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Fordyce C.B.,University of British Columbia | Douglas P.S.,Duke Clinical Research Institute
JACC: Cardiovascular Imaging | Year: 2017

The categories and quality of evidence documenting the value of noninvasive cardiovascular imaging have evolved substantially over the last several decades. From an initial emphasis on the diagnostic accuracy of various imaging modalities, cardiovascular imaging has matured into an outcomes-based field that now provides evidence on adverse events, safety, cost, and patient quality-of-life endpoints, and does so in the setting of large randomized trials. This review aims to highlight types of outcomes endpoints, including updating the hierarchy of evidence for diagnostic imaging as first proposed by Fryback and Thornbury, and critically reviewing their application in the current cardiovascular imaging evidence base. We describe the range of data categories generated to date for the various imaging modalities, and indicate how this provides insights into contemporary study design and future directions in cardiovascular imaging outcomes research. © 2017 American College of Cardiology Foundation


News Article | November 14, 2016
Site: www.eurekalert.org

BOSTON - A new study led by clinician-researchers at Beth Israel Deaconess Medical Center (BIDMC) testing the safety and effectiveness of anticoagulant strategies for patients with atrial fibrillation who undergo stenting procedures has shown that therapies combining the anticoagulant drug rivaroxaban with either single or dual anti-platelet therapy (DAPT) were more effective in preventing bleeding complications than the current standard of care. Principal Investigator C. Michael Gibson, MD, Chief of Clinical Research in the Division of Cardiovascular Medicine at BIDMC, reported the new research findings today online in The New England Journal of Medicine and simultaneously presented the findings at the American Heart Association's Scientific Sessions 2016 in New Orleans. The PIONEER AF-PCI randomized clinical trial involved more than 2,100 patients at 430 sites in 26 countries. Each year, nearly 1 million patients in the United States undergo percutaneous coronary intervention (PCI) and are implanted with stents positioned to treat narrowed coronary arteries. Following PCI, patients receive dual anti-platelet therapy - a combination of aspirin and a second blood-thinning medication - to prevent the formation of blood clots in the stent. Approximately 5 to 8 percent of patients undergoing PCI have atrial fibrillation, the most common type of cardiac arrhythmia and an important risk factor for stroke. These patients typically take a blood thinner, such as warfarin (Coumadin), to prevent stroke. "In managing the stented patient with atrial fibrillation, a pharmacologic strategy must carefully balance the risk of stent thrombosis, or blood clot, with the risk of bleeding complications," said Gibson, who is also Professor of Medicine at Harvard Medical School and chairman of the PERFUSE (Percutaneous/Pharmacologic Endoluminal Revascularization for Unstable Syndromes Evaluation) Study Group. "This trial, which tested two entirely new strategies, now provides us with randomized clinical trial data demonstrating that a combination of rivaroxaban with anti-platelet therapy is successful in minimizing bleeding while preventing clotting." Current guidelines call for combining three drugs - DAPT plus a vitamin K antagonist (VKA) anticoagulant - in a strategy known as "triple therapy." But as the authors note, this approach may result in excess major bleeding rates of 4 to 12 percent within the first year of treatment. The PIONEER AF-PCI trial studied men and women over age 18 with atrial fibrillation who had undergone a PCI procedure with stent placement. The study subjects were randomly assigned to one of three groups: Group 1 received reduced dose rivaroxaban plus a P2Y-12 inhibitor monotherapy; Group 2 received very low dose rivaroxaban plus DAPT; and Group 3 received VKA plus DAPT. The findings showed that among patients with atrial fibrillation who underwent intracoronary stent placement, the administration of rivaroxaban in one of two dose strategies reduced the risk of clinically significant bleeding in about one out of every 10 to 11 patients as compared with triple therapy including a vitamin K antagonist. The risks of rehospitalization and death from all causes were also reduced in about one out of every 10 to 15 cases. "This new treatment strategy benefits patient health as well as hospital finances," added Gibson. The PIONEER AF-PCI study is supported by Janssen Scientific Affairs LLC, and Bayer Health Care Pharmaceuticals. Study coauthors include BIDMC investigators Serge Korjian, MD and, Yazan Daaboul, MD,; Roxana Mehran, MD, and Jonathan Halperin, MD, of Mount Sinai Medical Center, New York; Christoph Bode, MD, of the University of Freiburg, Germany; Freek W.A. Verheugt, MD, of Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam; Peter Wildgoose, PhD, Mary Birmingham, PharmD, Juliana Ianus, PhD, and Paul Burton, MD, PhD, of Jansen Pharmaceuticals, Inc.; Martin van Eickels, MD, of Bayer Pharmaceuticals; Gregory Y.H. Lip, MD of The University of Birmingham Centre for Cardiovascular Services, Birmingham, UK; Marc Cohen, MD, of Newark Beth Israel Medical Center, Newark, NJ; Steen Husted, MD, of Aarhus University Hospital, Herning, Denmark; Eric D. Peterson, MD, MPH of Duke Clinical Research Institute, Durham, NC; and Keith AA Fox, MB, ChB, of the Royal Infirmary of Edinburgh, UK. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


Raghu G.,University of Washington | Anstrom K.J.,Duke Clinical Research Institute | King Jr. T.E.,University of California at San Francisco | Lasky J.A.,Tulane University | Martinez F.J.,University of Michigan
New England Journal of Medicine | Year: 2012

BACKGROUND: A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown. METHODS: In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups - receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo - in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period. RESULTS: When approximately 50% of data had been collected (with 77 patients in the combination- therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P = 0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here. CONCLUSIONS: Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.) Copyright © 2012 Massachusetts Medical Society.


Martinez F.J.,University of Michigan | Martinez F.J.,New York Medical College | De Andrade J.A.,University of Alabama at Birmingham | Anstrom K.J.,Duke Clinical Research Institute | And 2 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Acetylcysteine has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis, although data from placebo-controlled studies are lacking. METHODS: In our initial double-blind, placebo-controlled trial, we randomly assigned patients who had idiopathic pulmonary fibrosis with mild-to-moderate impairment in pulmonary function to receive a three-drug regimen of prednisone, azathioprine, and acetylcysteine; acetylcysteine alone; or placebo. The study was interrupted owing to safety concerns associated with the three-drug regimen. The trial continued as a two-group study (acetylcysteine vs. placebo) without other changes; 133 and 131 patients were enrolled in the acetylcysteine and placebo groups, respectively. The primary outcome was the change in forced vital capacity (FVC) over a 60-week period. RESULTS: At 60 weeks, there was no significant difference in the change in FVC between the acetylcysteine group and the placebo group (-0.18 liters and -0.19 liters, respectively; P = 0.77). In addition, there were no significant differences between the acetylcysteine group and the placebo group in the rates of death (4.9% vs. 2.5%, P = 0.30 by the log-rank test) or acute exacerbation (2.3% in each group, P>0.99). CONCLUSIONS: As compared with placebo, acetylcysteine offered no significant benefit with respect to the preservation of FVC in patients with idiopathic pulmonary fibrosis with mild-to-moderate impairment in lung function. Copyright © 2014 Massachusetts Medical Society.


Rao S.V.,Duke Clinical Research Institute | Bernat I.,University Hospital | Bertrand O.F.,Quebec Heart Lung Institute
European Heart Journal | Year: 2012

The adoption of transradial coronary angiography and coronary intervention is growing because of emerging data on its potential advantages over the femoral approach. As the adoption of radial procedures increases, it is important to understand the remaining challenges of both the technique and its implementation. In this review, we discuss four important issues related to transradial procedures-radial access site bleeding, radial artery injury and occlusion, radiation exposure, and implementation of a successful transradial primary percutaneous coronary intervention (PCI) programme. Although the radial artery is superficial and haemostasis can be achieved readily, access site bleeding can occur that, if left unchecked, can lead to forearm haematoma and, rarely, to compartment syndrome. Radial artery injury and occlusion are consequences of radial access, and randomized trials show that use of smaller diameter sheaths, adequate anticoagulation, and post-procedure 'patent' haemostasis reduce the risk of occlusion. The published literature demonstrates an association between transradial procedures and increased radiation exposure; therefore, reduction of radiation dosing during transradial procedures should be a priority for operators and catheterization laboratories. The potential reduction in mortality seen with transradial primary PCI must be balanced against the clinical imperative of timely reperfusion. Operators and catheterization laboratories should not begin a transradial primary PCI programme until sufficient radial experience has been gained in the elective setting. In addition, a protocol for femoral bailout should be considered to maintain door-to-reperfusion metrics. © 2012 The Author.


Naggie S.,Duke Clinical Research Institute | Naggie S.,Durham Veterans Affairs Medical Center | Sulkowski M.S.,Johns Hopkins University
Gastroenterology | Year: 2012

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients. © 2012 AGA Institute.


Chastain C.A.,Vanderbilt University | Naggie S.,Duke Clinical Research Institute
Current HIV/AIDS Reports | Year: 2013

Hepatitis C (HCV) coinfection is the leading cause of liver-related morbidity and is a leading cause of mortality in human immunodeficiency virus (HIV)-infected individuals in the antiretroviral therapy era. Direct-acting antiviral (DAA) therapies are transforming how HCV is treated with significant improvements in efficacy and tolerability. In this article, DAA agents expected to be available in 2014 are reviewed, including telaprevir, boceprevir, sofosbuvir, simeprevir, faldaprevir, and daclatasvir. Available data regarding clinical efficacy, adverse effects, and drug interactions in HIV-HCV coinfection are discussed. The management of adverse effects of HCV therapy and treatment considerations in patients with cirrhosis are also reviewed. © 2013 Springer Science+Business Media New York.


Dauerman H.L.,University of Vermont | Rao S.V.,Duke Clinical Research Institute | Resnic F.S.,Brigham and Women's Hospital | Applegate R.J.,Wake forest University
Journal of the American College of Cardiology | Year: 2011

Bleeding complications after coronary intervention are associated with prolonged hospitalization, increased hospital costs, patient dissatisfaction, morbidity, and 1-year mortality. Bleeding avoidance strategies is a term incorporating multiple modalities that aim to reduce bleeding and vascular complications after cardiovascular catheterization. Recent improvements in the rates of bleeding complications after invasive cardiovascular procedures suggest that the clinical community has successfully embraced specific strategies and improved patient care in this area. There remains controversy regarding the efficacy, safety, and/or practicality of 3 key bleeding avoidance strategies for cardiac catheterization and coronary intervention: procedural (radial artery approach, safezone arteriotomy), pharmacological (multiple agents), and technological (vascular closure devices) approaches to improved access. In this paper, we address areas of consensus with respect to selected modalities in order to define the role of each strategy in current practice. Furthermore, we focus on areas of controversy for selected modalities in order to define key areas warranting cautious clinical approaches and the need for future randomized clinical trials in this area. © 2011 American College of Cardiology Foundation.


Alexander K.P.,Duke Clinical Research Institute
Journal of the American Heart Association | Year: 2013

Cardiovascular medicine is widely regarded as a vanguard for evidence-based drug and technology development. Our goal was to describe the cardiovascular clinical research portfolio from ClinicalTrials.gov. We identified 40 970 clinical research studies registered between 2007 and 2010 in which patients received diagnostic, therapeutic, or other interventions per protocol. By annotating 18 491 descriptors from the National Library of Medicine's Medical Subject Heading thesaurus and 1220 free-text terms to select those relevant to cardiovascular disease, we identified studies that related to the diagnosis, treatment, or prevention of diseases of the heart and peripheral arteries in adults (n = 2325 [66%] included from review of 3503 potential studies). The study intervention involved a drug in 44.6%, a device or procedure in 39.3%, behavioral intervention in 8.1%, and biological or genetic interventions in 3.0% of the trials. More than half of the trials were postmarket approval (phase 4, 25.6%) or not part of drug development (no phase, 34.5%). Nearly half of all studies (46.3%) anticipated enrolling 100 patients or fewer. The majority of studies assessed biomarkers or surrogate outcomes, with just 31.8% reporting a clinical event as a primary outcome. Cardiovascular studies registered on ClinicalTrials.gov span a range of study designs. Data have limited verification or standardization and require manual processes to describe and categorize studies. The preponderance of small and late-phase studies raises questions regarding the strength of evidence likely to be generated by the current portfolio and the potential efficiency to be gained by more research consolidation.


Hess C.N.,Duke Clinical Research Institute
Journal of the American Heart Association | Year: 2014

Data regarding sex-based outcomes after percutaneous coronary intervention (PCI) for myocardial infarction are mixed. We sought to examine whether sex differences in outcomes exist in contemporary practice. We examined acute myocardial infarction patients undergoing PCI between April 2010 and October 2012 at 210 US hospitals participating in the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) observational study. Outcomes included 1-year risk of major adverse cardiac events and bleeding according to Global Utilization of Strategies To Open Occluded Arteries (GUSTO) and Bleeding Academic Research Consortium (BARC) definitions. Among 6218 patients, 27.5% (n=1712) were female. Compared with men, women were older, had more comorbidities, and had lower functional status. Use of multivessel PCI and drug-eluting stents was similar between sexes, while women received less prasugrel. Unadjusted cumulative incidence of 1-year major adverse cardiac events was higher for women than for men (15.7% versus 13.6%, P=0.02), but female sex was no longer associated with higher incidence of major adverse cardiac events after multivariable adjustment (hazard ratio 0.98, 95% CI 0.83 to 1.15). Female sex was associated with higher risks of post-PCI GUSTO bleeding (9.1% versus 5.7%, P<0.0001) and postdischarge BARC bleeding (39.6% versus 27.9%, P<0.0001). Differences persisted after adjustment (GUSTO: hazard ratio 1.32, 95% CI 1.06 to 1.64; BARC: incidence rate ratio 1.42, 95% CI 1.27 to 1.56). Female and male myocardial infarction patients undergoing PCI differ regarding demographic, clinical, and treatment profiles. These differences appear to explain the higher observed major adverse cardiac event rate but not higher adjusted bleeding risk for women versus men.

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