronary artery disease are among the highest risk patients for future cardiac events, not all patients with coronary disease will have an ischemic event (first or recurrent). Determining which of these patients will have an ischemic event is critical to the concept of personalized cardiovascular care. Increasingly, biomarkers that can be readily assayed from blood or other body fluids will be critical to risk stratification and effective application of secondary prevention strategies, just as they have played an increasingly prominent role in risk stratification of acute coronary syndrome patients.
PMCID: PMC3833693  PMID: 19773615
Coronary heart disease; prognosis; biomarkers
4.  Aspirin Exposure Reveals Novel Genes Associated with Platelet Function and Cardiovascular Events 
To develop RNA profiles that could serve as novel biomarkers for the response to aspirin.
Aspirin reduces death and myocardial infarction (MI) suggesting that aspirin interacts with biological pathways that may underlie these events.
We administered aspirin, followed by whole blood RNA microarray profiling, in a discovery cohort of healthy volunteers (HV1,n=50), and two validation cohorts of volunteers (HV2,n=53) or outpatient cardiology patients (OPC, n=25). Platelet function was assessed by platelet function score (PFS; HV1/HV2) or VerifyNow Aspirin (OPC). Bayesian sparse factor analysis identified sets of coexpressed transcripts, which were examined for association with PFS in HV1 and validated in HV2 and OPC. Proteomic analysis confirmed the association of validated transcripts in platelet proteins. Validated gene sets were tested for association with death/MI in two patient cohorts (n=587, total) from RNA samples collected at cardiac catheterization.
A set of 60 co-expressed genes named the “aspirin response signature” (ARS) was associated with PFS in HV1 (r = −0.31, p = 0.03), HV2 (r = −0.34, Bonferroni p = 0.03), and OPC (p = 0.046). Corresponding proteins for 17 ARS genes were identified in the platelet proteome, of which, six were associated with PFS. The ARS was associated with death/MI in both patient cohorts (odds ratio = 1.2, p = 0.01 and hazard ratio = 1.5, p = 0.001), independent of cardiovascular risk factors. Compared with traditional risk factors, reclassification (net reclassification index = 31 - 37%, p ≤ 0.0002) was improved by including the ARS or one of its genes, ITGA2B.
RNA profiles of platelet-specific genes are novel biomarkers for identifying those do not response adequately to aspirin and who are at risk for death/MI.
PMCID: PMC3786046  PMID: 23831034
aspirin; platelets; genes; myocardial infarction; biomarkers
5.  Embedding a randomized clinical trial into an ongoing registry infrastructure: Unique opportunities for efficiency in design of the Study of Access site For Enhancement of Percutaneous Coronary Intervention for Women (SAFE-PCI for Women) 
American heart journal  2013;166(3):421-428.
Women are at higher risk than men for bleeding and vascular complications after percutaneous coronary intervention (PCI). Compared with femoral access, radial access reduces these complications but may be more challenging in women because of higher rates of radial artery spasm, tortuosity, and occlusion as well as lower rates of procedure success. Whether the safety advantages of radial versus femoral access in women undergoing PCI are outweighed by reduced effectiveness has not been studied. The Study of Access site For Enhancement of PCI for Women is a prospective, randomized clinical trial comparing radial with femoral arterial access in women undergoing PCI. In conjunction with the US Food and Drug Administration‧s Critical Path Cardiac Safety Research Consortium, this study embeds the randomized clinical trial into the existing infrastructure of the National Cardiovascular Data Registry™ CathPCI Registry™ through the National Institute of Health‧s National Cardiovascular Research Infrastructure. The primary efficacy end point is a composite of bleeding (Bleeding Academic Research Consortium types 2, 3, or 5) or vascular complication requiring intervention occurring at 72 hours after PCI or by hospital discharge. The primary feasibility end point is procedure success. Secondary end points include procedure duration, contrast volume, radiation dose, quality of life, and a composite of 30-day death, vascular complication, or unplanned revascularization.
PMCID: PMC4169992  PMID: 24016489
6.  Improving population representation through geographic health information systems: mapping the MURDOCK study 
This paper highlights methods for using geospatial analysis to assess, enhance, and improve recruitment efforts to ensure representativeness in study populations. We apply these methods to the Measurement to Understand Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) study, a longitudinal population health study focused on the city of Kannapolis and Cabarrus County, NC. Although efforts have been made to recruit a participant registry that is representative of the 18 ZIP code catchment region inclusive of Cabarrus County and Kannapolis, bias in such recruitment is inevitable. Participants in the MURDOCK study are geospatially referenced at entry, providing information that can be used to monitor and guide recruitment efforts. MURDOCK participant population representativeness was assessed using chi-squared tests to compare the MURDOCK population with 2010 Census data, relative to both the entire 18 ZIP code catchment area and for individual Census tracts. A logistic regression model was fit to characterize Census tracts with low recruitment, defined by fewer than 56 participants from that tract. The distance to the site at which participants enrolled was calculated, and median distance to enrollment site was used in the logistic regression. Tracts with low recruitment rates contained higher minority and younger populations, suggesting specific strategies for improving recruitment in these areas. Areal units farther away from enrollment sites were also not well-sampled, despite being in the specified study area, indicating that distance traveled to enrollment may be a barrier. These results have implications for targeting recruitment efforts and representative samples more generally, including in other population-based studies.
PMCID: PMC4113502  PMID: 25075257
Geographic health information systems (GHIS); spatial analysis; sample recruitment; neighborhood; population-based studies
7.  Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness 
To identify novel biomarkers through metabolomic profiles that distinguish metabolically well (MW) from metabolically unwell (MUW) individuals, independent of body mass index (BMI).
This study was conducted as part of the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) project. Individuals from 3 cohorts were classified as lean (BMI<25 kg/m2), overweight (BMI≥25 kg/m2, BMI<30 kg/m2) or obese (BMI≥30 kg/m2). Cardiometabolic abnormalities were defined as: (1) impaired fasting glucose (≥100mg/dL and ≤126mg/dL); (2) hypertension; (3) triglycerides ≥150 mg/dL; (4) HDL-C <40 mg/dL in men, <50 mg/dL in women); and (5) insulin resistance (calculated Homeostatic Model Assessment (HOMA-IR) index of >5.13). MW individuals were defined as having <2 cardiometabolic abnormalities and MUW individuals had ≥two cardiometabolic abnormalities. Targeted profiling of 55 metabolites used mass-spectroscopy-based methods. Principal components analysis (PCA) was used to reduce the large number of correlated metabolites into clusters of fewer uncorrelated factors.
Of 1,872 individuals, 410 were lean, 610 were overweight, and 852 were obese. Of lean individuals, 67% were categorized as MUW, whereas 80% of overweight and 87% of obese individuals were MUW. PCA-derived factors with levels that differed the most between MW and MUW groups were factors 4 (branched chain amino acids [BCAA]) [p<.0001], 8 (various metabolites) [p<.0001], and 9 (C4/Ci4, C3, C5 acylcarnitines) [p<.0001] and 10 (amino acids) [p<.0002]. Further, Factor 4, distinguishes MW from MUW individuals independent of BMI.
BCAA and related metabolites are promising biomarkers that may aid in understanding cardiometabolic health independent of BMI category.
PMCID: PMC3691289  PMID: 23375209
Obesity; Metabolomics; Insulin Resistance; Metabolic Risk
8.  Implementation of standardized assessment and reporting of myocardial infarction in contemporary randomized controlled trials: a systematic review 
European Heart Journal  2013;34(12):894-902.
Myocardial infarction (MI) is a key endpoint in randomized controlled trials (RCTs), but heterogeneous definitions limit comparisons across RCTs or meta-analyses. The 2000 European Society of Cardiology/American College of Cardiology MI redefinition and the 2007 universal MI definition consensus documents made recommendations to address this issue. In cardiovascular randomized trials, we evaluated the impact of implementation of three key recommendations from these reports—troponin use to define MI; separate reporting of spontaneous and procedure-related MI; and infarct size reporting. We searched and MEDLINE databases for cardiovascular RCTs with more than 500 patients in which enrolment began between September 2000 and July 2012 and that listed MI in the primary endpoint. We searched English-language publications with primary results or design papers. Of 3222 studies screened, 96 (3.0%) met our criteria. We extracted enrolment start date, number of patients and MI events, follow-up duration, and coronary revascularization rate. Data extraction quality was assessed by duplicated extractions. Of 96 RCTs, 80 had a primary results publication, comprising 608 091 patients and 43 621 endpoint MIs. Myocardial infarction represented 45.3% (95% confidence interval, 40.2–50.4) of events in the primary composite endpoint. Troponin defined MI in 57% (53/93) of trials with an MI definition available. Of these RCTs, three used troponin only if creatine kinase-MB was unavailable, six used troponin to define peri-procedural MI, seven specified the 99th percentile as the MI decision limit, and three reported spontaneous and procedure-related MI separately. None reported biomarker-based infarct size, but five reported MI as multiples of the assay upper limit of normal. Although MI is a major component of cardiovascular RCT primary endpoints, standardized MI reporting and implementation of consensus document recommendations for MI definition are limited. Developing appropriate strategies for uniform implementation is required.
PMCID: PMC3604645  PMID: 23355654
Myocardial infarction; Clinical trials; Systematic reviews
9.  Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients 
Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD.
Methods and results:
We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (ORadj 0.15; 95% CI, 0.11–0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (ORadj 0.19 (0.14–0.25) and 0.37 (0.28–0.49), respectively).
Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.
PMCID: PMC3932771  PMID: 24562802
Acute coronary syndromes; angiography; atherosclerosis; coronary disease; infarction
10.  TransRadial Education And Therapeutics (TREAT): Shifting the balance of safety and efficacy of antithrombotic agents in percutaneous coronary intervention. A report from the Cardiac Safety Research Consortium 
American heart journal  2013;165(3):10.1016/j.ahj.2012.09.008.
Percutaneous coronary intervention (PCI) is an integral part of the treatment of coronary artery disease. The most common complication of PCI, bleeding, typically occurs at the vascular access site and is associated with short-term and long-term morbidity and mortality. Periprocedural bleeding also represents the primary safety concern of concomitant antithrombotic therapies essential for PCI success. Use of radial access for PCI reduces procedural bleeding and hence may change the risk profile and net clinical benefit of these drugs. This new drug-device safety interaction creates opportunities to advance the safe and effective use of antithrombotic agents during PCI. In June 2010 and March 2011, leaders from government, academia, professional societies, device manufacturing, and pharmaceutical industries convened for 2 think tank meetings. Titled TREAT I and II, these forums examined approaches to improve the overall safety of PCI by optimizing strategies for antithrombotic drug use and radial artery access. This article summarizes the content and proceedings of these sessions.
PMCID: PMC3886824  PMID: 23453103
11.  Identifying Factors that Influence Hospital Length of Stay in Patients with Non-ST-segment Elevation Myocardial Infarction: Insights from the Acute Coronary Treatment Intervention Outcomes Network Registry®-Get With The Guidelines™ 
The American journal of medicine  2012;125(11):10.1016/j.amjmed.2012.04.038.
Substantial heterogeneity in hospital length of stay (LOS) exists among patients admitted with non-ST-segment elevation myocardial infarction (NSTEMI). Furthermore, little is known about the factors that impact LOS and our ability to modify them.
We examined 39,107 NSTEMI patients admitted to 351 ACTION Registry®-GWTG™ hospitals from 1/1/07–3/31/09 who underwent cardiac catheterization and survived to discharge. Length of stay was categorized into four groups (≤2, 3–4, 5–7, and ≥8 days), where prolonged LOS was defined as >4 days.
The overall median (25th, 75th) LOS was 3 (2, 5) days. Patients with a LOS of >2 days were older with more comorbidities, but were less likely to receive evidence-based therapies or percutaneous coronary intervention (PCI). Among the factors associated with prolonged LOS >4 days were delay to cardiac catheterization >48 hours, heart failure or shock on admission, female gender, insurance type, and admission to the hospital on a Friday afternoon or evening. Hospital characteristics such as number of beds, academic versus non-academic, or urban versus rural setting, were not associated with prolonged LOS.
Patients with longer LOS have more comorbidities and in-hospital complications, yet paradoxically, are less often treated with evidence-based medications and are less likely to receive PCI. Hospital admission on a Friday afternoon or evening and delays to catheterization appear to significantly impact LOS. A better understanding of factors associated with LOS in patients with NSTEMI is needed to promote safe and early discharge in an era of increasingly restrictive healthcare resources.
PMCID: PMC3884687  PMID: 22921886
non-ST-segment elevation myocardial infarction; length of stay; hospital discharge
12.  Serious Infection Following Acute Myocardial Infarction: Incidence, Clinical Features, and Outcomes 
JACC. Cardiovascular interventions  2012;5(7):10.1016/j.jcin.2012.03.018.
Little is known about the incidence, location, etiologic organisms, and outcomes of infection in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI).
To address this knowledge gap using the database of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial. We also assessed the association between serious infections and 90-day death or death/MI.
We analyzed data from 5745 STEMI patients enrolled in the APEX-AMI trial. Detailed information on infection was collected on all patients. We describe characteristics of patients according to infection and details of infection. Cox proportional hazards models were used to assess 90-day outcomes among patients with and without infections after adjusting for associated clinical variables and using infection as a time-dependent covariate.
Overall, 138 patients developed a serious infection (2.4%), most of whom presented with a single-site infection. The median (25th, 75th percentile) time until diagnosis of infection was 3 (1, 6) days. The most commonly identified organism was Staphylococcus aureus, and the main location of infection was the bloodstream. These patients had more comorbidities and lower procedural success at index PCI than those without infections. Serious infection was associated with significantly higher rates of 90-day death (adjusted hazard ratio [HR] 5.6; 95% confidence interval [CI] 3.8-8.4) and death or MI (adjusted HR 4.9; 95% CI 3.4-7.1).
Infections complicating the course of patients with STEMI are uncommon but associated with markedly worse 90-day clinical outcomes. Mechanisms for early identification of these high-risk patients, as well as design of strategies to reduce their risk of infection, are warranted.
PMCID: PMC3883036  PMID: 22814783
ST-segment elevation myocardial infarction; percutaneous coronary intervention; infection; outcomes
13.  Diagnostic Time Course, Treatment, and In-Hospital Outcomes for STEMI Patients Presenting with Non-Diagnostic Initial ECG: A Report from the AHA Mission: Lifeline Program 
American heart journal  2012;165(1):50-56.
Prior studies indicate that a subset of patients diagnosed with ST-segment elevation myocardial infarction (STEMI) will have an initial non-diagnostic ECG during evaluation. However, the timing of diagnostic ECG changes in this group is unknown. Our primary aim was to describe the timing of ECG diagnosis of STEMI in patients whose initial ECG was non-diagnostic. Secondarily, we sought to compare the delivery of ACC/AHA guidelines-based care and in-hospital outcomes in this group compared to patients diagnosed with STEMI on initial ECG.
We analyzed data from 41,560 patients diagnosed with STEMI included in the NCDR® ACTION Registry®-GWTG™ from 01/2007 to 12/2010. We divided this study population into two groups: those diagnosed on initial ECG (N= 36,994) and those with an initial non-diagnostic ECG that were diagnosed on a follow-up ECG (N= 4,566).
In general, baseline characteristics and clinical presentations were similar between the two groups. For patients with an initial non-diagnostic ECG, 72.4% (N= 3,305)had an ECG diagnostic for STEMI within 90 minutes of their initial ECG. There did not appear to be significant differences in the administration of guidelines-recommended treatments for STEMI, in-hospital major bleeding (p 0.926), or death (p 0.475) between these groups.
In a national sample of patients diagnosed with STEMI, 11.0% had an initial non-diagnostic ECG. Of those patients, 72.4% had a follow-up diagnostic ECG within 90 minutes of their initial ECG. There did not appear to be clinically meaningful differences in guidelines-based treatment or major in-hospital outcomes between patients diagnosed with STEMI on an initial versus follow-up ECG.
PMCID: PMC3523309  PMID: 23237133
14.  Modifiable Factors Associated with Failure to Attain LDL Cholesterol Goal at 6-Months after Acute Myocardial Infarction 
American heart journal  2012;165(1):26-33.e3.
Although controversial, reducing low-density lipoprotein cholesterol (LDL-C) to target levels remains a common therapeutic goal after acute myocardial infarction (AMI). We sought to illuminate patient and provider characteristics associated with LDL-C goal nonattainment after AMI.
In an observational registry of 24 United States hospitals, we included 366 AMI patients who had baseline LDL-C levels ≥100 mg/dl and underwent 6-month fasting LDL-C reassessment. Our primary outcome was failure to reach the guidelines recommended LDL-C goal of <100 mg/dl at 6-months post-AMI.
One in 3 AMI patients with initially elevated LDL-C failed to attain LDL-C goal at 6-months. Compared with those who attained LDL-C goal, those who did not were more often discharged without a statin (21% vs. 9%, p<0.001), despite only 4% having documented contraindications. Patients not achieving LDL-C goal also more frequently discontinued statin use by 6-months (24% vs. 6%, p<0.001). Multivariable modeling (c index 0.78) revealed the absence of a statin prescription at discharge and lack of persistence on statin therapy as the strongest independent factors associated with failure to reach LDL-C goal. Additional independent risk factors were patient report of not consistently adhering to prescribed medications, not participating in cardiac rehabilitation, nonwhite race, and lack of insurance.
One-third of AMI patients with baseline hyperlipidemia do not attain the LDL-C goal of <100 mg/dl at 6-months. Our findings support targeted interventions in the transition of AMI care to promote affordable statin prescription at discharge, medication persistence and adherence, and cardiac rehabilitation participation.
PMCID: PMC3607508  PMID: 23237130
myocardial infarction; hyperlipidemia; LDL cholesterol; goal attainment; barriers
15.  Nighttime Blood Pressure Dipping in Postmenopausal Women With Coronary Heart Disease 
American Journal of Hypertension  2012;25(10):1077-1082.
Blunted nighttime blood pressure (BP) dipping is prognostic of cardiovascular morbidity and mortality. This relationship may be stronger among women than men. The present study hypothesized that coronary artery disease (CAD) and advancing age would be associated with reduced BP dipping in postmenopausal women. The effects of daytime physical activity and nighttime sleep quality on BP dipping were also examined.
54 postmenopausal women with CAD (≥50% occlusion of at least one major coronary vessel) and 48 age-matched (range 50–80 years) postmenopausal women without CAD (non-CAD) underwent 24-h ambulatory BP monitoring and actigraphic evaluations of daytime physical activity and nighttime sleep efficiency.
Women with CAD evidenced higher nighttime systolic BP (SBP) (P = 0.05) and blunted SBP dipping (P = 0.017), blunted diastolic BP (DBP) dipping (P = 0.047), and blunted pulse pressure dipping (P = 0.01), compared to non-CAD women. Multivariable regression models showed that the presence of CAD, age, daytime physical activity, and nighttime sleep efficiency were independently related to the magnitude of SBP dipping, together accounting for 25% of its variability. DBP dipping showed similar associations.
For postmenopausal women, the presence of CAD and advancing age are accompanied by blunted nighttime BP dipping, which may increase the risk of adverse cardiovascular events. Lifestyle changes that increase daytime physical activity and improve nighttime sleep quality may help improve cardiovascular risk by enhancing nighttime BP dipping.
American Journal of Hypertension, advance online publication 12 July 2012. doi:10.1038/ajh.2012.95
PMCID: PMC3578477  PMID: 22785406
ambulatory blood pressure monitoring; blood pressure; blood pressure dipping; coronary artery disease; hypertension; physical activity; sleep efficiency; women’s health
16.  Antithrombotic therapy for atrial fibrillation and coronary artery disease in older patients 
American heart journal  2012;164(4):607-615.
Older patients with atrial fibrillation (AF) and coronary artery disease (CAD) face high risk of stroke and bleeding with antithrombotic therapy. Balancing safe and effective use of aspirin, clopidogrel, and warfarin in this population is important.
From the Duke Databank for Cardiovascular Disease, we identified patients with AF ≥65 years old with angiographically confirmed CAD from 2000 to 2010. Antithrombotic use was described across age and Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack (CHADS2) stroke risk and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding scores. Death and the composite of death, myocardial infarction, and stroke by antithrombotic strategy were reported.
Of 2,122 patients ≥65 years old with AF and CAD, 477 (22.5%) were ≥80 years old; 1,133 (53.4%) had acute coronary syndromes. Overall rates of aspirin, clopidogrel, and warfarin use were 83.4%, 34.6%, and 38.9%, respectively. Compared with patients 65 to 79 years old, more patients ≥80 years old were at high stroke risk (CHADS2 ≥2, 84.7% vs 57.8%) and high bleeding risk (ATRIA 5-10, 55.8% vs 23.3%). Warfarin use in both age groups increased with higher CHADS2 scores and decreased with higher ATRIA scores. Of patients ≥80 years old with CHADS2 ≥2, 150 (38.2%) received warfarin. Antithrombotic strategy was not associated with improved 1-year adjusted outcomes.
Among older patients with AF and CAD, overall warfarin use was low. Patients ≥80 years old at highest stroke risk received warfarin in similar proportions to the overall cohort. Further investigation into optimizing antithrombotic strategies in this population is warranted.
PMCID: PMC3777661  PMID: 23067921
17.  Multi-Center Validation of the Diagnostic Accuracy of a Blood-based Gene Expression Test for Assessment of Obstructive Coronary Artery Disease in Non-Diabetic Patients 
Annals of internal medicine  2010;153(7):425-434.
Diagnosis of significant coronary artery disease (CAD) in at risk patients can be challenging, typically including non-invasive imaging modalities and ultimately the gold standard of coronary angiography. Previous studies suggested that peripheral blood gene expression can reflect the presence of CAD.
To validate a previously developed 23-gene expression-based classifier for diagnosis of obstructive CAD in non-diabetic patients.
Multi-center prospective trial with blood samples drawn prior to coronary angiography.
Thirty-nine US centers.
An independent validation cohort of 526 non-diabetic patients clinically-indicated for coronary angiography
Receiver-operator characteristics (ROC) analysis of classifier score measured by real-time polymerase chain reaction (RT-PCR), additivity to clinical factors, and reclassification of patient disease likelihood vs disease status defined by quantitative coronary angiography (QCA). Obstructive CAD defined as ≥50% stenosis in ≥1 major coronary artery by QCA.
The overall ROC curve area (AUC) was 0.70 ±0.02, (p<0.001); the classifier added to clinical variables (Diamond-Forrester method) (AUC 0.72 with classifier vs 0.66 without, p = 0.003). Net reclassification was improved by the classifier over Diamond-Forrester and an expanded clinical model (both p<0.001). At a score threshold corresponding to 20% obstructive CAD likelihood (14.75), the sensitivity and specificity were 85% and 43%, yielding NPV of 83% and PPV 46%, with 33% of patient scores below this threshold.
The study excluded patients with chronic inflammatory disorders, elevated white blood counts or cardiac protein markers, and diabetes.
This non-invasive whole blood test, based on gene expression and demographics, may be useful for assessment of obstructive CAD in non-diabetic patients without known CAD.
Primary Funding Source
CardioDx, Inc.
PMCID: PMC3786733  PMID: 20921541
18.  Baseline Risk of Major Bleeding in Non–ST-segment Elevation Myocardial Infarction: The CRUSADE Bleeding Score 
Circulation  2009;119(14):1873-1882.
Treatments for non–ST-segment elevation myocardial infarction (NSTEMI) reduce ischemic events but increase bleeding. Baseline prediction of bleeding risk can complement ischemic risk prediction for optimizing NSTEMI care; however, existing models are not well suited for this purpose.
Methods and Results
We developed (n=71,277) and validated (n=17,857) a model that identifies 8 independent baseline predictors of in-hospital major bleeding among community-treated NSTEMI patients enrolled in the CRUSADE Quality Improvement Initiative. Model performance was tested by c statistics in the derivation and validation cohorts and according to post-admission treatment (i.e., invasive and antithrombotic therapy). The CRUSADE bleeding score (range 1–100 points) was created by assigning weighted integers corresponding to the coefficient of each variable. The rate of major bleeding increased by bleeding risk score quintiles: 3.1% very low risk (≤20); 5.5% low risk (21–30); 8.6% moderate risk (31–40); 11.9% high risk (41–50); and 19.5% very high risk (>50) (Ptrend<0.001). The c statistics for the major bleeding model (derivation=0.72 and validation=0.71) and risk score (derivation=0.71 and validation=0.70) were similar. The c statistics for the model among treatment subgroups were: ≥2 antithrombotics=0.72; <2 antithrombotics=0.73; invasive approach=0.73; conservative approach=0.68.
The CRUSADE bleeding score quantifies risk for in-hospital major bleeding across all post-admission treatments, enhancing baseline risk assessment for NSTEMI care.
PMCID: PMC3767035  PMID: 19332461
non-ST-segment elevation myocardial infarction; bleeding; risk assessment
19.  Differences in Level of Care at the End of Life According to Race 
Tailoring care for patients and their families at the end-of-life is an important goal. This study examined factors associated with patient choices for level of care at the end of life.
Demographic data and level of care (full code, do not resuscitate, or withdrawal of life support) were collected on 1072 patients who died from January 1998 to June 2006 on a cardiac care unit. Logistic regression was used to identify factors associated with level of care.
Of 15,402 patients admitted during the study, 1072 died, comprising the study sample. Median age of blacks was 64 years (IQR, 50, 74) and whites, 70 years (IQR, 62, 78). At the time of death the level of care differed significantly in blacks versus whites. 41.8% (n = 112) of blacks versus 26.7% (n = 194) of whites chose full code (p <.0001); 37.3% (n = 96) of blacks versus 43.9% (n = 317) whites chose DNR (p = .026); and 20.9% (n=54) of blacks versus 29.3% (n=210) of whites chose withdrawal of life support (p = .005). After controlling for age, sex, diagnosis, length of intensive care stay, and length of hospital stay, blacks were more likely than whites to choose full code status at the time of death (OR 1.91 [95% CI, 2.63 – 1.39], p <0.0001).
Blacks are 1.9 times as likely as others to choose full code at time of death. These results suggest the need to acknowledge cultural differences when providing end of life care.
PMCID: PMC3766528  PMID: 20595215
End of life; disparities; race; withdrawal of life support; do not resuscitate; full code
20.  ALOX5AP Variants are Associated with In-Stent Restenosis After Percutaneous Coronary Intervention 
Atherosclerosis  2008;201(1):148-154.
Use of drug-eluting stents (DES) has reduced in-stent restenosis after percutaneous coronary intervention (PCI); however, DES are associated with late stent thrombosis. There is no accurate way to predict in-stent restenosis, although risk factors for atherosclerosis overlap those for in-stent restenosis. Therefore, we evaluated atherosclerosis candidate genes for association with in-stent restenosis.
We identified 46 consecutive cases that had undergone PCI with bare-metal stents who subsequently developed symptomatic in-stent restenosis of the target lesion (≥75% luminal narrowing) within six months. Forty-six age-, race-, vessel-diameter- and sex-matched controls without in-stent restenosis after PCI with bare-metal stent were also identified. Single-nucleotide polymorphisms (SNPs, N=82) from 39 candidate atherosclerosis genes were genotyped. Multivariable logistic regression models were used to test for association.
Five SNPs were associated with in-stent restenosis. Three ALOX5AP SNPs were most strongly associated, two with increased risk (OR 3.74, p=0.01; OR 3.46, p=0.02), and the third with decreased risk of in-stent restenosis (OR 0.09, p=0.004). Two ALOX5AP haplotypes were associated with in-stent restenosis (HapB: OR 3.13, p=0.03); and a haplotype similar to HapA: OR 0.14, p=0.0009).
ALOX5AP, a gene within the inflammatory leukotriene pathway linked to and associated with coronary atherosclerosis, is also associated with in-stent restenosis. Genotyping these variants may help identify those at risk for in-stent restenosis who would benefit most from use of DES.
PMCID: PMC3733458  PMID: 18374923
Genetics; Stent Restenosis; Coronary Artery Disease; Inflammation
21.  Metabolic Profiles Predict Adverse Events Following Coronary Artery Bypass Grafting 
Clinical models incompletely predict outcomes following coronary artery bypass grafting. Novel molecular technologies may identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in patients undergoing coronary artery bypass grafting.
The study population comprised 478 subjects from the CATHGEN biorepository of patients referred for cardiac catheterization who underwent coronary artery bypass grafting after enrollment. Targeted mass spectrometry-based profiling of 69 metabolites was performed in frozen, fasting plasma samples collected prior to surgery. Principal-components analysis and Cox proportional hazards regression modeling were used to assess the relation between metabolite factor levels and a composite outcome of post-coronary artery bypass grafting myocardial infarction, need for percutaneous coronary intervention, repeat coronary artery bypass grafting, or death.
Over a mean follow-up of 4.3 ± 2.4 years, 126 subjects (26.4%) suffered an adverse event. Three principal-components analysis-derived factors were significantly associated with adverse outcome in univariable analysis: short-chain dicarboxylacylcarnitines (factor 2, P=0.001); ketone-related metabolites (factor 5, P=0.02); and short-chain acylcarnitines (factor 6, P=0.004). These three factors remained independently predictive of adverse outcome after multivariable adjustment: factor 2 (adjusted hazard ratio 1.23; 95% confidence interval [1.10-1.38]; P<0.001), factor 5 (1.17 [1.01-1.37], P=0.04), and factor 6 (1.14 [1.02-1.27], P=0.03).
Metabolic profiles are independently associated with adverse outcomes following coronary artery bypass grafting. These profiles may represent novel biomarkers of risk that augment existing tools for risk stratification of coronary artery bypass grafting patients and may elucidate novel biochemical pathways that mediate risk.
PMCID: PMC3324120  PMID: 22306227
22.  Guidelines-based treatment of anaemic STEMI patients: practice patterns and effects on in-hospital mortality: a retrospective analysis from the NCDR 
Anaemia is associated with an increased risk for morbidity and mortality in ST-elevation myocardial infarction (STEMI) patients. While several physiological mechanisms have been proposed to explain this association, decreased receipt of guidelines-based care may also contribute. We examined the relationship between admission haemoglobin (Hgb) level, receipt of ACC/AHA guidelines-based treatments, and in-hospital outcomes among STEMI patients. We also evaluated whether administration of these treatments modified the association between anaemia and in-hospital mortality in this group.
Methods and results:
We analysed data from 92,686 patients diagnosed with STEMI included in the NCDR ACTION Registry-GWTG database from January 2007 to March 2011. Patients were stratified by initial Hgb value: 83.1% (n=77,035) were classified as non-anaemic (Hgb >13.0 g/dl for men, >12.0 g/dl for women), 11.6% (n=10,710) as mildly anaemic (11.1−13.0 g/dl for men, 11.1−12.0 g/dl for women), 4.4% (n=4059) as moderately anaemic (9.1−11.0 g/dl), and 1.0% (n=882) as severely anaemic (<9.0 g/dl). Anaemia was associated with a significantly increased prevalence of other baseline comorbidities and decreased odds of receiving several class I recommended pharmacological treatments (heparin, beta-blockers, and angiotensin-converting enzyme inhibitors, p<0.01). The overall use of reperfusion therapy (fibrinolytic therapy and/or percutaneous coronary intervention) was also lower in anaemic vs. non-anaemic patients (p<0.01). Anaemia was associated higher in-hospital mortality risk, which remained significant after adjustment for use of guidelines-recommended therapies and interventions (p<0.01).
In a national sample of STEMI patients, anaemia on presentation was associated with decreased receipt of ACC/AHA guidelines-based care and higher in-hospital mortality. However, the higher mortality rates could not be fully explained by differences in in-hospital treatment.
PMCID: PMC3760583  PMID: 24062932
Anaemia; guidelines; outcomes; ST-segment myocardial infarction (STEMI); treatment
23.  The MURDOCK Study: a long-term initiative for disease reclassification through advanced biomarker discovery and integration with electronic health records 
Facing critically low return per dollar invested on clinical research and clinical care, the American biomedical enterprise is in need of a significant transformation. A confluence of high-throughput “omic” technologies and increasing adoption of the electronic health record has fueled excitement for a new paradigm for biomedical research and practice. The ability to simultaneously measure thousands of molecular variables and assess their relationships with clinical data collected during the course of care could enable reclassification of disease not only by gross phenotypic observation but according to underlying molecular mechanism and influence of social determinants.In turn, this reclassification could enable development of targeted therapeutic interventions as well as disease prevention strategies at the individual and population levels.
The MURDOCK Study consists of distinct project “horizons” or stages. Horizon 1 entailed the generation and analysis of molecular data for existing large,clinically well-annotated cohorts in four disease areas. Horizon 1.5 involves creating and maintaining a 50,000-person,community volunteer registry for biomarker signature validation and prospective studies, including integration of environmental and social data. Horizon 2 leverages and prospectively recruits Horizon 1.5 volunteers, and extends the study to additional disease areas of interest. Horizon 3 will expand the study through regional, national,and international partnerships.
The MURDOCK Study embodies a new model of team science investigation and represents a significant resource for translational research. The study team invites inquiries to form new collaborations to exploit the rich resources provided by these biospecimens and associated study data.
PMCID: PMC3426390  PMID: 22937207
Stratified medicine; personalized medicine; biomarkers; disease reclassification; community registry; biorepository
25.  Changes in glycoprotein IIb/IIIa inhibitor excess dosing with site-specific safety feedback in the CRUSADE initiative 
American heart journal  2010;160(6):1072-1078.
Glycoprotein (GP) IIb/IIIa inhibitors can improve outcomes in patients with non–ST-segment elevation acute coronary syndromes (NSTE ACS) but raise the risk of bleeding, particularly if dosed in excess. The impact of GP IIb/IIIa dosing feedback on safety and major bleeding is unknown.
GP IIb/IIIa dosing feedback was added to the CRUSADE quarterly site reports in the first quarter (Q1) of 2006. We describe GP IIb/IIIa use and dosing among 25,641 NSTE ACS patients from Q4 2005–Q4 2006.
11,846 patients received GP IIb/IIIa inhibitors, including 4031 women and 2609 elderly patients (age ≥75 years). Among GP IIb/IIIa-treated patients, unadjusted rates of excess GP IIb/IIIa dosing declined overall (26.4–22.4%, Ptrend=0.01) and among the elderly (65.6–52.1%, Ptrend<0.001). After adjustment, declines in excess dosing remained significant only for the elderly, though over half of GP IIb/IIIa-treated elderly patients continued to receive excess dosing at the end of the study period (64.1–51.3%, Ptrend<0.001). There were concurrent declines in unadjusted major bleeding rates overall (9.6–8.0%, Ptrend=0.02), but declines among women (14.4–11.5%, Ptrend=0.08) and the elderly (17.1–11.0%, Ptrend=0.05) did not reach statistical significance. After adjustment for baseline characteristics and excess dosing, declines in major bleeding rates were no longer significant overall or for any subgroup.
Within 9 months of initiating a safety feedback program, we observed early decreases in excess GP IIb/IIIa dosing among the elderly but minimal changes in excess dosing overall. Further work is needed to promote safe and effective medication use in vulnerable patients who are most at risk of harm.
PMCID: PMC3058758  PMID: 21146660

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