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The impact of using direct-to-consumer wearable devices as a means to timely detect atrial fibrillation (AF) and to improve clinical outcomes is unknown. Heartline is a pragmatic, randomized, and decentralized application-based trial of US participants aged ≥65 years. Two randomized cohorts include adults with possession of an iPhone and without a history of AF and those with a diagnosis of AF taking a direct oral anticoagulant (DOAC) for ≥30 days. Participants within each cohort are randomized (3:1) to either a core digital engagement program (CDEP) via iPhone application (Heartline application) and an Apple Watch (Apple Watch Group) or CDEP alone (iPhone-only Group). The Apple Watch Group has the watch irregular rhythm notification (IRN) feature enabled and access to the ECG application on the Apple Watch. If an IRN notification is issued for suspected AF then the study application instructs participants in the Apple Watch Group to seek medical care. All participants were "watch-naïve" at time of enrollment and have an option to either buy or loan an Apple Watch as part of this study. The primary end point is time from randomization to clinical diagnosis of AF, with confirmation by health care claims. Key secondary endpoint are claims-based incidence of a 6-component composite cardiovascular/systemic embolism/mortality event, DOAC medication use and adherence, costs/health resource utilization, and frequency of hospitalizations for bleeding. All study assessments, including patient-reported outcomes, are conducted through the study application. The target study enrollment is approximately 28,000 participants in total; at time of manuscript submission, a total of 26,485 participants have been enrolled into the study. The Heartline Study will assess if an Apple Watch with the IRN and ECG application, along with application-facilitated digital health engagement modules, improves time to AF diagnosis and cardiovascular outcomes in a real-world environment. ClinicalTrials.gov Identifier: NCT04276441. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2009.10.034 Byline: Harvey D. White (a), Philip E. Aylward (b), Richard Gallo (c), Christoph Bode (d), Gabriel Steg (e), Steven R. Steinhubl (f), Gilles Montalescot (g) Abstract: Major bleeding significantly impacts outcomes in patients undergoing percutaneous coronary intervention (PCI). No uniform definitions exist for major and minor bleeding. Hematomas [greater than or equal to]5 cm at the femoral puncture site are considered major bleeding events in some trials and minor in others. Limited information is available on the incidence and clinical relevance of hematomas [greater than or equal to]5 cm in PCI patients. Author Affiliation: (a) Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand (b) Flinders Medical Centre, Bedford Park, SA, Australia (c) Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, Canada (d) Department of Internal Medicine III, Cardiology and Vascular Medicine, Universitatsklinikum Freiburg, Germany (e) Service de Cardiologie, HA[acute accent]pital Bichat, Paris, France (f) The Adjunct Faculty, Geisinger Clinic, Geisinger Center for Health Research, Danville, PA (g) Institut de Cardiologie (AP-HP) and INSERM Unit #856 Centre Hospitalier Universitaire Pitie-SalpA*triere, Paris, France Article History: Received 6 October 2009; Accepted 24 October 2009 Article Note: (footnote) RCT#: NCT00077844.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2008.09.011 Byline: Herbert D. Aronow (a), Steven R. Steinhubl (b), Danielle M. Brennan (c), Peter B. Berger (d), Eric J. Topol (e) Abstract: The optimal duration of dual antiplatelet therapy after percutaneous coronary intervention (PCI) is unknown. Incremental reductions in the risk of major adverse cardiovascular events may be partially offset by an increased incidence of bleeding in the months after a PCI. Author Affiliation: (a) Clinical Scholars Program, Michigan Heart and Vascular Institute at St. Joseph Mercy Hospital, Ann Arbor, MI (b) Division of Cardiology, University of Kentucky, Lexington, KY (c) Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH (d) Geisinger Clinic, Danville, PA (e) Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, CA Article History: Received 29 March 2008; Accepted 14 September 2008 Article Note: (footnote) The CREDO trial was funded by Bristol-Myers Squibb (New York, NY)/Sanofi-Synthelabo (Paris, France) partnership. The study sponsors played no role in the design of this substudy, nor in the collection, analysis, or interpretation of these data., Dr. Aronow is on the Speakers' Bureau for and has received grant funding from Bristol-Myers Squibb-Sanofi. Ms. Brennan has no conflicts of interest to disclose. Drs Topol and Steinhubl received research grants from Sanofi-Aventis and Bristol-Myers Squibb to conduct the trial; Dr. Steinhubl served as a consultant to this company in the clinical development of clopidogrel. Dr Steinhubl is currently employed by the Medicines Company (Parsippany, NJ). Dr Berger has received honoraria for speaking at Bristol-Myers Squibb-Sanofi-sponsored symposia.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2007.04.009 Byline: Steven R. Steinhubl (a), Adnan Kastrati (b), Peter B. Berger (c) Abstract: This review compares and contrasts the various criteria used to characterize bleeding (particularly major bleeding) during recent studies of antithrombotic therapies in acute coronary syndromes (ACSs) and/or percutaneous coronary intervention (PCI). Author Affiliation: (a) Gill Heart Institute, University of Kentucky, Lexington, KY (b) Deutsches Herzzentrum, Technische Universitat, Munich, Germany (c) Geisinger Medical Center, Danville, PA Article History: Received 26 January 2007; Accepted 1 April 2007 Article Note: (footnote) Disclosures: Dr Steinhubl received research support from and served as a consultant for Bristol-Myers Squibb, Sanofi-Aventis, and The Medicines Company and served as a consultant for AstraZeneca. Doctor Berger received consulting and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, Johnson & Johnson, Genentech, Guilford, Arginox, Schering-Plough, and Boston Scientific and is the medical director and owns equity in Lumen. Doctor Kastrati received lecture fees from Bristol-Myers Squibb, Lilly, and Sanofi-Aventis., Disclosures: Financial and editorial support for this publication has been provided by Sanofi-Aventis US Inc.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2005.10.005 Byline: Pranab Das, Khaled Ziada, Steven R. Steinhubl, David J. Moliterno, Hussam Hamdalla, Joseph Jozic, Debabrata Mukherjee Author Affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY Article History: Received 25 June 2005; Accepted 13 October 2005

Background: Heart failure and sleep-disordered breathing have been increasingly recognized as co-occurring conditions. Their bidirectional relationship warrants investigation into whether heart failure therapy improves sleep and sleep-disordered breathing. We sought to explore the effect of treatment with sacubitril/valsartan on sleep-related endpoints from the AWAKE-HF study.Methods and Results: AWAKE-HF was a randomized, double-blind study conducted in 23 centers in the United States. Study participants with heart failure with reduced rejection fraction and New York Heart Association class II or III symptoms were randomly assigned to receive treatment with either sacubitril/valsartan or enalapril. All endpoints were assessed at baseline and after 8 weeks of treatment. Portable sleep-monitoring equipment was used to measure the apnea-hypopnea index, including obstructive and central events. Total sleep time, wake after sleep onset and sleep efficiency were exploratory measures assessed using wrist actigraphy.the Results Were As Follows: 140 patients received treatment in the double-blind phase (sacubitril/valsartan, n = 70; enalapril, n = 70). At baseline, 39% and 40% of patients randomly assigned to receive sacubitril/valsartan or enalapril, respectively, presented with undiagnosed, untreated, moderate-to-severe sleep-disordered breathing (≥ 15 events/h), and nearly all had obstructive sleep apnea. After 8 weeks of treatment, the mean 4% apnea-hypopnea index changed minimally from 16.3/h to 15.2/h in the sacubitril/valsartan group and from 16.8/h to 17.6/h in the enalapril group. Mean total sleep time was long at baseline and decreased only slightly in both treatment groups at week 8 (-14 and -11 minutes for sacubitril/valsartan and enalapril, respectively), with small changes in wake after sleep onset and sleep efficiency in both groups.Conclusions: In a cohort of patients with heart failure with reduced rejection fraction who met prescribing guidelines for sacubitril/valsartan, one-third had undiagnosed moderate-to-severe obstructive sleep apnea. The addition of sacubitril/valsartan therapy did not significantly improve sleep-disordered breathing or sleep duration or efficiency. Patients who meet indications for treatment with sacubitril/valsartan should be evaluated for sleep-disordered breathing. [ABSTRACT FROM AUTHOR]

Background: Paroxysmal atrial fibrillation (PAF) is broadly defined despite high variability in the occurrence and duration of PAF episodes.Objective: The purpose of this study was to identify rhythm patterns in a large cohort of individuals with PAF who wore an ambulatory single-lead electrocardiogram (ECG) patch sensor as part of standard clinical care.Methods: We performed a retrospective analysis of longitudinal rhythm data obtained from 13,293 individuals with PAF.Results: In this study, 7934 men and 5359 women with PAF wore an ambulatory single-lead ECG patch sensor for 11.4 days on average, experiencing 1,041,504 PAF episodes. The median daily rate of PAF was 1.21 episodes per day (interquartile range [IQR] 0.31-4.99), and the median maximum duration per individual was 7.5 hours (IQR 2.4-18.6 hours). There was an inverse relationship between the duration of PAF episodes and the frequency in which they occurred, which became pronounced at moderate and high overall burdens of AF. This produced a spectrum of PAF flanked by 2 distinct subtypes of the disease: the staccato subtype, characterized by many, short AF episodes; and the legato subtype, characterized by fewer, longer episodes. Longer but less frequent episodes became more common with increasing age. Only 49.4% of individuals experienced an episode in the first 24 hours of monitoring, increasing to 89.7% after 1 week of monitoring.Conclusion: We identified subtypes of the disease that we labeled staccato and legato. Although further study is required, these subtypes may result from differing elements of pathophysiology and disease progression, and may confer differing stroke risks. [ABSTRACT FROM AUTHOR]

Efficient methods for screening populations for undiagnosed atrial fibrillation (AF) are needed to reduce its associated mortality, morbidity, and costs. The use of digital technologies, including wearable sensors and large health record data sets allowing for targeted outreach toward individuals at increased risk for AF, might allow for unprecedented opportunities for effective, economical screening. The trial's primary objective is to determine, in a real-world setting, whether using wearable sensors in a risk-targeted screening population can diagnose asymptomatic AF more effectively than routine care. Additional key objectives include (1) exploring 2 rhythm-monitoring strategies-electrocardiogram-based and exploratory pulse wave-based-for detection of new AF, and (2) comparing long-term clinical and resource outcomes among groups. In all, 2,100 Aetna members will be randomized 1:1 to either immediate or delayed monitoring, in which a wearable patch will capture a single-lead electrocardiogram during the first and last 2 weeks of a 4-month period beginning immediately or 4 months after enrollment, respectively. An observational, risk factor-matched control group (n = 4,000) will be developed from members who did not receive an invitation to participate. The primary end point is the incidence of new AF in the immediate- vs delayed-monitoring arms at the end of the 4-month monitoring period. Additional efficacy and safety end points will be captured at 1 and 3 years. The results of this digital medicine trial might benefit a substantial proportion of the population by helping identify and refine screening methods for undiagnosed AF. [ABSTRACT FROM AUTHOR]

So far, the digitization of health care is best exemplified by electronic medical records, which have been far from favorably or uniformly accepted. However, properly implemented digitization can enable better patient outcomes, improve convenience, potentially lower healthcare costs, and possibly lead to much greater physician satisfaction. Precision (also known as personalized or individualized) medicine is frequently discussed today, but, in reality, it is what physicians have attempted to do as best they could for millennia. But now we have new tools that can begin to give us a much more high-definition view of our patients; from affordable and rapid genetic testing to wearable sensors that track a wide range of important physiologic parameters continuously. Although seemingly counterintuitive, the digitization of health care can also markedly improve the physician-patient relationship, allowing more time for human interaction when care is bolstered by digital technologies that better individualize diagnostics and treatments. [ABSTRACT FROM AUTHOR]

Objective Early detection of Heart Failure (HF) could mitigate the enormous individual and societal burden from this disease. Clinical detection is based, in part, on recognition of the multiple signs and symptoms comprising the Framingham HF diagnostic criteria that are typically documented, but not necessarily synthesized, by primary care physicians well before more specific diagnostic studies are done. We developed a natural language processing (NLP) procedure to identify Framingham HF signs and symptoms among primary care patients, using electronic health record (EHR) clinical notes, as a prelude to pattern analysis and clinical decision support for early detection of HF. Design We developed a hybrid NLP pipeline that performs two levels of analysis: (1) At the criteria mention level, a rule-based NLP system is constructed to annotate all affirmative and negative mentions of Framingham criteria. (2) At the encounter level, we construct a system to label encounters according to whether any Framingham criterion is asserted, denied, or unknown. Measurements Precision, recall, and F -score are used as performance metrics for criteria mention extraction and for encounter labeling. Results Our criteria mention extractions achieve a precision of 0.925, a recall of 0.896, and an F -score of 0.910. Encounter labeling achieves an F -score of 0.932. Conclusion Our system accurately identifies and labels affirmations and denials of Framingham diagnostic criteria in primary care clinical notes and may help in the attempt to improve the early detection of HF. With adaptation and tooling, our development methodology can be repeated in new problem settings. [ABSTRACT FROM AUTHOR]

Background The electronic health record (EHR) contains a tremendous amount of data that if appropriately detected can lead to earlier identification of disease states such as heart failure (HF). Using a novel text and data analytic tool we explored the longitudinal EHR of over 50,000 primary care patients to identify the documentation of the signs and symptoms of HF in the years preceding its diagnosis. Methods and Results Retrospective analysis consisted of 4,644 incident HF cases and 45,981 group-matched control subjects. Documentation of Framingham HF signs and symptoms within encounter notes were carried out with the use of a previously validated natural language processing procedure. A total of 892,805 affirmed criteria were documented over an average observation period of 3.4 years. Among eventual HF cases, 85% had ≥1 criterion within 1 year before their HF diagnosis, as did 55% of control subjects. Substantial variability in the prevalence of individual signs and symptoms were found in both case and control subjects. Conclusions HF signs and symptoms are frequently documented in a primary care population as identified through automated text and data mining of EHRs. Their frequent identification demonstrates the rich data available within EHRs that will allow for future work on automated criterion identification to help develop predictive models for HF. [ABSTRACT FROM AUTHOR]

Objective: To determine if salivary biomarkers demonstrate utility for identifying aspects of myocardial necrosis. Methods: Twenty-one patients undergoing alcohol septal ablation (ASA) for treatment of hypertrophic cardiomyopathy provided serum and unstimulated whole saliva at baseline and incremental time points post-ASA. Samples were analyzed for seven biomarkers related to myocardial damage, inflammation, and tissue remodeling using immunosorbent assays. Levels were compared with baseline and levels observed in 97 healthy controls. Results: Biomarkers of myocardial damage and inflammation (ie, troponin I, creatine kinase-MB, myoglobin, C-reactive protein) rose in serum 2- to 812-fold after ASA (P < .01). Significant elevations of 2.0- to 3.5-fold were observed with C-reactive protein and troponin I in saliva (P < .02). Significant correlations between levels in serum and saliva were observed for C-reactive protein, matrix metalloproteinase-9, and myeloperoxidase (P < .001). Conclusions: Select salivary biomarkers reflect changes that occur during, and subsequent to, myocardial necrosis caused by ASA. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the utility of oral fluids for assessment of coronary and cardiovascular (CV) health. Study Design: Twenty-nine patients with preexisting CV disease underwent an invasive cardiac procedure (alcohol septal ablation or percutaneous coronary intervention) and provided unstimulated whole saliva (UWS), sublingual swabs (LS), gingival swabs (GS) and serum at 0, 8, 16, 24, and 48 hours. Concentrations of 13 relevant biomarkers were determined and correlated with levels in serum and the oral fluids. Results: Concentrations of the majority of biomarkers were higher in UWS than in LS and GS. Coronary and CV disease biomarkers in UWS correlated better with serum than with LS and GS based on group status and measures of time effect. Seven biomarkers demonstrated time effect changes consistent with serum biomarkers, including C-reactive protein and troponin I. Conclusions: Changes in serum biomarker profiles are reflected in oral fluids suggesting that oral fluid biomarkers could aid in the assessment of cardiac ischemia/necrosis. [Copyright &y& Elsevier]

Objectives: The aim of this study was to evaluate the relative frequency of access and nonaccess site bleeding, the association of these events with 1-year mortality, and the impact of randomized antithrombotic therapy. Background: Post-percutaneous coronary intervention (PCI) bleeding has been strongly associated with subsequent mortality. The extent to which access versus nonaccess site bleeding contributes to this poor prognosis and the role of antithrombotic therapies remains poorly understood. Methods: The incidence and impact of Thrombolysis In Myocardial Infarction (TIMI) major/minor 30-day bleeding and randomized antithrombotic therapy were examined in a combined dataset from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events), Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials in 17,393 PCI patients. Results: The TIMI major/minor bleeding occurred in 5.3% of patients, 61.4% of which (3.3%) were nonaccess site bleeds. After multivariable adjustment, TIMI bleeding was associated with an increased risk of 1-year mortality (hazard ratio [HR]: 3.17, 95% confidence interval [CI]: 2.51 to 4.00, p < 0.0001). The HR of a nonaccess site bleed was approximately 2-fold that of an access site bleed: HR: 3.94, 95% CI: 3.07 to 5.15, p < 0.0001 versus HR: 1.82, 95% CI: 1.17 to 2.83, p = 0.008, respectively. Randomization to bivalirudin versus heparin + a glycoprotein IIb/IIIa inhibitor resulted in 38% and 43% relative reductions in TIMI major/minor and TIMI major bleeding, respectively (p < 0.0001 for both), with significant reductions in both access and nonaccess site bleeding. Conclusions: Nonaccess site bleeding after PCI is common, representing approximately two-thirds of all TIMI bleeding events, and is associated with a 4-fold increase in 1-year mortality. Use of bivalirudin rather than heparin + a glycoprotein IIb/IIIa inhibitor significantly decreases both nonaccess site as well as access site bleeding events by approximately 40%. [Copyright &y& Elsevier]

Objectives: This study sought to determine the frequency of noncardiac surgery and adverse post-operative events among patients who recently received a drug-eluting stent (DES) following noncardiac surgery. Background: Little is known about frequency of and risks associated with noncardiac surgery after DES implantation. Methods: In the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry, consecutive patients who underwent attempted stent placement at 42 hospitals between July 2004 and September 2005 were enrolled and followed for 1 year. In this study, we analyzed patients who received ≥1 DES to determine the frequency of noncardiac surgery and cardiac death, myocardial infarction, or stent thrombosis in the following week. Results: Among 4,637 DES recipients, 206 (4.4%) underwent major noncardiac surgery in the following year (median days to surgery: 179 [interquartile range 112 to 266 days; range 13 to 360 days]). Overall, stent use averaged 1.5 per patient. The most frequent operations were orthopedic (36%), abdominal (31%), and vascular (20%). Compared with patients who did not undergo surgery, those who did were older, more likely to be women, and have had a prior stroke; the frequencies of prior myocardial infarction, prior coronary artery bypass graft, and diabetes were similar, as were left ventricular ejection fraction and indication for percutaneous coronary intervention. In the 7 days after surgery, 4 patients had a cardiac death, myocardial infarction, or stent thrombosis (1.9% [exact 95% confidence interval (CI): 0.5% to 4.9%]). The risk of the composite outcome was increased 27-fold in the week following noncardiac surgery compared with any other week after stent implantation (hazard ratio [HR]: 27.3 [95% CI: 10.0 to 74.2], p < 0.001). Conclusions: The frequency of major noncardiac surgery in the year after DES placement is >4%. Although the overall risk of adverse outcomes was less than previously reported when surgery is performed months after DES placement, it is significantly increased in the week after major noncardiac surgery. [Copyright &y& Elsevier]

Background: Pretreatment with clopidogrel reduces ischemic complications before percutaneous coronary intervention (PCI). Limited data exist regarding the effect of pretreatment for ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI. Methods: Prospective data were analyzed from a regional STEMI system using rapid transfer for primary PCI in 30 community hospitals. Zone 1 community hospitals are <60 miles and Zone 2 hospitals are 60 to 210 miles away from the PCI hospital. Compared with 63 minutes in the PCI hospital, median door-to-balloon times were 94 minutes in Zone 1 and 123 minutes in Zone 2 hospitals. All patients received aspirin, unfractionated heparin, and clopidogrel 600 mg in the emergency department of the presenting hospital within 15 minutes of diagnosis. Results: From April 2003 through December 2008, 2,014 consecutive STEMI patients were pretreated with clopidogrel before PCI, with a median (25th-75th percentile) duration from pretreatment to PCI of 75 (58-93) minutes. Patients with longer pretreatment duration had significantly reduced reinfarction/reischemia at 30 days (Zone 1: 0.85%, Zone 2: 0.9%) compared with nontransferred patients (3.2%, P = .001) as well as reduced stent thrombosis (Zone 1: 0.6%, Zone 2: 0.6% vs Abbott Northwestern: 2.0%; P = .04). Similarly, pretreatment duration of >60 minutes before PCI had reduced 30-day reinfarction/reischemia (1.0% vs 2.9%, P = .003). There were no significant differences in mortality or major bleeding. Conclusion: ST-segment elevation myocardial infarction patients undergoing primary PCI in a regional STEMI network who received earlier pretreatment with a 600-mg loading dose of clopidogrel had less ischemic complications without increased bleeding or mortality. [Copyright &y& Elsevier]

Objectives: Our purpose was to evaluate long-term mortality and identify factors associated with 1-year mortality in patients who underwent elective percutaneous coronary intervention (PCI). Background: While long-term outcomes in PCI patients have been reported previously, limited data are currently available regarding the comparative long-term outcomes in PCI patients who receive enoxaparin versus intravenous unfractionated heparin (UFH). Methods: We conducted a follow-up analysis of clinical outcomes at 1 year in patients enrolled in the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) trial of 3,528 patients undergoing elective PCI. Patients were randomized to receive either intravenous 0.50-mg/kg or 0.75-mg/kg enoxaparin or intravenous UFH during elective PCI procedures. All-cause mortality at 1 year after index PCI was the main outcome measure. Results: Mortality rates were 1.4%, 2.0%, and 1.5% from 1 month to 1 year, and 2.3%, 2.2%, and 1.9% from randomization to 1 year, after index PCI in patients receiving 0.50 mg/kg enoxaparin, 0.75 mg/kg enoxaparin, and UFH, respectively. Multivariate analysis identified nonfatal myocardial infarction and/or urgent target vessel revascularization up to 30 days after index PCI (hazard ratio: 3.5, 95% confidence interval: 1.7 to 7.3; p < 0.001), and major bleeding within 48 h (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.5; p = 0.04) as the strongest independent risk factors for 1-year mortality. Conclusions: The 1-year mortality rates were low and comparable between patients receiving enoxaparin and UFH during elective PCI. Periprocedural ischemic or bleeding events were the strongest independent predictors of 1-year mortality. (The STEEPLE Trial; NCT00077844) [Copyright &y& Elsevier]

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No prospective randomized trial has specifically examined the long-term outcomes of clopidogrel use in patients with chronic kidney disease. This study aimed to determine the risks and benefits of long-term clopidogrel administration in patients with diabetic nephropathy, the most common form of chronic kidney disease. We performed a post hoc analysis of the CHARISMA trial, which randomly assigned patients without active acute coronary syndrome, but with established atherosclerotic disease (symptomatic) or multiple risk factors for atherosclerotic disease (asymptomatic), to clopidogrel plus aspirin versus placebo plus aspirin. All CHARISMA patients (n = 15,603) were separated into the 3 groups: nondiabetic patients, diabetic patients without nephropathy, and diabetic patients with nephropathy. Within each group, outcomes of patients randomly assigned to clopidogrel were compared with those of patients randomly assigned to placebo. Outcomes in the prespecified CHARISMA subgroups of asymptomatic and symptomatic patients were also compared with respect to study drug assignment and nephropathy status. Patients with nephropathy who received clopidogrel had no difference in bleeding, but experienced significantly increased cardiovascular (CV) and overall mortality compared with those randomly assigned to placebo. There were no differences in bleeding, overall mortality, or CV mortality for nondiabetic or diabetic patients without nephropathy who received clopidogrel versus placebo. In the asymptomatic cohort, patients with nephropathy randomly assigned to clopidogrel had significantly increased overall and CV mortality compared with placebo, whereas asymptomatic patients without nephropathy randomly assigned to clopidogrel had no significant mortality difference compared with placebo. In conclusion, this post hoc analysis suggested that clopidogrel may be harmful in patients with diabetic nephropathy. Additional studies are needed to investigate this possible interaction. [Copyright &y& Elsevier]

Background: Thrombocytopenia and heparin-induced thrombocytopenia (HIT) are potentially devastating paradoxical side effects of heparin therapy. We explored the evaluation, management, and clinical consequences of thrombocytopenia occurring during heparin therapy in diverse clinical settings. Methods: CATCH was a prospective observational study that enrolled 3,536 patients in 48 US hospitals. Data were collected on 3 strata: patients receiving any form of heparin for ≥96 hours (n = 2,420); cardiac care unit (CCU) patients treated with heparin who developed thrombocytopenia (n = 1,090); patients who had an HIT assay performed (n = 449). Results: Thrombocytopenia occurred in 36.4% of patients in the prolonged heparin stratum and was associated with an increased risk of death or thromboembolic complication (OR 1.5, 95% CI 1.2-1.9). Among a subset of patients whose clinical presentation suggested they were at high risk for HIT, suspicion for HIT was uncommon (prolonged heparin stratum 19.8%, CCU stratum 37.6%) and often did not arise until ≥1 day after patients developed thrombocytopenia. Often patients were not evaluated for HIT until after they had had a thromboembolic complication (prolonged heparin stratum 43.8%, CCU stratum 61%). Even after HIT was suspected, patients often continued to receive heparin. Direct thrombin inhibitor use was infrequent (prolonged heparin stratum 29.4%, CCU stratum 35.6%). Among the few patients who underwent evaluation, HIT was confirmed in 46.7% of the prolonged heparin stratum and 31.4% of the CCU stratum. Conclusions: Thrombocytopenia is common among patients receiving heparin, and it is associated with substantial risk for catastrophic complications. Despite the high risk for HIT in this population, recognition, evaluation, and appropriate treatment are infrequent and delayed. [Copyright &y& Elsevier]

Objectives: This study sought to determine if the efficacy of bivalirudin alone versus heparin plus a glycoprotein (GP) IIb/IIIa inhibitor is dependent upon the duration of clopidogrel pre-treatment in patients undergoing percutaneous coronary intervention (PCI) in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. Background: The administration of a clopidogrel loading dose several hours before PCI reduces the risk of periprocedural thrombotic events. Methods: Patients with an acute coronary syndrome were randomized to heparin plus a GP IIb/IIIa inhibitor (control), bivalirudin plus a GP IIb/IIIa inhibitor, or bivalirudin alone. Dose and timing of clopidogrel were left to the investigator''s discretion. Results: Of 13,819 patients randomized, 7,789 underwent PCI. When clopidogrel was initiated at any time before angiography or within 30 min after PCI, randomization to bivalirudin alone (n = 2,284) or control (n = 2,189) was associated with similar ischemic outcomes (8.2% vs. 8.3%, risk ratio: 0.98, 95% confidence interval: 0.81 to 1.20). Those patients who received clopidogrel >30 min after PCI or not at all experienced an increase in ischemic events when randomized to bivalirudin alone (n = 290) versus control (n = 317) (14.1% vs. 8.5%, risk ratio: 1.66, 95% confidence interval: 1.05 to 2.63). Major bleeding was significantly less frequent in patients treated with bivalirudin alone. Conclusions: This post-hoc analysis suggests that in acute coronary syndrome patients, as long as clopidogrel is administered before or within 30 min of PCI treatment with bivalirudin alone is similarly effective to heparin plus a GP IIb/IIIa inhibitor in suppressing 30-day ischemic events with significantly less bleeding. If it is anticipated that clopidogrel will be given late or not at all after PCI, bivalirudin alone may be associated with worse ischemic outcomes. (Comparison of Angiomax Versus Heparin in Acute Coronary Syndromes; NCT00093158) [Copyright &y& Elsevier]

Background: Clopidogrel pretreatment before percutaneous coronary intervention (PCI) has been shown to reduce the risk of death and ischemic complications after PCI. However, the need for clopidogrel pretreatment is debated in patients receiving a glycoprotein IIb/IIIa inhibitor (GPI). Methods: We performed a collaborative meta-analysis of the results of 3 randomized trials of clopidogrel pretreatment: PCI-CURE, CREDO, and PCI-CLARITY. Patients were stratified based on GPI use at the time of PCI (a postrandomization subgroup analysis). Odds ratios (ORs) and 95% CIs for the effect of clopidogrel pretreatment versus placebo pretreatment on the incidence of cardiovascular death, myocardial infarction (MI), or stroke for up to 30 days after PCI were calculated for each trial within each GPI stratum and were combined using a random effects model. Results: Six thousand three hundred twenty-five patients were included, 32.4% of whom received a GPI. There was a consistent benefit of clopidogrel pretreatment in reducing the incidence of cardiovascular death, MI, or stroke after PCI both in patients who did not receive a GPI (OR 0.72, 95% CI 0.53-0.98, P = .03) and in those who did (OR 0.69, 95% CI 0.47-1.00, P = .05). There was no evidence of heterogeneity in the benefit of clopidogrel pretreatment between GPI use strata (P = .85 for heterogeneity). Clopidogrel pretreatment was not associated with a significant excess of TIMI major or minor bleeding, either in those who did not receive a GPI (OR 1.20, 95% CI 0.76-1.92) or in those who did (OR 1.22, 95% CI 0.71-2.09) (P = .97 for heterogeneity). Conclusion: Clopidogrel pretreatment before PCI is beneficial and safe regardless of whether a GPI is used at the time of PCI. [Copyright &y& Elsevier]

Background: Mild and moderate chronic kidney disease (CKD) is associated with decreased survival and increased adverse events after a percutaneous coronary intervention (PCI). Therapy with clopidogrel decreases adverse events in large patient populations. Therefore, we sought to determine the efficacy and safety of long-term clopidogrel therapy in patients with CKD. Methods: Two thousand two patients from the CREDO trial in whom an elective PCI of a single or multiple vessels was planned were analyzed. Patients were randomly assigned to a 300-mg loading dose of clopidogrel before PCI followed by clopidogrel 75 mg/d for a year versus a placebo loading dose at the time of the PCI procedure and clopidogrel 75 mg/d for 28 days and placebo for the remainder of a year. Patients were categorized by their estimated creatinine clearance (>90 [normal, n = 999], 60-89 [mild CKD, n = 672], <60 mL/min [moderate CKD, n = 331]). Results: Diminished renal function was associated with worse outcomes. Patients with normal renal function who received 1 year of clopidogrel had a marked reduction in death, myocardial infarction, or stroke compared with those who received placebo (10.4% vs 4.4%, P < .001), whereas patients with mild and moderate CKD did not have a significant difference in outcomes with clopidogrel therapy versus placebo (mild: 12.8% vs 10.3%, P = .30; moderate: 13.1% vs 17.8%, P = .24). Clopidogrel use was associated with an increased relative risk of major or minor bleeding, but this increased risk was not different based on renal function (relative risk 1.2, 1.3, 1.1). Conclusions: Clopidogrel in mild or moderate CKD patients may not have the same beneficial effect as it does in patients with normal renal function, but was not associated with a greater relative risk of bleeding based on renal function. Further studies are needed to define the role of clopidogrel therapy in patients with CKD. [Copyright &y& Elsevier]

Abstract: Background: Cangrelor is a direct, parenteral, and reversible inhibitor of the platelet P2Y12 receptor currently undergoing Phase III testing. As many individuals treated acutely with cangrelor will often be treated long-term with a thienopyridine, it is important to determine the effects of concurrent cangrelor and clopidogrel administration. Methods and results: Ten healthy volunteers received a 600 mg oral loading dose of clopidogrel and then underwent serial platelet function monitoring for 6 h. Two weeks later these same individuals received a 600 mg clopidogrel loading dose simultaneously with a cangrelor IV bolus (30 μg/kg) and a 2-hour infusion (4 μg/kg/min). A separate group of ten volunteers received a 600 mg clopidogrel loading dose after administration of a cangrelor bolus and a 1-hour infusion. The effects on ADP-induced platelet activation and aggregation were evaluated by flow cytometry, whole-blood electrical impedance, and light-transmittance aggregometry. Cangrelor and clopidogrel alone achieved the expected levels of platelet inhibition. However, the sustained platelet inhibition anticipated for clopidogrel treatment did not occur when cangrelor was initiated simultaneously. No such effect was found when clopidogrel was started upon completion of the cangrelor infusion. Conclusion: To achieve sustained platelet P2Y12 inhibition in patients treated with cangrelor, clopidogrel administration should be started when the cangrelor infusion is terminated. [Copyright &y& Elsevier]

Background: Patients with metabolic syndrome are at increased risk for cardiovascular complications. We sought to determine whether peroxisome proliferator–activated receptor gamma agonists had any beneficial effect on patients with metabolic syndrome undergoing percutaneous coronary intervention (PCI). Methods: A total of 200 patients with metabolic syndrome undergoing PCI were randomized to rosiglitazone or placebo and followed for 1 year. Carotid intima-medial thickness (CIMT), inflammatory markers, lipid levels, brain natriuretic peptide, and clinical events were measured at baseline, 6 months, and 12 months. Results: There was no significant difference in CIMT between the 2 groups. There was no difference in the 12-month composite end point of death, myocardial infarction (MI), stroke, or any recurrent ischemia (31.4% vs 30.2%, P = .99). The rate of death, MI, or stroke at 12 months was numerically lower in the rosiglitazone group (11.9% vs 6.4%, P = .19). There was a trend toward a greater decrease over time in high-sensitivity C-reactive protein values compared with baseline in the group randomized to rosiglitazone versus placebo both at 6 months (−35.4% vs −15.8%, P = .059) and 12 months (−40.0% vs −20.9%, P = .089) and higher change in high-density lipoprotein (+15.5% vs +4.1%, P = .05) and lower triglycerides (−13.9% vs +14.9%, P = .004) in the rosiglitazone arm. There was a trend toward less new onset diabetes in the rosiglitazone group (0% vs 3.3%, P = .081) and no episodes of symptomatic hypoglycemia. There was no excess of new onset of clinical heart failure in the rosiglitazone group, nor was there a significant change in brain natriuretic peptide levels. Conclusions: Patients with metabolic syndrome presenting for PCI are at increased risk for subsequent cardiovascular events. Rosiglitazone for 12 months did not appear to affect CIMT in this population, although it did have beneficial effects on high-sensitivity C-reactive protein, high-density lipoprotein, and triglycerides. Further study of peroxisome proliferator–activated receptor agonism in patients with metabolic syndrome undergoing PCI may be warranted. [Copyright &y& Elsevier]

Objectives: This study sought to determine the optimal timing of a 300-mg clopidogrel loading dose before percutaneous coronary intervention (PCI) in patients enrolled in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Background: A loading dose of clopidogrel before a PCI has become relatively commonplace, although the data supporting this practice are limited and sometimes conflicting. Methods: Patients were randomized to receive either 300 mg clopidogrel or a matching placebo administered a minimum of 3 h and a maximum of 24 h before PCI. The primary 28-day combined end point was death, myocardial infarction, or urgent target vessel revascularization. Linear splines were used to summarize the effect of the time of pre-treatment as a continuous variable. Results: A total of 1,762 patients were evaluated. For patients randomized to placebo, there was no relationship between the duration of pre-treatment and the occurrence of the primary end point, whereas longer durations of pre-treatment in patients randomized to clopidogrel were associated with improved outcomes. The event rates diverged maximally at 24 h. The difference in outcomes between placebo and clopidogrel pre-treated patients was not significant until ≥15 h pre-treatment, with a 58.8% (p = 0.028) reduction in the primary end point in patients pre-treated with clopidogrel ≥15 h compared with placebo. Conclusions: When a 300-mg loading dose of clopidogrel is used, little benefit is obtained compared with just 75 mg at the time of the PCI when the treatment duration is <12 h. In patients pre-treated for longer durations, the optimal duration seems to approach 24 h. [Copyright &y& Elsevier]

We sought to compare the risk of hemorrhage due to the low (&#60;100 mg), moderate (100 to 200 mg), and high (>200 mg) doses of aspirin (acetylsalicylic acid [ASA]) in 192,036 patients enrolled in 31 clinical trials. Despite substantial differences in the reporting patterns of bleeding complications, low-dose ASA was associated with the lowest risk, and moderate doses caused a relatively high hemorrhagic event rate, especially with regard to minor, gastrointestinal, and total bleeding, and stroke. These findings should be considered when using combination antiplatelets, anticoagulant therapy, or both, with ASA, especially with the daily dose of >100 mg. [Copyright &y& Elsevier]

Objectives: We sought to describe the responses of patients to clopidogrel using ex vivo measures of platelet aggregation and activation in a large, heterogeneous population. Background: Recently, a number of reports, using various definitions, have dichotomized patients who are treated with clopidogrel into a minority of “non-responders” and a majority of “responders.” Such classifications imply that treatment leads to an all-or-none response, with potentially important clinical implications. Methods: We conducted secondary post-hoc analyses of a dataset consisting of volunteers (n = 94) and patients after coronary stenting (n = 405), with heart failure (n = 25), and after stroke (n = 20). Results: The response of subjects to clopidogrel followed a normal, bell-shaped distribution, with a mean and standard deviation of 41.9 ± 20.8% when aggregation was induced by 5 μmol/l of adenosine diphosphate. When hyporesponsiveness and hyper-responsiveness to clopidogrel were considered to be two standard deviations less than and greater than the mean, respectively, the prevalence of hyporesponsiveness and hyper-responsiveness in these patients was 4.2% and 4.8%, respectively. Pretreatment platelet activity and clinical characteristics were not associated with responsiveness to clopidogrel. Conclusions: Individuals receiving clopidogrel exhibit a wide variability in response that follows a normal distribution. The clinical implications of this variability are unknown but potentially are important. Clinical trials are needed to define whether hyporesponders to clopidogrel are at increased risk for thrombotic events and whether hyper-responders are at increased risk for bleeding. If so, the individualization of antiplatelet therapy, including clopidogrel dosing, may be possible in the future but will require the ability to easily and reproducibly measure responsiveness by a method that has been proven to be predictive of clinical events. [Copyright &y& Elsevier]