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1.  Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial 
European Heart Journal  2013;35(4):233-241.
Aims
We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.
Methods and results
In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73–1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59–3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).
Conclusion
Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.
doi:10.1093/eurheartj/eht428
PMCID: PMC3896862  PMID: 24132190
Atrial fibrillation; Myocardial infarction; Coronary artery disease; Outcomes; Factor Xa; Rivaroxaban; Warfarin
2.  Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation 
Circulation  2014;129(18):1850-1859.
Background
During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.
Methods and Results
In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non–central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3–30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36–1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80–2.00]; P=0.32).
Conclusions
TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.
doi:10.1161/CIRCULATIONAHA.113.005754
PMCID: PMC4206548  PMID: 24552831
anticoagulation; atrial fibrillation; stroke
3.  Funding opportunities for clinical investigators in the early stages of career development in cardiovascular research 
Contemporary cardiovascular research offers junior investigators the opportunity to explore the gamut of biomedical questions. Despite the recent reduction in the availability of funding mechanisms that have historically served as the primary pathways for investigators in the early stages of career development, there remain numerous traditional and non-traditional funding opportunities. This article highlights these opportunities in order to assist early career investigators in the development of a personalized research trajectory, which optimizes the potential for career success.
doi:10.1007/s11239-013-0970-4
PMCID: PMC3906627  PMID: 23860882
Cardiovascular investigator; Grant opportunities; Funding; Junior researcher
4.  Factors Associated With Major Bleeding Events 
Objectives
This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
Background
The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.
Methods
The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.
Results
The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.
Conclusions
Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767)
doi:10.1016/j.jacc.2013.11.013
PMCID: PMC4206565  PMID: 24315894
anticoagulants; atrial fibrillation; hemorrhage
5.  Aspirin Exposure Reveals Novel Genes Associated with Platelet Function and Cardiovascular Events 
Objectives
To develop RNA profiles that could serve as novel biomarkers for the response to aspirin.
Background
Aspirin reduces death and myocardial infarction (MI) suggesting that aspirin interacts with biological pathways that may underlie these events.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jacc.2013.05.073
PMCID: PMC3786046  PMID: 23831034
aspirin; platelets; genes; myocardial infarction; biomarkers
6.  A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial 
European Heart Journal  2012;34(31):2481-2489.
Aims
We sought to determine the degree of anticoagulation reversal required to mitigate bleeding, and assess the feasibility of using pegnivacogin to prevent ischaemic events in acute coronary syndrome (ACS) patients managed with an early invasive approach. REG1 consists of pegnivacogin, an RNA aptamer selective factor IXa inhibitor, and its complementary controlling agent, anivamersen. REG1 has not been studied in invasively managed patients with ACS nor has an optimal level of reversal allowing safe sheath removal been defined.
Methods and results
Non-ST-elevation ACS patients (n = 640) with planned early cardiac catheterization via femoral access were randomized 2:1:1:2:2 to pegnivacogin with 25, 50, 75, or 100% anivamersen reversal or heparin. The primary endpoint was total ACUITY bleeding through 30 days. Secondary endpoints included major bleeding and the composite of death, myocardial infarction, urgent target vessel revascularization, or recurrent ischaemia. Enrolment in the 25% reversal arm was suspended after 41 patients. Enrolment was stopped after three patients experienced allergic-like reactions. Bleeding occurred in 65, 34, 35, 30, and 31% of REG1 patients with 25, 50, 75, and 100% reversal and heparin. Major bleeding occurred in 20, 11, 8, 7, and 10% of patients. Ischaemic events occurred in 3.0 and 5.7% of REG1 and heparin patients, respectively.
Conclusion
At least 50% reversal is required to allow safe sheath removal after cardiac catheterization. REG1 appears a safe strategy to anticoagulate ACS patients managed invasively and warrants further investigation in adequately powered clinical trials of patients who require short-term high-intensity anticoagulation. Clinical Trials Registration: ClinicalTrials.gov NCT00932100.
doi:10.1093/eurheartj/ehs232
PMCID: PMC3895957  PMID: 22859796
Acute coronary syndromes; Anticoagulation reversal; REG1
7.  Genetic Regulation of Platelet Receptor Expression and Function: Application in Clinical Practice and Drug Development 
Understanding genetic contributions to platelet function could have profound clinical ramifications for personalizing platelet-directed pharmacotherapy, by providing insight into the risks and possible benefits associated with specific genotypes. This article represents an integrated summary of presentations related to genetic regulation of platelet receptor expression and function given at the Fifth Annual Platelet Colloquium in January 2010. It is supplemented with additional highlights from the literature covering 1) approaches to determining and evidence for the associations of genetic variants with platelet hypo- and hyperresponsive phenotypes, 2) the ramifications of these polymorphisms with regard to clinical responses to antiplatelet therapies, and 3) the role of platelet function/genetic testing in guiding antiplatelet therapy.
doi:10.1161/ATVBAHA.110.218131
PMCID: PMC4118751  PMID: 21084706
8.  The Effect of Aspirin on Endothelial Progenitor Cell Biology: Preliminary Investigation of Novel Properties 
Thrombosis research  2010;126(3):10.1016/j.thromres.2009.11.017.
Atherosclerosis develops in an environment of endothelial injury and inflammation. Circulating endothelial progenitor cells (EPCs) are required for vascular repair and restoration of normal endothelial function. We tested the hypothesis that the nonselective cyclooxygenase (COX) inhibitor aspirin exerts an effect on circulating EPCs.
Methods
As part of a larger study evaluating the effect of aspirin dose in primary and secondary prevention, subjects (n=32) were assigned randomly to either 81mg or 325mg aspirin daily for two months, and circulating mononuclear cells were enumerated at the beginning of the study and after 2 months using fluorescent antibodies against CD34 and CD133 as well as based on aldehyde dehydrogenase (ALDH) activity. Brachial artery endothelial function via flow-mediated dilation (BAFMD) and light transmittance platelet aggregometry in response to physiologic agonists was also determined.
Results
Subjects taking aspirin at the time of study entry had a lower numbers of CD133+/34+ cells compared to those not previously exposed (0.01% vs. 0.05% of MNCs, P<0.03). After 2 months, subjects randomized to 81 vs. 325 mg of ASA had no significant differences in the median numbers of EPCs, although mean numbers trended lower in the high dose group. Patients on chronic ASA therapy continued to have lower numbers of EPCs. Similar effects were observed in CD34 and CD 133 single-positive cells, as well as ALDHbr cells. BAFMD did not differ nor change significantly over time between aspirin dose groups. All patients had decreased ex vivo platelet aggregation in response to arachidonic acid and ADP stimulation.
Conclusions
Our preliminary studies suggest that aspirin exerts a time-dependent effect on circulating EPCs. Short-term exposure to differing doses of ASA had indeterminate effects on EPCs levels, suggesting that time of ASA exposure may play a more important role than dose. Determining the responsible mechanism(s) and the overall clinical relevance of these findings will require further investigation.
doi:10.1016/j.thromres.2009.11.017
PMCID: PMC3834257  PMID: 20659762
9.  Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial 
Background
Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons.
Methods and Results
TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger‐stick point‐of‐care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non‐central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower‐risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non‐major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values.
Conclusions
The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.
doi:10.1161/JAHA.113.000521
PMCID: PMC4187517  PMID: 24755148
rivaroxaban; time in therapeutic range; warfarin
10.  The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized, PLATelet inhibition and patient Outcomes (PLATO) trial 
European Heart Journal  2014;35(23):1541-1550.
Aims
The aim of this study was to assess the relationship between sex and clinical outcomes and treatment-related complications in patients with ST-elevation or non-ST-elevation acute coronary syndromes (ACS) randomized to treatment with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial.
Methods
The associations between sex subgroup and the primary composite outcomes, secondary outcomes, and major bleeding endpoints as well as interaction of sex subgroup with treatment effects were analysed using Cox proportional-hazards models.
Results
Sex was not significantly associated with the probability of the primary composite endpoint [adjusted hazard ratio (HR): 1.02 (0.91−1.16)], or other adverse cardiovascular endpoints. Ticagrelor was similarly more effective than clopidogrel in reducing rates of the primary endpoint in women 11.2 vs. 13.2% [adjusted HR: 0.88 (0.74−1.06)] and men 9.4 vs. 11.1% [adjusted HR: 0.86 (0.76−0.97)] (interaction P-value 0.78), all-cause death in women 5.8 vs. 6.8% [adjusted HR: 0.90 (0.69−1.16)] and men 4.0 vs. 5.7% [adjusted HR: 0.80 (0.67−0.96)] (interaction P-value 0.49), and definite stent thrombosis in women 1.2 vs. 1.4% [adjusted HR: 0.71 (0.36−1.38)] and men 1.4 vs. 2.1% [adjusted HR: 0.63 (0.45−0.89)] (interaction P-value 0.78). The treatments did not differ for PLATO-defined overall major bleeding complications in women [adjusted HR: 1.01 (0.83−1.23)] or men [adjusted HR: 1.10 (0.98−1.24)]. Sex had no significant association with these outcomes (interactions P = 0.43−0.88).
Conclusion
Female sex is not an independent risk factor for adverse clinical outcomes in moderate-to-high risk ACS patients. Ticagrelor has a similar efficacy and safety profile in men and women.
doi:10.1093/eurheartj/ehu075
PMCID: PMC4057642  PMID: 24682844
Acute coronary syndromes; Sex; Platelets; P2Y12 receptor; Ticagrelor; Thrombosis
11.  Clinical strategies for selecting oral anticoagulants in patients with atrial fibrillation 
Atrial fibrillation is a common arrhythmia. One of the important aspects of the management of atrial fibrillation is stroke prevention. Warfarin has been the longstanding anticoagulant used for stroke prevention in patients with atrial fibrillation. There are now three novel oral anticoagulants, which have been studied in randomized controlled trials and subsequently approved by the Federal Drug Administration for stroke prevention in patients with atrial fibrillation. Special patient populations, including renal insufficiency, elderly, prior stroke, and extreme body weights, were represented to varying degrees in the clinical trials of the novel oral anticoagulants. Furthermore, there is variation in the pharmacokinetics and pharmacodynamics of each anticoagulant, which affect the patient populations differently. Patients and clinicians are faced with the task of selecting among the available anticoagulants, and this review is designed to be a tool for clinical decision-making.
doi:10.1007/s11239-013-0956-2
PMCID: PMC3937965  PMID: 23846737
Atrial fibrillation; Anticoagulation; Novel oral anticoagulants; Stroke; Warfarin
12.  Prevalence and Clinical Characteristics of Mental Stress–Induced Myocardial Ischemia in Patients With Coronary Heart Disease 
Objectives
The goal of this study was to evaluate the prevalence and clinical characteristics of mental stress–induced myocardial ischemia.
Background
Mental stress–induced myocardial ischemia is prevalent and a risk factor for poor prognosis in patients with coronary heart disease, but past studies mainly studied patients with exercise-induced myocardial ischemia.
Methods
Eligible patients with clinically stable coronary heart disease, regardless of exercise stress testing status, underwent a battery of 3 mental stress tests followed by a treadmill test. Stress-induced ischemia, assessed by echocardiography and electrocardiography, was defined as: 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥8%; and/or 3) horizontal or downsloping ST-segment depression ≥1 mm in 2 or more leads lasting for ≥3 consecutive beats during at least 1 mental test or during the exercise test.
Results
Mental stress–induced ischemia occurred in 43.45%, whereas exercise-induced ischemia occurred in 33.79% (p = 0.002) of the study population (N = 310). Women (odds ratio [OR]: 1.88), patients who were not married (OR: 1.99), and patients who lived alone (OR: 2.24) were more likely to have mental stress–induced ischemia (all p < 0.05). Multivariate analysis showed that compared with married men or men living with someone, unmarried men (OR: 2.57) and married women (OR: 3.18), or living alone (male OR: 2.25 and female OR: 2.72, respectively) had higher risk for mental stress-induced ischemia (all p < 0.05).
Conclusions
Mental stress-induced ischemia is more common than exercise-induced ischemia in patients with clinically stable coronary heart disease. Women, unmarried men, and individuals living alone are at higher risk for mental stress-induced ischemia. (Responses of Myocardial Ischemia to Escitalopram Treatment [REMIT]; NCT00574847)
doi:10.1016/j.jacc.2012.11.037
PMCID: PMC3913125  PMID: 23410543
mental and exercise stress; myocardial ischemia
14.  Hyperreactive platelet phenotypes: Relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation 
Thrombosis and haemostasis  2012;109(1):85-92.
Summary
The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics to platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modeling. Stimulation with submaximal (2 μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.
doi:10.1160/TH12-03-0202
PMCID: PMC3582386  PMID: 23223800
Platelets; platelet activity; serotonin; epinephrine; transporter
15.  A Functional Polymorphism in the 5HTR2C Gene Associated with Stress Responses Also Predicts Incident Cardiovascular Events 
PLoS ONE  2013;8(12):e82781.
Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (rs6318) of the 5HTR2C gene located on the X-chromosome is associated with hypothalamic-pituitary-adrenal axis response to a stress recall task, and with endophenotypes associated with cardiovascular disease (CVD). These findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository. Study population consisted of 6,126 Caucasian participants (4,036 [65.9%] males and 2,090 [34.1%] females). A total of 1,769 events occurred (1,544 deaths and 225 MIs; median follow-up time =  5.3 years, interquartile range  = 3.3–8.2). Unadjusted Cox time-to-event regression models showed, compared to Cys23 G carriers, males hemizygous for Ser23 C and females homozygous for Ser23C were at increased risk for the composite endpoint of all-cause death or MI: Hazard Ratio (HR)  = 1.47, 95% confidence interval (CI)  = 1.17, 1.84, p  = .0008. Adjusting for age, rs6318 genotype was not related to body mass index, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries, or left ventricular ejection fraction in either males or females. After adjustment for these covariates the estimate for the two Ser23 C groups was modestly attenuated, but remained statistically significant: HR  = 1.38, 95% CI = 1.10, 1.73, p = .005. These findings suggest that this functional polymorphism of the 5HTR2C gene is associated with increased risk for CVD mortality and morbidity, but this association is apparently not explained by the association of rs6318 with traditional risk factors or conventional markers of atherosclerotic disease.
doi:10.1371/journal.pone.0082781
PMCID: PMC3867393  PMID: 24386118
16.  Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy 
Objectives
To develop an integrated metric of non COX-1 dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics.
Background
NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established.
Methods
We administered 325mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures.
Results
The PFS strongly correlated with each measure of NCDPF in each cohort. After two or four weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, p<0.0001) and was higher (p < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final - Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = −0.45), HV2 (r = −0.54), DM (r = −0.68), p<0.0001 for all. AAA remained suppressed during aspirin therapy.
Conclusions
The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time.
doi:10.1007/s11239-012-0683-0
PMCID: PMC3337886  PMID: 22294277
aspirin; platelets; light transmittance aggregometry; PFA100; principal components analysis
18.  Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial 
Background
Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.
Methods and Results
TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i‐TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐TTR was 55.2% (SD 21.3%) and the median i‐TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i‐TTR, dominant determinants were previous warfarin use (mean i‐TTR of 61.1% for warfarin‐experienced versus 47.4% in VKA‐naïve patients) and geographic region where patients were managed (mean i‐TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐TTRs had INR distributions shifted toward lower INR values and had longer inter‐INR test intervals.
Conclusions
Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐TTR in global studies of warfarin. Regional differences in mean i‐TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.
Clinical Trial Registration
URL: ClinicalTrials.gov. Unique identifier: NCT00403767.
doi:10.1161/JAHA.112.000067
PMCID: PMC3603243  PMID: 23525418
anticoagulants; arrhythmia; embolism; prevention; risk factors
19.  Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment: Background, Design, and Method for the REMIT Trial 
American Heart Journal  2011;163(1):20-26.
Background
Mental stress induced myocardial ischemia (MSIMI) is common in patients with clinically stable coronary heart disease (CHD) and is associated with poor outcomes. Depression is a risk factor of MSIMI. The Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment (REMIT) trial investigates whether selective serotonin reuptake inhibitor (SSRI) treatment can improve MSIMI. The rationale and outline of the study are described.
Method
In this single center randomized clinical trial, adult patients with clinically stable CHD are recruited for baseline mental and exercise stress testing assessed by echocardiography. Additionally, psychometric questionnaires are administered and blood samples are collected for platelet activity analysis. Patients who demonstrate MSIMI, defined by new abnormal wall motion, ejection fraction reduction ≥8%, and/or development of ischemic ST change in electrocardiogram during mental stress testing, are randomized at a 1:1 ratio to escitalopram or placebo for 6 weeks. Approximately 120 patients with MSIMI are enrolled in the trial. The stress testing, platelet activity assessment and psychometric questionnaires are repeated at the end of the 6-week intervention. The hypothesis of the study is that SSRI treatment improves MSIMI via mood regulation and modification of platelet activity.
Conclusion
The REMIT study examines the effect of SSRI on MSIMI in vulnerable CHD patients and probes some potential underlying mechanisms.
doi:10.1016/j.ahj.2011.09.018
PMCID: PMC3254211  PMID: 22172432
20.  Associations of depressive symptoms, trait hostility, and gender with C-reactive protein and interleukin-6 response following emotion recall 
Psychosomatic medicine  2010;72(4):333-339.
Objective
Depressive symptoms moderate the effect of trait hostility on circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6). We extended these findings by examination of the effects of depressive symptoms and hostility on changes in CRP and IL-6 in response to an acute laboratory stressor.
Methods
The study included 307 men and 218 women, affording the opportunity to examine moderation by gender. Regression analyses were performed to examine depressive symptoms, hostility ratings, gender, and their interactions as predictors of CRP and IL-6 response to an emotion recall task. Analyses were adjusted for age, race, body mass index, and pre-recall task levels of either CRP or IL-6.
Results
The product term for depressive symptoms × hostility × gender was not significantly related to CRP nor IL-6 response. However, depressive symptoms × hostility did interact to predict CRP response (p = .002); those with the combination of high symptoms of depression and hostility had the largest CRP response. The depressive symptoms × gender interaction was also a predictor of both CRP (p = .001) and IL-6 (p = .04) response; for each inflammatory marker depressive symptoms were significantly associated with higher CRP response in women, as compared to men. Hostility did not moderate depressive symptoms, nor gender for IL-6.
Conclusions
Our findings extend prior research by suggesting that, broadly speaking, depression is related to inflammatory markers, however this relation appears complex. Depression seems to be related to inflammation more strongly among hostile individuals, and more strongly among women than among men.
doi:10.1097/PSY.0b013e3181d2f104
PMCID: PMC2869533  PMID: 20190126
C-reactive protein; Interleukin-6; Anger Recall; Depressive Symptoms; Hostility; Gender
21.  Sex Differences in Mortality Following Acute Coronary Syndromes 
Context
There is conflicting information about whether sex-differences modulate short-term mortality following acute coronary syndromes (ACS).
Objective
To investigate the relationship between sex and 30-day mortality in ACS, and determine whether this relationship is modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.
Design Setting and Participants
Data from 11 ACS trials from 1993 to 2006 were pooled. Of 136,247 patients, 38,048 (28%) were women; 102,004 (26% women) STEMI, 14,466 (29% women) NSTEMI and 19,777 (40% women) unstable angina (UA).
Main Outcome Measure
Thirty-day mortality following ACS.
Results
Mortality at 30 days was 9.6% in women and 5.3% in men (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.83–2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR 1.06, 95% CI 0.99–1.15). Importantly, a significant sex by type of ACS interaction was demonstrated (P<0.001). In STEMI, 30-day mortality was higher among women (adjusted OR 1.15, 95% CI 1.06–1.24), whereas NSTEMI (adjusted OR 0.77, 95% CI 0.63–0.95), and UA mortality was lower among women (adjusted OR 0.55, 95% CI 0.43–0.70). In a cohort of 35,128 patients with angiographic data, women more often had non-obstructive (15% vs. 8%,) and less often had 2-vessel (25% vs. 28%) and 3-vessel (23% vs. 26%) coronary disease regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (p-value for interaction =0.70),
Conclusions
Sex-based differences exist in 30-day mortality among ACS patients and vary depending on clinical presentation. However, these differences are markedly attenuated following adjustment for clinical differences and angiographic data.
doi:10.1001/jama.2009.1227
PMCID: PMC2778841  PMID: 19706861
22.  DVT: A New Era in Anticoagulant Therapy 
doi:10.1161/ATVBAHA.110.203497
PMCID: PMC2848496  PMID: 20139354
23.  The Worcester Venous Thromboembolism Study A Population-Based Study of the Clinical Epidemiology of Venous Thromboembolism 
BACKGROUND
While there have been marked advances in diagnostic and therapeutic strategies for venous thromboembolism, our understanding of its clinical epidemiology is based on studies conducted more than a decade ago.
OBJECTIVES
The purpose of this observational study was to describe the incidence and attack rates of venous thromboembolism in residents of the Worcester Statistical Metropolitan Area in 1999. We also describe demographic and clinical characteristics, management strategies, and associated hospital and 30-day outcomes.
DESIGN AND MEASUREMENTS
The medical records of all residents from Worcester, MA (2000 census = 477,800), diagnosed with International Classification of Diseases, 9th revision (ICD-9) codes consistent with possible venous thromboembolism during 1999 were independently validated, classified, and reviewed by trained abstractors.
RESULTS
A total of 587 subjects were enrolled with validated venous thromboembolism. The incidence and attack rates of venous thromboembolism were 104 and 128 per 100,000 population, respectively. Three quarters of patients developed their venous thromboembolism in the outpatient setting – a substantial proportion of these patients had undergone recent surgery or had a recent prior hospitalization. Less than half of the patients received anticoagulant prophylaxis during high-risk periods before their venous thromboembolism. Thirty-day rates of venous thromboembolism recurrence, major bleeding, and mortality were 4.8%, 7.7%, and 6.6%, respectively.
CONCLUSION
These data provide insights into recent incidence and attack rates, changing patient profiles, management strategies, and subsequent outcomes in patients with venous thromboembolism. The underutilization of prophylaxis before venous thromboembolism, and relatively high 30-day recurrence rates, suggest a continued need for the improvement of venous thromboembolism prophylaxis and management in the community.
doi:10.1111/j.1525-1497.2006.00458.x
PMCID: PMC1924694  PMID: 16808773
venous thromboembolism; deep vein thrombosis; pulmonary embolism; population-health
24.  COX-2 Inhibitors 
Texas Heart Institute Journal  2005;32(3):380-383.
PMCID: PMC1336714  PMID: 16392224
25.  Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study 
Platelets  2013;25(7):517-525.
In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as “on-treatment”. Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment (p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.
doi:10.3109/09537104.2013.842965
PMCID: PMC4220996  PMID: 24127651
Clopidogrel; coronary artery disease; platelet aggregation inhibitors; pneumonia; sepsis; ticagrelor

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