Mitchell W Krucoff

Duke University, Durham, North Carolina, United States

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Publications (264)1833.76 Total impact

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    ABSTRACT: This White Paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research Consortium (CSRC) and the US Food and Drug Administration (FDA) at the FDA's White Oak headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists even though NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular (CV) clinical trials and CV safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies, regulatory agencies, endpoint adjudication specialist groups, contract research organizations (CROs), and active, academically-based physicians.
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    ABSTRACT: Background Many patients have symptoms suggestive of coronary artery disease (CAD) and are often evaluated with the use of diagnostic testing, although there are limited data from randomized trials to guide care. Methods We randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure. Results The mean age of the patients was 60.8±8.3 years, 52.7% were women, and 87.7% had chest pain or dyspnea on exertion. The mean pretest likelihood of obstructive CAD was 53.3±21.4%. Over a median follow-up period of 25 months, a primary end-point event occurred in 164 of 4996 patients in the CTA group (3.3%) and in 151 of 5007 (3.0%) in the functional-testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; P=0.75). CTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%, P=0.02), although more patients in the CTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%). The median cumulative radiation exposure per patient was lower in the CTA group than in the functional-testing group (10.0 mSv vs. 11.3 mSv), but 32.6% of the patients in the functional-testing group had no exposure, so the overall exposure was higher in the CTA group (mean, 12.0 mSv vs. 10.1 mSv; P<0.001). Conclusions In symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550 .).
    New England Journal of Medicine 03/2015; DOI:10.1056/NEJMoa1415516 · 54.42 Impact Factor
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    ABSTRACT: The lack of consistent definitions and nomenclature across clinical trials of novel devices, drugs, or biologics poses a significant barrier to accrual of knowledge in and across peripheral artery disease therapies and technologies. Recognizing this problem, the Peripheral Academic Research Consortium, together with the U.S. Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, has developed a series of pragmatic consensus definitions for patients being treated for peripheral artery disease affecting the lower extremities. These consensus definitions include the clinical presentation, anatomic depiction, interventional outcomes, surrogate imaging and physiological follow-up, and clinical outcomes of patients with lower-extremity peripheral artery disease. Consistent application of these definitions in clinical trials evaluating novel revascularization technologies should result in more efficient regulatory evaluation and best practice guidelines to inform clinical decisions in patients with lower extremity peripheral artery disease. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    Journal of the American College of Cardiology 03/2015; 65(9):931-941. DOI:10.1016/j.jacc.2014.12.036 · 15.34 Impact Factor
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    ABSTRACT: Circulating levels of cardiac troponin I (cTnI) after ST-segment elevation myocardial infarction (STEMI) are associated with infarct size and chronic left ventricular dysfunction, but the relation to clinical end points and biochemical measures of global cardiac function remains less well defined. One thousand sixty-six patients receiving primary percutaneous coronary intervention (PCI) in the PROTECTION AMI trial were studied in a post hoc analysis. Cardiac troponin I was measured at several time points during the index hospitalization, and patients were followed up for 3 months before reassessment including N-terminal pro-B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF) measurements. The median (quartile 1-3) cTnI levels were 0.4 (0.1-0.4) μg/L at admission, 33.1 (12.8-72.1) μg/L after 16 to 24 hours, and 9.1 (3.9-17.5) μg/L after 70 to 80 hours. In adjusted models, all post-PCI single points, peak, and area under curve were found to be independently associated with clinical events, NT-proBNP >118 pmol/L, or LVEF <40% (P for all <.001). When cTnI was added to a baseline risk model for prediction of clinical events, the C statistic improved from 0.779 to 0.846 (16-24 hours) and 0.859 (70-80 hours). Quantified by integrated discrimination improvement, the addition of cTnI significantly augmented prediction ability (relative integrated discrimination improvement 44%-154%; P for all ≤.001). Consistent improvements in discrimination of NT-proBNP >118 pmol/L and LVEF <40% were observed. Cardiac troponin I measured after primary PCI for STEMI is independently associated with clinical outcomes and cardiac function through 3-month follow-up. These results suggest that cTnI levels are a useful risk stratification tool in STEMI patients. Copyright © 2014 Elsevier Inc. All rights reserved.
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    ABSTRACT: Background Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications, yet the benefits and risks of treatment beyond 1 year are uncertain. Methods Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a composite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding. Results A total of 9961 patients were randomly assigned to continue thienopyridine treatment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thienopyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyridine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thienopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombosis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment. Conclusions Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938 .).
    New England Journal of Medicine 11/2014; DOI:10.1056/NEJMoa1409312 · 54.42 Impact Factor
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    ABSTRACT: Background In the setting of ST segment elevation myocardial infarction (STEMI), timely restoration of normal blood flow is associated with improved myocardial salvage and survival. Despite improvements in door-to-needle and door-to-balloon times, there remains an unmet need with respect to improved symptom-to-door times. A prior report of an implanted device to monitor ST segment deviation demonstrated very short times to reperfusion among patients with an acute coronary syndrome (ACS) with documented thrombotic occlusion. The goal of the ANALYZE ST study is to evaluate the safety and effectiveness of a novel ST segment monitoring feature using an existing implantable cardioverter defibrillator (ICD) among patients with known coronary artery disease (CAD). Methods The ANALYZE ST study is a prospective, non-randomized, multicenter, pivotal Investigational Device Exemption (IDE) study enrolling 5,228 patients with newly implanted ICD systems for standard clinical indications who also have a documented history of CAD. Patients will be monitored for 48 months, during which effectiveness of the device for the purpose of early detection of cardiac injury will be evaluated by analyzing the sensitivity of the ST Monitoring Feature to identify clinical acute coronary syndrome events. In addition, the safety of the ST Monitoring Feature will be evaluated through the assessment of the percentage of patients for which monitoring produces a false positive event over the course of 12 months. Conclusions The ANALYZE ST trial is testing the hypothesis that the ST Monitoring Feature in the Fortify® ST ICD system (or other ICD systems with the ST Monitoring Feature) will accurately identify patients with clinical acute coronary syndrome events.
    American Heart Journal 10/2014; 168(4). DOI:10.1016/j.ahj.2014.05.010 · 4.56 Impact Factor
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    ABSTRACT: Although percutaneous coronary intervention with everolimus-eluting stent (EES) implantation for native coronary artery disease has favorable results compared to first-generation drug-eluting stents, outcomes with EES for the treatment of in-stent restenosis (ISR) are unknown.
    The Journal of invasive cardiology 09/2014; 26(9):420-426. · 0.82 Impact Factor
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    ABSTRACT: Significant improvements in door-to-balloon times have led to a reduction in mortality in ST-segment elevation myocardial infarction; however, mean symptom-to-door times remain at 2 to 3 hours. An intracardiac electrogram monitoring device may be beneficial in high-risk patients by alerting them to rapidly progressive ST-segment changes indicative of acute coronary occlusion. The Cardiosaver and DETECT phase I clinical studies demonstrated the safety, feasibility, and potential benefit of using an intracardiac electrogram monitoring device to alert the patient to seek medical attention. The goal of the randomized, prospective ALERTS Trial (Clinicaltrials.gov no. NCT00781118) is to evaluate the efficacy of an implantable monitoring device (IMD) in reducing the composite of either cardiac or unexplained death, new Q-wave myocardial infarction, or symptom-to-door time of >2 hours for confirmed thrombotic events. The IMD alerts the patient in real time when ST-segment deviation from a personalized baseline exceeds the trigger threshold. The trial is designed to enroll high-risk post-acute coronary syndrome patients or patients with previous multivessel coronary artery bypass surgery. All patients have the IMD implanted, with 1:1 unblinded randomization to the alerting feature being either turned on versus turned off for the first 6 months. Randomization occurs at the first follow-up visit, 7 to 14 days after the implantation of the IMD. Subjects then return for follow-up visits at months 1, 3, and 6 and thereafter every 6 months until closure of the investigational device exemption. Subjects who cannot be implanted successfully or who have the device explanted are removed from the study and followed up for a minimum of 30 days post-procedure. If a subject experiences a device-related complication and/or adverse experience, the subject is followed up until resolution or until the condition becomes stable and no further change is anticipated.
    American Heart Journal 08/2014; 168(2). DOI:10.1016/j.ahj.2014.05.008 · 4.56 Impact Factor
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    ABSTRACT: OBJECTIVES This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial. BACKGROUND Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear. METHODS Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population. RESULTS The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significant difference in the primary efficacy endpoint between radial or femoral access among women undergoing PCI (radial 1.2% vs. 2.9% femoral, odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.12 to 1.27); among women undergoing cardiac catheterization or PCI, radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR: 0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher among women assigned to radial access (PCI cohort: 6.1% vs. 1.7%; OR: 3.65; 95% CI: 1.45 to 9.17); total randomized cohort: (6.7% vs. 1.9%; OR: 3.70; 95% CI: 2.14 to 6.40). More women preferred radial access. CONCLUSIONS In this pragmatic trial, which was terminated early, the radial approach did not significantly reduce bleeding or vascular complications in women undergoing PCI. Access site crossover occurred more often in women assigned to radial access. (C) 2014 by the American College of Cardiology Foundation.
    JACC Cardiovascular Interventions 08/2014; 7(8):857-67. DOI:10.1016/j.jcin.2014.04.007 · 7.44 Impact Factor
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    ABSTRACT: Establishing epicardial flow with percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) is necessary but not sufficient to ensure nutritive myocardial reperfusion. We evaluated whether adding myocardial blush grade (MBG) and quantitative reperfusion ventricular arrhythmia "bursts" (VABs) surrogates provide a more informative biosignature of optimal reperfusion in patients with Thrombolysis in Myocardial Infarction (TIMI) 3 flow and ST-segment recovery (STR).
    07/2014; DOI:10.1177/2048872614532414
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    ABSTRACT: Objectives: The purpose of this study was to evaluate the 1-year clinical outcomes of more complex XIENCE V USA real-world patients with small versus non-small vessel lesions. Background: Patients with small vessel lesions undergoing coronary stent placement are at higher risk of major adverse cardiac events. Improved safety and efficacy of XIENCE V everolimus eluting stents (EES) have been previously demonstrated in selected low-risk small vessel populations in randomized clinical trials. Methods: The XIENCE V USA study was a condition of approval, single-arm study in unselected real-world patients. Baseline and 1-year clinical outcomes were compared between XIENCE V USA patients who received a single 2.5 mm stent (small vessel group, N = 838) and patients implanted with a single > 2.5 mm stent (non-small vessel group, N = 2015). Mean reference vessel diameter was 2.55 + 0.36 and 3.25 + 0.46 mm in the small and non-small vessel groups, respectively (p<0.001). Results: Small vessel group had more females, presented with a higher rate of diabetes, and had more complex lesion characteristics. The definite or probable ST rates analyzed using Kaplan-Meier method were low and not significantly different between the groups at 0.37% and 0.40% for the small and non-small vessel group (p=0.88), respectively. The composite rate of cardiac death or MI was comparable at 4.5% for the small and 5.1% for the non-small vessel 1 groups (p=0.57). The one-year target lesion revascularization rate was also comparable in the small vessel group (3.8% vs 3.0%, p=0.35) Conclusions: Despite gender difference, higher prevalence of diabetes and more complex lesions in the small vessel groups, the 1-year clinical outcomes were similar in both small and non-small vessel groups. These results demonstrate the therapeutic benefit of XIENCE V EES in a real-world all inclusive patient population with small vessel disease. © 2013 Wiley Periodicals, Inc.
    Catheterization and Cardiovascular Interventions 07/2014; 84(1). DOI:10.1002/ccd.25325 · 2.40 Impact Factor
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    ABSTRACT: Background Suspected coronary artery disease (CAD) is one of the most common, potentially life threatening diagnostic problems clinicians encounter. However, no large outcome-based randomized trials have been performed to guide the selection of diagnostic strategies for these patients. Methods The PROMISE study is a prospective, randomized trial comparing the effectiveness of two initial diagnostic strategies in patients with symptoms suspicious for CAD. Patients are randomized to either: 1) functional testing (exercise electrocardiogram, stress nuclear imaging, or stress echocardiogram); or 2) anatomic testing with >=64 slice multidetector coronary computed tomographic angiography. Tests are interpreted locally in real time by subspecialty certified physicians and all subsequent care decisions are made by the clinical care team. Sites are provided results of central core lab quality and completeness assessment. All subjects are followed for ≥1 year. The primary end-point is the time to occurrence of the composite of death, myocardial infarction, major procedural complications (stroke, major bleeding, anaphylaxis and renal failure) or hospitalization for unstable angina. Results Over 10,000 symptomatic subjects were randomized in 3.2 years at 193 US and Canadian cardiology, radiology, primary care, urgent care and anesthesiology sites. Conclusion Multi-specialty community practice enrollment into a large pragmatic trial of diagnostic testing strategies is both feasible and efficient. PROMISE will compare the clinical effectiveness of an initial strategy of functional testing against an initial strategy of anatomic testing in symptomatic patients with suspected CAD. Quality of life, resource use, cost effectiveness and radiation exposure will be assessed.
    American Heart Journal 06/2014; 167(6). DOI:10.1016/j.ahj.2014.03.003 · 4.56 Impact Factor
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    ABSTRACT: Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of delcasertib (50, 150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for ∼2.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed. Selective inhibition of delta-PKC with intravenous infusion of delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury. ClinicalTrials.gov Identifier: NCT00785954.
    European Heart Journal 05/2014; 35(37). DOI:10.1093/eurheartj/ehu177 · 14.72 Impact Factor
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    ABSTRACT: The annual cost of heart failure (HF) is estimated at $39.2 billion. This has been acknowledged to underestimate the true costs for care. The objective of this analysis is to more accurately assess these costs. Publicly available data sources were used. Cost calculations incorporated relevant factors such as Medicare hospital cost-to-charge ratios, reimbursement from both government and private insurance, and out-of-pocket expenditures. A recently published Atherosclerosis Risk in Communities (ARIC) HF scheme was used to adjust the HF classification scheme. Costs were calculated with HF as the primary diagnosis (HF in isolation, or HFI) or HF as one of the diagnoses/part of a disease milieu (HF syndrome, or HFS). Total direct costs for HF were calculated at $60.2 billion (HFI) and $115.4 billion (HFS). Indirect costs were $10.6 billion for both. Costs attributable to HF may represent a much larger burden to US health care than what is commonly referenced. These revised and increased costs have implications for policy makers.
    Clinical Cardiology 05/2014; 37(5):312-21. DOI:10.1002/clc.22260 · 2.23 Impact Factor
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    ABSTRACT: Adoption of TRI in the United States is low and may be related to challenges learning the technique. We examined the relationships between operator transradial percutaneous coronary intervention (TRI) volume and procedural metrics and outcomes. We used CathPCI Registry® data from 07/2009-12/2012 to identify new radial operators, defined by an exclusively femoral PCI approach for 6 months after their first PCI in the database and ≥15 total TRIs thereafter. Primary outcomes of fluoroscopy time, contrast volume, and procedure success were chosen as markers of technical proficiency. Secondary outcomes included in-hospital mortality, bleeding, and vascular complications. Adjusted outcomes were analyzed using operator TRI experience as a continuous variable with generalized linear mixed models. Among 54,561 TRI procedures performed at 704 sites, 942 operators performed 1-10 cases; 942 operators performed 11-50 cases; 375 operators performed 51-100 cases; and 148 operators performed 101-200 cases. As radial caseload increased, more TRIs were performed in women, in STEMI patients, and for emergency indications. Decreased fluoroscopy time and contrast use were non-linearly associated with greater operator TRI experience, with faster reductions observed for newer (<30-50 cases) compared with more experienced (>30-50 cases) operators. Procedure success was high, while mortality, bleeding, and vascular complications remained low across TRI volumes. As operator TRI volume increases, higher risk patients are chosen for TRI. Despite this, operator proficiency improves with greater TRI experience, and safety is maintained. The threshold to overcome the learning curve appears to be approximately 30-50 cases.
    Circulation 04/2014; 131(8). DOI:10.1161/CIRCULATIONAHA.113.006356 · 14.95 Impact Factor
  • Catheterization and Cardiovascular Interventions 02/2014; 83(2). DOI:10.1002/ccd.25209 · 2.40 Impact Factor
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    ABSTRACT: Bridging for antiplatelet therapy remains a subject of debate with data favoring GP blockers but at a risk of bleeding. This Conversation in Cardiology addresses a key and often asked question about use of alternatives to P2Y12 agents in patients requiring surgery within 6 months after drug eluting stent implantation. © 2013 Wiley Periodicals, Inc.
    Catheterization and Cardiovascular Interventions 12/2013; 83(5). DOI:10.1002/ccd.25319 · 2.40 Impact Factor
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    ABSTRACT: Women are at higher risk than men for bleeding and vascular complications after percutaneous coronary intervention (PCI). Compared with femoral access, radial access reduces these complications but may be more challenging in women because of higher rates of radial artery spasm, tortuosity, and occlusion as well as lower rates of procedure success. Whether the safety advantages of radial versus femoral access in women undergoing PCI are outweighed by reduced effectiveness has not been studied. The Study of Access site For Enhancement of PCI for Women is a prospective, randomized clinical trial comparing radial with femoral arterial access in women undergoing PCI. In conjunction with the US Food and Drug Administration's Critical Path Cardiac Safety Research Consortium, this study embeds the randomized clinical trial into the existing infrastructure of the National Cardiovascular Data Registry™ CathPCI Registry™ through the National Institute of Health's National Cardiovascular Research Infrastructure. The primary efficacy end point is a composite of bleeding (Bleeding Academic Research Consortium types 2, 3, or 5) or vascular complication requiring intervention occurring at 72 hours after PCI or by hospital discharge. The primary feasibility end point is procedure success. Secondary end points include procedure duration, contrast volume, radiation dose, quality of life, and a composite of 30-day death, vascular complication, or unplanned revascularization.
    American heart journal 09/2013; 166(3):421-428.e1. DOI:10.1016/j.ahj.2013.06.013 · 4.56 Impact Factor
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    ABSTRACT: Dual antiplatelet therapy (DAPT) cessation increases the risk of adverse events after percutaneous coronary intervention (PCI). Whether risk changes over time, depends on the underlying reason for DAPT cessation, or both is unknown. We assessed associations between different modes of DAPT cessation and cardiovascular risk after PCI. The PARIS (patterns of non-adherence to anti-platelet regimens in stented patients) registry is a prospective observational study of patients undergoing PCI with stent implantation in 15 clinical sites in the USA and Europe between July 1, 2009, and Dec 2, 2010. Adult patients (aged 18 years or older) undergoing successful stent implantation in one or more native coronary artery and discharged on DAPT were eligible for enrolment. Patients were followed up at months 1, 6, 12, and 24 after implantation. Prespecified categories for DAPT cessation included physician-recommended discontinuation, brief interruption (for surgery), or disruption (non-compliance or because of bleeding). All adverse events and episodes of DAPT cessation were independently adjudicated. Using Cox models with time-varying covariates, we examined the effect of DAPT cessation on major adverse events (MACE [composite of cardiac death, definite or probable stent thrombosis, myocardial infarction, or target-lesion revascularisation]). Incidence rates for DAPT cessation and adverse events were calculated as Kaplan-Meier estimates of time to the first event. This study is registered with ClinicalTrials.gov, number NCT00998127. We enrolled 5031 patients undergoing PCI, including 5018 in the final study population. Over 2 years, the overall incidence of any DAPT cessation was 57·3%. Rate of any discontinuation was 40·8%, of interruption was 10·5%, and of disruption was 14·4%. The corresponding overall 2 year MACE rate was 11·5%, most of which (74%) occurred while patients were taking DAPT. Compared with those on DAPT, the adjusted hazard ratio (HR) for MACE due to interruption was 1·41 (95% CI 0·94-2·12; p=0·10) and to disruption was 1·50 (1·14-1.97; p=0·004). Within 7 days, 8-30 days, and more than 30 days after disruption, adjusted HRs were 7·04 (3·31-14·95), 2·17 (0·97-4·88), and 1·3 (0·97-1·76), respectively. By contrast with patients who remained on DAPT, those who discontinued had lower MACE risk (0·63 [0·46-0·86]). Results were similar after excluding patients receiving bare metal stents and using an alternative MACE definition that did not include target lesion revascularisation. In a real-world setting, for patients undergoing PCI and discharged on DAPT, cardiac events after DAPT cessation depend on the clinical circumstance and reason for cessation and attenuates over time. While most events after PCI occur in patients on DAPT, early risk for events due to disruption is substantial irrespective of stent type. Bristol-Myers Squibb and Sanofi-Aventis.
    The Lancet 08/2013; 382(9906). DOI:10.1016/S0140-6736(13)61720-1 · 39.21 Impact Factor
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    ABSTRACT: Cangrelor is an intravenous P2Y12 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes. To determine the electrophysiologic safety of parenteral cangrelor, cardiac repolarization effects were measured in 67 healthy volunteers (ages 18-45 years) in a randomized crossover design including four treatment sequences of cangrelor therapeutic, cangrelor supratherapeutic, placebo, and moxifloxacin (positive control). Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and nine time points post-dose on Day 1. For both cangrelor and moxifloxacin, time-matched, placebo-adjusted change in QT from baseline was evaluated using an individual (QTcI) heart rate correction. After cangrelor dosing, change in QTcI was <5 milliseconds (ms) at all times points, and all corresponding upper two-sided 90% confidence intervals (CI) were <10 ms. While moxifloxacin failed to show a lower CI >5 ms, expected time trends and lower CI >4.0 ms demonstrate assay sensitivity. QTcI was not affected by plasma concentrations of cangrelor metabolites and cangrelor had no other adverse effects on electrocardiographic parameters. Clinically, cangrelor exposure was well tolerated. Thus, this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers. (clinicaltrials.gov identifier NCT00699504).
    Journal of cardiovascular pharmacology 08/2013; DOI:10.1097/FJC.0b013e3182a2630d · 2.11 Impact Factor

Publication Stats

7k Citations
1,833.76 Total Impact Points

Institutions

  • 1996–2015
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
  • 1988–2015
    • Duke University Medical Center
      • • Duke Clinical Research Institute
      • • Division of Cardiology
      • • Department of Medicine
      Durham, North Carolina, United States
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2001–2014
    • North Carolina Clinical Research
      Raleigh, North Carolina, United States
    • University of Santiago, Chile
      CiudadSantiago, Santiago Metropolitan, Chile
  • 2013
    • Thomas Jefferson University
      Filadelfia, Pennsylvania, United States
  • 2012
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2011
    • Stony Brook University Hospital
      Stony Brook, New York, United States
  • 2009
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • Hackensack University Medical Center
      Hackensack, New Jersey, United States
  • 2005
    • Sahlgrenska University Hospital
      • Department of Cardiology
      Goeteborg, Västra Götaland, Sweden
    • Columbia University
      • Division of Cardiology
      New York City, New York, United States
  • 2004
    • Brigham and Women's Hospital
      • TIMI Study Group
      Boston, MA, United States
  • 1999–2004
    • University of California, San Francisco
      • • Department of Physiological Nursing
      • • School of Nursing
      San Francisco, CA, United States
    • Pontifical Catholic University of Chile
      • División Enfermedades Cardiovasculares
      CiudadSantiago, Santiago Metropolitan, Chile
  • 1995
    • University of Arkansas
      Fayetteville, Arkansas, United States
  • 1986–1991
    • Georgetown University
      • Division of Cardiology
      Washington, Washington, D.C., United States