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1.  Clopidogrel and proton pump inhibitors 
doi:10.1503/cmaj.114-0015
PMCID: PMC3928218  PMID: 24549709
2.  Variation in CAD Secondary Prevention Prescription among Outpatient Cardiology Practices: Insights from the NCDR® 
Objectives
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®.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2013.09.053
PMCID: PMC3990248  PMID: 24184238
CAD; Outpatient Practice; Secondary Prevention
3.  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.
Objective
To examine whether rates of inappropriate PCI differ by demographic characteristics and insurance status.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jacc.2013.07.086
PMCID: PMC3864986  PMID: 24055743
4.  CPAP versus Oxygen in Obstructive Sleep Apnea 
The New England journal of medicine  2014;370(24):2276-2285.
Background
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.
Methods
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.
Results
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.
Conclusions
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 ClinicalTrials.gov number, NCT01086800.)
doi:10.1056/NEJMoa1306766
PMCID: PMC4172401  PMID: 24918372
5.  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.
doi:10.4065/mcp.2011.0010
PMCID: PMC3184025  PMID: 21964173
6.  Smoking, Clopidogrel, and Mortality in Patients with Established Cardiovascular Disease 
Circulation  2009;120(23):2337.
Background
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).
Conclusion
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.
doi:10.1161/CIRCULATIONAHA.109.866533
PMCID: PMC2814172  PMID: 19933933
Smoking; Clopidogrel; Mortality; Cardiovascular disease
7.  The Clinical Profile and Under-Diagnosis of Pulmonary Hypertension in U.S. Veteran Patients 
Circulation. Heart failure  2013;6(5):906-912.
Background
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.
Conclusions
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.
doi:10.1161/CIRCHEARTFAILURE.112.000091
PMCID: PMC3894604  PMID: 23811965
pulmonary hypertension; diagnostic method; population
9.  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.
doi:10.1093/hmg/ddt177
PMCID: PMC3888295
10.  Risk-Standardizing Survival for In-Hospital Cardiac Arrest to Facilitate Hospital Comparisons 
Objectives
The purpose of this study is to develop a method for risk-standardizing hospital survival after cardiac arrest.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2013.05.051
PMCID: PMC3769937  PMID: 23770167
cardiac arrest; risk adjustment; variation in care
11.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1136/openhrt-2014-000068
PMCID: PMC4189225  PMID: 25332804
CORONARY ARTERY DISEASE
12.  Metabolic Effects of Bariatric Surgery in Patients With Moderate Obesity and Type 2 Diabetes 
Diabetes Care  2013;36(8):2175-2182.
OBJECTIVE
To evaluate the effects of two bariatric procedures versus intensive medical therapy (IMT) on β-cell function and body composition.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc12-1596
PMCID: PMC3714483  PMID: 23439632
13.  Association Between Obstructive Sleep Apnea Severity and Endothelial Dysfunction 
Journal of sleep research  2013;22(4):443-451.
Summary
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.
doi:10.1111/jsr.12026
PMCID: PMC4011016  PMID: 23331757
Sleep apnea; Cardiovascular disease; Endothelial dysfunction
14.  Non‐ST‐Elevation Myocardial Infarction in the United States: Contemporary Trends in Incidence, Utilization of the Early Invasive Strategy, and In‐Hospital Outcomes 
Background
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).
Conclusions
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.
doi:10.1161/JAHA.114.000995
PMCID: PMC4310389  PMID: 25074695
early invasive strategy; in‐hospital mortality; non‐ST‐elevation myocardial infarction; temporal trends
15.  Obstructive sleep apnea and diurnal nondipping hemodynamic indices in patients at increased cardiovascular risk 
Journal of hypertension  2014;32(2):267-275.
Rationale
We hypothesized increasing obstructive sleep apnea (OSA) severity would be associated with nondipping blood pressure (BP) in increased cardiovascular disease (CVD) risk.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/HJH.0000000000000011
PMCID: PMC4096765  PMID: 24351803
cardiovascular disease; hypertension; hypoxia; sleep apnea
16.  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.
Background
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).
Conclusions
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.
doi:10.1161/CIRCHEARTFAILURE.110.959171
PMCID: PMC4096790  PMID: 21447803
heart failure; discharge status; disposition; skilled nursing facility; outcomes; risk; mortality; rehospitalization
18.  Socioeconomic Disparities in Use of Cardioprotective Medications Among Patients with Peripheral Artery Disease—An Analysis of the American College of Cardiology’s NCDR PINNACLE Registry® 
Objective
Examine disparities in use of cardioprotective medications in treatment of peripheral artery disease (PAD) by socioeconomic status (SES).
Background
PAD is associated with increased cardiovascular risk and is more prevalent among those of lower SES. However, the use of guideline-recommended secondary preventive measures for the treatment of PAD across diverse income subgroups and the influence of practice site on potential treatment disparities by SES are unknown.
Methods
Within the National Cardiovascular Disease Registry (NCDR®) PINNACLE Registry®, 62,690 patients with PAD were categorized into quintiles of SES, as defined by the median income of each patient’s zip code. The association between SES and secondary prevention treatment with antiplatelet and statin medications was evaluated using sequential hierarchical modified Poison models, adjusting first for practice site and then for clinical variables.
Results
Compared with the highest SES quintile (median income >$60,868), PAD patients in the lowest SES quintile (median income <$34,486) were treated less often with statins (72.5 % vs. 85.8%; RR 0.84 [0.83–0.86]; P<0.001) and antiplatelet therapy (79.0% vs. 84.6 %; RR 0.93 [95% CI: 0.91–0.94]; P<0.001). These differences were markedly attenuated after controlling for practice site variation: statins (adjusted RR: 0.97 [0.95–0.99]; P=0.003) and antiplatelet therapy (adjusted RR 0.98 [0.97–1.00]; P=0.012). Additional adjustment for patients’ clinical characteristics had minimal impact with slight further attenuation: statins (adjusted RR: 1.00 [0.99–1.01]; p=0.772) and antiplatelet therapy (adjusted RR: 1.00 [0.99–1.01]; p=0.878).
Conclusion
Among PAD patients, the practice site at which patients received care largely explained the observed SES differences in treatment with guidelines-recommended secondary prevention medications. Future efforts to reduce treatment disparities in these vulnerable populations should target systems improvement at practices serving high proportions of patients with low SES.
doi:10.1016/j.jacc.2013.04.018
PMCID: PMC3912073  PMID: 23643497
19.  Age Differences in the Use of Implantable Cardioverter-Defibrillators Among Older Patients Hospitalized With Heart Failure 
Introduction
Practice guidelines recommend the use of ICDs in patients with heart failure (HF) and a left ventricular ejection fraction (LVEF) of ≤ 35% in the absence of contraindications.
Methods and Results
We performed an analysis of ICD use among patients admitted with HF with LVEF of ≤ 35% and discharged alive from 251 hospitals participating in the American Heart Association’s Get With The Guidelines-HF Program between January 2005 and September 2011. Among 35,772 guideline-eligible patients, 17,639 received an ICD prior to hospitalization (10,886), during hospitalization (4,876), or were discharged with plans to undergo ICD placement after hospitalization (1,877). After adjustment, increasing age was associated with lower ICD use (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.87–0.91 per 5-year increase in age, p<0.0001). Compared with patients age < 55 years, older age groups ≥ 65 years were less likely to receive an ICD (p<0.003). Compared with men in the same age group, women were significantly less likely to receive an ICD; this difference was more marked with increasing age (p-value for interaction=0.006). There was a temporal increase in ICD use (adjusted OR 1.23, 95% CI 1.15–1.31 of ICD use per year) that was similar in each age group (p-value for interaction =0.665).
Conclusions
Eligible older HF patients age ≥ 65 years were significantly less likely to receive an ICD. With increasing age, women were less likely to receive an ICD than men. ICD use significantly increased over time in all age groups; however, age-related differences in ICD use persisted.
doi:10.1111/jce.12100
PMCID: PMC4076932  PMID: 23437793
defibrillator; implantable; heart failure; healthcare disparities; age; sex
20.  Patterns of Care Quality and Prognosis Among Hospitalized Ischemic Stroke Patients With Chronic Kidney Disease 
Background
Relatively little is known about the quality of care and outcomes for hospitalized ischemic stroke patients with chronic kidney disease (CKD). We examined quality of care and in‐hospital prognoses among patients with CKD in the Get With The Guidelines–Stroke (GWTG‐Stroke) program
Methods and Results
We analyzed 679 827 patients hospitalized with ischemic stroke from 1564 US centers participating in the GWTG‐Stroke program between January 2009 and December 2012. Use of 7 predefined ischemic stroke performance measures, composite “defect‐free” care compliance, and in‐hospital mortality were examined based on glomerular filtration rate (GFR) categorized as a dichotomous (+CKD as <60) or rank‐ordered variable: normal (≥90), mild (≥60 to <90), moderate (≥30 to <60), severe (≥15 to <30), and kidney failure (<15 or dialysis). There were 236 662 (35%) ischemic stroke patients with CKD. Patients with severe renal dysfunction or failure were significantly less likely to receive guideline‐based therapies. Compared with patients with normal kidney function (≥90), those with CKD (adjusted OR 0.91 [95% CI: 0.89 to 0.92]), moderate dysfunction (adjusted OR 0.94 [95% CI: 0.92 to 0.97]), severe dysfunction (adjusted OR 0.80 [95% CI: 0.77 to 0.84]), or failure (adjusted OR 0.72 [95% CI: 0.68 to 0.0.76]), were less likely to receive 100% defect‐free care measure compliance. Inpatient mortality was higher for patients with CKD (adjusted odds ratio 1.44 [95% CI: 1.40 to 1.47]), and progressively rose with more severe renal dysfunction.
Conclusions
Despite higher in‐hospital mortality rates, ischemic stroke patients with CKD, especially those with greater severity of renal dysfunction, were less likely to receive important guideline‐recommended therapies.
doi:10.1161/JAHA.114.000905
PMCID: PMC4309090  PMID: 24904017
chronic kidney disease; glomerular Filtration Rate; guidelines; ischemic stroke; outcomes; prognosis; quality indicators; renal
21.  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, Jessic A. | 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(8):1663-1678.
Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10−6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
doi:10.1093/hmg/dds555
PMCID: PMC3657476  PMID: 23303523
22.  Computed tomography-based diagnosis of diffuse compensatory enlargement of coronary arteries using scaling power laws 
Glagov's positive remodelling in the early stages of coronary atherosclerosis often results in plaque rupture and acute events. Because positive remodelling is generally diffused along the epicardial coronary arterial tree, it is difficult to diagnose non-invasively. Hence, the objective of the study is to assess the use of scaling power law for the diagnosis of positive remodelling of coronary arteries based on computed tomography (CT) images. Epicardial coronary arterial trees were reconstructed from CT scans of six Ossabaw pigs fed on a high-fat, high-cholesterol, atherogenic diet for eight months as well as the same number of body-weight-matched farm pigs fed on a lean chow (101.9±16.1 versus 91.5±13.1 kg). The high-fat diet Ossabaw pig model showed diffuse positive remodelling of epicardial coronary arteries. Good fit of measured coronary data to the length–volume scaling power law ( where Lc and Vc are crown length and volume) were found for both the high-fat and control groups (R2 = 0.95±0.04 and 0.99±0.01, respectively). The coefficient, KLV, decreased significantly in the high-fat diet group when compared with the control (14.6±2.6 versus 40.9±5.6). The flow–length scaling power law, however, was nearly unaffected by the positive remodelling. The length–volume and flow–length scaling power laws were preserved in epicardial coronary arterial trees after positive remodelling. KLV < 18 in the length–volume scaling relation is a good index of positive remodelling of coronary arteries. These findings provide a clinical rationale for simple, accurate and non-invasive diagnosis of positive remodelling of coronary arteries, using conventional CT scans.
doi:10.1098/rsif.2012.1015
PMCID: PMC3627114  PMID: 23365197
coronary compensatory enlargement; scaling power law; computed tomography
23.  P2RY1 and P2RY12 polymorphisms and on-aspirin platelet reactivity in patients with coronary artery disease 
SUMMARY
Introduction
Association of P2RY1 and P2RY12 polymorphisms with on-aspirin platelet reactivity was investigated.
Materials and Methods
Platelet reactivity was assessed by light transmission aggregometry and TxB2 assay in 423 CAD (coronary artery disease) patients on aspirin. High residual platelet reactivity (RPR) was defined by≥20% and ≥70% maximal aggregation stimulated with 0.5 mg/mL AA and 10 μM ADP, respectively. Moderate RPR was considered aggregation ≥20% with AA, ≥70% with ADP, or ≥1 ng/mL stimulated TxB2. Fourteen P2RY1 and 35 P2RY12 SNPs were genotyped.
Results
High RPR was detected in 24% of the patients. Moderate RPR was observed in 31% with AA, 57% with 5 μM ADP, and 82% with 10 μM ADP. Stimulated TxB2 was ≥1 ng/mL in 23% of patients. P2RY12 SNP rs9859538 was associated with high RPR (OR=2.16, 95% CI=1.24–3.75, p-value=0.004). Four P2RY12 SNPs, rs1491974, rs10513398, rs3732765, and rs10935841, showed association with moderate RPR (OR=1.79–2.94, p-value=0.04–0.028), while five, rs7615865, rs1388623, rs1388622, rs7634096, and rs7637803, were associated with low RPR (OR=0.50–0.55, p-value=0.008–0.026), following ADP stimulation. TxB2 level <1 ng/mL was linked to five P2RY1 SNPs, rs1439010, rs1371097, rs701265, rs12497578, and rs2312265, (OR=0.36–0.54, p-value=0.003–0.039).
Conclusions
Polymorphisms in P2RY1 and P2RY12 are associated with on-aspirin platelet reactivity in CAD patients.
doi:10.1111/j.1751-553X.2012.01420.x
PMCID: PMC3419334  PMID: 22574824
Coronary artery disease; aspirin; platelet reactivity; P2RY1 and P2RY12 receptors; SNP
24.  Use of Hydralazine‐Isosorbide Dinitrate Combination in African American and Other Race/Ethnic Group Patients With Heart Failure and Reduced Left Ventricular Ejection Fraction 
Background
Hydralazine‐isosorbide dinitrate (H‐ISDN) therapy is recommended for African American patients with moderate to severe heart failure with reduced ejection fraction (<40%) (HFrEF), but use, temporal trends, and clinical characteristics associated with H‐ISDN therapy in clinical practice are unknown.
Methods and Results
An observational analysis of 54 622 patients admitted with HFrEF and discharged home from 207 hospitals participating in the Get With The Guidelines–Heart Failure registry from April 2008 to March 2012 was conducted to assess prescription, trends, and predictors of use of H‐ISDN among eligible patients. Among 11 185 African American patients eligible for H‐ISDN therapy, only 2500 (22.4%) received H‐ISDN therapy at discharge. In the overall eligible population, 5115 of 43 498 (12.6%) received H‐ISDN at discharge. Treatment rates increased over the study period from 16% to 24% among African Americans and from 10% to 13% among the entire HFrEF population. In a multivariable model, factors associated with H‐ISDN use among the entire cohort included younger age; male sex; African American/Hispanic ethnicity; and history of diabetes, hypertension, anemia, renal insufficiency, higher systolic blood pressure, and lower heart rate. In African American patients, these factors were similar; in addition, being uninsured was associated with lower use.
Conclusions
Overall, few potentially eligible patients with HFrEF are treated with H‐ISDN, and among African‐Americans fewer than one‐fourth of eligible patients received guideline‐recommended H‐ISDN therapy. Improved ways to facilitate use of H‐ISDN therapy in African American patients with HFrEF are needed.
doi:10.1161/JAHA.113.000214
PMCID: PMC3828812  PMID: 23966379
guideline adherence; heart failure; quality; race/ethnicity; registry
25.  Polyvascular Disease and Long-term Cardiovascular Outcomes in Older Patients with Non–ST-segment Elevation Myocardial Infarction 
Background
The impact of polyvascular disease (peripheral arterial disease [PAD] and/or cerebrovascular disease [CVD]) on long-term cardiovascular outcomes among older patients with acute myocardial infarction (MI) has not been well studied.
Methods
Non–ST-elevation MI (NSTEMI) patients aged ≥65 years from the CRUSADE registry who survived to hospital discharge were linked to longitudinal data from the Centers for Medicare and Medicaid Services (n=34,205). All patients were presumed to have coronary artery disease (CAD) and were classified into 4 groups: 10.7% had prior CVD (CAD+CVD group); 11.5% had prior PAD (CAD+PAD); 3.1% had prior PAD and CVD (CAD+PAD+CVD); and 74.7% had no polyvascular disease (CAD alone). Cox proportional hazard modeling was used to examine the hazard of long-term mortality and the composite of death, readmission for MI, or readmission for stroke (median follow-up 35 months, IQR 17–49) among the 4 groups.
Results
Compared with the CAD-alone group, patients with polyvascular disease had a greater comorbidity burden, were less likely to undergo revascularization, and less often received recommended discharge interventions. Three-year mortality rates increased with a greater number of arterial beds involved: 33% for CAD alone, 49% for CAD+PAD, 52% for CAD+CVD, and 59% for CAD+PAD+CVD. Relative to the CAD-alone group, patients with all 3 arterial beds involved had the highest risk of long-term mortality (adjusted HR [95% CI]: 1.49 [1.38–1.61], with a lower risk for those with CAD+CVD, 1.38 [1.31–1.44], and those with CAD+PAD, 1.29 [1.23–1.35]). Similarly, the adjusted risk of long-term composite ischemic events was highest among the CAD+PAD+CVD group.
Conclusions
Older NSTEMI patients with polyvascular disease have substantially higher long-term risk, such that the 3-year mortality rate is >50%. Future studies targeting greater adherance to secondary prevention strategies and novel therapies are needed to help reduce long-term cardiovascular events in this vulnerable population.
doi:10.1161/CIRCOUTCOMES.111.964379
PMCID: PMC3707283  PMID: 22715460

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