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1.  Ethnic Differences in Cardiovascular Risks and Mortality in Atherothrombotic Disease: Insights From the REduction of Atherothrombosis for Continued Health (REACH) Registry 
Mayo Clinic Proceedings  2011;86(10):960-967.
OBJECTIVE: To determine whether ethnic-specific differences in the prevalence of cardiovascular risk factors and outcomes exist worldwide among individuals with stable arterial disease.
PATIENTS AND METHODS: From December 1, 2003, to June 30, 2004, the prospective, observational REduction of Atherothrombosis for Continued Health (REACH) Registry enrolled 49,602 out-patients with coronary artery disease, cerebrovascular disease, and/or peripheral arterial disease from 7 predefined ethnic/racial groups: white, Hispanic, East Asian, South Asian, Other Asian, black, and Other (comprising any race distinct from those specified). The baseline demographic and risk factor profiles, medication use, and 2-year cardiovascular outcomes were assessed among these groups.
RESULTS: The prevalence of traditional atherothrombotic risk factors varied significantly among the ethnic/racial groups. The use of medical therapies to reduce risk was comparable among all groups. At 2-year follow-up, the rate of cardiovascular death was significantly higher in blacks (6.1%) compared with all other ethnic/racial groups (3.9%; P=.01). Cardiovascular death rates were significantly lower in all 3 Asian ethnic/racial groups (overall, 2.1%) compared with the other groups (4.5%; P<.001).
CONCLUSION: The REACH Registry, a large international study of individuals with atherothrombotic disease, documents the important ethnic-specific differences in cardiovascular risk factors and variations in cardiovascular mortality that currently exist worldwide.
PMCID: PMC3184025  PMID: 21964173
2.  Smoking, Clopidogrel, and Mortality in Patients with Established Cardiovascular Disease 
Circulation  2009;120(23):2337.
Smoking increases platelet aggregability, and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown.
Methods and Results
We evaluated the relationship between smoking status (current smoker (CS), former smoker (FS), and never smoker (NS)) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12,152 participants from the CHARISMA trial with established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, [1.85–3.60]), cardiovascular (HR 2.26, [1.48–3.45]), and cancer mortality (HR 4.16, [2.46–7.03]) compared to NS. The impact of clopidogrel and mortality differed by smoking status (P for interaction = 0.018 for current smokers). Among CS, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, [0.49–0.94]); clopidogrel did not reduce all cause mortality among FS (HR 0.95, [0.75–1.19]) or NS (HR 1.14, [0.83–1.58]). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding seemed to differ according to smoking status; randomized clopidogrel was associated with a significantly increased hazard of severe or moderate bleeding (HR 1.62, P=0.04) among CS, but a smaller and nonsignificant increase among NS (HR 1.31, P=0.15).
Clopidogrel therapy may be more effective, but with a greater bleeding risk in CS than in patients who are not smokers. Further studies are needed to investigate this possibility.
PMCID: PMC2814172  PMID: 19933933
Smoking; Clopidogrel; Mortality; Cardiovascular disease
4.  Real world effectiveness of primary implantable cardioverter defibrillators implanted during hospital admissions for exacerbation of heart failure or other acute co-morbidities: cohort study of older patients with heart failure 
Objectives To examine the effectiveness of primary implantable cardioverter defibrillators (ICDs) in elderly patients receiving the device during a hospital admission for exacerbation of heart failure or other acute co-morbidities, with an emphasis on adjustment for early mortality and other factors reflecting healthy candidate bias rather than the effect of the ICD.
Design Retrospective cohort study.
Setting Linked data from the Centers for Medicare and Medicaid Services and American College of Cardiology-National Cardiovascular Data Registry ICD registry, nationwide heart failure registry, and Medicare claims data 2004-09.
Population 23 111 patients aged ≥66 who were admitted to hospital for exacerbation of heart failure or other acute co-morbidities and eligible for primary ICDs.
Main outcome measures All cause mortality and sudden cardiac death. Latency analyses with Cox regression were used to derive crude hazard ratios and hazard ratios adjusted for high dimension propensity score for outcomes after 180 days from index implantation or discharge.
Results Patients who received an ICD during a hospital admission had lower crude mortality risk than patients who did not receive an ICD (40% v 60% at three years); however, with conditioning on 180 day survival and with adjustment for high dimension propensity score, the apparent benefit with ICD was no longer evident for sudden cardiac death (adjusted hazard ratio 0.95, 95% confidence interval 0.78 to 1.17) and had a diminished impact on total mortality (0.91, 0.82 to 1.00). There were trends towards a benefit with ICD in reducing mortality or sudden cardiac death in patients who had had a myocardial infarction more than 40 days previously, left bundle branch block, or low serum B type natriuretic peptide; however, these trends did not reach significance.
Conclusion After adjustment for healthy candidate bias and confounding, the benefits of primary ICD therapy seen in pivotal trials were not apparent in patients aged 66 or over who received ICDs during a hospital admission for exacerbation of heart failure or other acute co-morbidities. Future research is warranted to further identify subgroups of elderly patients who are more likely to benefit from ICDs. Recognition of those patients whose dominant risk factors are from decompensated heart failure and non-cardiac co-morbidities will allow better focus on ICDs in those patients for whom the device offers the most benefit and provides meaningful prolonging of life.
PMCID: PMC4501450  PMID: 26174233
5.  Multi-parameter assessment of platelet inhibition and its stability during aspirin and clopidogrel therapy 
Thrombosis research  2014;134(1):96-104.
Poor response to antiplatelet drugs is associated with adverse outcomes. We assessed platelet inhibition and its stability and tested correlation and agreement between platelet function assays.
Peripheral blood from 58 patients on both aspirin and clopidogrel who underwent percutaneous coronary intervention (PCI) was collected at hospital discharge (visit-1) and at 30–90 days (visit-2). Platelet function was measured using light transmission aggregometry (LTA-AA and LTA-ADP), VerifyNow (Aspirin; ARU and P2Y12; PRU), ex vivo TxB2, urinary 11dhTxB2, and VASP (PRI) assays. Data were analyzed as continuous, quartiles and binary. Patients were defined as aspirin poor responder (PR) with ARU ≥550, LTA-AA maximum ≥20%, TxB2 ≥1 ng/mL or 11dhTxB2 ≥1,500 pg/mg of creatinine and as clopidogrel PR with PRU ≥240, PRU ≥208, LTA-ADP maximum ≥40%, PRI ≥50%, or PRI ≥66%.
Aspirin PR was 3–33% and clopidogrel PR was 10–35% in visit-1. LTA-AA, 11dhTxB2, and all clopidogrel-response measures showed correlation and agreement between visit-1 and visit-2. The highest agreement between two visits was revealed by PRU ≥240 and PRI ≥66% (PRU-κ=0.7, 95% CI=0.47, 0.93; PRI-κ=0.69, 95% CI=0.42, 0.95, p-values<0.001). Comparison of platelet function assays in a single visit (Visit-1) revealed a poor correlation between LTA-AA and 11dhTxB2 assays and no agreement among aspirin-response assays. The highest correlation and agreement were obtained between VerifyNow P2Y12 and VASP assays (rho=0.7, p-value<0.001 and PRU ≥208-PRI-κ=0.41–0.42, 95% CI=0.13, 0.69, p-values<0.001).
Platelet inhibition is stable during aspirin and clopidogrel treatment. Clopidogrel-response assays correlate and agree with each other better than aspirin-response assays.
PMCID: PMC4097303  PMID: 24852729
Aspirin; cardiovascular diseases; clopidogrel; drug resistance; percutaneous coronary intervention; platelet function assay
7.  Temporal trends in clinical characteristics of patients without known cardiovascular disease with a first episode of myocardial infarction 
American heart journal  2014;167(4):480-488.e1.
Recent initiatives have focused on primary prevention to delay time to first myocardial infarction (MI). The aim of this study was to evaluate the change in risk factor profile over time in patients without known cardiovascular disease presenting with first MI.
In the American Heart Association's Get With The Guidelines–Coronary Artery Disease national registry, 100,884 patients without known cardiovascular disease presenting with acute MI from 408 hospitals were evaluated between 2002 and 2008. The time trends of the proportion of patients with cardiovascular risk factors (nonmodifiable: age >45 years for men or >55 years for women, male sex, modifiable: diabetes mellitus, hypertension, hyperlipidemia, tobacco use) were analyzed. Analyses were stratified by non–ST-segment elevation MI (NSTEMI) versus ST-segment elevation MI (STEMI).
The proportion of patients with ≥3 of 6 traditional risk factors slightly decreased over time in the NSTEMI (69.5%-66.8%, P < .0001) and STEMI (68.9%-66.4%, P < .0001) cohorts. The proportion of patients with ≥2 of 4 modifiable risk factors increased from 52% to 59% and then declined to 52.1% (P < .0001) in the NSTEMI cohort but declined slightly in the STEMI cohort (50.9%-47.3%, P < .0001). After adjusting for age and gender, the time trend of proportion with diabetes mellitus, hypertension, and tobacco use declined in both cohorts. However, the proportion of patients with hyperlipidemia remained similar.
Although risk factor profiles in patients presenting with first MI have shown improvements over time, the changes are modest.
PMCID: PMC3964370  PMID: 24655696
8.  Heart Rate at Hospital Discharge in Patients With Heart Failure Is Associated With Mortality and Rehospitalization 
Whether heart rate upon discharge following hospitalization for heart failure is associated with long‐term adverse outcomes and whether this association differs between patients with sinus rhythm (SR) and atrial fibrillation (AF) have not been well studied.
Methods and Results
We conducted a retrospective cohort study from clinical registry data linked to Medicare claims for 46 217 patients participating in Get With The Guidelines®–Heart Failure. Cox proportional‐hazards models were used to estimate the association between discharge heart rate and all‐cause mortality, all‐cause readmission, and the composite outcome of mortality/readmission through 1 year. For SR and AF patients with heart rate ≥75, the association between heart rate and mortality (expressed as hazard ratio [HR] per 10 beats‐per‐minute increment) was significant at 0 to 30 days (SR: HR 1.30, 95% CI 1.22 to 1.39; AF: HR 1.23, 95% CI 1.16 to 1.29) and 31 to 365 days (SR: HR 1.15, 95% CI 1.12 to 1.20; AF: HR 1.05, 95% CI 1.01 to 1.08). Similar associations between heart rate and all‐cause readmission and the composite outcome were obtained for SR and AF patients from 0 to 30 days but only in the composite outcome for SR patients over the longer term. The HR from 0 to 30 days exceeded that from 31 to 365 days for both SR and AF patients. At heart rates <75, an association was significant for mortality only for both SR and AF patients.
Among older patients hospitalized with heart failure, higher discharge heart rate was associated with increased risks of death and rehospitalization, with higher risk in the first 30 days and for SR compared with AF.
PMCID: PMC4579947  PMID: 25904590
heart failure; heart rate; mortality
10.  Design and rationale for the randomised, double-blinded, placebo-controlled Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) crossover study 
Glucagon-like peptide-1 is an incretin hormone essential for normal human glucose homeostasis. Expression of the glucagon-like peptide-1 receptor in the myocardium has fuelled growing interest in the direct and indirect cardiovascular effects of native glucagon-like peptide-1, its degradation product glucagon-like peptide-1(9-36), and the synthetic glucagon-like peptide-1 receptor agonists. Preclinical studies have demonstrated cardioprotective actions of all three compounds in the setting of experimental myocardial infarction and left ventricular systolic dysfunction. This has led to Phase 2 trials of native glucagon-like peptide-1 and incretin-based therapies in humans with and without Type 2 diabetes mellitus. These studies have demonstrated the ability of glucagon-like peptide-1, independent of glycaemic control, to positively modulate the metabolic and haemodynamic parameters of individuals with coronary artery disease and left ventricular systolic dysfunction. We aim to add to this growing body of evidence by studying the effect of chronic glucagon-like peptide-1 receptor activation on exercise-induced ischaemia in patients with chronic stable angina managed conservatively or awaiting revascularisation. The hypothesis being liraglutide, a subcutaneously injectable glucagon-like peptide-1 receptor agonist, is able to improve exercise haemodynamics in patients with obstructive coronary artery disease when compared with saline placebo.
Methods and design
The Liraglutide to Improve corONary haemodynamics during Exercise streSS (LIONESS) trial is an investigator-initiated single-centre randomised double-blinded placebo-controlled crossover proof-of-principle physiological study. Primary endpoints are change in rate pressure product at 0.1 mV ST-segment depression and change in degree of ST-segment depression at peak exercise during sequential exercise tolerance testing performed over a 6-week study period in which 26 patients will be randomised to either liraglutide or saline with crossover to the opposing regimen at week 3.
The study will be conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The local Research Ethics Committee and Medicines and Healthcare Products Regulatory Agency have approved the study.
Trial registration
National Institute of Health Research Clinical Research Network (NIHR CRN) Portfolio ID 11112 and Identifier NCT02315001.
PMCID: PMC4358711  PMID: 25848859
Glucagon-like peptide-1 receptor agonist; Incretin hormone; Liraglutide; Chronic stable angina; Exercise-induced ischaemia, Type 2 diabetes mellitus
11.  Clopidogrel and proton pump inhibitors 
PMCID: PMC3928218  PMID: 24549709
12.  Variation in CAD Secondary Prevention Prescription among Outpatient Cardiology Practices: Insights from the NCDR® 
This study assesses practice variation of secondary prevention medication prescription among coronary artery disease (CAD) patients treated in outpatient practices participating in the NCDR® PINNACLE Registry®.
Among patients with CAD, secondary prevention with a combination of beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and statins reduces cardiac mortality and myocardial infarction (MI). Accordingly, every CAD patient should receive the combination of these medications for which they are eligible. However, little is known about current prescription patterns of these medications and the variation in use among outpatient cardiology clinics.
Using data from NCDR® PINNACLE Registry®, a national outpatient cardiology practice registry, we assessed medication prescription patterns among eligible CAD patients between July 2008 and December 2010. Overall rates of prescription and variation by practice were calculated, adjusting for patient characteristics.
Among 156,145 CAD patients in 58 practices, 103,830 (66.5%) were prescribed the optimal combination of medications for which they were eligible. The median rate of optimal combined prescription by practice was 73.5% and varied from 28.8% to 100%. After adjustment for patient factors, the practice median rate ratio for prescription was 1.25 (95% CI 1.2,1.32), indicating a 25% likelihood that 2 random practices would differ in treating identical CAD patients.
Among a national registry of CAD patients treated in outpatient cardiology practices, over one-third of patients failed to receive their optimal combination of secondary prevention medications. Significant variation was observed across practices, even after adjusting for patient characteristics, suggesting that quality improvement efforts may be needed to support more uniform practice.
PMCID: PMC3990248  PMID: 24184238
CAD; Outpatient Practice; Secondary Prevention
13.  Patient and Hospital Characteristics Associated with Inappropriate Percutaneous Coronary Interventions 
Journal of the American College of Cardiology  2013;62(24):10.1016/j.jacc.2013.07.086.
To examine whether rates of inappropriate PCI differ by demographic characteristics and insurance status.
Prior studies have found that blacks, women and those with public or no health insurance are less likely to undergo percutaneous coronary intervention (PCI). Whether this reflects potential overuse in whites, men, and privately insured patients, in addition to underuse in disadvantaged populations, is unknown.
Within the NCDR® CathPCI Registry®, we identified 221,254 non-acute PCIs performed between July 2009 and March 2011. PCI appropriateness was determined using Appropriate Use Criteria (AUC) for coronary revascularization. Multivariable hierarchical regression models evaluated the association between patient demographics and insurance status with AUC-defined inappropriate PCI.
Of 211,254 non-acute PCIs, 25,749 (12.2%) were classified as inappropriate. After multivariable adjustment, men (adjusted OR, 1.08 [95% CI: 1.05–1.11]; P<0.001) and whites (adjusted OR, 1.09 [1.05–1.14]; P<0.001) were more likely to undergo an inappropriate PCI, compared with women and non-whites. Compared with privately insured patients, those with Medicare (adjusted OR, 0.85 [0.83–0.88]), other public insurance (adjusted OR, 0.78 [0.73–0.83]) and no insurance (adjusted OR, 0.56 [0.50–0.61]) were less likely to undergo an inappropriate PCI (P<0.001). Additionally, compared with urban hospitals, those admitted at rural hospitals were less likely to undergo inappropriate PCI, whereas those at suburban hospitals were more likely.
For non-acute indications, PCIs categorized as inappropriate were more commonly performed in men, patients of white race, and those with private insurance. Higher rates of PCI in these patient populations may be, in part, due to procedural overuse.
PMCID: PMC3864986  PMID: 24055743
14.  CPAP versus Oxygen in Obstructive Sleep Apnea 
The New England journal of medicine  2014;370(24):2276-2285.
Obstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk.
We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea–hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure.
Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (−2.4 mm Hg; 95% confidence interval [CI], −4.7 to −0.1; P = 0.04) or the group receiving supplemental oxygen (−2.8 mm Hg; 95% CI, −5.1 to −0.5; P = 0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.
In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT number, NCT01086800.)
PMCID: PMC4172401  PMID: 24918372
15.  Short‐ and Long‐term Rehospitalization and Mortality for Heart Failure in 4 Racial/Ethnic Populations 
The degree to which outcomes following hospitalization for acute heart failure (HF) vary by racial and ethnic groups is poorly characterized. We sought to compare 30‐day and 1‐year rehospitalization and mortality rates for HF among 4 race/ethnic groups.
Methods and Results
Using the Get With The Guidelines–HF registry linked with Medicare data, we compared 30‐day and 1‐year outcomes between racial/ethnic groups by using a multivariable Cox proportional hazards model adjusting for clinical, hospital, and socioeconomic status characteristics. We analyzed 47 149 Medicare patients aged ≥65 years who had been discharged for HF between 2005 and 2011: there were 39 213 whites (83.2%), 4946 blacks (10.5%), 2347 Hispanics (5.0%), and 643 Asians/Pacific Islanders (1.4%). Relative to whites, blacks and Hispanics had higher 30‐day and 1‐year unadjusted readmission rates but lower 30‐day and 1‐year mortality; Asians had similar 30‐day readmission rates but lower 1‐year mortality. After risk adjustment, blacks had higher 30‐day and 1‐year CV readmission than whites but modestly lower short‐ and long‐term mortality; Hispanics had higher 30‐day and 1‐year readmission rates and similar 1‐year mortality than whites, while Asians had similar outcomes. When socioeconomic status data were added to the model, the majority of associations persisted, but the difference in 30‐day and 1‐year readmission rates between white and Hispanic patients became nonsignificant.
Among Medicare patients hospitalized with HF, short‐ and long‐term readmission rates and mortality differed among the 4 major racial/ethnic populations and persisted even after controlling for clinical, hospital, and socioeconomic status variables.
PMCID: PMC4323790  PMID: 25324354
health policy and outcome research; heart failure; race/ethnicity; rehospitalization
16.  The Clinical Profile and Under-Diagnosis of Pulmonary Hypertension in U.S. Veteran Patients 
Circulation. Heart failure  2013;6(5):906-912.
Pulmonary hypertension (PH) is a key contributor to cardiovascular morbidity and early mortality; however, reports are lacking on the epidemiology of PH in at-risk patient populations.
Methods and Results
The echocardiography registries from two major Veterans Affairs hospitals were accessed to identify patients with at least moderate PH, defined here as a pulmonary artery systolic pressure (PASP) ≥60 mmHg detected echocardiographically. From a total of 10,471 individual patient transthoracic echocardiograms, we identified moderate or severe PH in 340 patients (332 men; mean 77 y, mean PASP 69.4 ± 10.5 mmHg), of which PH was listed as a diagnosis in the medical record for only 59 (17.3%). At a mean of 832 days (0-4817 d) following echocardiography diagnosing PH, 150 (44.1%) patients were deceased. Pulmonary hypertension was present without substantial left heart remodeling: the mean left ventricular (LV) ejection fraction was 0.50 ± 0.16, LV end-diastolic dimension was 4.9 ± 1.0 cm, and left atrial dimension was 4.4 ± 0.7 cm. Cardiac catheterization (n=122, 36%) demonstrated a mean pulmonary artery pressure of 40.5 ± 11.4 mmHg, pulmonary capillary wedge pressure of 22.6 ± 8.9 mmHg, and pulmonary vascular resistance of 4.6 ± 2.9 Wood units. Diagnostic strategies for PH were variable and often incomplete; for example, only 16% of appropriate patients were assessed with a nuclear ventilation/perfusion (V/Q) scan for thromboembolic causes of PH.
In an at-risk patient population, PH is under-diagnosed and associated with substantial mortality. Enhanced awareness is necessary among practitioners regarding contemporary PH diagnostic strategies.
PMCID: PMC3894604  PMID: 23811965
pulmonary hypertension; diagnostic method; population
17.  Loci influencing blood pressure identified using a cardiovascular gene-centric array 
Ganesh, Santhi K. | Tragante, Vinicius | Guo, Wei | Guo, Yiran | Lanktree, Matthew B. | Smith, Erin N. | Johnson, Toby | Castillo, Berta Almoguera | Barnard, John | Baumert, Jens | Chang, Yen-Pei Christy | Elbers, Clara C. | Farrall, Martin | Fischer, Mary E. | Franceschini, Nora | Gaunt, Tom R. | Gho, Johannes M.I.H. | Gieger, Christian | Gong, Yan | Isaacs, Aaron | Kleber, Marcus E. | Leach, Irene Mateo | McDonough, Caitrin W. | Meijs, Matthijs F.L. | Mellander, Olle | Molony, Cliona M. | Nolte, Ilja M. | Padmanabhan, Sandosh | Price, Tom S. | Rajagopalan, Ramakrishnan | Shaffer, Jonathan | Shah, Sonia | Shen, Haiqing | Soranzo, Nicole | van der Most, Peter J. | Van Iperen, Erik P.A. | Van Setten, Jessica | Vonk, Judith M. | Zhang, Li | Beitelshees, Amber L. | Berenson, Gerald S. | Bhatt, Deepak L. | Boer, Jolanda M.A. | Boerwinkle, Eric | Burkley, Ben | Burt, Amber | Chakravarti, Aravinda | Chen, Wei | Cooper-DeHoff, Rhonda M. | Curtis, Sean P. | Dreisbach, Albert | Duggan, David | Ehret, Georg B. | Fabsitz, Richard R. | Fornage, Myriam | Fox, Ervin | Furlong, Clement E. | Gansevoort, Ron T. | Hofker, Marten H. | Hovingh, G. Kees | Kirkland, Susan A. | Kottke-Marchant, Kandice | Kutlar, Abdullah | LaCroix, Andrea Z. | Langaee, Taimour Y. | Li, Yun R. | Lin, Honghuang | Liu, Kiang | Maiwald, Steffi | Malik, Rainer | Murugesan, Gurunathan | Newton-Cheh, Christopher | O'Connell, Jeffery R. | Onland-Moret, N. Charlotte | Ouwehand, Willem H. | Palmas, Walter | Penninx, Brenda W. | Pepine, Carl J. | Pettinger, Mary | Polak, Joseph F. | Ramachandran, Vasan S. | Ranchalis, Jane | Redline, Susan | Ridker, Paul M. | Rose, Lynda M. | Scharnag, Hubert | Schork, Nicholas J. | Shimbo, Daichi | Shuldiner, Alan R. | Srinivasan, Sathanur R. | Stolk, Ronald P. | Taylor, Herman A. | Thorand, Barbara | Trip, Mieke D. | van Duijn, Cornelia M. | Verschuren, W. Monique | Wijmenga, Cisca | Winkelmann, Bernhard R. | Wyatt, Sharon | Young, J. Hunter | Boehm, Bernhard O. | Caulfield, Mark J. | Chasman, Daniel I. | Davidson, Karina W. | Doevendans, Pieter A. | FitzGerald, Garret A. | Gums, John G. | Hakonarson, Hakon | Hillege, Hans L. | Illig, Thomas | Jarvik, Gail P. | Johnson, Julie A. | Kastelein, John J.P. | Koenig, Wolfgang | März, Winfried | Mitchell, Braxton D. | Murray, Sarah S. | Oldehinkel, Albertine J. | Rader, Daniel J. | Reilly, Muredach P. | Reiner, Alex P. | Schadt, Eric E. | Silverstein, Roy L. | Snieder, Harold | Stanton, Alice V. | Uitterlinden, André G. | van der Harst, Pim | van der Schouw, Yvonne T. | Samani, Nilesh J. | Johnson, Andrew D. | Munroe, Patricia B. | de Bakker, Paul I.W. | Zhu, Xiaofeng | Levy, Daniel | Keating, Brendan J. | Asselbergs, Folkert W.
Human Molecular Genetics  2013;22(16):3394-3395.
PMCID: PMC3888295
18.  Risk-Standardizing Survival for In-Hospital Cardiac Arrest to Facilitate Hospital Comparisons 
The purpose of this study is to develop a method for risk-standardizing hospital survival after cardiac arrest.
A foundation with which hospitals can improve quality is to be able to benchmark their risk-adjusted performance against other hospitals, something that cannot currently be done for survival after in-hospital cardiac arrest.
Within the Get With The Guidelines (GWTG)-Resuscitation registry, we identified 48,841 patients admitted between 2007 and 2010 with an in-hospital cardiac arrest. Using hierarchical logistic regression, we derived and validated a model for survival to hospital discharge and calculated risk-standardized survival rates (RSSRs) for 272 hospitals with at least 10 cardiac arrest cases.
The survival rate was 21.0% and 21.2% for the derivation and validation cohorts, respectively. The model had good discrimination (C-statistic 0.74) and excellent calibration. Eighteen variables were associated with survival to discharge, and a parsimonious model contained 9 variables with minimal change in model discrimination. Before risk adjustment, the median hospital survival rate was 20% (interquartile range: 14% to 26%), with a wide range (0% to 85%). After adjustment, the distribution of RSSRs was substantially narrower: median of 21% (interquartile range: 19% to 23%; range 11% to 35%). More than half (143 [52.6%]) of hospitals had at least a 10% positive or negative absolute change in percentile rank after risk standardization, and 50 (23.2%) had a ≥20% absolute change in percentile rank.
We have derived and validated a model to risk-standardize hospital rates of survival for in-hospital cardiac arrest. Use of this model can support efforts to compare hospitals in resuscitation outcomes as a foundation for quality assessment and improvement.
PMCID: PMC3769937  PMID: 23770167
cardiac arrest; risk adjustment; variation in care
19.  Efficacy of cilostazol on platelet reactivity and cardiovascular outcomes in patients undergoing percutaneous coronary intervention: insights from a meta-analysis of randomised trials 
Open Heart  2014;1(1):e000068.
Cilostazol overcomes high on-treatment platelet reactivity (HTPR) and reduces adverse cardiovascular (CV) outcomes after percutaneous coronary intervention (PCI). However, the role for triple antiplatelet therapy (TAPT) with cilostazol in addition to aspirin and clopidogrel after PCI is not well defined.
We conducted a MEDLINE/EMBASE/CENTRAL search for randomised trials, until May 2014, evaluating TAPT compared with dual antiplatelet therapy (DAPT) of aspirin and clopidogrel alone in patients undergoing PCI and reporting platelet reactivity and/or CV outcomes. The primary platelet reactivity outcome was differences in platelet reactivity unit (PRU) with secondary outcomes of %platelet inhibition and rate of HTPR. The primary CV outcome was major adverse cardiovascular events (MACE), with secondary outcomes of death, cardiovascular death, myocardial infarction, stent thrombosis (ST), target lesion revascularisation (TLR) and target vessel revascularisation (TVR) as well as safety outcomes of bleeding and drug discontinuations.
In 17 trials that evaluated platelet reactivity outcomes, the mean PRU value was 47.73 units lower with TAPT versus DAPT (95% CI −61.41 to −34.04, p<0.0001; mean PRU 182.90 vs 232.65). TAPT also increased platelet inhibition by 12.71% (95% CI 10.76 to 14.67, p<0.0001), and led to a 60% reduction in the risk of HTPR (relative risk=0.40; 95% CI 0.30 to 0.53) compared with DAPT. Moreover, among the 34 trials that evaluated CV outcomes, TAPT reduced the risk of MACE (incident rate ratio (IRR)=0.68; 95% CI 0.60 to 0.78), TLR (IRR=0.57; 95% CI 0.44 to 0.73), TVR (IRR=0.69; 95% CI 0.59 to 0.81) and ST (IRR=0.63; 95% CI 0.40 to 0.98) with no difference for other outcomes including bleeding, even in trials using drug-eluting stents. Drug discontinuation due to adverse effects was, however, higher with TAPT vs DAPT (IRR=1.59; 95% CI 1.32 to 1.91).
In patients undergoing PCI, addition of cilostazol to DAPT results in decreased platelet reactivity and a significant reduction in CV outcomes including ST, even in the drug-eluting stent era.
PMCID: PMC4189225  PMID: 25332804
20.  Metabolic Effects of Bariatric Surgery in Patients With Moderate Obesity and Type 2 Diabetes 
Diabetes Care  2013;36(8):2175-2182.
To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition.
This was a prospective, randomized, controlled trial of 60 subjects with uncontrolled type 2 diabetes (HbA1c 9.7 ± 1%) and moderate obesity (BMI 36 ± 2 kg/m2) randomized to IMT alone, IMT plus Roux-en-Y gastric bypass, or IMT plus sleeve gastrectomy. Assessment of β-cell function (mixed-meal tolerance testing) and body composition was performed at baseline and 12 and 24 months.
Glycemic control improved in all three groups at 24 months (N = 54), with a mean HbA1c of 6.7 ± 1.2% for gastric bypass, 7.1 ± 0.8% for sleeve gastrectomy, and 8.4 ± 2.3% for IMT (P < 0.05 for each surgical group versus IMT). Reduction in body fat was similar for both surgery groups, with greater absolute reduction in truncal fat in gastric bypass versus sleeve gastrectomy (−16 vs. −10%; P = 0.04). Insulin sensitivity increased significantly from baseline in gastric bypass (2.7-fold; P = 0.004) and did not change in sleeve gastrectomy or IMT. β-Cell function (oral disposition index) increased 5.8-fold in gastric bypass from baseline, was markedly greater than IMT (P = 0.001), and was not different between sleeve gastrectomy versus IMT (P = 0.30). At 24 months, β-cell function inversely correlated with truncal fat and prandial free fatty acid levels.
Bariatric surgery provides durable glycemic control compared with intensive medical therapy at 2 years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic β-cell function and reduces truncal fat, thus reversing the core defects in diabetes.
PMCID: PMC3714483  PMID: 23439632
21.  Association Between Obstructive Sleep Apnea Severity and Endothelial Dysfunction 
Journal of sleep research  2013;22(4):443-451.
The objective of the study is to examine whether increasing OSA severity is associated with worsening endothelial function.
The design is a cross-sectional examination of the baseline assessment of a multicenter randomized controlled clinical trial examining the effects of oxygen, CPAP therapy, or lifestyle modifications on cardiovascular biomarkers. Participants were recruited from cardiology clinics at four sites. Participants with an Apnea Hypopnea Index (AHI) of 15 to 50 and known cardio/cerebrovascular disease (CVD) or CVD risk factors were included.
OSA severity indices (oxygen desaturation index [ODI], AHI, and percent sleep time below 90% oxygen saturation [TST<90]) and a measure of endothelium mediated vasodilatation (Framingham Reactive Hyperemia Index, F-RHI derived from peripheral arterial tonometry, PAT) were assessed.
The sample included 267 individuals with a mean AHI of 25.0 ± 8.5 (SD) and mean F-RHI 0.44 ± 0.38. In adjusted models, the slope of the relationship between ODI and F-RHI differed above and below an ODI of 24.6 (p=0.04), such that above an ODI of 24.6 there was a marginally significant decline in the geometric mean of the PAT ratio by 3% (95% CI: (0%, 5%); p=0.05) while below this point, there was a marginally significant incline in the geometric mean of the PAT ratio by 13% (95% CI: (0%, 27%); p=0.05) per 5-unit increase in ODI. A similar pattern was observed between AHI and F-RHI. No relation was noted with TST<90 and F-RHI.
There was evidence of a graded decline in endothelial function in association withn higher levels of intermittent hypoxemia.
PMCID: PMC4011016  PMID: 23331757
Sleep apnea; Cardiovascular disease; Endothelial dysfunction
22.  Non‐ST‐Elevation Myocardial Infarction in the United States: Contemporary Trends in Incidence, Utilization of the Early Invasive Strategy, and In‐Hospital Outcomes 
There has been a paradigm shift in the definition of timing of early invasive strategy (EIS) for patients admitted with non‐ST‐elevation myocardial infarction (NSTEMI) in the last decade. Data on trends of EIS for NSTEMI and associated in‐hospital outcomes are limited. Our aim is to analyze temporal trends in the incidence, utilization of early invasive strategy, and in‐hospital outcomes of NSTEMI in the United States.
Methods and Results
We analyzed the 2002–2011 Nationwide Inpatient Sample databases to identify all patients ≥40 years of age with the principal diagnosis of acute myocardial infarction (AMI) and NSTEMI. Logistic regression was used for overall, age‐, sex‐, and race/ethnicity‐stratified trend analysis. From 2002 to 2011, we identified 6 512 372 patients with AMI. Of these, 3 981 119 (61.1%) had NSTEMI. The proportion of patients with NSTEMI increased from 52.8% in 2002 to 68.6% in 2011 (adjusted odds ratio [OR; per year], 1.055; 95% confidence interval [CI], 1.054 to 1.056) in the overall cohort. Similar trends were observed in age‐, sex‐, and race/ethnicity‐stratified groups. From 2002 to 2011, utilization of EIS at day 0 increased from 14.9% to 21.8% (Ptrend<0.001) and utilization of EIS at day 0 or 1 increased from 27.8% to 41.4% (Ptrend<0.001). Risk‐adjusted in‐hospital mortality in the overall cohort decreased during the study period (adjusted OR [per year], 0.976; 95% CI, 0.974 to 0.978).
There have been temporal increases in the proportion of NSTEMI and, consistent with guidelines, greater utilization of EIS. This has been accompanied by temporal decreases in in‐hospital mortality and length of stay.
PMCID: PMC4310389  PMID: 25074695
early invasive strategy; in‐hospital mortality; non‐ST‐elevation myocardial infarction; temporal trends
23.  Obstructive sleep apnea and diurnal nondipping hemodynamic indices in patients at increased cardiovascular risk 
Journal of hypertension  2014;32(2):267-275.
We hypothesized increasing obstructive sleep apnea (OSA) severity would be associated with nondipping blood pressure (BP) in increased cardiovascular disease (CVD) risk.
Baseline data from 298 cardiology patients recruited for a multicenter randomized controlled trial were examined. Dipping was defined as a sleep-related BP or heart rate (HR) reduction of at least 10%. Logistic regression models were fit, adjusting for age, sex, race, BMI, CVD risk factors, CVD, and study site.
There was a statistically significant 4% increase in the odds of nondipping SBP per 1-unit increase in both Apnea Hypopnea Index (AHI) and Oxygen Desaturation Index (ODI). There was no significant relationship between AHI and nondipping mean arterial pressure (MAP); however, a 3% increase in the odds of nondipping MAP per 1-unit increase in ODI was observed (odds ratio, OR =1.03; 95% confidence interval, CI 1.00–1.05). At severe OSA levels, a 10 and 4% increase in odds of nondipping DBP per 1-unit increase in AHI and ODI were observed, respectively. A 6% [OR =1.06; 95% CI (1.01–1.10)] increase in nondipping HR odds was observed with each increase in ODI until the upper quartile of ODI.
In patients at cardiovascular risk and moderate-to-severe OSA, increasing AHI and/or ODI were associated with increased odds of nondipping SBP and nondipping MAP. More severe levels of AHI and ODI also were associated with nondipping DBP. These results support progressive BP burden associated with increased OSA severity even in patients managed by cardiology specialty care.
PMCID: PMC4096765  PMID: 24351803
cardiovascular disease; hypertension; hypoxia; sleep apnea
24.  Discharge to a Skilled Nursing Facility and Subsequent Clinical Outcomes Among Older Patients Hospitalized for Heart Failure 
Circulation. Heart failure  2011;4(3):293-300.
Heart failure (HF) is the leading cause of hospitalization among older Americans. Subsequent discharge to skilled nursing facilities (SNF) is not well described.
Methods and Results
We performed an observational analysis of Medicare beneficiaries ≥65 years of age, discharged alive to SNF or home after ≥3-day hospitalization for HF in 2005 and 2006 within the Get With The Guidelines–HF Program. Among 15 459 patients from 149 hospitals, 24.1% were discharged to an SNF, 22.3% to home with home health service, and 53.6% to home with self-care. SNF use varied significantly among hospitals (median, 10.2% versus 33.9% in low versus high tertiles), with rates highest in the Northeast. Patient factors associated with discharge to SNF included longer length of stay, advanced age, female sex, hypotension, higher ejection fraction, absence of ischemic heart disease, and a variety of comorbidities. Performance measures were modestly lower for patients discharged to SNF. Unadjusted absolute event rates were higher at 30 days (death, 14.4% versus 4.1%; rehospitalization, 27.0% versus 23.5%) and 1 year (death, 53.5% versus 29.1%; rehospitalization, 76.1% versus 72.2%) after discharge to SNF versus home, respectively (P<0.0001 for all). After adjustment for measured patient characteristics, discharge to SNF remained associated with increased death (hazard ratio, 1.76; 95% confidence interval, 1.66 to 1.87) and rehospitalization (hazard ratio, 1.08; 95% confidence interval, 1.03 to 1.14).
Discharge to SNF is common among Medicare patients hospitalized for HF, and these patients face substantial risk for adverse events, with more than half dead within 1 year. These findings highlight the need to better characterize this unique patient population and understand the SNF care they receive.
PMCID: PMC4096790  PMID: 21447803
heart failure; discharge status; disposition; skilled nursing facility; outcomes; risk; mortality; rehospitalization

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