Late-Breaking Clinical Trial Abstracts
2012 Late-Breaking Clinical Trial Abstracts
Late-Breaking Clinical Trials: Practice Implications for CAD and VTE
Aspirin for The Prevention of Recurrent Venous Thromboembolism After a First Unprovoked Event: Results of the ASPIRE Randomized Controlled Trial
Timothy Brighton1, John Eikelboom2, Kristy Mann3, Rebecca Mister4, Alexander Gallus5, Paul Ockelford6, Harry Gibbs7, Wendy Hague8, Denis Xavier9, Rafael Diaz10, Adrienne Kirby3, John Simes3 1South Eastern Area Laboratory Services (SEALS), Prince of Wales Hosp, Sydney, Australia 2McMaster Clinic, Hamilton, Canada 3NHMRC Clinical Trials Cntr, Camperdown, Australia 4NHMRC Clinical Trials Cntr, Univ of Sydney, Camperdown, Australia 5Flinders Med Cntr, Adelaide, Australia 6Auckland Hosp, Auckland, New Zealand 7Alfred Hosp, Melbourne, Australia 8NHMRC Clinical Trials Cntr, Sydney, Australia 9St Johns Rsch Institute, Koramangala, India 10Estudios Clínicos Latino America, Rosario, Argentina
Background: Patients with a first episode of unprovoked venous thromboembolism (VTE) have a high risk of recurrence once anticoagulant therapy is discontinued. Aspirin may be effective for preventing recurrent VTE in these patients. Methods: 822 patients who had completed 3–24 months of anticoagulant therapy after a first unprovoked VTE were randomized to aspirin, 100 mg daily, or placebo for up to 4 years. The primary outcome was recurrent VTE (symptomatic deep-vein thrombosis (DVT), pulmonary embolism (PE) or fatal PE), & prespecified secondary outcomes were a composite of VTE, MI, stroke and CVD death and a composite for net clinical benefit.* All events were independently adjudicated. Analysis was by intention-to-treat. Results: Mean patient age was 54 years, and 54% were men. The qualifying event was DVT in 57%, PE in 28%, and DVT and PE in 14%. Duration of prior anticoagulation was <3 mos in 26%, 3–6 in 47% and >6 months in 27%. The median time on study was 40.5 months in the aspirin and 35.9 in the placebo group. By 2 years, an estimated 22% allocated aspirin and 28% on placebo had discontinued study medication. New VTEs occurred in 73 patients on placebo (30 PE) and 57 on aspirin (18 PE), a nonsignificant reduction of 26%. Aspirin significantly reduced the composite outcome, VTE, MI, stroke and CVD death, by 34% (P=0.01) and improved net clinical benefit by 33% (P=0.01), without significantly increasing bleeding. Treatment effects were consistent among important subgroups (all interaction P for trend >0.5). Conclusion: In patients who had completed anticoagulation therapy after a first unprovoked VTE, aspirin was associated with a nonsignificant risk reduction in recurrent VTE. It significantly reduced major thrombotic events and CVD mortality, and significantly improved net clinical benefit. The results substantiate earlier trial evidence and support aspirin being routinely considered for patients with unprovoked VTE for whom anticoagulant therapy has been discontinued.
Author Disclosures: T. Brighton: Research Grant; Modest; Bayer. J. Eikelboom: Research Grant; Modest; Boehringer Ingelheim. Honoraria; Modest; Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Janssen Pharmaceuticals, Daiichi Sankyo. K. Mann: None. R. Mister: None. A. Gallus: Consultant/Advisory Board; Modest; Bayer, Pfizer, Bristol-Myers Squibb, Boehringer-Ingelheim, Astellas, Daiichi-Sankyo. P. Ockelford: Research Grant; Modest; Bayer, Boehringer Ingelheim, Daiichi-Sankyo. Honoraria; Modest; Novo Nordisk, Bayer. Consultant/Advisory Board; Modest; Novo Nordisk, Bayer, Biogen. H. Gibbs: Honoraria; Modest; Covidien, Boehringer Ingelheim, Bayer, AstraZeneca, Sanofi Aventis. Consultant/Advisory Board; Modest; Boehringer Ingelheim, Bayer, Pfizer. W. Hague: None. D. Xavier: Research Grant; Significant; Boehringer Ingelheim, Bristol-Myers Squibb, Cadila Pharma, Sanofi Aventis, GlasoSmithKline, AstraZeneca, Pfizer. R. Diaz: None. A. Kirby: None. J. Simes: Research Grant; Modest; Bayer.
Key Words: Venous thrombosis, Antiplatelet drugs, Cardiovascular disease prevention, Clinical trials
A Randomized Trial of Bedside Platelet Function Monitoring to Adjust Antiplatelet Therapy Versus Standard of Care in Patients Undergoing Drug Eluting Stent Implantation: The ARCTIC Study
Gilles Montalescot1, Jean-Philippe Collet1, Eric Vicaut2, Guillaume Cayla3, Thomas Cuisset4, Simon Elhadad5, Grégoire Rangé6 1Pitié-Salpêtrière Univ Hosp, Paris, France 2Hôpital Lariboisière-St. Louis, Paris, France 3CHU Nîmes, Nîmes, France 4Hôpital de la Timone, Marseille, France 5CH de Lagny, Lagny-sur-Marne, France 6CH Louis Pasteur, Le Coudray, France
Background: Individual response to oral antiplatelet therapy (APT) is subject to variability and bedside monitoring offers the opportunity of individualizing therapy for stent implantation. Study design: The ARCTIC randomized trial was designed to demonstrate the superiority of a strategy of platelet function monitoring with drug and/or dose adjustments of APT in suboptimal responders as compared to a more conventional strategy without monitoring and without drug and/or dose changes to reduce the primary endpoint evaluated one year after elective drug eluting stent (DES) implantation. We used the VerifyNowTMP2Y12/Aspirin point of care assay for platelet function monitoring on whole blood in the catheterization laboratory just before stent implantation and in the outpatient clinic for maintenance therapy. High on-clopidogrel platelet reactivity was defined by a PRU value >235 and/or a % inhibition<15%. High on-aspirin platelet reactivity was defined by an ARU value >550. In 40 centers, 2,500 patients with stable angina/ischemia or non-ST-elevation ACS undergoing PCI were randomized by IVRS after the coronary angiogram and before stent implantation. When randomized to platelet function monitoring, patients with high on-treatment platelet reactivity had their treatment adjusted in the catheterization laboratory before start of procedure using higher doses of aspirin and/or clopidogrel, prasugrel or GPIIbIIIa inhibitors. Platelet function analyses were repeated 2–4 weeks after PCI for adjustment of maintenance APT using higher or lower MD of aspirin/clopidogrel or switch to prasugrel. The primary end point is the time to first occurrence of all-cause mortality, non-fatal myocardial infarction, definite/probable stent thrombosis, urgent revascularization or non-fatal stroke at 1-year follow-up. Safety end points include major bleedings using different definitions of bleeding. Final results will be presented at the meeting. Conclusion: ARCTIC is the first large scale trial evaluating by randomization the hypothesis of personalized antiplatelet therapy at the time and after DES implantation to improve clinical outcome.
Author Disclosures: G. Montalescot: Research Grant; Significant; Abbott Vascular, Asante, AstraZeneca, Biotronik, Boston Scientific, Brahms, Cordis, Daiichi-Sankyo, Eli-Lilly, Fédération Française de Cardiologie, Fondation de France, Indegene, INSERM, Institut de France, Medtronic, Nanospheres, Pfizer, Roche, Sanofi-Aventis, Stentys, SGAM, Société Française de Cardiologie, Thrombosis Research Institute, The Medicines Company. Consultant/Advisory Board; Modest; Atrium, Bayer, BMS, Boehringer-Ingelheim, Choice Pharma, CCS, CHUV, Duke Institute, Europa, EuroRSCG, GLG, GSK, HUG, Iroko, Lead-Up, McKinsey, MSD, Navigant, Novartis, Portola, Royal College Physicians, Springer, TIMI Group, US Zurich, WebMD, Wolters. J. Collet: Research Grant; Significant; BMS, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Fondation de France, INSERM, Féderation Française de Cardiologie, Société Française de Cardiologie. Consultant/Advisory Board; Modest; Sanofi-Aventis, Eli Lilly, BMS. Other; Modest; BMS (lecture fees), Sanofi-Aventis (lecture fees), Eli Lilly (lecture fees), AstraZeneca (lecture fees). E. Vicaut: Consultant/Advisory Board; Modest; Abbott, Amgen, Eli Lilly, Pfizer, Sanofi-Aventis, Servier. G. Cayla: Research Grant; Significant; Fédération Française de Cardiologie. Consultant/Advisory Board; Modest; Abbott Vascular, AstraZeneca, CLS Behring, Daiichi Sankyo, Eli Lilly. Other; Modest; Abbott Vascular (lecture fees), AstraZeneca (lecture fees), Biotronik (lecture fees), CLS Behring (lecture fees), Daiichi Sankyo (lecture fees), Eli Lilly (lecture fees), Iroko Cardio (lecture fees). T. Cuisset: Consultant/Advisory Board; Modest; Daiichi Sankyo, Eli Lilly. Other; Modest; AstraZeneca (lecture fees), Abbott Vascular (lecture fees), Biotronik (lecture fees), Boston Scientific (lecture fees), Cordis (lecture fees), Daiichi Sankyo (lecture fees), Edwards Life Sciences (lecture fees), Eli Lilly (lecture fees), Iroko Cardio (lecture fees), Sanofi-Aventis (lecture fees), Servier (lecture fees). S. Elhadad: None. G. Rangé: None.
Key Words: Antiplatelet drugs, Percutaneous coronary intervention, Drug eluting stents
First Large-Scale Platelet Function Evaluation in an Acute Coronary Syndromes Trial - The TRILOGY ACS Platelet Function Sub-Study
Paul A. Gurbel1, David Erlinge2, E. M. Ohman3, Joseph A. Jakubowski4, Shaun G. Goodman5, Kurt Huber6, Mark Y. Chan7, Jan H. Cornel8, Harvey D. White9, Keith A. Fox10, Dorairaj Prabhakaran11, Paul W. Armstrong12, Udaya S. Tantry13, Matthew T. Roe14 1Sinai Hosp Cntr for Thrombosis Rsch, Baltimore, MD, 2Skåne Univ Hosp, Lund, Sweden 3Duke Univ Med Cntr, Durham, NC, 4Eli Lilly and Company, Indianapolis, IN, 5St. Michael's Hosp/Univ of Toronto, Toronto, Canada 6Dept of Cardiology, Wilhelminenspital, Vienna, Austria 7National Univ Heart Cntr, National Univ of Singapore, Singapore, Singapore 8Medisch Centrum Alkmaar, Alkmaar, Netherlands 9Green Lane Cardiovascular Service/Auckland City Hosp, Auckland, New Zealand 10Cntr for Cardiovascular Science, Univ of Edinburgh, Edinburgh, United Kingdom 11Cntr for Chronic Disease Control, Vasant Kunj - New Delhi, India 12Candian VIGOUR Cntr - Univ of Alberta, Edmonton, Canada 13Sinai Hosp of Baltimore, Baltimore, MD, 14Duke Clinical Rsch Institute, Durham, NC
Background: The role of platelet function testing for delineating the prognosis of patients with acute coronary syndromes treated with antiplatelet therapy has not been evaluated in a large-scale trial. Methods: TRILOGY ACS is a double-blind, placebo-controlled, randomized trial comparing prasugrel (10 or 5 mg/d) + aspirin vs. clopidogrel (75 mg/d) + aspirin in 9,326 high-risk UA/NSTEMI patients managed medically without revascularization. A 5 mg prasugrel maintenance dose was given for those ≥75 y and/or<60 kg; all others received a 10 mg dose. All subjects at sites participating in the platelet function sub-study had the VerifyNow P2Y12 assay performed before study drug and at 1, 3, 6, 12, 18, 24 and 30 months. Stratification by pre-randomization use of clopidogrel was: Stratum 1 - no clopidogrel; Stratum 2 - started on clopidogrel in-hospital before randomization; Stratum 3 - home maintenance clopidogrel continued until randomization. The primary clinical endpoint was CV death, MI, or stroke. Bleeding was assessed with TIMI and GUSTO scales. Results: From 2008–2011, 2690 patients (28% of the total trial population) were enrolled in 25 countries. The United States, Ukraine, India, China, and Bulgaria were the top enrolling countries. Baseline characteristics for the sub-study patients (Table) are representative of the overall trial population. Final sub-study results will be available for an AHA 2012 presentation. The primary hypothesis is that a lower risk of the primary clinical endpoint will be seen among patients with a lower level of platelet aggregation (tested as a time-dependent covariate in a Cox regression model). Similar analyses will be performed for bleeding endpoints. Conclusions: The TRILOGY platelet function sub-study (the largest and most global study of platelet function measurements) will delineate the role of platelet function testing for determining the prognosis of patients treated with antiplatelet therapy post-UA/NSTEMI.
Author Disclosures: P.A. Gurbel: Research Grant; Significant; NIH, Daiichi Sankyo, Lilly, CSL, Harvard Clinical Research Institute, Duke Clinical Research Institute, Haemonetics. Speakers Bureau; Modest; Lilly, Pozen, Nanosphere, Sanofi-Aventis, Iverson Genetics. Speakers Bureau; Significant; Daiichi Sankyo, Merck. Consultant/Advisory Board; Modest; Daiichi Sankyo, Lilly, Pozen, Novartis, Bayer, AstraZeneca, Nanosphere, Sanofi-Aventis, Boehringer Ingelheim, Merck, Medtronic, Iverson Genetics, CSL, Haemonetics. Other; Modest; Patent - Personalized antiplatelet therapy, Patent - Interventional cardiology. D. Erlinge: Research Grant; Significant; Lilly. Speakers Bureau; Modest; Lilly. E.M. Ohman: Research Grant; Significant; Daiichi Sankyo, Lilly, Datascope. Consultant/Advisory Board; Modest; AstraZeneca, Boehringer Ingelheim, BMS, Liposcience, Merck, Sanofi-Aventis, The Medicines Company, Pozen. Consultant/Advisory Board; Significant; Gilead Sciences, WebMD. J.A. Jakubowski: Employment; Significant; Lilly. Ownership Interest; Significant; Lilly. S.G. Goodman: Research Grant; Significant; AstraZeneca, BMS, Daiichi Sankyo, Lilly, Sanofi-Aventis. Honoraria; Modest; AstraZeneca, BMS, Lilly, Sanofi-Aventis. Consultant/Advisory Board; Modest; AstraZeneca, BMS, Lilly, Sanofi-Aventis. K. Huber: Honoraria; Modest; AstraZeneca, Lilly, Daiichi Sankyo. M.Y. Chan: Research Grant; Significant; Bayer Yakuhin. Honoraria; Significant; Bayer Singapore. J.H. Cornel: Consultant/Advisory Board; Modest; Merck, Lilly, Daiichi Sankyo, AstraZeneca. H.D. White: Consultant/Advisory Board; Modest; Merck Sharpe & Dohme, Regado Biosciences. Research Grant; Significant; Sanofi Aventis, Eli Lilly, Medicines Company, NIH, Pfizer, Roche, Johnson & Johnson, Schering Plough, Merchk Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, Bristol-Myers Squibb. K.A. Fox: Honoraria; Modest; Bayer, Johnson & Johnson, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Lilly/Daiichi Sankyo, Astra Zeneca, Sanofi, Boehringer Ingelheim. Research Grant; Significant; Bayer, Johnson & Johnson, Lilly, AstraZeneca, Sanofi, Boehringer Ingelheim, Lilly. D. Prabhakaran: Research Grant; Significant; NHLBI, United Health Group, NICHD/FIC. Other Research Support; Significant; Lilly. Honoraria; Significant; Torrent Pharmaceuticals India. P.W. Armstrong: Consultant/Advisory Board; Modest; Axio/Orexigen, Merck. Other; Modest; Astra Zeneca and Eli Lilly. Research Grant; Significant; Boehringer Ingelheim, Hoffmann LaRoche & sanofiaventis Canada Inc, Eli Lily, Merck Sharp & Dohme Corp in conjunction with Duke Clinical Research Institute, GlaxoSmithKline, Amylin Pharmaceuticals, Merck & Company Inc.. Consultant/Advisory Board; Significant; F. Hoffmann-La Roche Ltd. U.S. Tantry: Honoraria; Modest; Accumetrics. M.T. Roe: Research Grant; Significant; Lilly, BMS, Novartis, Hoffman-La Roche. Consultant/Advisory Board; Modest; Daiichi Sankyo, AstraZeneca, Helsinn. Consultant/Advisory Board; Significant; BMS, Hoffman-La Roche, KAI, Merck, Sanofi-Aventis, Regeneron.
Key Words: Acute coronary syndromes, Platelet receptor blockers, Prasugrel
Results of the Trial to Assess Chelation Therapy
Gervasio A. Lamas1, Robin Boineau2, Christine Goertz3, Daniel B. Mark4, Theodore C. Rozema5, Richard L. Nahin6, Yves Rosenberg7, Mario Stylianou7, Jeanne Drisko8, Kerry L. Lee4 1Mount Sinai Med Cntr, Miami, FL, 2National Heart Lung & Blood Institute, Bethesda, MD, 3Palmer College of Chiropractic, Davenport, IA, 4Duke Clinical Rsch Institute, Durham, NC, 5Biogenesis Med Cntr, Landrum, SC, 6National Cntr of Complementary and Alternative Medicine, Bethesda, MD, 7National Heart, Lung & Blood Institute, Bethesda, MD, 8Integrative Medicine, the Univ of Kansas Med Cntr, Kansas City, KS
Background: Some physicians who employ complementary and alternative approaches for the treatment of atherosclerosis prescribe chelation therapy with disodium ethylenediaminetetraacetic acid (EDTA). Existing clinical data do not permit accurate conclusions about either efficacy or safety of this therapy. Nonetheless, the number of Americans using this therapy is increasing, according to CDC reports. Methods: The Trial to Assess Chelation Therapy (TACT) is an NIH-sponsored randomized, double blind, placebo-controlled, 2×2 factorial clinical trial testing the benefits and risks of 40 infusions of a multi-component disodium EDTA-chelation solution compared with placebo, and of an oral, high-dose multivitamin and mineral supplement compared with oral placebo. All study participants also receive standard care. TACT has randomized and followed 1708 post-MI patients for an average of 4 years at 134 sites in the US and Canada between September 2003 and October 2010. The primary endpoint is a composite of all cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A composite secondary endpoint addresses irreversible ischemic events (CV death, non-fatal MI, non-fatal stroke). Pre-specified subgroup analyses of the primary endpoint include age, gender, race and diabetes status. A 911 patient substudy examines quality of life outcomes. The trial has >85% power to detect a 25% reduction in the primary endpoint for each treatment factor. Results: Baseline characteristics of the study population are presented in Table 1. A total of 55,222 EDTA or placebo infusions were administered. Database lock will take place July 2012. Conclusions: The results of TACT will show whether disodium EDTA chelation or high-dose oral vitamin therapy offer net benefit for patients with coronary disease and a prior MI.
Author Disclosures: G.A. Lamas: None. R. Boineau: None. C. Goertz: None. D.B. Mark: None. T.C. Rozema: None. R.L. Nahin: None. Y. Rosenberg: None. M. Stylianou: None. J. Drisko: None. K.L. Lee: None.
Key Words: Coronary artery disease, Myocardial infarction, Prevention, Pharmacology, Vitamins
Main Results of the Future REvascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) Trial
Valentin Fuster, Michael E. Farkouh Mount Sinai Sch of Medicine, New York, NY
Background: Prior randomized trials suggested that coronary artery bypass grafting (CABG) produced results superior to balloon angioplasty or bare-metal stenting in patients with diabetes. Whether this remains the case in the current era in which drug eluting stents (DESs) are available and routinely used is unknown. FREEDOM is an NHLBI -sponsored, international, randomized controlled trial designed to determine whether CABG or percutaneous coronary intervention (PCI) is the superior approach for revascularization of diabetic patients with multivessel coronary disease (MVD). Methods: In the FREEDOM trial, a total of 1900 diabetic subjects with MVD were randomized to PCI or CABG worldwide from April 2005-March 2010 and followed for a mean of 4.37 years (minimum 2 years). FREEDOM was designed to have 80% power to detect a 27.0% relative reduction in a composite endpoint composed of all-cause mortality, nonfatal myocardial infarction, or stroke (ClinicalTrials.gov number, NCT 00086450). Results: The randomized cohort was 63.1±9.1 years old and 29% female with median diabetes duration 10.2±8.9 years. Results for the primary outcome measure will be available November 2012. Conclusions: The FREEDOM trial definitively determines whether PCI or CABG results in a superior outcome (all cause mortality, myocardial infarction or stroke) in patients with diabetes and multivessel coronary artery disease.
Author Disclosures: V. Fuster: None. M.E. Farkouh: Research Grant; Modest; Genentech. Consultant/Advisory Board; Modest; Eli Lilly, Genetech, Sanofi-Aventis, Novartis.
Key Words: Coronary artery disease, Percutaneous coronary intervention, Angiogenesis
Late-Breaking Clinical Trials: Health Economics and Quality of Life in Contemporary Trials
Prospective Evaluation of Outcomes With Stress Perfusion Imaging Versus Stress Wall Motion Imaging During Dobutamine or Exercise Echocardiography
Thomas R. Porter, Lynette M. Smith, Feng Xie, Juefei Wu, Deepak Thomas, Stacey L. Therrien, Monique G. Smith, John T. Haas, Eric Williams, Samer Sayyed Univ of Nebraska Med Cntr, Omaha, NE
Background: Retrospective studies examining real-time myocardial contrast echocardiography (RTMCE) during an intravenous (IV) microbubble infusion have improved the detection of coronary artery disease (CAD) during exercise or pharmacologic stress echocardiography (SE). These studies were performed with experienced reviewers in selected patients. The purpose of this study was to prospectively compare the predictive value of RTMCE with conventional stress echo (CSE), where contrast is used only for the Food and Drug Administration indication of left ventricular opacification. Methods: A total of 2063 patients with intermediate pre-test probability undergoing either dobutamine or exercise SE were prospectively randomized to either RTMCE or CSE as their imaging modality during SE. A continuous infusion of Definity (Lantheus Medical) was used for all RTMCE studies to examine for both myocardial perfusion and wall motion, while Definity was used for CSE only when endocardial border delineation was inadequate (46% of all studies). RTMCE was performed with real-time pulse sequence schemes (mechanical index <0.25; frame rate 20–25 Hz). Studies were interpreted immediately by either an experienced reviewer (R1; n=1257) in perfusion imaging, or four Level III reviewers with basic training in perfusion imaging (R2; n=806). Results: Follow-up was available in 2014 patients (median follow up 2.5 yrears). Mean age was 59×13 years (53% women). Patients randomized to RTMCE had slightly lower ejection fraction and higher frequency of prior revascularization (both P<0.005). Abnormal RTMCE studies were more frequent than abnormal CSE (P<0.001), and more frequently abnormal in a multi-vessel territory (P<0.005). Overall event free survival (EFS) in those with positive or negative studies were not different between CSE and RTMCE. The predictive value of a positive study for both CSE and RTMCE was significant for R1 but not for R2 reviewers. Conclusions. Abnormal studies are more frequently detected with RTMCE. ALthough the predictive value of SE with contrast is improved with experienced contrast users, the overall positive or negative predictive value of a dobutamine or exercise SE, when performed with RTMCE versus CSE in general practice, is not different.
Author Disclosures: T.R. Porter: Other Research Support; Modest; GE Healthcare, Philips Research North America. Research Grant; Significant; Lantheus Medical Imaging, Astellas Pharma, Philips Healthcare. L.M. Smith: None. F. Xie: None. J. Wu: None. D. Thomas: None. S.L. Therrien: None. M.G. Smith: None. J.T. Haas: None. E. Williams: None. S. Sayyed: None.
Key Words: Echocardiography, Contrast echo, Efficacy
Economic Outcomes of Percutaneous Coronary Intervention Performed at Sites With and Without On-Site Cardiac Surgery
Eric L. Eisenstein1, Linda Davidson-Ray1, Rex Edwards1, Kevin J. Anstrom1, Patricia A. Cowper1, Daniel B. Mark1, Thomas R. Aversano2 1Duke Clinical Rsch Institute, Durham, NC, 2Johns Hopkins Med, Baltimore, MD
Background: The Cardiovascular Patient Outcomes Research Team Non-Primary PCI (CPORT-E) trial randomly assigned subjects to undergo percutaneous coronary intervention (PCI) at a hospital without on-site surgery (No-SOS site; n=14,149) or to be transferred to a hospital with on-site surgery for PCI (SOS site; n=4718). No-SOS versus SOS subjects had similar 6-week mortality (0.9% versus 1.0%; P=0.004 for non-inferiority) and 9-month major adverse cardiac event rates (12.1% versus 11.2%; P=0.05 for non-inferiority). While No-SOS versus SOS subjects had fewer staged procedures (26% versus 68%; P<0.001) and catheterization laboratory visits (1.28 versus 1.73; P<.001) during their index PCI; they also had higher rates of any subsequent revascularization at 9 months (8.5% versus 7.0%; P=0.001). Methods: We conducted a prospective economic study to determine whether total medical costs at 9 months were lower for No-SOS versus SOS subjects. Coordinators at CPORT-E sites collected inpatient bills from each subject's index diagnostic catheterization through 9 months follow-up. We estimated medical costs for outpatient cardiac procedures, acute care and observational stays, and emergency department visits using hospital department-specific ratios of cost-to-charge. Physician costs for inpatient care were estimated from care templates with costs assigned using national Medicare reimbursements. Ambulance transportation costs were estimated using site-specific Medicare reimbursements. Economic results are reported as mean values by treatment strategy, with differences in those values, 95% confidence intervals and p-values. Results: Economic results for the entire CPORT-E population will be reported for the index procedure, follow-up period and 9 months cumulative. Economic outcomes include resource use, length of stay, and medical costs for cardiac procedures (diagnostic catheterization, PCI staged and not staged, and coronary artery bypass graft surgery), other hospitalizations (cardiovascular and non-cardiovascular), and emergency department visits. Conclusion: Economic analyses will be completed and full results reported at the November 2012 AHA meeting.
Author Disclosures: E.L. Eisenstein: Other Research Support; Significant; Medtronic Endovascular Therapies, Eli Lilly & Company. L. Davidson-Ray: Other Research Support; Significant; AstraZeneca, Eli Lilly & Company. R. Edwards: Other Research Support; Significant; Medtronic Endovascular Therapies. K.J. Anstrom: Research Grant; Significant; AstraZeneca, Eli Lilly and Co., Medtronic Endovascular Therapies, Proctor and Gamble. Consultant/Advisory Board; Modest; Abbott Vascular, AstraZeneca, Bristol-Meyers Squibb, Ikaria. Other; Modest; Pfizer, Vertex. P.A. Cowper: Other Research Support; Significant; Eli Lilly & Company, AstraZeneca, Bristol-Meyers Squibb, Medtronic Endovascular Therapies. D.B. Mark: Research Grant; Significant; AstraZeneca, Gilead, Eli Lilly and Company, Medtronic Endovascular Therapies. Consultant/Advisory Board; Modest; Gilead. T.R. Aversano: Consultant/Advisory Board; Modest; Science First.
Key Words: Cost-effectiveness, Percutaneous coronary intervention
Quality of Life Outcomes in the Trial to Assess Chelation Therapy (TACT)
Daniel B. Mark1, Kevin J. Anstrom2, Robin Boineau3, Christine Goertz4, Theodore C. Rozema5, J. David Knight2, Nancy E. Clapp-Channing2, Diane M. Liu2, Richard L. Nahin6, Yves Rosenberg3, Jeanne Drisko7, Kerry L. Lee2, Gervasio A. Lamas8 1Duke Univ Med Cntr, Durham, NC, 2Duke Clinical Rsch Institute, Durham, NC, 3National Heart, Lung, & Blood Institute, Bethesda, MD, 4Palmer College of Chiropractic, Davenport, IA, 5Biogenesis Med Cntr, Landrum, SC, 6National Cntr of Complementary and Alternative Medicine, Bethesda, MD, 7Integrative Medicine, the Univ of Kansas Med Cntr, Kansas City, KS, 8Mount Sinai Med Cntr, Miami, FL
Background: The Trial to Assess Chelation Therapy (TACT) is an NIH-funded, randomized, double-blind, placebo-controlled, 2×2 factorial trial comparing 40 infusions of a multicomponent disodium EDTA chelation solution with placebo and oral, high-dose multivitamin and mineral supplement with placebo in post-MI patients. A quality of life (QOL) substudy was conducted to assess patient-reported outcomes. Methods: The TACT QOL battery included the Medical Outcomes Study Short Form-36 (SF-36); the Duke Activity Status Index (DASI); the Seattle Angina Questionnaire (SAQ) Anginal Frequency, Anginal Stability, and Quality of Life subscales; the EQ-5D; a 0–100 health rating; and the Bypass Angioplasty Revascularization Investigation (BARI) work items. QOL data were collected at baseline and at 6, 12, and 24 months post randomization. Results: TACT enrolled 1,708 patients between September 2003 and October 2010, and follow-up QOL data were collected in a randomly selected subset of 911 patients. We collected baseline data on 100% of the QOL subset, with 95% of expected QOL data collected during follow-up. Conclusions: Comparison by intention-to-treat of the QOL endpoints will be presented after the presentation of the TACT clinical results.
Author Disclosures: D.B. Mark: Research Grant; Significant; Eli Lilly & Company, Gilead, Medtronic, AstraZeneca. Honoraria; Modest; Gilead. K.J. Anstrom: None. R. Boineau: None. C. Goertz: None. T.C. Rozema: None. J. Knight: None. N.E. Clapp-Channing: None. D.M. Liu: None. R.L. Nahin: None. Y. Rosenberg: None. J. Drisko: None. K.L. Lee: None. G.A. Lamas: None.
Key Words: Cardiovascular disease, Quality of life, Vitamins, Coronary artery disease, Evidence-based medicine
Cost-Effectiveness of PCI With Drug Eluting Stents versus Bypass Surgery for Patients With Diabetes and Multi-Vessel Coronary Artery Disease: Results From the FREEDOM Trial
Elizabeth A. Magnuson1, Valentin Fuster2, Michael Farkouh2, Kaijun Wang1, Katharine Vilain1, Haiyan Li1, Jaime Appelwick1, Victoria Muratov3, Lynn A. Sleeper3, Mouin Abdallah1, David J. Cohen1 1Saint Luke's Mid America Heart Institute, Kansas City, MO, 2Mount Sinai Sch of Medicine, New York, NY, 3New England Rsch Institutes, Watertown, MA
Background: Previous studies have demonstrated that for patients undergoing multi-vessel revascularization, initial costs are lower for PCI with drug-eluting stents (DES-PCI) than CABG, although this cost difference narrows substantially over time. No study to date has specifically examined the relative cost-effectiveness of DES-PCI vs. CABG among diabetic patients. Methods: Between 2005 and 2010, 1900 patients with diabetes and multi-vessel coronary artery disease (CAD) were randomized to undergo either DES-PCI (n=953) or CABG (n=947). A formal health economic substudy was included in order to evaluate the relative costs and benefits of PCI vs. CABG for this population. Costs will be assessed over a 4-year follow-up period from the perspective of the U.S. healthcare system using a combination of resource-based costing (for procedures), Medicare data (for other hospital costs, physician fees, and outpatient services) and the Drug Topics Red book (for medications). Health-related quality of life and health state utility are assessed over the same time period using the Seattle Angina Questionnaire and the EuroQOL. The in-trial results relating to clinical outcomes, quality of life and costs are being applied in the development of a patient-level microsimulation model for the evaluation of lifetime cost-effectiveness. Results: Among patients assigned to DES-PCI, the initial procedure required an average of 4.2 stents; staged PCI procedures were performed in 33% (see Table). Initial hospital length of stay and ICU length of stay were substantially shorter after PCI. Final results including total 4-year costs and quality-adjusted life expectancy will be available for presentation in 11/12, along with results from a lifetime cost-effectiveness analysis. Conclusions: The results of this prospective economic substudy will complement the primary clinical outcomes of FREEDOM and provide a comprehensive evaluation of DES-PCI vs. CABG for patients with diabetes.
Author Disclosures: E.A. Magnuson: Research Grant; Significant; Abbott Vascular, Boston Scientific, Medtronic, Edwards Lifesciences, Eli Lilly, Daiichi Sankyo, Astra Zeneca. V. Fuster: None. M. Farkouh: Research Grant; Modest; Genentech. Consultant/Advisory Board; Modest; Eli Lilly, Genetech, Sanofi-Aventis, Novartis. K. Wang: None. K. Vilain: None. H. Li: None. J. Appelwick: None. V. Muratov: None. L.A. Sleeper: None. M. Abdallah: None. D.J. Cohen: Research Grant; Significant; Abbott Vascular, Boston Scientific, Medtronic, Edwards Lifesciences, Biomet, Eli Lilly, Daiichi Sankyo, Astra Zeneca. Consultant/Advisory Board; Modest; Abbott Vascular, Medtronic.
Key Words: Cost-effectiveness, Percutaneous coronary intervention, Cardiac surgery, Coronary artery disease, Type 2 Diabetes
Late-Breaking Clinical Trials: Treatments for Prevention of Cardiovascular Events: A Population Perspective
Omega-3 Fatty Acids for the Prevention of Recurrent Symptomatic Atrial Fibrillation: Results of a Double-Blind Randomized Clinical Trial (FORWARD) (NCT00597220)
Alejandro Macchia1, Hugo Grancelli2, Sergio Varini2, Daniel Nul2, Daniel Ferrante2, Javier Mariani2, Nicolas Laffaye2, Raul Badra3, Julio Figal4, Silvina Ramos5, Gianni Tognoni1, Hernan Doval2 1Consorzio Mario Negri Sud, Santa Maria Imb, Italy 2Fundacion GESICA, Buenos Aires, Argentina 3Hosp Privado de la Comunidad, Mar del Plata, Argentina 4Fundacion Favaloro, Buenos Aires, Argentina 5Clinica Constituyentes, Buenos Aires, Argentina
Introduction: Current pharmacological treatments to limit recurrent atrial fibrillation (AF) in patient with previous AF have limited efficacy and high rates of adverse events. Results of trials which tested the efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFA) provided heterogeneous results. Hypothesis: To evaluate the efficacy of chronic supplementation with n-3 PUFA for the prevention of recurrent symptomatic AF in patients with previous AF who were at normal sinus rhythm at randomization. Methods: Prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial involving 586 outpatient participants with confirmed symptomatic paroxysmal AF that required cardioversion (n=428), at least two episodes of AF in the 6 months before randomization (n=55), or both criteria (103). Patients were recruited from January 2008 to March 2011 (final follow-up was February 2012) to receive one gram/day of n-3 PUFA or placebo for one-year. The primary end point was symptomatic recurrence of AF (first recurrence). All participants were followed for 12 months, or time to death or recurrent AF. Results: There were no significant differences between patients allocated to placebo and those who received n-3 PUFA for the main outcome. At 12 months, 56 of 297 participants (18.9%) in the placebo group and 69 of 289 participants (24.0%) in the n-3 PUFA group had a recurrent symptomatic AF (HR 1.28; 95% CI 95% 0.90–1.83;, P=0.17). There was no difference between treatment with placebo and n-3 PUFA for any other prespecified end points. The composite of all-cause mortality, non-fatal stroke, non-fatal AMI, systemic embolism, heart failure development or severe bleeding occurred in 20 (6.7%) and 16 (5.5%) patients randomized to placebo or n-3 PUFA, respectively (HR 0.86; 0.44–1.66; P=0.65). A total of 2.7% of those receiving placebo and 2.0% of those receiving prescription omega-3 discontinued due to intolerance. Conclusion: Pharmacological supplementation with 1 g/day of n-3 PUFA for 1 year did not reduce recurrent AF. Trial Registration clinicaltrials.gov Identifier: NCT00402363.
Author Disclosures: A. Macchia: None. H. Grancelli: None. S. Varini: None. D. Nul: None. D. Ferrante: None. J. Mariani: None. N. Laffaye: None. R. Badra: None. J. Figal: None. S. Ramos: None. G. Tognoni: None. H. Doval: None.
Key Words: Atrial fibrillation, Fish oils
Fish Oil for the Prevention of Post-Operative Atrial Fibrillation - The Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation (OPERA) Trial
Roberto Marchioli1, Dariush Mozaffarian2, Giusi Silletta1, Alejandro Macchia3, Paolo Ferrazzi4, Timothy Gardner5, Roberto Latini6, Peter Libby2, Federico Lombardi7, Patrick O'Gara2, Richard Page8, Massimo Santini9, Luigi Tavazzi10, Gianni Tognoni1, . On behalf of the OPERA Investigators11 1Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy 2Harvard Med Sch, Boston, MA, 3GESICA Foundation, Buenos Aires, Argentina 4Ospedali Riuniti di Bergamo, Bergamo, Italy 5Christiana Care Health System, Newark, DE, 6Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy 7Univ of Milan, Milan, Italy 8Univ of Wisconsin, Madison, WI, 9Ospedale San Filippo Neri, Rome, Italy 10GVM Hosps of Care and Rsch, Cotignola, Italy 11Multiple, Multiple
Background: Post-operative atrial fibrillation/flutter (PoAF) is a major complication of cardiac surgery, with associated increased morbidity, higher long-term mortality, and healthcare costs. A few small trials have evaluated whether fish oil reduces PoAF, with mixed results. Methods: OPERA is a randomized, double-blind, placebo-controlled, clinical trial to investigate effects of fish oil supplementation on risk of PoAF. A total of 1,516 patients ≥age 18 undergoing any cardiac surgery were recruited from 28 centers in Argentina, the US, and Italy and block-randomized to fish oil (omega-3 polyunsaturated fatty acids) or placebo (olive oil). Study drug was provided by a total preoperative loading dose of 8–10 g divided over 2–5 days, followed by 2 g/d post-operatively until hospital discharge or for 10 days, whichever occurred first. The primary endpoint was occurrence of any PoAF >30 sec, confirmed by rhythm strip or 12-lead ECG and adjudicated by a centralized events committee. Secondary endpoints included prolonged (>1 hr) or symptomatic PoAF, other arrhythmias, cognitive decline, major adverse cardiovascular events, other adverse events (including bleeding), hospital length-of-stay, and 30-day and 1-year mortality. OPERA was designed to provide 90% power to detect 25% reduction in PoAF, based on estimated 30% event rate in controls and two-sided alpha=0.05. Results: Between Aug 2010 and Jun 2012, 1,516 patients were enrolled, with mean±SD age 64±13 years, 72% male, and 41% undergoing coronary bypass alone, 52% valve surgery with or without coronary bypass, and 7% other cardiac surgery. The overall rate of the primary endpoint was 29%, achieving our estimates for power calculations. The main findings for the primary endpoint and most secondary endpoints will be presented at the AHA meeting as late-breaking clinical trial results. Conclusions: OPERA will provide robust evidence on whether fish oil reduces risk of post-op AF in an appropriately powered, multinational clinical trial including a broad cross-section of real-world patients. Findings will directly inform potential clinical use of this simple, low-cost intervention to prevent PoAF.
Author Disclosures: R. Marchioli: Research Grant; Significant; GlaxoSmithKline, Sigma Tau, and Pronova, for the current trial. Other Research Support; Modest; Sigma-Tau. Speakers Bureau; Modest; Ferrer, Pronova Biocare. Honoraria; Modest; Ferrer, Pronova Biocare. D. Mozaffarian: Research Grant; Significant; Funding from GSK, Sigma Tau, and Provono for this current trial. Honoraria; Modest; Bunge, UpToDate. Consultant/Advisory Board; Modest; Unilever North America, Foodminds, McKinsey Health Systems Institute. G. Silletta: None. A. Macchia: None. P. Ferrazzi: None. T. Gardner: None. R. Latini: None. P. Libby: Consultant/Advisory Board; Modest; AstraZeneca, Merck, Novartis, Pfizer, Athera Biotechnologies, Carolus, Interleukin Genetics, BIND Biosciences. F. Lombardi: None. P. O'Gara: None. R. Page: None. M. Santini: None. L. Tavazzi: Speakers Bureau; Modest; Pfizer. G. Tognoni: None. On behalf of the OPERA Investigators: None.
Key Words: Atrial fibrillation, Fish oils, Prevention, Cardiac surgery
A Randomized Trial of a Multivitamin in the Prevention of Cardiovascular Disease in Men: The Physicians' Health Study II
Howard D. Sesso, J. Michael Gaziano Brigham and Womens Hosp, Boston, MA
Background: Multivitamin preparations are the most common dietary supplements taken by a large proportion of US adults. Though multivitamins are aimed at preventing vitamin and mineral deficiency, there is a perception that multivitamins may prevent the development of major morbidity and mortality, including cardiovascular disease (CVD). Observational studies testing regular multivitamin use have provided inconsistent evidence of an association with CVD. Notably, there are no long-term clinical trials to provide more conclusive evidence regarding the long-term effects of multivitamin use. We therefore designed the Physicians' Health Study II (PHS II) to test the effects of multivitamin supplementation on the risk of CVD. Methods: The PHS II tested a common multivitamin (Centrum Silver daily) on the risk of major cardiovascular events in a randomized, double-blind, placebo-controlled trial of 14,641 U.S. male physicians initially aged ≥50 years, including 754 (5.1%) with prevalent CVD at randomization. Treatment and follow-up occurred from 1997 through June 1, 2011. We identified major cardiovascular events (including nonfatal myocardial infarction (MI), nonfatal stroke, and fatal CVD) that occurred prior to the scheduled end of the trial. All endpoints are reviewed and confirmed by an Endpoints Committee of physicians blinded to randomized treatment assignment. High rates of morbidity and mortality follow-up have been maintained in PHS II. Results: During a median (interquartile range) follow-up of 11.2 (10.7 to 13.3) years among men with a mean (±standard deviation) baseline age of 64.3 (±9.2) years, 1,732 men had major cardiovascular events and there were 2,757 deaths. We will present analyses of major cardiovascular events, MI, and stroke according to randomized multivitamin treatment assignment, as well as the effects of compliance, effect modification by coronary risk factors, baseline CVD, and other PHS II randomized treatments, and potential side effects. Conclusions: These data from a large prevention trial with more than a decade of treatment and follow-up will inform clinical and public health recommendations regarding whether multivitamin supplementation has any benefits or harm on the risk of CVD.
Author Disclosures: H.D. Sesso: Other Research Support; Significant; Pfizer has provided pills and packaging for the PHS II. J. Gaziano: Other Research Support; Significant; Pfizer has provided pills and packaging for the PHS II.
Key Words: Vitamins, Cardiovascular disease, Clinical trials, Nutrition, Prevention
Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE)
Simon A. Thom1, Jane Field1, Neil R. Poulter1, Anushka Patel2, Dorairaj Prabhakaran3, Alice Stanton4, Diederick E. Grobbee5, Michiel L. Bots5, K S. Reddy6, Raghu Cidambi7, Anthony Rodgers8 1Imperial College London, London, United Kingdom 2George Institute for Global Health, Hyderabad, India 3Cntr for Chronic Disease Control, New Delhi, India 4Royal College of Surgeons in Ireland, Dublin, Ireland 5Univ Med Cntr Utrecht, Utrecht, Netherlands 6Public Health Foundation of India, New Delhi, India 7Dr Reddy's Laboratories, Hyderabad, India 8George Institute for Global Health, Sydney, Australia
Background: The majority of CVD patients do not receive recommended medications long-term. Even in high income countries, one third to a half do not take all recommended medications a year or more after an acute event. In low income countries, where most cardiovascular deaths now occur, treatment gaps frequently exceed 90%. The “Use of a Multidrug Pill In Reducing cardiovascular Events” (UMPIRE) trial tested the hypothesis: that a fixed dose combination (FDC)-based CVD prevention strategy for delivery of indicated medications (aspirin, statin and ≥2 BP lowering agents) compared to usual care might enhance adherence to guideline-indicated therapy and improve systolic blood pressure (SBP) and LDL-cholesterol in people with or at high risk of CVD. Methods: We conducted a PROBE-design clinical trial involving 2004 participants with established CVD or an estimated 5-year CVD risk of ≥15% in India and Europe. 2004 comparatively well treated participants were randomised to a FDC-based strategy or usual care. The FDC version 1 contained aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and atenolol 50 mg; version 2 contained hydrochlorothiazide 12.5mg instead of atenolol. Primary outcomes were adherence to indicated medication (self-reported use of antiplatelet, statin and ≥2 BP-lowering therapy) and changes in SBP and LDL-cholesterol from baseline. Findings: The FDC improved adherence by a third (RR 1.33 [95% CI 1.26, 1.41]). This was reflected by improvements in SBP (−2.6 mmHg −4.0, −1.1] P=0.0005) and LDL-cholesterol (−0.11 mmol/L −0.17, −0.05] P=0.0005) which were sustained throughout the follow-up interval of 15 months. Interpretation: Among this population of patients with CVD or similarly high risk, provision of indicated preventive medications as a FDC led to improvements in adherence, SBP and LDL-cholesterol. Funding: UMPIRE was funded by the European Commission Seventh Framework Programme under grant agreement number 241849.
Author Disclosures: S.A. Thom: None. J. Field: None. N.R. Poulter: None. A. Patel: None. D. Prabhakaran: None. A. Stanton: None. D.E. Grobbee: None. M.L. Bots: None. K.S. Reddy: None. R. Cidambi: Employment; Significant; Dr Reddy's Laboratories. A. Rodgers: None.
Key Words: Cardiovascular disease prevention, Adherence, Pharmacology
Late-Breaking Clinical Trials: Novel Treatments for Managing Lipid Disorders
Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD): Results From a Phase 2, Randomized, Double-Blind, Placebo-Controlled Trial
Frederick Raal1, Evan Stein2, Rob Scott3, Ransi Somaratne4, Ian Bridges3, Scott M. Wasserman3 1Carbohydrate & Lipid Metabolism Rsch Unit, Div of Endocrinology & Metabolism, Dept of Medicine, Univ of Witwatersrand, Johannisburg, South Africa 2Metabolic and Atherosclerotic Rsch Cntr, Cincinnati, OH, 3Amgen Inc., Thousand Oaks, CA, 4Amgen Inc, Thousand Oaks, CA
Background: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder usually due to mutations in the LDL receptor gene, resulting in reduced plasma LDL-C clearance and premature CAD. A gain-of-function mutation in proprotein convertase subtilisin/kexin type 9 (PCSK9) is an unusual cause of severe HeFH. AMG 145, a fully human monoclonal antibody to PCSK9 demonstrated rapid, large, sustained LDL-C reductions with every-4-week (Q4W) dosing in Phase 1 studies, which included a few HeFH subjects. Methods: RUTHERFORD (NCT01375751), a global, 12-week, randomized, double-blind, placebo-controlled study assessed the efficacy, safety, and tolerability of AMG 145 in HeFH patients. Adult patients with LDL-C ≥100 mg/dL, on a stable dose of statin,±ezetimibe, for ≥4 weeks were randomized 1:1:1 to subcutaneous AMG 145 350 mg, 420 mg, or placebo Q4W. Primary endpoint was percentage change from baseline in LDL-C by ultracentrifugation at week 12. Key secondary endpoints included changes in other lipid, safety, and tolerability. Results: Of 168 patients randomized, 167 received investigational product and completed the study: mean (SD) age, 50 (13) years; 53% male; mean (SD) pretreatment LDL-C, 156 (42) mg/dL; ezetimibe use, 64%. Mean percentage changes in LDL-C from baseline at week 12 were 43% to 55% (table). Mean (SE) changes from baseline at week 12 in Lp(a) were 4.1 (3.1)%, –19.1 (3.1)%, and –27.4 (3.1)% for placebo, AMG 145 350 mg, and 420 mg, respectively. Serious adverse events (AEs) were reported in 2 patients in the AMG 420 mg group; none were related to investigational product. The 3 most commonly reported treatment-emergent AEs in the AMG 145 groups combined were nasopharyngitis, injection site pain, and headache. Conclusion: AMG 145 administered Q4W yielded rapid and substantial reductions in LDL-C with minimal AEs and good tolerability in HeFH patients with elevated LDL-C despite intensive lipid lowering therapy. This study was funded by Amgen Inc.
Author Disclosures: F. Raal: Honoraria; Modest; AstraZeneca, Pfizer, Merck, Schering-Plough, Genzyme/Isis. Consultant/Advisory Board; Modest; AstraZeneca, Pfizer, Merck, Genzyme/Isis. E. Stein: Consultant/Advisory Board; Modest; Adnexus Therapeutics/BMS, Amgen, Regeneron, Sanofi. R. Scott: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. R. Somaratne: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. I. Bridges: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. S.M. Wasserman: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc.
Key Words: Hyperlipidemia, Drugs, Monoclonal antibodies
Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects (GAUSS): Interim Results from a Randomized, Double-Blind, Placebo-Controlled Study
David Sullivan1, Anders Olsson2, Rob Scott3, Jae B. Kim3, Allen Xue4, Thomas Liu3, Scott M. Wasserman3, Evan Stein5 1Royal Prince Alfred Hosp, Camperdown, NSW, Australia 2Stockholm Heart Cntr, Stockholm, Sweden 3Amgen Inc., Thousand Oaks, CA, 4Amgen Inc, Thousand Oaks, CA, 5Metabolic and Atherosclerosis Rsch Cntr, Cincinnati, OH
Background: Low-density lipoprotein cholesterol (LDL-C) is an important risk factor for coronary heart disease (CHD). Statins are the first-line therapy for LDL-C reduction, but many patients cannot tolerate statins or adequate statin doses and cannot reach LDL-C goals with alternative therapies. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, increasing circulating LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, lowered LDL-C in Phase I studies. Methods: GAUSS (NCT01375764) was a 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study to assess the efficacy, safety, and tolerability of AMG 145 in patients unable to tolerate effective statin doses due to muscle-related side effects. Adult patients with LDL-C ≥100 to ≥160 mg/dL (depending on CHD risk), and triglycerides ≤400 mg/dL were randomized 1:1:1:1:1 to subcutaneous (SC) AMG 145 280, 350, or 420 mg every 4 weeks (Q4W); daily ezetimibe 10 mg and SC AMG 145 420 mg Q4W; or daily ezetimibe 10 mg and SC placebo Q4W. The primary endpoint was percentage change from baseline in LDL-C by ultracentrifugation at week 12 (4 weeks after the last dose). Results: Of 236 patients screened, 160 were randomized (mean age 62 years, 64% female, mean pre-treatment LDL-C 193 mg/dL). Baseline characteristics were comparable among groups. At week 12, mean percentage changes in LDL-C from baseline were –41%, –43%, –51%, –63%, and –15% in the 5 treatment groups (Table). Four serious adverse events (AEs) were reported; none were treatment-related. The most common AEs for AMG 145-only, AMG 145/ezetimibe, and placebo/ezetimibe were myalgia 7.4%, 20.0%, 3.1%; nasopharyngitis 5.3%, 10.0%, 15.6%; nausea 4.2%, 0%, 3.1%; and fatigue 4.2%, 0%, 6.3%. Conclusions: Administration of AMG 145 Q4W in statin-intolerant patients was well-tolerated and associated with significant reductions in LDL-C compared to placebo/ezetimibe. The study was funded by Amgen, Inc.
Author Disclosures: D. Sullivan: Research Grant; Modest; AstraZeneca, Merck, Sanofi Aventis, Amgen. Consultant/Advisory Board; Modest; Abbott, Pfizer Australia. A. Olsson: Honoraria; Modest; Amgen, AstraZeneca, MSD, Sanofi Aventis, Roche. Consultant/Advisory Board; Modest; Amgen, AstraZeneca, MSD, Sanofi Aventis, Roche. R. Scott: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. J.B. Kim: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. A. Xue: None. T. Liu: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. S.M. Wasserman: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. E. Stein: Consultant/Advisory Board; Modest; Adnexus Therapeutics/BMS, Amgen, Regeneron, Sanofi.
Key Words: Cholesterol-lowering drugs
Effects of 12 Weeks of Treatment With RN316 (PF-04950615), a Humanized IgG2Δa Monoclonal Antibody Binding Proprotein Convertase Subtilisin Kexin Type 9, in Hypercholesterolemic Subjects on High and Maximal Dose Statins
Barry Gumbiner1, Tenshang Joh1, Chandrasekhar Udata1, Philippe Forgues2, Charles M. Baum1, Pamela D. Garzone2 1Pfizer, Inc., San Diego, CA, 2Pfizer, Inc., South San Francisco, CA
Background: RN316 binds to Proprotein Convertase Subtilisin Kexin type 9 (PCSK9), preventing PCSK9-mediated down-regulation of the low density lipoprotein (LDL) receptor, improving LDL cholesterol (LDL-C) clearance from serum, and reducing LDL-C levels. Two Phase 2, double-blind, randomized, placebo (PBO)-controlled studies assessed efficacy, safety and tolerability of RN316 in hypercholesterolemic (HC) subjects on ongoing high to maximal doses of atorvastatin (A), rosuvastatin (R) or simvastatin (S). Methods: In Study #1, 90 HC subjects with stable medical conditions (SMC e.g. coronary artery disease, hypertension, diabetes) and LDL-C ≥100 mg/dL on A or S 40 or 80 mg or R 20 or 40 mg, were treated with 1 of 5 intravenous (IV) treatments: 0.25, 1, 3 & 6 mg/kg RN316 or PBO. In Study #2, 45 HC subjects with SMC on A 80 mg or R 40 mg and LDL-C ≥80 mg/dL were treated with 1 of 3 IV treatments: 1 and 3 mg/kg RN316 or PBO. In both studies, subjects were treated every 4 weeks (wks) for 12 wks (3 infusions) with follow-up for at least 8 wks. Dosing was interrupted when LDL-C was ≤25 mg/dL and resumed when LDL-C returned to ≥40 mg/dL. Results from the 2 studies were combined. Results: In the PBO, 0.25, 1, 3 & 6 mg/kg groups, baseline mean LDL-Cs were 124, 123, 115, 127 & 128 mg/dL. At Wks 4 & 12 LDL-Cs the mean % changes from baseline (CFB) LDL-Cs were –5 & –4%, –9 & –13%, –15 & –12%, –58 & –46% (CFB P<0.0001) and –80 & –56% (CFB P<0.0001) in PBO, 0.25, 1, 3 & 6 mg/kg, respectively. In the 3 & 6 mg/kg groups, dosing was interrupted due to LDL ≤25 mg/dL in 31% & 29% of subjects at Wk 4 only, in 22% & 29% of subjects at Wk 8 only, and in 6% & 12% of subjects at both Wks 4 & 8, respectively. Without dose interruption, Wk 12 LDL-C lowering would have been similar to Wk 4 because RN316 does not accumulate when dosed every 4 wks. In both studies, most adverse events (AEs) were mild, not considered to be related to RN316 and resolved by Wk 12. Three serious AEs occurred (0.25 mg/kg: depression; 1 mg/kg: abdominal pain and noncardiac chest pain) and 2 subjects were discontinued due to AEs (PBO: neuralgic amyotrophy ; 6 mg/kg: elevated GGT). These AEs were not considered related to RN316. Conclusions: RN316 significantly lowered LDL-C in HC subjects on high to maximal doses of statins. RN316 was generally safe and well tolerated in these studies.
Author Disclosures: B. Gumbiner: Employment; Significant; Pfizer, Inc. T. Joh: Employment; Modest; Pfizer, Inc. C. Udata: Employment; Modest; Pfizer, Inc. P. Forgues: Employment; Modest; Pfizer, Inc. C.M. Baum: Employment; Modest; Pfizer, Inc. P.D. Garzone: Employment; Modest; Pfizer, Inc.
Key Words: Hyperlipidemia, Cholesterol-lowering drugs, Lipids, Clinical trials
Effects of the Cholesteryl Ester Transfer Protein Inhibitor Dalcetrapib in Patients With Recent Acute Coronary Syndrome
Gregory G. Schwartz1, Anders G. Olsson2, Markus Abt3, Christie M. Ballantyne4, Philip Barter5, Bernard R. Chaitman6, Ingar M. Holme7, David Kallend3, Lawrence A. Leiter8, Eran Leitersdorf9, John J. McMurray10, Hardi Mundl3, Stephen Nicholls11, Prediman K. Shah12, Jean-Claude Tardif13, R S. Wright14 1VA Med Cntr and Univ of Colorado, Denver, CO, 2Stockholm Heart Cntr, Stockholm, Sweden 3Roche Pharmaceuticals, Basel, Switzerland 4Baylor College of Medicine, Houston, TX, 5Heart Rsch Institute, Sydney, Australia 6St Louis Univ, St Louis, MO, 7Oslo Univ, Oslo, Norway 8St Michael's Hosp and Univ of Toronto, Toronto, Canada 9Hebrew Univ, Jerusalem, Israel 10Glasgow Univ, Glasgow, United Kingdom 11South Australian Health and Med Rsch Institute, Adelaide, Australia 12Cedars Sinai Med Cntr, Los Angeles, CA, 13Montreal Heart Institute, Montreal, Canada 14Mayo Clinic, Rochester, MN
Background: In observational analyses, higher levels of HDL cholesterol (HDL-C) are associated with lower risk of coronary heart disease events. However, it remains uncertain whether raising HDL-C therapeutically reduces cardiovascular risk. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL-C concentration and might therefore improve cardiovascular outcomes. Methods: We randomly assigned 15,871 patients with recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib 600 mg daily or placebo, in addition to optimal, evidence-based care. The primary efficacy end point was a composite of coronary heart disease death, non-fatal myocardial infarction, ischemic stroke, unstable angina, or resuscitated cardiac arrest. Results: At randomization, mean HDL-C and LDL-C were 42 and 76 mg per deciliter, respectively. Dalcetrapib raised HDL-C concentration by approximately 30% compared with placebo and had minimal effect on LDL-C. Patients were followed for a median of 31 months. At a pre-specified interim analysis including 1135 (71% of planned) primary end point events, the independent Data Safety Monitoring Board recommended termination of the trial for futility. Dalcetrapib did not alter the risk of the primary end point compared with placebo (cumulative event rate 8.3% versus 8.0%, hazard ratio 1.04, 95% CI 0.93–1.16, P=0.52) and did not affect any component of the primary end point or total mortality. Median C-reactive protein was 18% higher (P<0.001) and mean systolic blood pressure 0.6 mm Hg higher (P<0.001) with dalcetrapib, compared with placebo. Conclusions: In patients with recent acute coronary syndrome, dalcetrapib increased HDL-C concentration, but did not reduce the risk of recurrent cardiovascular events.
Author Disclosures: G.G. Schwartz: Research Grant; Significant; Roche, Anthera, Resverlogix. Other Research Support; Modest; Sanofi. A.G. Olsson: Honoraria; Modest; Amgen, AstraZeneca, Merck, Sanofi, Roche. Consultant/Advisory Board; Modest; Amgen, AstraZeneca, Merck, Sanofi, Roche. M. Abt: Employment; Significant; Roche. C.M. Ballantyne: Research Grant; Significant; Abbott, Amarin, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Genentech, Kowa, Merck, Novartis, Roche, Sanofi, Takeda. Speakers Bureau; Significant; Abbott, GlaxoSmithKline, Merck. Honoraria; Significant; Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi, Takeda. Consultant/Advisory Board; Significant; Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera, Kowa, Merck, Novartis, Omthera, Pfizer, Resverlogix, Roche, Sanofi, Takeda. P. Barter: Research Grant; Modest; Pfizer. Research Grant; Significant; Merck. Honoraria; Modest; Abbott, Kowa, Novartis, Pfizer, Roche. Honoraria; Significant; AstraZeneca, Merck. Consultant/Advisory Board; Modest; AstraZeneca, CSL, Eli Lilly, Merck, Novartis, Pfizer, Roche. B.R. Chaitman: Research Grant; Significant; Roche. Consultant/Advisory Board; Modest; Eli Lilly, Forest, Merck, Pfizer, Takeda. Consultant/Advisory Board; Significant; Roche. I.M. Holme: Honoraria; Modest; Roche. D. Kallend: Employment; Significant; Roche. L.A. Leiter: Other Research Support; Significant; Roche, AstraZeneca, Eli Lilly, Merck, Sanofi. Speakers Bureau; Significant; AstraZeneca, Eli Lilly, Merck, Roche. Consultant/Advisory Board; Modest; Abbott, Amgen. Consultant/Advisory Board; Significant; AstraZeneca, Eli Lilly, Merck, Roche, Sanofi. E. Leitersdorf: Consultant/Advisory Board; Significant; Merck, Novartis, Roche. J.J. McMurray: Other Research Support; Significant; Roche. H. Mundl: Employment; Significant; Roche. S. Nicholls: Research Grant; Significant; AstraZeneca, Roche, Eli Lilly, Resverlogix, Anthera, Novartis. Honoraria; Modest; Merck, Omthera, Takeda, CSL Behring, Boehringer Ingleheim. Honoraria; Significant; AstraZeneca, Roche. P.K. Shah: Honoraria; Modest; Roche. J. Tardif: Research Grant; Significant; Roche, Cerenis. Honoraria; Significant; Roche. R.S. Wright: Research Grant; Significant; Roche. Other Research Support; Modest; 3M. Consultant/Advisory Board; Significant; Roche.
Key Words: CETP inhibitors, Acute coronary syndromes, HDL elevating therapies
Late-Breaking Clinical Trials: Cell-Based Therapies for Myocardial Regeneration
Results of the Swiss Multicenter Intracoronary Stem Cells Study in Acute Myocardial Infarction (Swiss Ami) Trial
Daniel Sürder1, Robert Manka2, Tiziano Moccetti1, Kaspar Rufibach3, Giuseppe Astori1, Viviano Lo Cicero1, Sabrina Soncin1, Lucia Turchetto1, Marina Radrizzani1, Stephan Windecker4, Aris Moschovitis4, Andreas Wahl4, Paul Erne5, Christoph Auf der Maur5, Gianni Soldati1, Ines Bühler2, Christophe Wyss2, Jürg Schwitter2, Ulf Landmesser2, Thomas F. Lüscher2, Roberto Corti2 1Fondazione Cardiocentro Ticino, Lugano, Switzerland 2Univ Hosp, Zurich, Switzerland 3Rufibach rePROstat, Bern, Switzerland 4Inselspital, Berne, Switzerland 5Cantonal Hosp, Lucerne, Switzerland
Background: Intracoronary administration of autologous bone marrow derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction (AMI). The optimal time point of cellular administration has never been addressed prospectively in clinical trials. Methods: In a multi-centre study, we randomized 200 patients with large, successfully reperfused STEMI in a 1:1:1 pattern in an open-labeled control (n=67) and two BM-MNC treatment groups according to the time point of cell administration, either “early” (at 5–7 days) or “late” (at 3–4 weeks) after AMI (n=66 and 67, respectively). Cardiac magnetic resonance imaging (CMR) was done at one week and after 4 months, and analyzed in a blind CMR core-lab. BM-MNC isolation was performed in a centralized laboratory by density gradient centrifugation. Primary endpoint was change in global LV ejection fraction (LVEF) between each treatment group and control at 4 months compared to baseline. Secondary endpoints comprised the change in global LVEF from baseline to 4 months between control and a combined therapy group, as wells as changes in LV-EDV and LV-ESV, change in infarct size, change in the proportion of scar mass to total LV mass and changes in global and regional myocardial thickening. Intervention: Intracoronary infusion of a median of 156 millions BM-MNC at a median of 6 days after AMI (early group) or after a median of 24 days (late group). Results: Baseline LVEF was 37.4%, creatinin kinase (CK) was 3919 U/l and the groups were well matched. Absolute change in LVEF at 4 months was –0.4±8.8% (mean±SD; P= 0.74 vs. baseline) in the control group, 1.8±8.4% (p=0.12 vs. baseline) in the early group and 0.8±7.6% (p=0.45 vs. baseline) in the late group. Between-group mean difference was –2.1%; 95% CI –5.27 to 0.99; p=0.18 early vs. control) and −1.2%; 95% CI −4.32 to 1.91; p=0.45 (late vs. control). No significant between-group difference was found for the secondary endpoints between the control and both therapy groups. Conclusions: Among patients with STEMI and LV dysfunction following reperfusion with PCI, intracoronary infusion of BM-MNC either 5–7 days or 3–4 weeks after AMI, did not improve LV-function at 4 months.
Author Disclosures: D. Sürder: None. R. Manka: None. T. Moccetti: None. K. Rufibach: None. G. Astori: None. V. Lo Cicero: None. S. Soncin: None. L. Turchetto: None. M. Radrizzani: None. S. Windecker: None. A. Moschovitis: None. A. Wahl: None. P. Erne: None. C. Auf der Maur: None. G. Soldati: None. I. Bühler: None. C. Wyss: None. J. Schwitter: None. U. Landmesser: None. T.F. Lüscher: None. R. Corti: None.
Key Words: Progenitor cell, Myocardial infarction, STEMI
The ALCADIA (Autologous Human Cardiac-Derived Stem Cell To Treat Ischemic Cardiomyopathy) Trial
Naofumi Takehara, Takehiro Ogata, Midori Nakata, Daisuke Kami, takeshi nakamura, Satoaki Matoba, Satoshi Gojo, Takahisa Sawada, Hitoshi Yaku, Hiroaki Matsubara Kyoto Prefectual Univ of Medicine, Kyoto, Japan
Introduction: Cardiac-derived stem cells (CSCs) have great potential to ameliorate the loss of cardiac function resulting from ischemic injury. However, in cell-based therapies, most transplanted cells cannot survive in the host environment of the damaged heart. The aim of this study was to evaluate the safety and efficacy of transplanting autologous CSCs with controlled release of basic fibroblast growth factor (bFGF) using biodegradable gelatin-hydrogel to overcome poor survival of engrafting cells and enhance the efficacy of CSC implantation. Methods: In September 2009, we started a Phase I trial for 6 ischemic cardiomyopathy patients with left ventricular (LV) dysfunction (15% ≤ ejection fraction (EF) ≤35%) by cellular intervention using autologous CSCs. This trial is registered under ClinicalTrials. gov (NCT00981006) as the ALCADIA trial. We generated autologous CSCs enriched with Es-marker genes and mesenchymal features from infinitesimal cardiac samples obtained from endomyocardial biopsy. At 4 weeks after biopsy, all patients received an injection of CSCs (0.5 million cells/kg) and implantation of gelatin-hydrogel incorporating bFGF (200 μg), during coronary artery bypass grafting, in and around the scar detected by late-enhancement of cardiac magnetic resonance imaging (MRI). Results: Interim results with follow-up for 1 year (the last patient has now been followed for 5 months) have shown no adverse events in any cases. NYHA functional class of the 5 enrolled patients has improved from 3.8±0.4 to 1.4±0.17 (P<0.0001), associated with improved exercise tolerance as evaluated by peak VO2 (from 12.2±3.0% before hybrid therapy to 16.7±3.6% after 6 months, P=0.037). Loss of LV function in patients was restored to 12.1±4.9% of LVEF (MRI; from 22.6±4.5% to 34.7±7.9%, P=0.028), accompanied by improvements in global wall motion score (MRI; from 17.0±3.4% to 6.6±3.8%, P=0.0023) and a tendency toward decreasing infarct size (MRI; from 21.8±4.9% to 17.8±4.8%, P=0.116). Our findings suggest that transplantation of CSCs with controlled release of bFGF is safe and effective in injured human hearts with reconstruction of the post-ischemic environment. This novel biotherapy may have potential to achieve functional repair in the injured heart.
Author Disclosures: N. Takehara: None. T. Ogata: None. M. Nakata: None. D. Kami: None. T. nakamura: None. S. Matoba: None. S. Gojo: None. T. Sawada: None. H. Yaku: None. H. Matsubara: None.
Key Words: Cardiac regeneration, Stem cell therapy, Ischemic heart disease, Tissue engineering, Heart failure
The Effect of Timing of Stem Cell Delivery Following Acute Myocardial Infarction: The NHLBI and CCTRN TIME Trial
Jay H. Traverse1, Timothy D. Henry1, Carl J. Pepine2, James T. Willerson3, David X. Zhao4, Stephen G. Ellis5, Linda B. Piller6, Emerson C. Perin3, Marc S. Penn7, Jeffrey Chambers8, Kenneth W. Baran9, Ganesh Raveendran10, Charles Lambert11, Adrian P. Gee12, John R. Forder2, Doris A. Taylor13, Christopher R. Cogle2, James D. Thomas5, Ray F. Ebert14, Sonia I. Skarlatos14, Lemuel A. Moye6, Robert D. Simari15 1Minneapolis Heart Institute at Abbott Northwestern Hosp, Minneapolis, MN, 2Univ of Florida College of Medicine, Gainesville, FL, 3Texas Heart Institute, St. Luke's Episcopal Hosp, Houston, TX, 4Vanderbilt Univ Sch of Medicine, Nashville, TN, 5The Cleveland Clinic Foundation, Cleveland, OH, 6The Univ of Texas Sch of Public Health, Houston, TX, 7Summa Cardiovascular Institute, Rootstown, OH, 8Metro Cardiology, Mercy Hosp, Coon Rapids, MN, 9St. Paul Heart Clinic, United Hosp, St Paul, MN, 10Lillehei Heart Institute, Univ of Minnesota, Minneapolis, MN, 11Patel Rsch Institute, Pepin Heart Hosp, Tampa, FL, 12Baylor College of Medicine, Houston, TX, 13Texas Heart Institute, St. Luke's Episcopal Hosp, Minneapolis, MN, 14National Heart, Lung and Blood Institute, Bethesda, MD, 15Mayo Clinic, Rochester, MN
Timing of stem cell delivery following ST-elevation myocardial infarction (STEMI) may be a critical determinant of efficacy given the temporal changes in the myocardium and bone marrow that occur over the first week that may affect stem cell engraftment and survival. However, no trial has been sufficiently powered to determine the optimal time of stem cell delivery following STEMI. TIME, an NHLBI sponsored study of the Cardiovascular Cell Therapy Research Network (CCTRN), is a randomized, double-blind, placebo-controlled trial investigating the safety and therapeutic efficacy of intracoronary autologous bone marrow mononuclear cells (BMCs) delivered at 3 versus 7-days following STEMI in patients with successful primary PCI and post-PCI LV ejection fraction ≤45% by echocardiography.All patients underwent bone marrow aspiration and isolation of BMCs using a local distributed, standardized, automated system (Sepax device, Biosafe SA, Geneva, Switzerland) followed by intracoronary infusion of 150 million BMCs or cell free solution (2:1 BMC:Placebo) within 12 hours of bone marrow harvest. The co-primary endpoints were change in global LVEF and regional LV function between baseline and 6 months as assessed by cardiac MRI.A total of 120 patients (105 M, 15 F) 57±11 years old, were enrolled at 5 CCTRN Centers and their satellites between July 2008 and Nov 2011. At 6 mo, LVEF increased similarly in both the BMC (45.2±10.6 to 48.3±13.3 %) and placebo groups (44.5±10.8 to 47.8 ±13.6 %) and no treatment effect was observed in the infarct or border zones. Differences between therapy groups in the change in LVEF and regional function over time when treated at Day 3 or Day 7 were not significant and did not differ from placebo. Younger patients (age<median) randomized to BMCs at Day 7 had a significant improvement in LVEF compared to placebo (P<0.05). In conclusion, recovery of global and regional LV function during the 6 mo following MI was not improved by intracoronary autologus BMCs at either 3 or 7 days compared to placebo. Younger patients randomized to BMCs at Day 7 showed improved recovery of LVEF compared to placebo.
Author Disclosures: J.H. Traverse: None. T.D. Henry: None. C.J. Pepine: None. J.T. Willerson: None. D.X. Zhao: None. S.G. Ellis: None. L.B. Piller: None. E.C. Perin: None. M.S. Penn: Research Grant; Modest; Athersys. Ownership Interest; Modest; Juventas. Consultant/Advisory Board; Significant; Juventas. J. Chambers: None. K.W. Baran: None. G. Raveendran: None. C. Lambert: None. A.P. Gee: None. J.R. Forder: None. D.A. Taylor: None. C.R. Cogle: None. J.D. Thomas: None. R.F. Ebert: None. S.I. Skarlatos: None. L.A. Moye: None. R.D. Simari: None.
Key Words: Stem cell therapy, Myocardial infarction, STEMI, Clinical trials, Cardiac MRI
Randomized Comparison of Allogeneic vs Autologous Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy
Joshua M. Hare1, Alan W. Heldman1, Ian McNiece1, Darcy L. DiFede Velazquez1, Juan P. Zambrano1, Viky Suncion1, Melissa Tracy1, Gary Gerstenblith2, Joel E. Fishman1, Eduard Ghersin1, Peter Johnston2, Jeffrey Brinker2, Elayne Breton2, Janice Davis2, John Byrnes1, Adam M. Mendizabal3, Maureen H. Lowery1, Jose Da Silva1, Ivonne Schulman1, Phillip Ruiz1, Alexandra Amador1, Peter Altman4, Didier Rouy5, Cheryl Wong Po Foo5 1Univ of Miami Miller Sch of Medicine, Miami, FL, 2The Johns Hopkins Univ Sch of Medicine, Baltimore, MD, 3EMMES Corp, Rockville, MD, 4Biocardia, San Carlos, CA, 5Biocardia Corp, San Carlos, CA
Mesenchymal stem cells (MSCs) are a promising cell-based therapy under evaluation for ischemic cardiomyopathy (ICM). Although MSCs may be used as an allograft, they have never been compared head-to-head with autologous MSCs for heart disease. Accordingly, we conducted the POSEIDON trial, an NIH-funded, randomized, dose-finding comparison of identically prepared autologous (auto) vs allogeneic (allo) bone marrow-derived MSCs. Doses of 20, 100, or 200 million cells were delivered by transendocardial stem cell injection (TESI) in patients with chronic ICM. Thirty patients (5 each dose and cell type) received TESI in 10 left ventricular sites using the Biocardia Helical Infusion Catheter. Patients were followed for 13 months for safety and efficacy endpoints: ejection fraction (EF), infarct volume, LV volumes, sphericity index, 6-minute walk test (6 MWT), NYHA class, and Minnesota Living with Heart Failure questionnaire (MLWHF).Within 30-days, one patient in each group (Treatment Emergent-Serious Adverse Event (SAE) rate of 6.7%) was hospitalized for heart failure, less than the pre-specified stopping event rate of 25%. The one-year incidence of SAEs was not different between cell types, except for fewer ventricular arrhythmias in allogeneic recipients. Relative to baseline, allogeneic and autologous MSC therapy similarly improved the 6-minute walk and the MLHF questionnaire score, but not the exercise VO2 max. Finally, MSCs reduced infarct size, LV volumes, and sphericity index and improved EF similarly in allogeneic and autologous groups. Importantly, allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions.Allogeneic and autologous MSCs have similar safety and efficacy in ICM patients. Both MSCs favorably affect cardiac structure and function, patient functional capacity and quality of life. These data have implications for cell-based therapy including the possibility of allogeneic MSCs as an “off-the-shelf” therapeutic.
Author Disclosures: J.M. Hare: Research Grant; Modest; Biocardia. Other Research Support; Modest; NHLBI. Ownership Interest; Modest; Vestion. Consultant/Advisory Board; Modest; Vestion. Research Grant; Significant; Significant. Other Research Support; Significant; Significant. Ownership Interest; Significant; Significant. Consultant/Advisory Board; Significant; Significant. A.W. Heldman: None. I. McNiece: None. D.L. DiFede Velazquez: None. J.P. Zambrano: None. V. Suncion: None. M. Tracy: None. G. Gerstenblith: None. J.E. Fishman: None. E. Ghersin: None. P. Johnston: None. J. Brinker: None. E. Breton: None. J. Davis: None. J. Byrnes: None. A.M. Mendizabal: None. M.H. Lowery: None. J. Da Silva: None. I. Schulman: None. P. Ruiz: None. A. Amador: None. P. Altman: None. D. Rouy: None. C. Wong Po Foo: None.
Key Words: Stem cell therapy, Heart failure
Effect of Cardiac Stem Cells in Patients With Ischemic Cardiomyopathy: Interim Results of the SCIPIO Trial Up to 2 Years After Therapy
Roberto Bolli1, Atul Chugh1, Domenico D'Amario2, John H. Loughran1, Marcus F. Stoddard1, Sohail Ikram1, Stephen G. Wagner1, Garth M. Beache1, Annarosa Leri3, Toru Hosoda3, Polina Goihberg2, Claudia Fiorini3, Naresh Solankhi1, Ibrahim Fahsah1, Julius B. Elmore1, D. G. Rokosh1, Mark S. Slaughter1, Jan Kajstura3, Piero Anversa3 1Univ of Louisville, Louisville, KY, 2Brigham and Women's Hosp, Harvard Med Sch, boston, MA, 3Brigham and Women's Hosp, Harvard Med Sch, Boston, MA
SCIPIO (Stem Cell Infusion in Patients with Ischemic CardiOmyopathy) is a phase I, randomized, open-label trial of c-kit+, lineage− cardiac stem cells (CSCs) in patients with postinfarction LV dysfunction (EF<40%) who undergo CABG surgery. We have recently reported initial results at 4 and 12 months after CSCs; here, we report the complete results at 4 months after CSCs for all patients (20 treated and 13 controls) and the initial results at 2 years. At 4 months, in the 20 treated patients LVEF (3D echo) increased from 29.0± 1.7% before CSC infusion to 36.0±2.5% 4 months later (P<0.001) (Figure). This was associated with an improvement in regional wall motion score (echo) in the infused LV regions (2.00±0.12 vs. 1.85±0.11, P=0.012) as well as in all segments (1.94±0.08 vs. 1.78±0.08, P=0.003) and improved quality of life (Minnesota Living with Heart Failure Questionnaire [MLHFQ]: 45.3±4.3 vs. 26.6±3.9, P<0.001) (Figure). In contrast, in the 13 controls there was no improvement in LVEF (29.2±1.9% vs. 29.4±1.8%) or MLHFQ score (43.9±6.2 vs. 40.8±6.9). Importantly, the salubrious effects of CSCs noted at 4 months persisted and became progressively greater at 1 and 2 years (e.g., LVEF increased by 8.1% vs. pre-CSC at 1 year [P<0.001, n=17] and 12.9% at 2 years [P=0.008, n=8] [Figure]). In the 9 CSC-treated patients who underwent MRI, there was a profound reduction in infarct size (measured by a semi-automated method) at 4 months (from 34.9±2.3 to 21.6±2.7 g, P<0.001) and even more at 1 year (33.9±3.0 to 18.7±3.6 g, P=0.003, n=6). Viable LV tissue increased at 4 months (+11.6±5.2 g, P=0.055) and 1 year (+31.5±11.0 g, P=0.035). No adverse effects attributable to CSCs have been recorded up to 2 years after therapy. Thus, a single infusion of CSCs was sufficient to improve ischemic cardiomyopathy for at least 2 years. These results suggest that infusion of autologous CSCs in patients with ischemic heart failure is safe and that its beneficial effects are sustained and actually increase over time.
Author Disclosures: R. Bolli: None. A. Chugh: None. D. D'Amario: None. J.H. Loughran: None. M.F. Stoddard: None. S. Ikram: None. S.G. Wagner: None. G.M. Beache: None. A. Leri: None. T. Hosoda: None. P. Goihberg: None. C. Fiorini: None. N. Solankhi: None. I. Fahsah: None. J.B. Elmore: None. D.G. Rokosh: None. M.S. Slaughter: None. J. Kajstura: None. P. Anversa: None.
Key Words: Cardiac regeneration, Heart failure, Ischemic heart disease, Stem cell therapy, Stem/progenitor cells
Late-Breaking Clinical Trials: Management of LV Dysfunction: Devices and Drugs
MADIT Randomized Trial to Reduce Inappropriate Therapy (MADIT-RIT)
Arthur J. Moss1, Claudio Schuger2, Christopher Beck1, Mary Brown1, David Cannom3, James Daubert4, Mark Estes5, Henry Greenberg6, W. Jackson Hall1, David Huang1, Joseph Kautzner7, Helmut Klein1, Scott McNitt1, Brian Olshansky8, Morio Shoda9, David Wilber10, Wojciech Zareba1 1Univ of Rochester Med Cntr, Rochester, NY, 2Henry Ford Hosp, Detroit, MI, 3Good Samaritan Hosp, Los Angles, CA, 4Duke Univ Med Cntr, Durham, NC, 5Tufts New England Med Cntr, Boston, MA, 6St. Lukes-Roosevelt Hosp, New York, NY, 7Univ of Rochester Med Cntr, Prague, Czech Republic 8Univ of Iowa Med Cntr, Iowa City, IA, 9Tokyo Womens Med Cntr, Tokyo, Japan 10Loyola Univ Med Cntr, Chicago, IL
The implantable cardioverter defibrillator (ICD) is effective in reducing mortality from ventricular tachyarrhythmias in high-risk cardiac patients. Inappropriate therapies (antitachycardia pacing [ATP]and/or shock) resulting mostly from improperly sensed supraventricular tachyarrhythmias remain significant side effects of ICD therapy affecting 8–40% of treated patients. MADIT-RIT is a prospective, three-arm trial involving 98 centers and 1497 patients randomized to three treatment arms. The objective of MADIT-RIT is to determine if dual-chamber ICD or CRT-D devices with high-rate therapy (Treatment Arm B [device therapy at 200 bpm or faster]) or duration-delay therapy (Treatment Arm C [60sec monitoring before device firing at 170 bpm or faster]) are associated with fewer patients experiencing 1st inappropriate therapy than with conventional programming (Treatment Arm A [device therapy at 170 bpm or faster] during 1.4-year follow-up. The analyses utilized the Kaplan-Meir method and Cox's proportional-hazards regression.Results: Device therapy set at 200 bpm (Treatment Arm B) was associated with a significant 81% reduction in 1st inappropriate therapy (Fig. 1; Hazard Ratio=0.19, P=0.001) and a 55% reduction in all-cause mortality (Hazard Ratio=0.45, P=0.02) when compared to conventional device programming (Treatment Arm A), with similar results when comparing Treatment Arm C to Treatment Arm A.Conclusion: ICD programming with device therapy set for tachyarrhythmias at 200 bpm or faster or with 60sec duration-delay monitoring beginning at 170 bpm result in reductions in both inappropriate therapy and all-cause mortality.
Author Disclosures: A.J. Moss: Research Grant; Significant; Boston Scientific to the University of Rochester. C. Schuger: Research Grant; Significant; Boston Scientific. C. Beck: Research Grant; Significant; Boston Scientific. M. Brown: Research Grant; Significant; Boston Scientific. D. Cannom: Research Grant; Significant; Boston Scientific. J. Daubert: Research Grant; Significant; Boston Scientific. M. Estes: Research Grant; Significant; Boston Scientific. H. Greenberg: Research Grant; Significant; Boston Scientific. W. Hall: Research Grant; Significant; Boston Scientific. D. Huang: Research Grant; Significant; Boston Scientific. J. Kautzner: Research Grant; Significant; Boston Scientific. H. Klein: Research Grant; Significant; Boston Scientific. S. McNitt: Research Grant; Significant; Boston Scientific. B. Olshansky: Research Grant; Significant; Boston Scientific. M. Shoda: Research Grant; Significant; Boston Scientific. D. Wilber: Research Grant; Significant; Boston Scientific. W. Zareba: Research Grant; Significant; Boston Scientific.
Key Words: Device, Resynchronization, Implantable cardioconvert defibrillator, Pacing
Biventricular versus Right Ventricular Pacing in Patients With Left Ventricular Dysfunction and Atrioventricular Block (BLOCK HF Study)
Anne B. Curtis1, Seth J. Worley2, Philip B. Adamson3, Eugene S. Chung4, Imran Niazi5, Lou Sherfesee6, Timothy S. Shinn7, Martin St. John Sutton8 1Univ at Buffalo, Buffalo, NY, 2Lancaster General Hosp, Lancaster, PA, 3Oklahoma Foundation for Cardiovascular Rsch, Oklahoma City, OK, 4The Heart and Vascular Cntr at The Christ Hosp, Cincinnati, OH, 5St. Luke's Med Cntr, Milwaukee, WI, 6Medtronic, Minneapolis, MN, 7St Joseph Mercy, Ann Arbor, MI, 8Univ of Pennsylvania Med Cntr, Philadelphia, PA
Background: In patients with atrioventricular (AV) block requiring pacing, studies suggest that right ventricular (RV) pacing may be detrimental to ventricular function in some patients. The BLOCK HF trial tests the hypothesis that biventricular (BiV) pacing is superior to RV pacing in patients with left ventricular (LV) dysfunction who require pacing for AV block. Design: BLOCK HF is a prospective, multi-center (60 sites in the US and Canada), randomized, double-blind, controlled trial. The inclusion criteria were 1) AV block necessitating pacing; 2) no previous pacemaker or implantable cardioverter defibrillator (ICD); 3) LVEF ≤50%; 4) NYHA functional class I-III; and 5) absence of a class I indication for resynchronization therapy. Patients were implanted with a cardiac resynchronization therapy pacemaker (CRT-P) or a CRT-defibrillator (CRT-D) according to guidelines for primary prevention ICD implantation and randomized 1:1 to BiV or RV pacing after a 30–60 day period. Echocardiography was performed at randomization and at 6, 12, 18, and 24 months. The primary endpoint is an intention to treat composite of all-cause mortality, HF-related urgent care (any unplanned visit requiring intravenous HF therapy), and an increase in left ventricular end systolic volume index (LVESVI) ≥15%. Demographics: In total, 918 patients were enrolled with 809 satisfying criteria for heart block during a pre-implant electrophysiology study. Of 809 attempted implants, 757 (94%) were successful and 691 patients were randomized; 484 received a CRT-P and 207 a CRT-D. Among randomized subjects, the mean age was 73 years; 75% were male; mean LVEF was 40%. Degree of AV block was marked first degree AV block in 20%, Type 1 second degree AV block in 11%, Type 2 second degree AV block in 21%, and complete AV block in 48%. NYHA class at enrollment was 16% NYHA I, 57% NYHA II, and 27% NYHA III. Results: Currently, 337 randomized subjects have met an endpoint with 153 deaths during a mean follow-up of ∼36 months. We anticipate that a primary objective stopping rule may be met in June 2012 when the last patient randomized reaches the 6 month follow-up visit. Primary endpoint analysis will be performed and reviewed by the Data Monitoring Committee in August 2012 and available for the AHA presentation.
Author Disclosures: A.B. Curtis: Honoraria; Modest; St. Jude Medical, Sanofi-Aventis, Medtronic, Inc. Consultant/Advisory Board; Modest; St. Jude Medical, Janssen Pharmaceuticals, Bristol Myers Squibb, Biosense Webster, Sanofi-Aventis, Medtronic, Inc. S.J. Worley: Consultant/Advisory Board; Modest; Medtronic. P.B. Adamson: Consultant/Advisory Board; Modest; Medtronic. E.S. Chung: Consultant/Advisory Board; Modest; Medtronic, Boston Scientific. Consultant/Advisory Board; Significant; CardioMEMS. I. Niazi: Research Grant; Modest; Medtronic. L. Sherfesee: Employment; Significant; Medtronic. Ownership Interest; Significant; Medtronic. T.S. Shinn: Research Grant; Modest; Medtronic. Other Research Support; Modest; Medtronic, Biotronik, Boston Scientific, Forrest Pharmaceutical, St. Jude Medical. Consultant/Advisory Board; Modest; Medtronic. M. St. John Sutton: Consultant/Advisory Board; Modest; Medtronic.
Key Words: Resynchronization therapy, Heart failure, Heart block, Pacemakers
Pilot Trial of Two Levels of Hypothermia in Comatose Survivors From Out-of-Hospital Cardiac Arrest
Esteban Lopez-de-Sa1, Juan R. Rey1, Eduardo Armada1, Pablo Salinas2, Ana Viana3, Ervigio Corral4, Sandra Espinosa-Garcia1, Mercedes Martinez-Moreno1, Jose Lopez-Sendon1 1Hosp Universitario La Paz, Madrid, Spain 2Hosp Universitario Fundación Alcorcon, Alcorcon, Spain 3Hosp Universitario Gregorio Maranon, Madrid, Spain 4SAMUR-Protección Civil, Madrid, Spain
Background: Based in 2 clinical trials, ILCOR recommend that comatose survivors of out-of-hospital cardiac arrest (OHCA) should be cooled to 32°-34°C for 12–24 h. However, the optimal temperature is unknown. Purpose: The aim of this pilot trial is to provide initial information of the primary outcome measure, in order to perform a sample size calculation for a larger trial in comatose survivors of OHCA. Methods: Patients were eligible if they had a witness OHCA apparently related to heart disease from March 2008 and August 2011. Major exclusion criteria were Glasgow coma scale >8, cardiogenic shock or terminal illness. Target temperature was randomly assigned to 32°C or 34°C. Enrolment was stratified on the basis of the initial rhythm, shockable rhythm (VF/VT) or asystole. The target temperature was maintained 24 h followed by 12–24 h controlled rewarming. The primary outcome measure was survival free from severe dependence (defined as a Barthel index >59 points) at 6 months. Results: During the study period, 73 patients were assessed for eligibility; and 36 were enrolled in the trial (10 with initial rhythm of asystole and 26 VF/VT), 18 assigned to 34°C and 18 to 32°C. All patients enrolled completed the cooling treatment assigned and data was available in all patients at 6 months. Eight of 18 patients in the 32°C group (44.4 %) were alive free from severe dependence at 6 months, as compared with 2 of 18 in the 34°C group (11.1 %), (figure 1A; Log-Rank p=0.12). All randomized patients whose initial rhythm was asystole died before 6 months in both groups. In patients with VF/VT as initial rhythm, there was a higher survival rate free from severe dependence at 6 months in those assigned to 32°C (61.5%) versus those assigned to 34°C (14.3%) (figure 1B; Log-Rank P=0.029). Conclusion: these findings are consistent with animal studies and support the need of a larger trial of different levels of target temperature in comatose survivors of OHCA.ClinicalTrials.gov Identifier: NCT01155622.
Author Disclosures: E. Lopez-de-Sa: None. J.R. Rey: None. E. Armada: None. P. Salinas: None. A. Viana: None. E. Corral: None. S. Espinosa-Garcia: None. M. Martinez-Moreno: None. J. Lopez-Sendon: None.
Key Words: Cardiopulmonary resuscitation, Hypothermia, Cardiac arrest, Resuscitation
The RELAXin in Acute Heart Failure (RELAX-AHF) Trial
John R. Teerlink1, Gad Cotter2, Beth A. Davison2, G. Michael Felker3, Gerasimos Filippatos4, Barry H. Greenberg5, Piotr Ponikowski6, Elaine Unemori7, Adriaan A. Voors8, Angelo Trapani9, Christopher Bush9, Rajnish Saini10, Christoph Schumacher11, Thomas Severin11, Marco Metra12 1San Francisco VAMC UCSF, San Francisco, CA, 2Momentum-Rsch Inc, Durham, NC, 3Duke Clinical Rsch Institute, Durham, NC, 4Athens Univ Hosp Attikon, Athens, Greece 5Univ of California, San Diego, San Diego, CA, 6Med Univ, Military Hosp, Wroclaw, Poland 7Corthera, Inc., San Carlos, CA, 8Univ of Gronignen, Univ Med Cntr Groningen, Groningen, Netherlands 9Novartis Pharmaceuticals Corp, East Hanover, NJ, 10Novartis Pharmaceuticals Corp, East Hanover, NJ, 11Novartis Pharma AG, Basel, Switzerland 12Cardiology, Univ, Brescia, Italy
Background: Acute heart failure remains a major public health burden with an increasing prevalence and high morbidity and mortality. Serelaxin is recombinant relaxin-2, a naturally occurring vasoactive peptide neurohormone that increases cardiac output, arterial compliance, and renal blood flow. In a pilot study, serelaxin administered to patients with acute heart failure was safe and well-tolerated with positive clinical outcome efficacy signals. Methods: RELAXin in Acute Heart Failure (RELAX-AHF) was an international, multicenter, double-blind, placebo-controlled trial that randomized 1161 patients hospitalized for acute heart failure to standard care plus 48-hour intravenous infusions of placebo or serelaxin (30 μg/kg/day) within 16 hours from presentation. All patients had dyspnea, congestion on chest radiograph, increased BNP or NT-proBNP, mild-to-moderate renal insufficiency and systolic blood pressure greater than 125 mmHg. Results: Serelaxin improved the primary efficacy endpoint representing dyspnea relief, the visual analog scale area under the curve to day 5 (P=0.007), meeting the pre-specified criterion for demonstrating efficacy in the trial, but did not significantly improve the other primary endpoint, change in dyspnea by Likert scale during the first 24 hours. No significant effects on the secondary end-points of death or hospitalization for heart failure/ renal failure or days alive out of the hospital through day 60 were observed. Serelaxin reduced cardiovascular mortality (HR 0.62, 95%CI 0.40–0.95; P=0.03) and all-cause mortality (HR 0.63, 95% CI 0.43–0.93; P=0.02) at 180 days. In-hospital worsening heart failure, worsening renal function, signs of congestion, use of vasoactive therapies, and length of index hospital and duration of intensive care were also reduced with serelaxin. Conclusions: Treatment of acute heart failure with serelaxin was associated with dyspnea relief, improved decongestion, and reduced 180-day mortality, but had no effect on rehospitalizations for heart failure or renal failure.
Author Disclosures: J.R. Teerlink: Employment; Significant; Department of Veterans Affairs. Research Grant; Significant; Novartis, Amgen, Cytokinetics, Corthera. Consultant/Advisory Board; Modest; Johnson & Johnson. Consultant/Advisory Board; Significant; Novartis, Amgen, Cytokinetics, Corthera, St. Jude, CardioMEMS. G. Cotter: Employment; Significant; Momentum-Research Inc. Ownership Interest; Significant; Momentum-Research Inc. B.A. Davison: Employment; Significant; Momentum-Research Inc. Ownership Interest; Significant; Momentum-Research Inc. G. Felker: Research Grant; Significant; Amgen, Otsuka. Consultant/Advisory Board; Significant; Novartis, Trevena, Amgen. G. Filippatos: Research Grant; Modest; Bayer. Research Grant; Significant; Corthera/Novartis, European Union. Consultant/Advisory Board; Significant; Corthera. B.H. Greenberg: Honoraria; Significant; Novartis. P. Ponikowski: Research Grant; Significant; Novartis. Consultant/Advisory Board; Significant; Novartis. E. Unemori: Employment; Significant; Corthera, Inc. Ownership Interest; Significant; Corthera, Inc. A.A. Voors: Research Grant; Significant; Novartis. Consultant/Advisory Board; Significant; Novartis. A. Trapani: Employment; Significant; Novartis Pharmaceuticals Corporation. Ownership Interest; Significant; Novartis Pharmaceuticals Corporation. C. Bush: Employment; Significant; Novartis. Ownership Interest; Significant; Novartis. R. Saini: Employment; Significant; Novartis. Ownership Interest; Significant; Novartis. C. Schumacher: Employment; Significant; Novartis. Ownership Interest; Significant; Novartis. T. Severin: Employment; Significant; Novartis. Ownership Interest; Significant; Novartis. M. Metra: Research Grant; Significant; Novartis.
Key Words: Acute heart failure, Cardiovascular therapeutics, Clinical trials, Outcomes, Vasodilator agents
Cardiorenal Rescue Study in Acute Decompensated Heart Failure: Results of CARRESS-HF, for the Heart Failure Clinical Research Network
Bradley A. Bart1, Steven R. Goldsmith2, Kerry L. Lee3, Lynne W. Stevenson4, Christopher M. O'Connor3, David A. Bull5, Margaret M. Redfield6, Anita Deswal7, Jean L. Rouleau8, Martin M. LeWinter9, Elizabeth O. Ofili10, Micheal M. Givertz4, Marc J. Semigran11, G M. Felker3, Horng H. Chen6, Adrian F. Hernandez3, Kevin J. Anstrom3, Steven E. McNulty3, Eric J. Velazquez3, Alice M. Mascette12, Eugene Braunwald13 1Hennepin County Med Ctr., Minneapolis, MN, 2Hennepin County Med Ctr, Minneapolis, MN, 3Duke Univ, Durham, NC, 4Brigham and Women's Hosp, Boston, MA, 5Univ of Utah, Salt Lake City, UT, 6Mayo Clinic, Rochester, MN, 7Baylor College and VA Med Cntr, Houston, TX, 8Montreal Heart Institute, Montreal, Canada 9Univ of Vermont, Berlington, VT, 10Morehouse Sch of Medicine, Atlanta, GA, 11Massachusetts General Hosp, Boston, MA, 12NHLBI, Bethesda, MD, 13Harvard Med Sch, Boston, MA
Background and Objective: Patients on intensified loop diuretics (LD) for acute decompensated heart failure (ADHF) often develop worsening renal function (WRF) despite persistent congestion. It is unclear if LD directly contribute to WRF in this setting. Veno-venous ultrafiltration (UF) is an alternative decongestive modality to LD which does not directly activate neurohormones. As such, UF might offer advantages compared to LD when WRF develops. The CARdiorenal REScue Study in acute decompensated HF (CARRESS HF) is a randomized controlled trial conducted by the NHLBI Heart Failure Clinical Research Network comparing an intensified LD-based medical approach versus UF in patients with ADHF, persistent congestion and WRF (defined as a rise in serum Cr of 0.3 mg/dl or greater) while receiving LD therapy. The hypothesis is that UF will result in improved renal function and relief of congestion compared to stepped pharmacologic care. Methods: 188 patients with WRF on LD therapy for ADHF were randomized 1:1 to a stepped pharmacologic care algorithm based on intensified LD therapy, or to UF at a nominal rate of 200 cc/hour. The primary endpoint is a bivariate measure of change in weight and change in serum creatinine 96 hours from the time of enrollment. Secondary endpoints include changes in weight and renal function at discharge, rates of clinical decongestion, changes in symptoms, rates of death and heart failure hospitalizations, and serious adverse events. Patient Characteristics: The mean age was 68 years, 75% were male, 31% were members of racial/ethnic minorities, 62% had coronary disease, 84% had hypertension, 66% had diabetes, 51% had 2 or more heart failure admissions in the year prior to enrollment, the mean ejection fraction was 33%, and the mean creatinine at the time of enrollment was 2.11 mg/dL. Results and Implications: Primary and secondary endpoint data will be presented. CARRESS HF is the first prospective, randomized comparison of medical therapy versus UF in ADHF patients with WRF and persistent congestion. The results will provide important information as to the appropriate approach for treating such patients.
Author Disclosures: B.A. Bart: Research Grant; Modest; Gambro. S.R. Goldsmith: Speakers Bureau; Significant; Gambro. K.L. Lee: None. L.W. Stevenson: None. C.M. O'Connor: None. D.A. Bull: None. M.M. Redfield: None. A. Deswal: None. J.L. Rouleau: None. M.M. LeWinter: None. E.O. Ofili: None. M.M. Givertz: None. M.J. Semigran: None. G.M. Felker: None. H.H. Chen: None. A.F. Hernandez: None. K.J. Anstrom: None. S.E. McNulty: None. E.J. Velazquez: None. A.M. Mascette: None. E. Braunwald: None.
Key Words: Acute heart failure, Diuretics, Renal function, Device
2012 Clinical Science: Special Reports Abstracts
Clinical Science: Special Reports: Prevention and Treatment of Ischemic Heart Disease: Novel Approaches
Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease [LoDoCo]: A Randomized Controlled Trial
Stefan M. Nidorf1, John W. Eikelboom2, Charley Budgeon3, Peter L. Thompson4 1Heart Care WA, Perth, Australia 2McMaster Univ, Hamilton, Canada 3Univ of Western Australia, Perth, Australia 4Sir Charles Gairdner Hosp, Perth, Australia
Background: Despite routine use of anti-platelet and statin therapy, patients with stable coronary disease continue to be at risk of recurrent ischemic events. The presence of activated neutrophils in culprit atherosclerotic plaques of patients with unstable CAD raises the possibility that inhibition of neutrophil function with colchicine may reduce the risk of plaque instability and thereby improve the clinical outcome in patients with stable coronary disease. Methods: Using a Prospective Randomized Observer Blinded End-point design, 532 patients with stable coronary disease receiving aspirin and/or clopidogrel (93%) and high dose statins (95%), were randomly assigned colchicine 0.5 mg/day or no colchicine and followed for a median of 3 years. The primary outcome was the composite, acute coronary syndrome, out-of-hospital cardiac arrest or non-cardio-embolic ischemic stroke. The primary analysis was by intention-to-treat. Results: The primary outcome occurred in 15/282 (5.3%) patients assigned colchicine and 40/250 (16.0%) patients assigned no colchicine (hazard ratio 0.33, 95% CI: 0.15, 0.60; P=0.0002; number needed to treat 11). In a pre-specified secondary analysis that excluded 32 patients (11%) assigned to Colchicine who withdrew within 30 days due to intestinal intolerance and a further 7 patients (2%) who did not start treatment, the primary outcome occurred in 7/243 (4.5%) vs. 40/250 (16.0%) (hazard ratio 0.29, 95% CI; 0.15, 0.56; P=0.0003). Conclusion: Colchicine 0.5 mg/d given in addition to anti-platelet and high dose statin therapy appears effective for the prevention of major cardiovascular events in patients with stable coronary disease.
Author Disclosures: S.M. Nidorf: None. J.W. Eikelboom: None. C. Budgeon: None. P.L. Thompson: None.
Key Words: Ischemic heart disease, Prevention, Drugs
Results of the Responses of Myocardial Ischemia to Escitalopram Treatment Trial
Wei Jiang, Stephen H. Boyle, Zainab Samad, Eric J. Velazquez, Maragatha Kuchibhatla, Richard C. Becker, Redford Williams, Cynthia Kuhn, Thomas L. Ortel, Joseph Rogers, Christopher O'Connor Duke Univ Med Cntr, Durham, NC
Background: Mental stress induced myocardial ischemia is an intermediate biomarker representing the pathophysiological link between psychosocial risk and adverse outcome of coronary heart disease. However, pharmacotherapy aimed at reducing such ischemia remains poorly studied. Objectives: To examine the effects of escitalopram, compared to placebo, on mental stress induced myocardial ischemia and other psychological stress related physiological and emotional measures. Methods: One hundred twenty seven patients with coronary heart disease and ischemia documented during mental stress testing were randomized to Escitalopram (dose began at 5 mg/day with titration to 20 mg/day in three weeks, N=64) or placebo (N=63) for a 6-week intervention. Occurrence of myocardial ischemia, defined as, relative to rest, 1) development or worsening of regional wall motion abnormality; 2) left ventricular ejection fraction reduction ≥8%, and/or; 3) horizontal or downsloping ST segment depression ≥1 mm in 2 or more leads lasting for ≥3 consecutive beats during one or more of three mental tasks. Platelet serotonin receptor transporter, blood pressure, heart rate, depression, anxiety, and stress level were also assessed at baseline and the end of intervention. Same assessments were repeated at the end of the 6-week intervention prior to tapering of the study medication. Results: One hundred eleven (96.1%) patients completed the endpoint assessments (N=56 in each arm). At the end of 6 weeks, a larger percentage of patients taking escitalopram (29.7%) did not show mental stress induced ischemia, compared to 14.3% in patients taking placebo based on intention-to-treat and baseline observation brought forward on missing endpoint. Analysis demonstrated a significant difference between the two groups (Odds ratio=2.53, 95% confidence interval=1.04–6.15). Escitalopram in addition resulted in significant alteration of platelet serotonin receptor transporter function, reduction in mental stress induced heart rate, rate-pressure product, and increase of positive emotions (ps<0.05). Conclusion: The results of the REMIT trial demonstrate that 6-week escitalopram treatment reduces mental stress induced ischemia in patients with coronary heart disease.
Author Disclosures: W. Jiang: Research Grant; Significant; NHLBI. S.H. Boyle: None. Z. Samad: None. E.J. Velazquez: None. M. Kuchibhatla: None. R.C. Becker: None. R. Williams: None. C. Kuhn: None. T.L. Ortel: None. J. Rogers: None. C. O'Connor: Research Grant; Significant; NHLBI.
Key Words: Stress echocardiography, Ischemic heart disease, Behavioral medicine, Anxiety, Depression
Safety and Efficacy of Losmapimod in Non-ST-Segment Elevation Acute Myocardial Infarction: Results of the SOLSTICE Phase 2 Randomized Trial
L Kristin Newby1, Lea Sarov-Blat2, Chiara Melloni1, Manesh R. Patel1, John F. Heitner3, Christian W. Hamm4, Philip Aylward5, Jean-Francois Tanguay6, Robbert J. De Winter7, Michael S. Marber8, John J. Lepore2, Amir Lerman9, Vic Hasselblad10, Hussein Al-Khalidi10, Dennis L. Sprecher2, Christopher B. Granger1 1Duke Univeresity Med Cntr, Durham, NC, 2GlaxoSmithKline, King of Prussia, PA, 3New York Methodist Hosp, Brooklyn, NY, 4Kerckhoff Heart Cntr, Bad Neuheim, Germany 5South Australian Health and Med Rsch Institute, Flinders Med Cntr, Flinders, Australia 6Université de Montréal, Montreal, Canada 7Academic Med Cntr—Univ of Amsterdam, Amsterdam, Netherlands 8King's College London BHF Cntr, London, United Kingdom 9Mayo Clinic, Rochester, MN, 10Duke Clinical Rsch Institute, Durham, NC
Background: Inflammation is fundamental to acute coronary syndromes (ACS). p38-mitogen-activated protein kinase (MAPK) is a nexus in inflammation, sensing and stimulating cytokine production and driving cell migration and cell death. In ACS, p38-MAPK inhibition may stabilize ruptured and active plaques, improve microvascular function and directly protect the myocardium, and thereby reduce infarct size and adverse outcomes. Study design: SOLSTICE (Study Of LoSmapimod Treatment on Inflammation and InfarCt SizE) is a randomized, double-blind, placebo-controlled, parallel group, multicenter phase 2 study to evaluate safety and efficacy of 2 dose regimens of losmapimod (GW856553), a potent oral p38-MAPK inhibitor, versus placebo (randomized 3:3:2) during 12-week treatment in patients with non-ST-segment elevation myocardial infarction (NSTEMI) expected to undergo an invasive strategy. Primary safety assessments are adverse events and results of liver function testing. Co-primary efficacy endpoints are reduction in markers of inflammation at 12 weeks and infarct size (troponin area under the curve) at 72 hours. Secondary outcome measures include B-type natriuretic peptide levels at 72 hours and 12 weeks (a marker of cardiac remodeling/ventricular strain) and 12-week death, MI, recurrent ischemia, heart failure or stroke. Substudies include cardiac magnetic resonance imaging (N=117) and assessment of coronary flow reserve (N=13). Results: Of 535 patients randomized in SOLSTICE, 526 received >=1 dose of study drug. Preliminary baseline characteristics of these 526 patients are in the Table. The database was locked May 30, 2012 and primary results will be presented. Conclusion: The SOLSTICE trial will provide information on safety, biologic activity and preliminary efficacy measures of losmapimod treatment for NSTEMI patients. Results will inform potential testing of this novel anti-inflammatory treatment in larger-scale clinical trials.
Author Disclosures: L. Newby: Research Grant; Significant; GlaxoSmithKline. Other; Modest; all my RWI are available at https://www.dcri.org/about-us/conflict-of-interest/. Other; Significant; https://www.dcri.org/about-us/conflict-of-interest/. L. Sarov-Blat: Employment; Significant; GlaxoSmithKline. Ownership Interest; Significant; GlaxoSmithKline. C. Melloni: Research Grant; Significant; GlaxoSmithKline. M.R. Patel: Consultant/Advisory Board; Modest; Genzyme, Ostuka, Baxter, theheart.org. Research Grant; Significant; Johnson and Johnson, NHBLI, AHRQ, Astra Zeneca,. Consultant/Advisory Board; Significant; Bayer, Jansen. J.F. Heitner: Research Grant; Significant; GlaxoSmithKline. C.W. Hamm: Research Grant; Significant; GlaxoSmithKline. P. Aylward: Research Grant; Modest; Eli Lilly,Sanofi. Speakers Bureau; Modest; Astra Zeneca, Bayer. Consultant/Advisory Board; Modest; Astra Zeneca, Boehringer Ingelheim, Bayer/Jand J. Research Grant; Significant; GlaxoSmithKline,Merck. J. Tanguay: Research Grant; Significant; GlaxoSmithKline. R.J. De Winter: Research Grant; Significant; GlaxoSmithKline. M.S. Marber: Research Grant; Significant; GlaxoSmithKline. Consultant/Advisory Board; Significant; GlaxoSmithKline. J.J. Lepore: Employment; Significant; GlaxoSmithKline. Ownership Interest; Significant; GlaxoSmithKline. A. Lerman: Consultant/Advisory Board; Modest; Itamar Medical. V. Hasselblad: None. H. Al-Khalidi: None. D.L. Sprecher: Employment; Significant; GlaxoSmithKline. Ownership Interest; Significant; GlaxoSmithKline. C.B. Granger: Research Grant; Significant; GlaxoSmithKline. Other; Modest; all RWI are at https://www.dcri.org/about-us/conflict-of-interest/. Other; Significant; all RWI are at https://www.dcri.org/about-us/conflict-of-interest/.
Key Words: Myocardial infarction, NSTEMI, Inflammation, Infarct size, Acute coronary syndromes, Clinical trials
EnligHTN™ I, First-in-Man Multi-Center Study of a Novel Multi-Electrode Renal Denervation Catheter in Patients With Drug-Resistant Hypertension
Vasilios Papademetriou1, Stephen G. Worthley2, Costas Tsioufis3, Matthew Worthley4, Derek Chew5, Ajay Sinhal5, Ian Meredith6, Yuvaraj Malaiapan7 1VA Med Ctr, Washington, DC, 2Cardiovascular Rsch Cntr, Royal Adelaide Hosp and Dept of Med, Univ of Adelaide, Adelaide, Australia 3: First Cardiology Clinic, Univ of Athens, Hippokration Hosp, Athens, Greece 4Univ of Adelaide, Adelaide, Australia 5Flinders Univ/Flinders Med Cntr, Adelaide, Australia 6Monash Heart and Monash Cardiovascular Rsch Cntr, Melbourne, Australia 7Monash Med Cntr, MonashHeart and Monash Cardiovascular Rsch Cntr, Melbourne, Australia
Introduction: Renal denervation has emerged as a novel approach for the treatment of patients with drug-resistant hypertension. Single-tip electrode radiofrequency ablation catheters have been used to achieve sympathetic fiber interruption through the renal artery wall. However systems designed to create predetermined stereotactic lesion pattern have not been tested. We investigated the safety and efficacy of a multi-electrode catheter ablation system (EnligHTN) developed by St Jude Medical. Methods: The EnligHTN catheter has 4 electrodes attached on a basket mounted at the tip of the catheter. The basket is collapsed and can be expanded via an external mechanism once the catheter is placed in the desired location of the renal artery. The electrodes can then be activated sequentially to achieve the desired lesion pattern. The basket can be repositioned for a new set of lesions if so desired, in order to optimize renal denervation. In the EnligHTN-I study we assessed 46 patients (av. age 60±10yrs on av. 4.0±0.6 meds). Bilateral renal artery ablation was done using a percutaneous femoral approach. On av. 7.7±0.8 lesions were created in the right renal artery and 7.4±1.4 in the left renal artery. The median procedure time was 34 minutes. The primary end point of the study was change in office BP at 6 month. Results: Baseline av. office BP was 176/96 mmHg and av. 24 hr ABPM 150/83 mmHg. Average reductions (mmHg) at one month were: office BP –28/10 (av.148/89 mmHg) (P<0.001), 24hr BP –10/5 (av.140/78 mmHg), and daytime BP –10/5 (av.143/80 mmHg). At three months similar results were seen for office, 24 hr ambulatory, and daytime BP values. The % of subjects that were dippers at baseline was 26%, at one month was 30% and at 3 months 35%. At 6 months results remained essentially unchanged. There continues to be no significant change in av serum creatinine or eGFR. No serious or life threatening procedure related complications occurred. Small hematomas were noted in 4 subjects, pseudoaneurysm in 1, vaso-vagal reaction in 3 and transient bradycardia in 1. Conclusions: We conclude that data so far demonstrate that the EnligHTN ablation system is safe and effective in the treatment of patients with resistant hypertension. Detailed results for all subjects to be presented at the meeting.
Author Disclosures: V. Papademetriou: Research Grant; Modest; St Jude Medical. Speakers Bureau; Significant; Astra Zeneca. Honoraria; Modest; Modest. Consultant/Advisory Board; Modest; Modest. S.G. Worthley: None. C. Tsioufis: Research Grant; Significant; St Jude Medical. Honoraria; Modest; St Jude Medical. M. Worthley: None. D. Chew: None. A. Sinhal: None. I. Meredith: None. Y. Malaiapan: None.
Key Words: Hypertension, Renal circulation
Clinical Science: Special Reports: New Insights into Management of Common Cardiovascular Disorders
A Randomised Trial to Assess Catheter Ablation versus Rate Control in the Management of Persistent Atrial Fibrillation in Chronic Heart Failure
David G. Jones1, Shouvik K. Haldar1, Rakesh Sharma1, Shelley L. Rahman-Haley2, Darrel P. Francis3, Theresa A. McDonagh1, Wala Mattar2, Richard Underwood1, Wajid Hussain1, Vias Markides1, Tom Wong1 1Royal Brompton & Harefield, Imperial College, London, United Kingdom 2Royal Brompton & Harefield, London, United Kingdom 3Imperial College Healthcare, London, United Kingdom
Background: The optimal therapy for atrial fibrillation (AF) in the context of heart failure (HF) is unclear. Drug-based rhythm control has not proved clinically beneficial. Catheter ablation-based rhythm control improves cardiac function in patients with HF, but impact on physiological performance has not been formally evaluated in a randomised trial. Methods: We conducted a randomised controlled trial (ARC-HF; NCT00878384) comparing catheter ablation with rate control in adults with symptoms of congestive heart failure, radionuclide left ventricular ejection fraction (EF) ≤35%, and persistent AF. The primary outcome was change in peak oxygen consumption (VO2) at cardiopulmonary exercise test. Secondary endpoints were change in quality of life (Minnesota), 6 minute walk, BNP, and EF. Patients were followed up for 12 months, and results analysed by intention to treat. Results: 52 patients (63±9y, 7 female, EF 24±8%, VO2 17.3±5.1ml/kg/min, 51±60 months AF, LA 48±7mm) were randomised, 26 each to the ablation and rate control arms. In the ablation arm, 20 patients had 1 procedure, 4 had 2, 1 had 3, and 1 declined ablation. At 12 month follow up, 88% maintained SR, with a single procedure success of 69%. In the rate control arm, rate criteria were achieved in 96% of patients at 12 months. At 12 months peak VO2 had increased by 2.13 (95%CI –0.1 to 4.36) ml/kg/min in the ablation arm, compared with a decrease (-0.94ml/kg/min, 95%CI –2.21 to 0.32) under rate control (mean difference +3.07ml/kg/min, 95% CI 0.56–5.59, P=0.018). The change appeared progressive, with a difference of only 0.79ml/kg/min at 3 months (95% CI –1.01 to 2.60, P=0.38). Compared with rate control, the ablation arm had significantly reduced 12-month Minnesota score (P=0.019) and BNP (P=0.045), and showed trends toward increased 6 min walk distance (P=0.095) and EF (P=0.055). LA size also fell significantly after ablation. (P=0.001). Conclusions: Catheter ablation of persistent AF in patients with HF, with the ablation strategy achieving sinus rhythm in the majority, improves prognostically important objective cardiopulmonary exercise performance, symptoms and neurohormonal status. The effects are clear at 1 year but less distinct earlier, suggesting a period of cardiac remodelling and recovery.
Author Disclosures: D.G. Jones: Research Grant; Significant; St Jude Medical UK. S.K. Haldar: Research Grant; Significant; St Jude Medical UK. R. Sharma: None. S.L. Rahman-Haley: None. D.P. Francis: None. T.A. McDonagh: None. W. Mattar: None. R. Underwood: None. W. Hussain: None. V. Markides: None. T. Wong: Research Grant; Significant; St Jude Medical UK, Boston Scientific UK.
Key Words: Atrial fibrillation, Heart failure, Ablation, Exercise tests, Biomarkers
Pulmonary Antrum Radial-Linear Ablation of Paroxysmal Atrial Fibrillation: First-in-Human Multicenter Clinical Outcome
Xue Zhao1, JiaYou Zhang1, Jianqiang Hu1, Dening Liao1, Yinxiang Zhu1, Xiang Mei1, Jun Sheng1, Fang Yuan1, Wenliang Lu2, Li Dai2, Xingui Guo3, Yawei Xu4, Yanzhou Zhang5, Ben He6, Zhenguo Liu7 1Shanghai Changzheng Hosp,Second Military Med Univ, Shanghai, China 2Huadong Hosp, Fudan Univ, Shanghai, China 3Shanghai Huadong Hosp, Fudan Univ, Shanghai, China 4Shanghai Tenth People's Hosp,Tongji Univ, Shanghai, China 5Shanghai Renji Hosp,Shanghai Jiao Tong Univ, Shanghai, China 6Renji Hosp, Shanghai Jiao Tong Univ, Shanghai, China 7Ohio State Univ Med Cntr, Columbus, OH
Background: Substrate abnormality in pulmonary vein (PV) antrum plays a critical role in mechanism of atrial fibrillation (AF). The present study aimed to examine the efficacy and safety of an organized substrate modification strategy by PV antrum radial-linear ablation (PARA) in patients with paroxysmal AF. Methods and Results: A total of 86 patients with paroxysmal AF were randomly assigned to PARA group or PV isolation group. The mapping of PARA was based on morphology of PVs and local potentials.The local electrogram in PV antrum target area was characterized by double potentials with a duration of ≥50 ms (the combined potentials from PV and LA) or CFAEs if AF occurred. All the radial-linear lesions were created with radiofrequency ablation from PV ostium to the PV-LA junction,where PV potential disappeared and only LA potential was recorded. The procedural end points were completion of all the radial lines, AF non-inducible and no PV isolation. The procedure time was 161±21 minutes in PARA and 199±39 minutes in PV isolation (P<0.01). The fluoroscopy time was 25±5 minutes in PARA and 32±9 minutes in PV isolation (P<0.001). At 14 (12–15) months of follow-up, 36 of 42 patients (85.7%) in PARA and 26 of 44 patients (59.1%) in PV isolation had no recurrence of AF with antiarrhythmic medication (P=0.006); and 31 of 42 (73.8%) patients in PARA and 22 of 44 patients (50.0%) in PV isolation had no recurrence of AF without antiarrhythmic medication (P=0.025). PARA resulted in significant reduction of LA diameter than PV isolation. Multivariate Cox regression showed that only ablation strategy was independently associated with AF recurrence (HR, 0.311; 95%CI: 0.123–0.784; P=0.013). No major adverse event related to the procedures occurred. Conclusion: This randomized multicenter study demonstrates thesuperiority of PARA over PV isolation in patients with paroxysmal AF with regard to maintenance of sinus rhythm and improvement in LA remodeling.
Author Disclosures: X. Zhao: None. J. Zhang: None. J. Hu: None. D. Liao: None. Y. Zhu: None. X. Mei: None. J. Sheng: None. F. Yuan: None. W. Lu: None. L. Dai: None. X. Guo: None. Y. Xu: None. Y. Zhang: None. B. He: None. Z. Liu: None.
Key Words: Atrial fibrillation, Ablation, radiofrequency
Prospective Randomized Study to Assess the Efficacy of Site and Rate of Atrial Pacing on Long-Term Progression of Atrial Fibrillation in Sick Sinus Syndrome-Septal Pacing for Atrial Fibrillation Suppression Evaluation [SAFE] Study
Hung-Fat Tse1, Chun-Chieh Wang2, Tachapong Ngamukos3, You-Ho Kim4, Chi-Woon Kong5, Razali Omar6, Charn Sriratanasathavorn7, Ruth Kam8, Christophe Bailleul,9, Chu-Pak Lau1 1The Univ of Hong King, Hong Kong, Hong Kong 2Chang Gung Memorial Hosp, Linkou, Taiwan 3Ramathibodi Hosp, Mahidol Univ, Bangkok, Thailand 4Asan Med Cntr, Seoul, Korea, Democratic People's Republic of 5Taipei Veterans General Hosp, Taipei, Taiwan 6Institut Jantung, Negara, Malaysia 7Siriraj Hosp, Mahidol Univ, Bangkok, Thailand 8Changi General Hosp, Singapore, Singapore 9St. Jude Med, Zaventem, Belgium
Background: Atrial-based pacing is associated with lower risk of atrialfibrillation (AF) in sick sinus syndrome (SSS) compared with ventricularpacing; nevertheless, the impact of site and rate of atrial pacing onprogression of AF remains unclear. This study aimed To evaluate whether long-term atrial pacing at the right atrial (RA) appendage versus low RA septum with (ON) or without (OFF) a continuous atrial overdrive pacing algorithm can prevent the development of persistent AF. Methods: A multicenter, randomized, parallel, 4 group study of 385 patients (pts) with paroxysmal AF and SSS in whom a pacemaker was indicated. Between May 2005 and November 2011 pts were randomized to pacing at the RA appendage-ON (n=98), RA appendage-OFF (n=99), RA septum-ON (n=92) or RA septum-OFF (n=96). All pts were followed-up every 6 months for at least 3 years. The primary outcome was time to the occurrence of persistent AF (AF documented on two ECGs a minimum of 7 days apart or the need for cardioversion). Results: There were no significant differences in clinical demographics or pacing parameters between the 4 groups (all P>0.05). After a mean follow-up of 3.1-years, persistent AF occurred in 99 patients (25.8%, annual rate of persistent AF: 8.3%). There were no significant differences in the incidence of persistent AF between the 4 groups (all log-rank P>0.05). Alternative site pacing at the RA septum versus conventional RA appendage (HR=1.18; 95%CI: 0.79–1.75, P=0.65) or continuous atrial overdrive pacing ON versus OFF (HR=1.17; 95%CI: 0.79–1.74, P=0.69) did not prevent the development of persistent AF. Conclusion: In pts with paroxysmal AF and SSS who require pacemaker implantation, an alternative atrial pacing site at the RA septum or continuous atrial overdrive pacing did not provide incremental benefit to atrial-based pacing with minimized ventricular pacing in preventing the development of persistent AF.
Author Disclosures: H. Tse: Research Grant; Modest; St Jude Medical, Boston Scientific. Consultant/Advisory Board; Modest; St Jude Medical, Boehringer Ingelheim, Sanofi, MSD, Takeda. C. Wang: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical. T. Ngamukos: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical. Y. Kim: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical. C. Kong: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical. R. Omar: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical. C. Sriratanasathavorn: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical. R. Kam: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical. C. Bailleul,: Employment; Significant; St Jude Medical. C. Lau: Research Grant; Modest; St Jude Medical. Consultant/Advisory Board; Modest; St Jude Medical, Boston Scienific.
Key Words: Atrial fibrillation, Pacing
Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT)
Marc Semigran1, Diana Bonderman2, Stefano Ghio3, Stephan B. Felix4, Hossein A. Ghofrani5, Evangelos D. Michelakis6, Veselin Mitrovic7, Ronald J. Oudiz8, Lothar Roessig9, Andrea V. Scalise10 1Massachusetts General Hosp Heart Cntr, Boston, MA, 2Med Univ of Vienna, Vienna, Austria 3Fondazione Policlinico S. Matteo, Pavia, Italy 4Ernst-Moritz-Arndt Univ of Greifswald, Greifswald, Germany 5Univ Hosp Giessen and Marburg, Gieβen, Germany 6Univ of Alberta, Edmonton, Canada 7Kerckhoff Heart Cntr, Bad Nauheim, Germany 8Los Angeles Biomedical Rsch Institute at Harbor-UCLA Med Cntr, Torrance, CA, 9Bayer Pharma AG, Berlin, Germany 10Bayer Hispania, S.L., Barcelona, Spain
Introduction: Pulmonary hypertension (PH) due to systolic left ventricular dysfunction (sLVD) frequently complicates heart failure (HF) and greatly worsens exercise capacity and prognosis in patients with sLVD. Preclinical and small clinical studies suggest deficient nitric oxide-cGMP-soluble guanylate cyclase (sGC) signaling in patients with HF. Hypothesis: The double-blind, phase IIb LEPHT study (NCT01065454) characterized the safety and hemodynamic effects of 16 weeks' treatment with the oral sGC stimulator riociguat in patients with chronic systolic HF (LV ejection fraction ≤40%) and mean pulmonary arterial pressure (mPAP) ≥25 mmHg. Methods: Patients with PH-sLVD receiving optimized therapy for HF were randomized in four parallel arms to double-blind treatment with riociguat (0.5, 1 or 2 mg titration target doses three-times daily) or placebo. Results: Of 201 randomized and treated patients, 160 underwent right heart catheterization at 16 weeks. Although the decrease in mPAP in the riociguat 2 mg arm (−6.1±1.3 mmHg [mean±SEM]; P<0.0001 vs baseline) was not significantly different from placebo (−2.7 mmHg [95% confidence interval −6.0 to 0.6]; P=0.10, primary endpoint), riociguat increased cardiac index significantly from 2.2±0.08 to 2.6±0.08 L/min/m2 (2 mg arm: P=0.0001 vs placebo) without changing heart rate or systemic blood pressure vs placebo. Pulmonary (PVR) and systemic vascular resistance (SVR) decreased from 291±24 to 213±26 dyn · s/cm5 (P=0.033 vs placebo) and from 1593±57 to 1262±47 dyn · s/cm5 (P=0.0002 vs placebo), respectively. Riociguat decreased the Minnesota Living with Heart Failure total score from 44±3 to 35±2 (2 mg arm: P=0.0018 vs placebo), and prolonged time to clinical worsening in patients with clinical worsening events (2 mg arm: P=0.0082 vs placebo; pre-specified non-powered exploratory analysis). Discontinuation of study treatment was similar between treatment arms: 2 (3%) patients in the 2 mg riociguat arm discontinued study drug due to serious adverse events vs 5 (7%) in the placebo arm. Conclusions: Riociguat was well tolerated in patients with advanced systolic HF and secondary PH, and improved cardiac index, PVR, SVR, and quality of life, without significantly changing mPAP or systemic blood pressure.
Author Disclosures: M. Semigran: Research Grant; Modest; Bayer Inc. D. Bonderman: Research Grant; Significant; Bayer. Honoraria; Modest; Bayer, Actelion, AOP, Pfizer. Consultant/Advisory Board; Modest; Bayer, Actelion, United Therapeutics. S. Ghio: Honoraria; Modest; Lilly, Pfizer, Actelion, GlaxoSmithKline. S. Felix: Research Grant; Modest; Bayer Healthcare. Other Research Support; Modest; Bayer Healthcare. Honoraria; Modest; Bayer Healthcare. Consultant/Advisory Board; Modest; Bayer Healthcare. H. Ghofrani: Research Grant; Modest; Actelion, Bayer, Ergonex, Pfizer. Speakers Bureau; Modest; Actelion, Bayer, Ergonex, Gilead, GlaxoSmithKline, Novartis, Pfizer. Honoraria; Modest; Actelion, Bayer, Ergonex, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer. Consultant/Advisory Board; Modest; Actelion, Bayer, Ergonex, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer. E. Michelakis: Consultant/Advisory Board; Modest; Bayer. V. Mitrovic: Other Research Support; Modest; Novartis, Bayer. Honoraria; Modest; Novartis, Bayer, GlaxoSmithKline. Expert Witness; Modest; Novartis, Bayer, CardioPep. Consultant/Advisory Board; Modest; Cardiorentis, Bayer. R. Oudiz: Research Grant; Significant; Actelion, Bayer, Gilead, Ikaria, Lung LLC, Novartis, Pfizer, United Therapeutics. Speakers Bureau; Modest; Gilead, Lung LLC, United Therapeutics. Consultant/Advisory Board; Modest; Actelion, Bayer, Gilead, Lung LLC, Novartis, United Therapeutics. L. Roessig: Employment; Significant; Bayer Pharma AG. A. Scalise: Employment; Significant; Bayer Hispania, S.L..
Key Words: Heart failure, Pulmonary hypertension, Vasodilator agents
Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction in Patients With Preserved Ejection Fraction - A Prospective, Double Blinded Placebo-Controlled Randomized Trial (SIDAMI)
Mads J. Andersen1, Mads Ersbøll1, Finn Gustaffson1, Christian Hassager1, Anna Axelsson1, Lars Køber1, Barry A. Borlaug2, Søren Boesgaard1, Jacob E. Møller1 1Rigshospitalet, København Ø, Denmark 2Mayo Clinic, Rochester, MN
Background: Diastolic dysfunction is frequently seen after myocardial infarction (MI) which is characterized by a disproportionate increase in filling pressure during exercise to maintain stroke volume. Observational studies have suggested increased risk for adverse outcome in these patients irrespective of left ventricular ejection fraction (LVEF). The optimal management of these patients is unknown. Sildenafil, a PDE-5 inhibitor, is currently being used to treat erectile dysfunction and pulmonary hypertension yet recent studies have suggested in patients with heart failure that Sildenafil has a positive effect. We hypothesized that Sildenafil would improve central hemodynamics with exercise in patients with diastolic dysfunction after MI. Methods: SIldenafil and Diastolic dysfunction after Acute Myocardial Infarction = SIDAMI is a randomized 1:1 double-blinded placebo-controlled clinical trial. A total of 70 patients with diastolic dysfunction (diastolic E/e' ratio >8 and left atrial volume index >34 ml/m2) and LVEF >45 % on echocardiography performed within 48 hours after MI were enrolled. Eligible patients received either Sildenafil 40 mg thrice daily (TID) or placebo TID for 9 weeks. Before treatment was started a simultaneous echocardiography and right heart catheterization at rest and during a symptom limited semi-supine cycle exercise test was performed, which was repeated after 9 weeks. Primary endpoint was pulmonary wedge pressure (PCWP) at peak exercise after 9 weeks treatment, and the study was powered to detect a difference in PCWP at peak exercise after intervention of at least 3.2 mmHg (α=0.05, power 0.9), Secondary endpoints comprised cardiac index (CI) and mean pulmonary arterial pressure at peak exercise. Preliminary results: Baseline resting PCWP (n=70) prior to randomization was 13±4 which increased to 33±8 mmHg with exercise. Resting mean pulmonary arterial pressure was 20±5 increasing to 46±10 mmHg at peak exercise and resting CI was 2.7±0.6 increasing to 7.2±1.3 L/min/m2 at peak exercise. Conclusion: SIDAMI will provide detailed insight into central hemodynamics and the effect of Sildenafil at rest and during exercise in patients with exercise induced pulmonary venous hypertension. Full results will be presented.
Author Disclosures: M.J. Andersen: None. M. Ersbøll: None. F. Gustaffson: None. C. Hassager: None. A. Axelsson: None. L. Køber: None. B.A. Borlaug: None. S. Boesgaard: None. J.E. Møller: None.
Key Words: Myocardial infarction, Diastolic function, Stress echocardiography, Exercise tests
Clinical Science: Special Reports: Emerging Therapeutics for Diabetes and Dyslipidemia
Impact of LX4211, a Dual Inhibitor of Sodium Glucose Transporter 1 and 2 on Cardiovascular Risk Factors in Type 2 Diabetes
Julio Rosenstock1, Brian Zambrowicz2, Pablo Lapuerta2, Ike Ogbaa2, Phillip Banks2, Joel Freiman2, Kenny Frazier2, Kristi Boehm2, Mike Kelly2, Arthur Sands2 1Dallas Diabetes and Endocrine Cntr., Dallas, TX, 2Lexicon Pharmaceuticals, Inc., The Woodlands, TX
Background: LX4211, a dual inhibitor of SGLT 1 and 2, reduces the amount of glucose that enters the bloodstream from the gastrointestinal (GI) tract by inhibiting SGLT1, the major transporter for GI glucose absorption, and enhances urinary glucose excretion (UGE) by inhibiting SGLT2, the major transporter for glucose reabsorption by the kidney. Methods: In this 12-week dose-ranging study (52 sites in the United States), 299 patients (pts) with poorly controlled type 2 diabetes (T2DM) on metformin therapy were randomly assigned to either LX4211 or placebo. The primary endpoint was the change from baseline to Week 12 in HbA1C; secondary endpoints included changes in blood pressure (BP) and weight. LX4211 was dosed at 75 mg, 200 mg qd, 200 mg bid (split dose), or 400 mg qd. At baseline, mean pt age was 55.9 years (range, 30.0–79.0) and 55% were female. Mean body mass index was 33.1 kg/m2, weight 93.7 kg, plasma HbA1c 8.1%, systolic BP 124.9 mmHg, and diastolic BP 79.2 mmHg. Results: LX4211 markedly reduced HbA1c in a dose-dependent manner (−0.43% to −0.95% for LX4211 vs −0.09% for placebo). The 400 mg dose reduced HbA1c more than the 200 mg dose without any further increase in the urine glucose to creatinine ratio, indicating that both SGLT1 and 2 mechanisms contribute to the efficacy of 400 mg. In addition, significant reductions in systolic BP (−0.1 to −6.0 mmHg for LX4211 vs −0.3 mmHg for placebo) and body weight (−1.0 to −2.7 kg for LX4211 vs −0.4 kg for placebo) were observed. Adverse events (AEs) were generally mild to moderate; the overall incidence of AEs with LX4211 was similar to placebo. Frequency of urinary tract infections with LX4211 was similar to placebo (0% to 1.8% for LX4211 vs 1.7% for placebo); Genital infections (0% to 5%) were limited to LX4211 dose groups. Importantly, the GI safety profile of LX4211 was similar to placebo and there were no hypoglycemic events reported. Conclusions: LX4211 produced clinically and statistically significant reductions in HbA1c and other metabolic parameters important to the development of cardiovascular disease. Dual inhibition of SGLT1 and SGLT2 by LX4211 has potential to demonstrate both enhanced glycemic control and reduction of cardiovascular risk in pts with T2DM in future phase 3 trials.
Author Disclosures: J. Rosenstock: Honoraria; Modest; Roche, sanofi-aventis, Novo Nordisk, Eli Lily, MannKind, GlaxoSmithKline, Takeda, Daiichi Sankyo, Johnson & Johnson, Novartis, Boehringer Ingelheim, Lexicon Pharmaceuticals, Inc. Consultant/Advisory Board; Modest; Roche, sanofi-aventis, Novo Nordisk, Eli Lily, MannKind, GlaxoSmithKline, Takeda, Daiichi Sankyo, Johnson & Johnson, Novartis, Boehringer Ingelheim, Lexicon Pharmaceuticals, Inc. Research Grant; Significant; Merck, Pfizer, sanofi-aventis, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca,, Amylin, Johnson & Johnson, Daiichi Sankyo, MannKind, Boehringer Ingelheim, Lexicon Pharmaceuticals, Inc. B. Zambrowicz: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Significant; Lexicon Pharmaceuticals, Inc. P. Lapuerta: Employment; Significant; Lexicon Pharmaceuticals, Inc. I. Ogbaa: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Modest; Lexicon Pharmaceuticals, Inc. P. Banks: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Modest; Lexicon Pharmaceuticals, Inc. J. Freiman: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Significant; Lexicon Pharmaceuticals, Inc. K. Frazier: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Significant; Lexicon Pharmaceuticals, Inc. K. Boehm: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Modest; Lexicon Pharmaceuticals, Inc. M. Kelly: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Modest; Lexicon Pharmaceuticals, Inc. A. Sands: Employment; Significant; Lexicon Pharmaceuticals, Inc. Ownership Interest; Significant; Lexicon Pharmaceuticals, Inc.
Key Words: Blood pressure, Obesity, Glucose, Cardiovascular, Type 2 Diabetes
LAPLACE-TIMI 57 Primary Results
Robert P. Giugliano1, Nihar R. Desai1, Payal Kohli1, Ransi Somaratne2, Fannie Huang2, Satishkumar Mohanavelu3, Shannon T. McDonald1, Timothy E. Abrahamsen1, Scott M. Wasserman2, Robert Scott2, Marc S. Sabatine1 1Brigham and Womens Hosp, Boston, MA, 2Amgen, Inc, Thousand Oaks, CA, 3Brigham Womens Hosp, Boston, MA
Background: Statins are the first-line agents for lowering low density lipoprotein cholesterol (LDL-C), but many patients are unable to achieve optimal lipid targets despite maximally tolerated statin. Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, targeting them for degradation. AMG 145 is a fully human monoclonal antibody against PCSK9 and was well-tolerated and effective in animal models and Phase 1 human studies. Methods: LAPLACE-TIMI 57 (NCT01380730) was a 12-week, randomized, double-blind, dose-ranging, placebo-controlled study that assessed the efficacy, safety, and tolerability of AMG 145 when added to statin therapy in patients with hypercholesterolemia. Subjects age 18–80 years, with LDL-C ≥85 mg/dL on a stable dose of statin (× ezetimibe) for ≥4 weeks were randomized equally across 8 treatment arms: AMG 145 (70 mg, 105 mg, 140 mg) vs. matching placebo every 2 weeks (Q2W); or AMG 145 (280 mg, 350 mg, 420 mg) vs. matching placebo every 4 weeks (Q4W). The primary endpoint was the % change in LDL-C (via preparative ultracentrifugation) from baseline after 12 weeks of AMG 145 versus placebo in those who received ≥1 dose of study drug. Results: A total of 631 subjects were randomized and 629 received at least 1 dose of study drug (median age 62, 51% females, 35% with prior cardiovascular disease). The mean (SD) baseline LDL-C was 123 (SD 28) mg/dL. Treatment with AMG 145 resulted in statistically-significant, dose-dependent reductions in LDL-C up to 66% and 50% at 140 mg Q2W and 420 mg Q4W, respectively, compared with placebo (Table). There were no treatment-related serious adverse events. Conclusion: In patients with hypercholesterolemia already receiving stable statin therapy, the addition of AMG 145 was associated with significant reductions in LDL-C of up to 66%. Treatment with AMG 145 was well-tolerated. The results of the LAPLACE-TIMI 57 trial support further evaluation of AMG 145 in a large, phase III cardiovascular outcomes trial.
Author Disclosures: R.P. Giugliano: Research Grant; Significant; Amgen, Merck. Honoraria; Modest; Merck. Consultant/Advisory Board; Modest; Amgen, Merck. N.R. Desai: Research Grant; Significant; Amgen. P. Kohli: Research Grant; Significant; Amgen. R. Somaratne: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. F. Huang: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. S. Mohanavelu: Research Grant; Significant; Amgen. S.T. McDonald: Research Grant; Significant; Amgen. T.E. Abrahamsen: Research Grant; Significant; Amgen. S.M. Wasserman: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. R. Scott: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. M.S. Sabatine: None.
Key Words: Cholesterol-lowering drugs, Hyperlipidemia, Hyperlipoproteinemia, Lipids, Lipoproteins
Efficacy and Safety of a Fully Human Monoclonal Antibody Against PCSK9 as Monotherapy for Hypercholesterolemia: Results from the MENDEL Study, a Global Phase 2 Trial of AMG 145
Michael J. Koren1, Robert Scott2, Jae B. Kim2, Beat Knusel2, Thomas Liu2, Lei Lei2, Michael Bolognese3, Scott M. Wasserman2 1Jacksonville Cntr for Clinical Rsch, Jacksonville, FL, 2Amgen Inc., Thousand Oaks, CA, 3Bethesda Health Rsch Cntr, Bethesda, MD
Background: Proprotein convertase subtilisin kexin type 9 (PCSK9), a serine protease that lowers the concentration of hepatic low-density lipoprotein receptors and raises LDL cholesterol (LDL-C), has emerged as a target for treating hyperlipidemia. We evaluated subcutaneous (SC) AMG 145, a fully human monoclonal antibody (mAb) to PCSK9, as monotherapy to reduce LDL-C. Methods: In this global, multicenter, blinded, placebo- and ezetimibe-controlled trial, subjects aged 18–75 yrs on no lipid-lowering therapy (LDL-C ≥100,<190 mg/dL; triglycerides ≤400 mg/dL; 10-yr Framingham CHD risk score ≤10%) were randomized equally to 9 groups: AMG 145 75, 105 or 140 mg every 2 wks (Q2W); AMG 145 280, 350 or 420 mg Q4W; placebo SC Q2W or Q4W; or ezetimibe open label. The primary endpoint was percent change from baseline in LDL-C at wk 12. Secondary endpoints included percent change from baseline at wk 12 in apolipoprotein B (ApoB), lipoprotein (a) (Lp(a)), and ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C). Tolerability and safety were also evaluated. Results: Subjects (N=406) were 34% male, mean (SD) age 51 (12) yrs, baseline LDL-C 142 (22) mg/dL. Baseline characteristics were comparable among groups. At wk 12, AMG 145 reduced mean LDL-C from baseline up to 51% (table). AMG 145 LDL-C percent reductions from baseline were 37%- 53% greater than placebo and 25%–37% greater than ezetimibe. AMG 145 reduced ApoB 32%–44%, Lp(a) 11%–29%, and TC/HDL-C 29%–38% vs placebo. No serious treatment-related adverse events (AEs) were reported. The most common AEs overall (AMG 145, placebo) were upper respiratory tract infection (6.3%, 7.8%), nasopharyngitis (4.1%, 3.3%), back pain (3.3%, 4.4%), and diarrhea (3.7%, 3.3%). Injection site reactions occurred in 5.5% of AMG 145 and 4.4% of placebo subjects. Conclusions: In this first multicenter PCSK9 mAb monotherapy study, AMG 145 produced robust reductions in LDL-C compared with placebo or ezetimibe and was well tolerated.
Author Disclosures: M.J. Koren: Employment; Significant; Jacksonville Center for Clinical Research, which received grants from Amgen Inc. R. Scott: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. J.B. Kim: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. B. Knusel: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. T. Liu: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. L. Lei: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc. M. Bolognese: Research Grant; Significant; Amgen Inc., Unigene Laboratories Inc., Eli Lilly, Radius Health Inc. Speakers Bureau; Modest; Amgen Inc., Eli Lilly and Company, Genentech. S.M. Wasserman: Employment; Significant; Amgen Inc. Ownership Interest; Significant; Amgen Inc.
AMG 145, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9), Facilitates Achievement of NCEP LDL-Cholesterol Goals in High-Risk Patients
Nihar R. Desai1, Payal Kohli1, Robert P. Giugliano1, Jae B. Kim2, Satishkumar Mohanavelu2, Elaine Hoffman1, Thomas Liu2, Robert Scott2, Scott Wasserman2, Marc S. Sabatine1 1TIMI Study Group, Div of Cardiovascular Medicine, Brigham and Women's Hosp, Boston, MA, 2Amgen, Inc, Thousand Oaks, CA
Background: Many patients are unable to achieve their LDL-cholesterol (LDL-C) goals with existing lipid lowering therapies. AMG 145, a fully human monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), demonstrated significant LDL-C reductions in phase 1 studies and may enable a greater proportion of patients to achieve desired LDL targets. Methods: LAPLACE-TIMI 57 was a phase 2, randomized, double-blind, placebo-controlled, dose-ranging study of AMG 145 v. placebo in 629 hypercholesterolemic subjects on a stable background regimen of a statin with or without ezetimibe. Patients were classified as high risk based on the presence of coronary heart disease (CHD) or CHD equivalents as defined by the National Cholesterol Education Program (NCEP). Intensive background therapy was defined as simvastatin 80 mg, atorvastatin ≥40 mg, rosuvastatin ≥20 mg, or any statin taken with ezetimibe. We examined the proportion of patients with high NCEP risk achieving an LDL-C ≤70 mg/dL after 12 weeks of treatment. Results: Of 284 subjects (45% of trial population) with high NCEP risk, 222 had established vascular disease. Intensive background lipid-lowering therapy was employed in 41% of high NCEP risk subjects. AMG 145 significantly reduced LDL-C after 12 weeks, by a mean of 40 to 64% in a dose-related fashion compared with placebo (P<0.001). Whereas<4% of patients in the placebo arms had an LDL-C ≤70 mg/dL, 53 to 90% of subjects treated with AMG 145 achieved this NCEP goal (P<0.001, Figure), with a median achieved LDL-C in one of the treatment arms of 43 mg/dL (IQR, 28–59 mg/dL). Treatment with AMG 145 was well-tolerated. Conclusion: AMG 145 leads to robust reductions in LDL-C and significantly increases the ability to achieve NCEP target LDL-C of ≤70 mg/dL for patients with CHD or CHD risk equivalents receiving standard background therapy. AMG 145 may help address an important unmet clinical need in the management of hypercholesterolemia.
Author Disclosures: N.R. Desai: Other Research Support; Significant; Amgen, Inc. P. Kohli: Other Research Support; Significant; Amgen, Inc. Honoraria; Modest; Daiichi-Sankyo. R.P. Giugliano: Research Grant; Modest; Merck,. Research Grant; Significant; Amgen. Honoraria; Modest; Amgen, Merck, Regeneron, Sanofi-Aventis. J.B. Kim: Other; Significant; Employee and Stockholder of Amgen, Inc. S. Mohanavelu: Other Research Support; Significant; Amgen, Inc. E. Hoffman: Other Research Support; Significant; Amgen, Inc. T. Liu: Other; Significant; Employee and Stockholder of Amgen, Inc. R. Scott: Other; Significant; Employee and Stockholder of Amgen, Inc. S. Wasserman: Other; Significant; Employee and Stockholder of Amgen, Inc. M.S. Sabatine: None.
Key Words: Lipids, Cholesterol-lowering drugs, Quality improvement
Clinical Science: Special Reports: Valvular Heart Disease, PAD, Atrial Fibrillation: International Perspectives
EndOVascular Treatment for Infra-Inguinal Vessel, in Patients With Critical Limb Sichemia (olive) Registry in Japan
Masato Nakamura1, Osamu Iida2, Daizo Kawasaki3, Yasutaka Yamauchi4, Yashiaki Yokoi5, Yoshimitsu Soga6, Kan Zen7 1Toho Univ, Ohashi medical Cntr, Tokyo, Japan 2Kansai Rosai Hosp, Amagasaki shi, Japan 3Hyogo Collage of Medicine, Nishinomiyashi, Japan 4Kikuna Memorial Hosp, Yokohama shi, Japan 5Kishiwada Tokusyukai Hosp, Kishiwada shi, Japan 6Kokura Memorial Hosp, Kitakyusyushi, Japan 7Onihanchiman Community Med Cntr, Onihachimanshi, Japan
Background: Although bypass surgery is a durable, limb-preserving standard treatment modality for patients with critical limb ischemia (CLI), some patients have comorbidities that preclude bypass surgery. Recent technical advances have made endovascular treatment (EVT) an alternative first-line treatment for CLI. Methods and Results: A prospective multicenter study was conducted to evaluate the clinical outcomes of 314 Japanese CLI patients (mean age: 73±10 years) with infrainguinal arterial lesions who underwent EVT. Patients were enrolled from December 2009 to July 2011 and followed for 12 months. The chief comorbidities were diabetes mellitus (71%) and end-stage renal disease requiring dialysis (52%). The primary endpoint was amputation-free survival (AFS) at 12 months. Secondary endpoints were anatomical, clinical, and hemodynamic measures, including 12-month freedom from major adverse limb events (MALE). The 12-month AFS rate was 74%, with body mass index (BMI)<18.5 (hazard ratio [HR]: 2.22, P=0.0078), heart failure (HR: 1.73, P=0.0405) and wound infection (HR: 1.89, P=0.0283) predicting a poor prognosis for AFS. The 12-month MALE-free rate was 88%, with hemodialysis (HR: 1.98, P=0.0052), heart failure (HR: 1.69, P=0.0230) and Rutherford classification 6 (HR: 2.25, P=0.0016) predicting a poor prognosis for MALE. The median time to wound healing was 97days, with BMI <18.5 (HR: 0.54, P=0.0347) and wound infection (HR: 0.596, P=0.0411) being significant risk factors for unhealed wounds up to 97 days after EVT. At 12 months, 81% of the patients were alive, 92% had preserved limbs, 34% had undergone reintervention (bypass surgery: 2.6%, repeat EVT: 31.7%), and 73% were MAE (major adverse event)-free. Conclusions: High reintervention rate notwithstanding, EVT was an effective treatment for Japanese CLI patients with infrainguinal disease, with satisfactory AFS and MALE-free rates. These results will serve as a landmark for future evaluation of CLI therapy.
Author Disclosures: M. Nakamura: None. O. Iida: None. D. Kawasaki: None. Y. Yamauchi: None. Y. Yokoi: None. Y. Soga: None. K. Zen: None.
Key Words: Angioplasty, Peripheral arterial disease, Outcomes
Management and One Year Outcome of Atrial Fibrillation in Middle Eastern Cohort Enrolled in the Observational Gulf Survey of Atrial Fibrillation Events (Gulf SAFE)
Mohammad Zubaid1, Wafa Rashed2, Alawi A. Alsheikh-Ali3, Ibrahim Al-Zakwani4, Wael AlMahmeed3, Abdullah Shehab5, Kadhim Sulaiman6, Ahmed Al Qudaimi7, Nidal Asaad8, Haitham Amin9 1Faculty of Medicine, Kuwait Univ, Kuwait City, Kuwait 2Mubarak Al-Kabeer Hosp, Ministry of Health, Kuwait City, Kuwait 3Sheikh Khalifa Med City, Abu Dhabi, United Arab Emirates 4College of Medicine & Health Sciences, Sultan Qaboos Univ, Muscat, Oman 5Faculty of Medicine, UAE Univ, Al Ain, United Arab Emirates 6Royal Hosp, Muscat, Oman 7Al Thawra hospital, Sana'a, Yemen 8Hamad Med Corp, Doha, Qatar 9Mohammed Bin Khalifa Cardiac Cntr, Manama, Bahrain
Background: Atrial fibrillation (AF) poses a major health burden as it is associated with significant mortality and morbidity. Most of our knowledge about AF outcomes is derived from data on Caucasian populations. We studied characteristics, management and one-year outcomes of Middle Eastern patients with AF. Methods: Gulf SAFE was an observational, prospective registry of consecutive patients with AF presenting to emergency rooms (ER) of 23 hospitals in six Middle Eastern Gulf countries. Patients were recruited between October 2009 and June 2010 and were followed-up for one year. Key outcome data like mortality, stroke and bleeding were known for all patients who completed one year follow-up (96%). Multivariate logistic regression models were constructed to identify factors independently associated with the outcomes of stroke/transient ischemic attack (TIA) at 12-months of follow-up. Results: Of 2043 AF patients enrolled, 1721 with non-valvular AF were included in this analysis (age 59±16, 44% female, 59% with hypertension, 33% with diabetes, 70% overweight or obese, 32% with history of coronary artery disease and 27% with history of heart failure). The majority (71%) were managed with a rate control strategy in ER and 81% were admitted to hospital. 40% of patients with CHADS2score ≥2 were not prescribed warfarin at discharge. During follow up, internationalnormalized ratio (INR) was <2 in 28%, 2–3 in 56% and >3 in 16%. Cumulative one-year rates of all-cause mortality and stroke/TIA were 15% and 4.4%, respectively. The following variables were independentlyassociated with risk of stroke/TIA at one-year follow-up: smoking (OR, 2.17; 95% CI, 1.26–3.73), CHADS2 score of 1 (OR, 2.58; 95% CI, 1.09–6.07), CHADS2 score ≥2 (OR, 4.33; 95% CI, 1.97–9.51), lack ofanticoagulation (OR, 2.46; 95% CI, 1.13–5.33), and CHA2DS2-VASc score ≥2 (OR, 5.09; 95% CI, 1.94–13.3). Conclusion: Middle Eastern patients with non-valvular AF are relatively young and have high incidence of metabolic risk factors. The ER management resulted in high hospital admission rates. Their anticoagulation management is suboptimal and stroke/TIA events at one year are relatively high.
Author Disclosures: M. Zubaid: Research Grant; Modest; Boehringer Ingleheim. Honoraria; Modest; Sanofi, Boehringer Ingleheim, AstraZeneca, Servier, Bayer. Consultant/Advisory Board; Modest; Sanofi, Boehringer Ingleheim, Pfizer. W. Rashed: None. A.A. Alsheikh-Ali: Honoraria; Modest; Sanofi, Boehringer Ingleheim. Consultant/Advisory Board; Modest; Boehringer Ingleheim, Pfizer, Sanofi. I. Al-Zakwani: Honoraria; Modest; Sanofi. W. AlMahmeed: Honoraria; Modest; Sanofi, Boehringer Ingleheim. Consultant/Advisory Board; Modest; Sanofi, Boehringer Ingleheim. A. Shehab: None. K. Sulaiman: None. A. Al Qudaimi: None. N. Asaad: None. H. Amin: None.
Key Words: Atrial fibrillation
Clinical Implications of Device-Detected Atrial Tachyarrhythmias: Results From the Registry of Atrial Tachycardia and Atrial Fibrillation Episodes in the Cardiac Rhythm Management Device Population (RATE)
Steven Swiryn1, David G. Benditt2, John P. DiMarco3, Donald M. Lloyd-Jones1, Michael V. Orlov4, Mara T. Slawsky5, Melanie Turkel6, Albert L. Waldo7 1Northwestern Univ, Chicago, IL, 2Univ of Minnesota, Minneapolis, MN, 3Univ of Virginia, Charlottesville, VA, 4Tufts Univ, Boston, MA, 5Tufts Univ, Springfield, MA, 6St. Jude Med, Sunnyvale, CA, 7Case Western Reverve Univ, Cleveland, OH
The clinical implications of device-documented atrial tachycardia and fibrillation (AT/AF) remain uncertain. The “RATE Registry” was designed to follow 5,000 patients, with no history of AT/AF over the prior three months, for two years after implant of a pacemaker (PM) or ICD. Hypothesis: A definable AT/AF burden predicts clinical outcomes, including progression to symptomatic AT/AF or to sustained AT/AF, heart failure, and/or increased risk of stroke. All event electrograms (EGM) were evaluated in 600 randomly selected patients (300 PM and 300 ICD) by teams of 2 adjudicators documenting all rhythms and AT/AF characteristics (duration, atrial rate, regularity and EGM morphology.) Inter-observer agreement ranged from 93.4% for AT/AF presence to 83% for AT/AF morphology. In addition, every EGM from patients with a pre-specified clinical event during f/u as well as from a 2:1 case-control match of these patients was adjudicated, yielding an additional 327 patients not already in the random sample. Clinical events were adjudicated by a separate team of two cardiologists blinded to EGMs. Between 2007 and 2012, 5,379 patients were enrolled and followed in the RATE Registry; 3,141 with PMs and 2,238 with ICDs; 3,319 (61.7%) men and 2,060 (38.3%) women; age 18–100 (70±13) years. CHADS2 scores ranged from 0–6 (2±1). Average f/u was 20±7 months. More than 20,000 EGMs were adjudicated. From the random sample, 50% of patients (48% of PM, 52% of ICD) had at least one EGM demonstrating AT/AF. There were 2,232 hospitalizations and 361 deaths. There were 478 hospitalizations for pre-defined clinical events, including AT/AF (n=94), cardiac death (n=11), heart failure (n=265), stroke or TIA (n=47), cardiac syncope (n=12), and ventricular arrhythmia (n=49). In this study, with far more patients, much longer f/u, and many more events than prior studies, we will report, based upon adjudicated data, whether episodes of device-documented AT/AF (even very brief episodes <10 beats) predicted clinical events. We will examine the predictive value, if any, of AT/AF duration, including very short AT/AF duration which is often recorded during device f/u visits but was not addressed in prior studies.
Author Disclosures: S. Swiryn: Consultant/Advisory Board; Modest; St. Jude Medical. D.G. Benditt: Consultant/Advisory Board; Modest; St. Jude Medical, Medtronic. J.P. DiMarco: Research Grant; Modest; Sanofi. Consultant/Advisory Board; Modest; St. Jude Medical, Medtronic, Merck. D.M. Lloyd-Jones: Consultant/Advisory Board; Modest; St. Jude Medical. M.V. Orlov: Research Grant; Modest; Phillips Healthcare. Consultant/Advisory Board; Modest; St. Jude Medical, Phillips Healthcare. M.T. Slawsky: Consultant/Advisory Board; Modest; St. Jude Medical. M. Turkel: Employment; Modest; St. Jude Medical. A.L. Waldo: Consultant/Advisory Board; Modest; St. Jude Medical, Biotronik, Daiichi Sankyo, Boehringer Ingelheim, Janssen, and Bristol-Myers Squibb.
Key Words: Atrial fibrillation, Clinical trials, Device, Stroke, Pacemaker, artificial
Antithrombotic Treatments and Associated Outcomes in Patients with Atrial Fibrillation: The Global Anticoagulant Registry in the FIELD (GARFIELD)
Ajay K. Kakkar Thrombosis Rsch Institute, London, United Kingdom
Background: Limited data are available for VKA use or effectiveness in routine practice. Data from the 1st cohort of the GARFIELD Registry (enroll. Dec 2009–Oct 2011) will present the final picture of AF management and outcomes in real-life clinical practice during the transition from VKAs as the only available oral anticoagulant (AC) to the availability of several oral ACs. Aim: To describe clinical outcomes in relation to patient risk profiles and antithrombotic treatments in a representative worldwide AF population, and to understand the benefits and risks of anticoagulation in everyday practice. Methods: GARFIELD is an observational prospective registry of adults (≥18 yrs) diagnosed with non-valvular AF within the past 6 weeks and with ≥1 additional risk factor for stroke (not restricted to stroke risk factors identified in existing risk scores). In Cohort 1, 10,609 patients were enrolled consecutively at 543 randomly selected sites representative of AF care settings. Of these patients, 39% were ≥75 yrs, 21% had CHF, 78% hypertension, 22% diabetes, and 14% prior stroke/TIA. Follow-up data were available for 6267 patients at the time of this analysis (mean [SD] follow-up 15.8 [7.0] months). Of the 4217 (67%) patients treated with VKA, 3417 (81%) had INR values available. Results: The overall annual rate of stroke/TIA was 1.8%, major bleeding 0.7%, and mortality 2.5%. Events according to treatment strategy are shown in the Table. INR was well controlled in 41% of patients treated with VKAs. Patients with INR not well controlled had higher rates of events than those with well-controlled INR. Conclusions: These data confirm that well-controlled anticoagulation with VKAs is an effective way of reducing risk of stroke/TIA and mortality in AF patients. However, in a large proportion of patients treated with VKAs, coagulation is not well controlled, which is associated with an important detrimental effect across outcomes regardless of individual risk factors and CHADS2 score.
Author Disclosures: A.K. Kakkar: Research Grant; Significant; Bayer HealthCare.
Key Words: Atrial fibrillation, Anticoagulation, Outcomes
Randomized Comparison of the Effects of Two Doses of Dabigatran Etexilate on Clinical Outcomes Over 4.3 Years: Results of the Rely-Able Double-Blind Randomized Trial
Stuart J. Connolly1, Paul A. Reilly2, Janice Pogue3, John Eikelboom1, Jonas Oldgren4, Michael D. Ezekowitz5, Lars Wallentin4, Salim Yusuf1 1McMaster Univ, Hamilton, Canada 2Boehringer-Ingelheim, Ridgefield, CT, 3Population Health Rsch Institute, Hamilton, Canada 4Uppsala Univ, Uppsala, Sweden 5Lankenau Institute for Med Rsch, Wynnewood, PA
Background: RE-LY demonstrated the efficacy and safety of dabigatran etexilate (DE) (110 mg bid and DE 150 mg bid). The net clinical balance and appropriate use of the two doses remains controversial, with major national differences in regulatory labeling. Anticoagulation in AF is usually lifelong and long-term efficacy and safety of data on DE is desirable. RELY-ABLE provides 2.3 years of additional double-blind randomized follow up of patients receiving DE 110 or DE 150, after RE-LY. Methods: Patients were eligible if they completed RE-LY still receiving double-blind DE. Enrolled patients continued to receive the same double-blind DE dose in RELY-ABLE. The primary outcomes were the occurrence of major ischemic and hemorrhagic outcomes, as well as death and net clinical benefit (composite of all major ischemic, hemorrhagic and fatal outcomes). Results: Of the 12,091 patients receiving DE in RE-LY, 5,851 patients entered RELY-ABLE, 2,914 on DE 110 and 2,937 on DE 150. Patients continuing in RELY-ABLE differed from RELY patients who did not continue; with more permanent AF (38% vs. 33%) and less heart failure (27% vs. 35%). The rates of major bleeding were 2.99%/year on DE 110 and 3.74%/year on DE 150 (HR 1.26, 95% CI, 1.04–1.53, P=0.02); with GI major bleeding occurring at rates of 0.99%/year and 0.97%/year. Rates of ischemic stroke were 1.24 on DE 110%/year and 1.13%/year on DE 150 (HR 0.91; 95%CI 0.66–1.25;P=0.56). Rates of hemorrhagic stroke were 0.14%/year on both doses. The two doses of DE had similar mortality rates (HR 0.97, 95% CI, 0.80–1.19, P=0.79) and net clinical benefit. Combined data from all patients randomized to DE 110 or 150 in RE-LY and RELY-ABLE show that DE 150 reduced ischemic stroke (HR 0.78, 95% CI 0.64–0.94; P=0.01) and increased major bleeding by 20% (HR 1.20, 95%CI 1.07–1.35; P= 0.002); . Both doses have similar, very low, rates of hemorrhagic stroke. Conclusions: During >2 years of randomized follow up after RELY, rates of stroke and hemorrhage, on DE 110 and DE 150 were highly consistent with rates during RE-LY. Combined RELY and RELY-ABLE data show that DE150 reduces ischemic stroke by 22%, with a 20% higher rate of major hemorrhage. Hemorrhagic stroke rates were very low. Mortality and net clinical benefit are virtually identical between the doses.
Author Disclosures: S.J. Connolly: Research Grant; Significant; Boehringer Ingelheim. Honoraria; Significant; Boehringer Ingelheim. Consultant/Advisory Board; Significant; Boehringer Ingelheim. P.A. Reilly: Employment; Significant; Boehringer Ingelheim. J. Pogue: None. J. Eikelboom: Research Grant; Significant; Boehringer Ingelheim. Honoraria; Significant; Boehringer Ingelheim. Consultant/Advisory Board; Significant; Boehringer Ingelheim. J. Oldgren: Research Grant; Significant; Boehringer Ingelheim. Honoraria; Significant; Boehringer Ingelheim. Consultant/Advisory Board; Significant; Boehringer Ingelheim. M.D. Ezekowitz: Research Grant; Significant; Boehringer Ingelheim. Honoraria; Significant; Boehringer Ingelheim. Consultant/Advisory Board; Significant; Boehringer Ingelheim. L. Wallentin: Research Grant; Significant; Boehringer Ingelheim. Honoraria; Significant; Boehringer Ingelheim. Consultant/Advisory Board; Significant; Boehringer Ingelheim. S. Yusuf: Research Grant; Significant; Boehringer Ingelheim. Honoraria; Significant; Boehringer Ingelheim. Consultant/Advisory Board; Significant; Boehringer Ingelheim.
Key Words: Anticoagulants, Atrial fibrillation
2012 Late-Breaking Resuscitation Science Abstracts
Late-Breaking Abstracts in Resuscitation Science
Noninvasive Regional Cerebral Oxygen Saturation Is A Reliable and Readily Available Neurological Prognostic Indicator in Out-of-Hospital Cardiac Arrest Patients: A Multicenter Prospective Cohort Study
Noritoshi Ito1, Kei Nishiyama2, Clifton W. Callaway3, Ayumu Tsuruoka1, Hideki Arimoto4, Takaya Morooka4, Kei Hayashida5, Takashi Unoki6, Mitsuru Abe6, Tomohiko Orita7, Akira Murai8, Tomoyuki Endo9, Tomoaki Watanabe10, Masafumi Otsuka11, Tsuyoshi Hatada12, Noriaki Yamada13, Masahiro Mizobuchi14, Hideto Yasuda15, Yosuke Honma16, Yasuji Doi1, Tatsuro Kai1, Yuka Tsujimura17, Issei Komuro18 1Osaka Saiseikai Senri Hosp, Suita, Japan 2Kyoto Univ Graduate Sch of Med, Kyoto, Japan 3Pittsburgh Univ, Pittuburgh, PA, 4Osaka City General Hosp, Osaka, Japan 5Keio Univ Sch of Medicine, Tokyo, Japan 6National Hosp Organization Kyoto Med Cntr, Kyoto, Japan 7Saiseikai Yokohamashi Tobu Hosp, Yokohama, Japan 8Fukuoka Univ Hosp, Fukuoka, Japan 9Tohoku Univ Hosp, Sendai, Japan 10Nara Med Univ Hosp, Kashihara, Japan 11Fujisawa City Hosp, Fujisawa, Japan 12Mie Univ Hosp, Tsu, Japan 13Gifu Univ Hosp, Gifu, Japan 14Kyoto Katsura Hosp, Kyoto, Japan 15Japanese Red Cross Musashino Hosp, Musashino, Japan 16St Luke's International Hosp, Tokyo, Japan 17Kyoto Univ Graduate Sch of Medicine, Kyoto, Japan 18Osaka Univ Graduate Sch of Med, Suita, Japan
Background: Cardiocerebral resuscitation (CCR) is critically important in patients (pts) with out-of-hospital cardiac arrest (OHCA). However, there is no established real-time indicator of cerebral perfusion or function during CCR efforts. Regional cerebral oxygen saturation (rSO2) is a potential noninvasive measure of cerebral perfusion even in pts with cardiac arrest because a near-infrared spectroscopy (NIRS) does not require vascular pulsation. Objective: To validate in a multicenter prospective cohort study whether rSO2 at hospital arrival can predict neurological outcomes at 90 days after OHCA similar to our previous single center cohort study. Methods: The J-POP registry (conducted at 14 tertiary emergency hospitals in Japan) prospectively measured rSO2 once in OHCA pts immediately after hospital arrival, using a NIRS device (INVOS; Covidien, Boulder, CO) placed on the forehead. We excluded pts with 1) trauma, 2) accidental hypothermia, 3) age <18, 4) do not attempt resuscitation order, and 5) Glasgow Coma Scale >8 at hospital arrival. Regardless of the rSO2, all pts received the best available therapy. Good neurological outcome was defined as Cerebral Performance Category (CPC) 1 or 2 after 90 days. Results: Among 764 OHCA pts, 42 (5.5%) had good neurological outcome and 722 (94.5%) had poor neurological outcome. Pts with good outcome had significantly higher rSO2 (57.3+/−19.2% vs. 20.8+/−13.1%, P<0.001). Receiver operating curve analysis indicated an optimal rSO2 cutoff point of >40% for predicting good outcome with an area under the curve of 0.91. In a post-hoc analysis, good outcome occurred in 3 (0.6%)/486, 3 (1.6%)/190, and 36 (41%)/88 pts with rSO2 values of 15%, 16–40%, and >40% (P<0.001), respectively. Conclusions: Our study validates that rSO2 at hospital arrival can predict neurological outcomes at 90 days after OHCA. Future studies should corroborate if rSO2 can serve as a real-time indicator of cerebral perfusion during CCR efforts.
Author Disclosures: N. Ito: None. K. Nishiyama: None. C. Callaway: Ownership Interest; Significant; University of Pittsburgh licensed a patent to Medtronic ERS for technology related to ECG waveform analysis in ventricular fibrillation; coinventor (may receive royalties)†; Owns stock. Other; Significant; University of Pittsburgh licensed a patent to Medtronic ERS for technology related to ECG waveform analysis in ventricular fibrillation; coinventor (may receive royalties)*; Owns stock. A. Tsuruoka: None. H. Arimoto: None. T. Morooka: None. K. Hayashida: None. T. Unoki: None. M. Abe: None. T. Orita: None. A. Murai: None. T. Endo: None. T. Watanabe: None. M. Otsuka: None. T. Hatada: None. N. Yamada: None. M. Mizobuchi: None. H. Yasuda: None. Y. Honma: None. Y. Doi: None. T. Kai: None. Y. Tsujimura: None. I. Komuro: Ownership Interest; Significant; Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., Shionogi & Co., Ltd., Takeda Pharmaceutical Co., Ltd., MSD K.K., Daiichi Sankyo Co.
Key Words: Cardiac arrest, Emergency care, Prognosis
Echocardiography as a Tool to Guide Complex Resuscitation is Feasible and Changes Care in Critically Ill Patients
Sarah B. Murthi, John R. Hess, Matthew E. Lissauer, Lynn G. Stansbury, Caron M. Hong, Samuel M. Galvagno, Thomas M. Scalea Univ of Maryland Med Sch, Baltimore, MD
Background: Invasive monitors to guide treatment in the ICU have failed to show benefit, possibly because they measure cardiac pressures, not volumes, and provide limited functional data. To guide care during complex resuscitation, we developed a bedside transthoracic, functionally interpreted, echocardiographic exam and determined its feasibility and utility. Methods: Rather than on anatomy, the focused rapid echocardiographic evaluation (FREE) concentrates on quantative and qualitiative assessments of cardiac function, volume status, and vascular resistance. Treatment recommendations based on the FREE combined with the patient's clinical status are generated using an algorithm. A prospectively collected quality-assurance database was analyzed to determine the feasibility and utility of the exam. Results: Over a 30-month period, we did 556 FREEs. The exam was found useful in 93% of patients, and changed care in 56%. The most common change was additional fluid administration in 38%, followed by addition/titration of a catecholamine in 29%, and fluid removal in 19%. In several patients more than one change was made as a result of the FREE. In 20% the change was from an intervention to observation. The left ventricular (LV) ejection fraction was assessable in 96% of patients, the stroke volume and cardiac index in 92%, right ventricular function in 94%, and diastolic function and/or a measure of pulmonary capillary wedge pressure in 86%. Volume assessments were able to be made in 80%, and pulmonary artery pressure in 77%. Conclusions: The FREE is feasible and changes care in critically ill patients undergoing complex resuscitation. Further studies are needed to determine the impact of functionally interpreted, bedside echocardiography on patient outcome.
Author Disclosures: S.B. Murthi: None. J.R. Hess: None. M.E. Lissauer: None. L.G. Stansbury: None. C.M. Hong: None. S.M. Galvagno: None. T.M. Scalea: None.
Key Words: Echocardiography, Resuscitation, Stroke volume
Prehospital Lactate is Superior to Systolic Blood Pressure for Predicting the Need for Resuscitative Care in Trauma
Francis Guyette1, Eric Meier2, Barbara McKnight2, Judy Powell2, Eileen Bulger3, Patricia Klotz2, Timothy Fabian4, Mohamud Daya5, Craig Newgard5, J. Weinberg1, Karen Brasel6, Jorge Mena-Munoz1, Mario R. Collela7, Ahamed Idris8, Jeffery Beason9, Jeffery Kirby10, Rardi VanHeest11, Carolyn Williams10, David Hoyt12, Steve Wheeler11, ROC Investigators 1U OF Pittsburgh, Pittsburgh, PA, 2U OF Washington, Seattle, WA, 3U OF Washington, Seatle, WA, 4U OF Texas, Houston, Houston, TX, 5Oregon Health Sciences Univ, Portland, OR, 6Med College of Wisconsin, Milwaukee, WI, 7Med College of WIsconsin, Milwaukee, WI, 8U OF Texas, Southwestern, Dallas, TX, 9Parkland Memorial Hosp, Dallas, TX, 10U OF Alabama, Birmingham, Birmingham, AL, 11U OF British Columbia, Vancouver, Canada 12American College of Surgeons, Chicago, IL
Background: Trauma triage guidelines rely on vital signs, which may not predict the need for surgical resources. Lactate is a byproduct of anaerobic metabolism, a marker of oxygen supply/demand mismatch, and a metric of resuscitation. The role of prehospital lactate (P-LAC) is unknown. Objective: To compare P-LAC to systolic blood pressure (SBP) ≤90 for predicting the need for resuscitative care (RC) in trauma patients with 70 <SBP ≤100 mm Hg across sites in the Resuscitation Outcomes Consortium (ROC). Methods: We conducted a prospective observational study at 9 ROC sites. We collected blinded P-LAC values in patients transported by ground EMS with IV's to a level I or II trauma center with a 70 <SBP ≤100. The primary endpoint was the need for RC defined as any of the following outcomes occurring within 6 hours of ED arrival: death, blood transfusion, or intervention for hemorrhage using thoracotomy, laparotomy, pelvic fixation or embolization. We compared the sensitivity of P-LAC ≥2.4 to that of SBP ≤90 and shock index (SI) ≥1.0 using McNemar's test. The P-LAC and SI cutoffs were selected, by an a priori decision rule, such that their specificities were equivalent to the reference specificity of SBP ≤90. We also compared the receiver operator characteristic area under the curve (AUC) of P-LAC to SBP and SI. Results: We enrolled 361 patients between March 2011 and August 2012, 81 (22%) required RC. We observed a median P-LAC of 4.8 mmol/L (IQR 3.4–7.6) in those requiring RC and 2.6 (1.8–3.9) in those who did not (P<0.0001). AUC analysis demonstrated that P-LAC (0.76) is superior to both SBP (0.58 P<0.0001) and SI (0.66 P=0.013) for the prediction of RC [Figure]. Sensitivity for P-LAC ≥2.4 at the reference specificity (0.47) is 0.91 (CI: 0.83–0.96) compared to 0.67 (0.55–0.77) for SBP ≤ 90 (P=0.0003) and 0.74 (0.63–0.83) for SI (P=0.003). Conclusion: P-LAC is superior to SBP and SI in predicting the need for RC in trauma patients with 70 <SBP ≤100 mm Hg.
Author Disclosures: F. Guyette: None. E. Meier: None. B. McKnight: None. J. Powell: None. E. Bulger: None. P. Klotz: None. T. Fabian: None. M. Daya: None. C. Newgard: None. J. Weinberg: None. K. Brasel: None. J. Mena-Munoz: None. M.R. Collela: None. A. Idris: None. J. Beason: None. J. Kirby: None. R. VanHeest: None. C. Williams: None. D. Hoyt: None. S. Wheeler: None.
Key Words: Biomarkers, Resuscitation
Optimization of a Hibernation Based Small Volume Resuscitation Fluid
Cecilia E. Perez de Lara Rodriguez, Alison Kingsbury, Lester R. Drewes, Matthew T. Andrews Univ of Minnesota Duluth, Duluth, MN
Background: Traumatic injury is the main cause of death among individuals ages 1 to 44 in the US. Hibernation depicts a notable physiological state featuring low cardiac output and blood flow similar in degree to hemorrhagic shock, yet the brain and other tissues of hibernators are naturally shielded from ischemia and reperfusion injury during arousal from torpor. A small volume resuscitation fluid based on hibernation physiology has been developed in our laboratory. The current formula of 4 M D β-hydroxybutyrate (BHB), 43 mM melatonin, and 20% DMSO has proven effective in extending survival in rat and pig models of hemorrhagic shock. The research described here intends to optimize the therapeutic concentrations of BHB, melatonin, and dimethyl sulfoxide (DMSO) as well as the delivery of this therapy. Methods and Results: Following surgical preparation, rats underwent hemorrhagic shock by the controlled withdrawal of 60% of their blood volume. Previously, our therapy had been infused in two phases: 1) a bolus of 1 ml/kg over a ten minute period and 2) a slow infusion of 100 μl/hr over one hour. Acute (no blood return) surgeries were performed on groups receiving either 1) a bolus plus slow infusion or 2) the bolus only. No statistical difference (P>0.05) was observed. Subsequently, blood return surgeries were performed. Dose ranging studies of BHB and melatonin were done independently. BHB concentrations used were 4 M, 2 M, and 0.4 M. No significant difference (p>0.05) was observed. However, a dose dependent trend was noted. The dose ranging study of melatonin included concentrations of 43 mM, 4.3 mM, and 0 mM. All treatments had 4 M BHB. There was no statistical difference (P>0.05) in survival between 43 mM and 4.3 mM melatonin. At 4.3 mM, melatonin was statistically (P<0.05) more efficient at achieving 10 day survival compared to 0 mM melatonin. Conclusions: The infusion of a 1 ml/kg bolus of our small volume resuscitation fluid is just as effective in expanding the “golden hour” as the continuation of the infusion at a slow rate. BHB has a dose dependent effect on survival and for that reason we have decided to fix the concentration of BHB for all further formulations at 4 M. Melatonin enhances survival, yet its therapeutic effects can still be observed at low concentrations.
Author Disclosures: C.E. Perez de Lara Rodriguez: None. A. Kingsbury: None. L.R. Drewes: Research Grant; Significant; W81XWH-11-1-0409 U.S. Army Medical Research and Materiel Command. M.T. Andrews: Research Grant; Significant; W81XWH-11-1-0409 U.S. Army Medical Research and Materiel Command.
Key Words: Resuscitation, Reperfusion injury, Drug administration
Best Original Resuscitation Science Poster Session and Luncheon
Resveratrol Decreases Inflammation in the Hippocampus of Mice Suffering From Moderate TBI
Joshua Gatson, Ming-Mei Liu, Jane G. Wigginton, Steve Wolf, Joseph P. Minei UT Southwestern.edu, Dallas, TX
Introduction: Following a traumatic brain injury (TBI) event, the secondary brain injury that persists after the initial concussion consists of excitotoxicity from increased neurotransmitter release, decreased cerebral glucose levels, oxidant injury, mitochondrial dysfunction, inflammation, and subsequent neuronal cell death. To date, there are no effective interventions used at decreasing secondary brain injury after TBI. Methods: In this study, using the controlled cortical impact device we produced a moderate head injury in young adult C57 Bl/6 mice. At 30 minutes, 12 hours, and 24 hours after injury, the mice were treated subcutaneously with either placebo or resveratrol (anti-oxidant; 100 mg/kg). At 72 hours after injury, the animals were intracardially perfused with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for apoptosis using the TUNEL assay or markers of inflammation such as CD4, CD19, CD40, and CD45. Inflammatory cytokines (TNF-alpha, IL-12) were detected using the ELISA assay at 4 hours after injury. Results: In this study we found that treatment with resveratrol led to a dramatic reduction of TUNEL + staining (P<0.04) and the levels of CD19 (P<0.01), CD40 (P<0.05), and CD45 (P<0.03). In addition, the levels of TNF-alpha were also dramatically reduced (P<0.001) in the treatment group. Conclusions: These results suggest that resveratrol reduces neuroinflammation in mice affected by moderate TBI. Resveratrol may be an ideal therapy to treat moderate TBI in the clinical setting if administered soon after injury.
Author Disclosures: J. Gatson: None. M. Liu: None. J.G. Wigginton: None. S. Wolf: None. J.P. Minei: None.
Key Words: Brain, Inflammation, Apoptosis
Intravascular Flocculation and Sequestration of Bone Marrow Fat and Thromboembolic Events Associated With Intraosseous Infusions
Bernard J. Rubal1, Belinda L. Meyers2, Sarah A. Kramer1, William L. Pomeroy1, Robert A. DeLorenzo2 1San Antonio Military Med Cntr, Fort Sam Houston, TX, 2US Army Institute of Surgical Rsch, Fort Sam Houston, TX
Objective: In a study designed to assess the threshold for fat intravasation from intraosseous (IO) infusions in the proximal tibia of a swine model, ultrasound imaging was employed to examine temporal changes in echo density within the femoral vein during the time course of IO flushes and infusions. Methods: In 70 experiments on 35 swine in which intraosseous cannulas were placed in the proximal tibiae, time-density curves of vascular opacification were obtained by frame-by-frame analysis in cross-sectional ultrasound views of the femoral vein obtained with a 6.6 MHz vascular transducer. Results: Maximal opacification was observed immediately following IO flush with homogenous echo densities carried in discrete but dynamic vascular flow paths throughout infusions consistent with microembolism. Additional larger echo reflective masses were observed as meteoric projections through the viewing plane. Also observed was the accumulation of a layer of echo bright densities on the superior margin of the femoral vein consistent with flocculation of low density fat-laded material. In longitudinal views, the buoyant masses moved slowly near the boundary layer with a tendency to sequester into larger clusters particularly in low flow states. Rapid manual compression of the femoral region dislodged the buoyant echo densities into faster venous flow fields. The distal propagation of compression waves dislodged up-stream fat emboli. Adherent echo densities promoted further accumulations that were observed to become foci for venous thrombus following repeated IO flushes and infusions. Conclusions: Although our observations are limited to an animal model designed to assess the threshold for fat intravasation with IO infusions, they suggest bone marrow fat emboli associated with IO infusions are carried in fast and slow phases in the blood that depend on the size and density of the emboli and the velocity of venous flow. We also demonstrate the potential for thrombus formation from bone marrow intravasation. (The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense.)
Author Disclosures: B.J. Rubal: None. B.L. Meyers: None. S.A. Kramer: None. W.L. Pomeroy: None. R.A. DeLorenzo: None.
Key Words: Embolism, Resuscitation, Research
Intensive Glycemic Control Increases Hypoglycemic Events Without Reducing Mortality or Improving Neurological Outcome: A Meta-Analysis of Randomized Controlled Trials
Alexandre Benjo1, Klio Chantziara2, Christos Maniotis3, Shashi Kumar1, Erdal Gursoy1, Todd Kobrinski1, Walter Pierce1, Eyal Herzog1, Emad Aziz1 1St.Luke's-Roosevelt Hosp Cntr/Columbia College of Physicians, New york, NY, 2St.Luke's-Roosevelt Hosp Cntr/Columbia College of Physicians and Evengelismos Hosp, Athens, Greece, New york, NY, 3St.Luke's-Roosevelt Hosp Cntr/Columbia College of Physicians and Hellenic Red Cross Hosp, Athens, Greece, New york, NY
Background: Acute Critically ill patients with brain injury may experience a wide variation in serum glucose; hyperglycemia is suggested to be related to poor clinical outcomes in such patients. Objectives: To compare the clinical outcomes of intensive and conventional glucose control in brain injury patients. Methods: All randomized controlled trials involving glucose control in critically ill adult patients were sought in PubMed and Scopus databases until July 2012. Intensive glucose control was defined as blood glucose ≤140 mg/dl (8.0 mmol/L). A worse neurological outcome was defined as a Glasgow Outcome Scale ≤4, a National Institutes of Health Stroke Scale (NIHSS) ≤2, a Modified Ranking Scale (mRS) ≤ 2 and a Karnofsky scores <60. Data was independently extracted by 4 reviewers and analyzed with RevMan 5.1 software. Results: Among 3081 citations, 11 studies including a total of 1775 critically ill brain injured adult patients were analyzed. In-hospital and overall mortality were similar in both strategies as demonstrated in Figure 1 (A and B). Furthermore, there was an almost 7 fold increase in the chance of having hypoglycemic events without neurological benefit with the intensive glycemic control strategy (Figure 1, C and D). Conclusions: Acute critically ill brain injured adult patients carry a higher rate of hypoglycemic events with intensive glycemic control. The aggressive management does not demonstrates neurological or survival benefit. A tighter glucose control is not warranted for this group of patients.
Author Disclosures: A. Benjo: None. K. Chantziara: None. C. Maniotis: None. S. Kumar: None. E. Gursoy: None. T. Kobrinski: None. W. Pierce: None. E. Herzog: None. E. Aziz: None.
Key Words: Glucose, Brain, Insulin
Functional Network Coherence in Comatose Survivors of Cardiac Arrest
Robert D. Stevens1, Haris Sair1, Shanshan Li2, Vincent Perlbarg3, Charles-Edouard Luyt3, Brian Caffo2, Joshua Kornbluth1, James Pekar1, Steven Laureys4, Audrey Vanhaudenhuyse4, Habib Benali3, Damien Galanaud3, Louis Puybasset3 1Johns Hopkins Univ Sch of Medicine, Baltimore, MD, 2Johns Hopkins Bloomberg Sch of Public Health, Baltimore, MD, 3Groupe Hospier Pitié–Salpêtrière, Paris, France 4Univ of Liège, Liège, Belgium
Introduction: Major neurological disorders are linked to anatomical and physiological changes in discrete large-scale neural networks. We used resting functional MRI to determine the significance of network coherence in unconscious survivors of cardiac arrest (CA). Hypothesis: Functional connectivities within and between selected brain networks are altered in comatose survivors of CA, and connectivity changes have prognostic significance. Methods: Adult patients without prior neurological disease who were comatose following CA were prospectively enrolled in 2 centers. Principal endpoint was 12 month extended Glasgow Outcome Scale (eGOS), unfavorable outcome defined as an eGOS <5. Patients underwent MRI without sedation using a standardized acquisition protocol. After image preprocessing, 36 regions of interest were selected from 7 canonical networks (auditory, dorsal attention, default mode, executive control, salience, somatomotor and visual). Blood oxygen level dependent (BOLD) signal time-courses were extracted and correlation coefficients computed pairwise and averaged to estimate functional connectivity within (WNFC) and between networks. MRI data were acquired and analyzed in identical fashion in age-matched healthy volunteers. Results: Twenty-seven CA patients and 39 control subjects were enrolled, mean age 48 yrs in both groups. MRI was obtained a median of 9 (range 5–35) days following CA. WNFC in CA patients was decreased significantly in default mode (P=0.000001 vs controls), visual (P=0.003), auditory (P=0.01), and attention (P=0.02) networks. At follow up 16 patients were dead, one was in a vegetative state, and 10 had moderate or no disability. In patients with unfavorable outcome, WNFC was reduced in salience (P=0.00005 vs favorable outcome patients), motor (P=0.008), visual (P=0.03) and attention (P=0.04) networks. Expected anticorrelated activity between default mode and attention and salience networks was diminished in patients (respectively P<0.000001 and P=0.001 vs controls). Conclusions: In comatose CA patients evaluated acutely with functional MRI, patterns of resting BOLD signal coherence are altered within and between discrete brain networks, and such alterations are linked to long-term outcome.
Author Disclosures: R.D. Stevens: None. H. Sair: None. S. Li: None. V. Perlbarg: None. C. Luyt: None. B. Caffo: None. J. Kornbluth: None. J. Pekar: None. S. Laureys: None. A. Vanhaudenhuyse: None. H. Benali: None. D. Galanaud: None. L. Puybasset: None.
Key Words: Cardiac arrest, Prognosis, Magnetic resonance imaging
The Interaction of Chest Compression Rates With the Impedance Threshold Device and Association With Survival Following Out-of-Hospital Cardiac Arrest
Ahamed H. Idris1, Danielle Guffey2, Paul E. Pepe1, Siobhan P. Brown2, Tom P. Aufderheide3, Steven C. Brooks4, Clifton W. Callaway5, Jim Christenson6, Dan P. Davis7, Mohamud R. Daya8, Randal Gray9, Peter J. Kudenchuk2, Jonathan Larsen10, Steve Lin11, James J. Menegazzi12, Kellie Sheehan2, George Sopko13, Ian G. Stiell14, Graham Nichol2, The ROC Investigators 1UT SOUTHWESTERN MEDICAL CENTER, Dallas, TX, 2Univ of Washington, Seattle, WA, 3Med College of Wisconsin, Milwaukee, WI, 4Queen's Univ, Toronto, Canada 5Univ of Pittsburgh, pittsburgh, PA, 6Univ of British Columbia, Vancouver, Canada 7UCSD Med Cntr, San Diego, CA, 8Oregon Health & Science Univ, Portland, OR, 9Univ of Alabama at Birmingham, Birmingham, AL, 10Seattle Fire Dept, Seattle, WA, 11Rescu, Li Ka Shing Knowledge Institute, St. Michael's Hosp, Toronto, Canada 12Univ of Pittsburgh, Pittsburgh, PA, 13National Institutes of Health, Bethesda, MD, 14Univ of Ottawa, Ottawa, Canada
Background: The Resuscitation Outcomes Consortium (ROC) PRIMED trial found no difference in survival to hospital discharge with a Modified Rankin Score (mRS) ≤3 with standard CPR plus a sham versus active ITD when used by emergency medical services in adults with out-of-hospital cardiac arrest. Objective: We evaluated the potential interaction of chest compression rate with the sham versus active ITD and outcome. Methods: Data were abstracted from monitor-defibrillator recordings during the first 5 minutes of CPR in patients enrolled in the ROC PRIMED ITD Trial. We retrospectively estimated the interaction between compression rate and ITD on survival to hospital discharge with mRS ≤3. We fit a natural cubic spline curve to characterize the relationship between compression rate and outcomes. Results: Of 8,755 patients enrolled from 6/2007 to 11/2009, 6,188 had chest compression rate and fraction data and 4,170 also had chest compression depth data available, constituting the final study population. Mean age was 68. Mean chest compression rate was 106 compressions/min. The unadjusted cubic spline curves (Figs. 1 & 2) showed peak survival for the sham and active ITD groups occurred at chest compression rates of 118 and 101 compressions/minute, respectively (P=0.47) (Fig. 1). Peak survival with mRS ≤3 occurred at 118 and 99 compressions/minute for the sham and active ITD groups, respectively (P=0.58) (Fig. 2). After adjustment for sex, age, bystander CPR, arrest location, ROC site, first EMS rhythm, witnessed status, and quality of CPR (chest compression fraction and depth), the interaction between rate and ITD for survival with mRS ≤3 was statistically significant (P=0.036), but not for all survival irrespective of mRS score (P=0.093). Conclusion: In the adjusted model, we observed a significant chest compression rate-dependent interaction with active ITD use for survival with mRS ≤3. Optimal CPR rates were different with standard CPR and a sham versus active ITD. This research has received full or partial funding support from the American Heart Association.
Author Disclosures: A.H. Idris: Consultant/Advisory Board; Modest; Philips Healthcare unpaid volunteer, American Heart Association volunteer. Research Grant; Significant; NIH-NHLBI. D. Guffey: None. P.E. Pepe: None. S.P. Brown: None. T.P. Aufderheide: Employment; Significant; NIH-NHLBI. Consultant/Advisory Board; Modest; Medtronic, Inc., American Heart Association (volunteer), Citizen CPR Foundation (volunteer). S.C. Brooks: None. C.W. Callaway: Research Grant; Significant; NIH-NHLBI. J. Christenson: Research Grant; Significant; NHLBI/CIHR. D.P. Davis: Research Grant; Significant; NIH-NHLBI. M.R. Daya: Research Grant; Significant; NIH-NHLBI. Consultant/Advisory Board; Modest; Philips Medical Systems (volunteer). R. Gray: None. P.J. Kudenchuk: Research Grant; Significant; NIH-NHLBI. J. Larsen: None. S. Lin: None. J.J. Menegazzi: None. K. Sheehan: None. G. Sopko: None. I.G. Stiell: Research Grant; Significant; NHLBI/CIHR. G. Nichol: Research Grant; Significant; NIH-NHLBI. Consultant/Advisory Board; Modest; American Heart Association Volunteer.
Key Words: Cardiac arrest, Cardiopulmonary resuscitation, Emergency care
Delayed Time to Epinephrine and Survival Following In-Hospital Cardiac Arrest
Michael W. Donino1, Justin D. Salciccioli1, Michael D. Howell1, Michael N. Cocchi1, Brandon Giberson1, Katherine Berg1, Shiva Gautam1, Clifton Callaway2 1Beth Israel Deaconess Med Cntr, Boston, MA, 2Univ of Pittsburgh, Pittsburgh, PA
Objective: The objective of this study was to evaluate whether delayed time to epinephrine was associated with worse outcome for in-hospital cardiac arrest patients with non-shockable rhythms. Background: Approximately 200,000 patients suffer cardiac arrest each year in hospitals throughout the United States, with survival rates of 7–26%. Aside from basic cardiopulmonary resuscitation, there is no intervention with proven benefit for patients with non-shockable cardiac arrest rhythms (pulseless electrical activity and asystole). Methods: We queried the Get With the Guidelines-Resuscitation database for adults suffering cardiac arrest with non-shockable rhythms. The primary outcome was survival to hospital discharge. Multivariable logistic regression was used to assess the relationship between time to epinephrine administration and outcomes, adjusting for age, sex, arrest characteristics, hospital characteristics and comorbidities. Secondary outcomes included return of spontaneous circulation, 24-hour survival, and survival with favorable neurologic status. Results: We identified 29,470 adults with in-hospital cardiac arrest with non-shockable rhythms. Median time to administration of the first dose of epinephrine was 3 minutes (IQR: 1–5). Analyzing time by 3-minute intervals, there was a stepwise decrease in survival with increasing interval of time to epinephrine (minutes 1–3 odds ratio, 1.0 [reference group]; minutes 4–6 adjusted odds ratio, 0.91 [95% CI, 0.82–0.99; P=0.04]; minutes 7–9 adjusted odds ratio, 0.76 [95% CI, 0.65–0.89, P<0.001]; and ≥10 minutes adjusted odds ratio, 0.65 [95% CI, 0.54–0.77; P<0.001]). The stepwise effect on outcomes was seen across all outcome variables. Conclusion: In hospitalized patients with non-shockable cardiac arrest, delay in epinephrine is associated with lower probability of return of spontaneous circulation, in-hospital survival, and neurologically-intact survival.
Author Disclosures: M.W. Donino: None. J.D. Salciccioli: None. M.D. Howell: None. M.N. Cocchi: None. B. Giberson: None. K. Berg: None. S. Gautam: None. C. Callaway: None.
Key Words: Cardiac arrest
Three-Year Survey of Telephone-Assisted Instruction of Cardiopulmonary Resuscitation (t-CPR) for Victims Presumed to Be in Cardiac Arrest
Hideo Inaba1, Tetsuo Maeda1, Taiki Nishi1, Yukihiro Wato2, Yoshikazu Goto3, Masaaki Hashimoto4 1Kanazawa Univ. Graduate Sch. Med, Kanazawa, Japan 2Kanazawa Med Univ, Uchinada, Japan 3Kanazawa Univ. Hosp, Kanazawa, Japan 4Noto General Hosp, Nanao, Japan
Backgrounds and Aims: The aim of this study is to analyze the factors affecting the dispatcher's detection of cardiac arrest and bystander's acceptance of the instruction after the initiation of a continuousquality improvement program for the t-CPR. Materials and Methods: All fire departments prospectively collected the basal data regarding their t-CPR during the period of Jan. 2009 to Dec. 2011. Simultaneously, Utstein-based cardiac arrest data were collected. The two data sets were combined and analyzed. Results: As shown in Figure, the t-CPR was attempted in 2,747 cases, of which postmortem changes were present and resuscitation was not attempted by EMTs in 508 cases (18%). Both unresponsiveness and abnormal respiration were confirmed by dispatchers only in 1,445 (65%) out of the 2,229 resuscitation-attempted cases. In the remaining cases, the dispatchers initiated the t-CPR after they obtained other information suggestive of cardiac arrest (specific locations, obvious conditions and acute onset). The t-CPR was accepted in 1,384 (76%) of the 2,229 cases. The presence of bystander CPR was attributed to the t-CPR in 491 (69%) of the 711 bystander-witnessed cases with bystander CPR. Multiple logistic regression analysis revealed that dispatch system, patient's age and sex, location-home, arrest witness, etiology of arrest, bystander's age, absence of helper, and call made away from the scene are independent factors related to the t-CPR attempt, and that dispatch system, patient's sex and location-home are independent factors related to the acceptance of t-CPR. Bystanders performed CPR in 126 cases that were not in cardiac arrest at EMT arrival. At present, no complications of CPR have been reported. Conclusions: Dispatchers should be aware of backgrounds and characteristics of cardiac arrests related to the detection of arrest. Systemic education for dispatchers and citizens to detect cardiac arrest is needed.
Author Disclosures: H. Inaba: None. T. Maeda: None. T. Nishi: None. Y. Wato: None. Y. Goto: None. M. Hashimoto: None.
Key Words: Cardiopulmonary resuscitation, Surveillance, Symptom management
An Analysis of Quality of Bystander-Performed Basic Life Support (BLS) In Out-of-Hospital Cardiac Arrests Managed With Public Use of Automated External Defibrillator (AED): A Six-Year Survey In Ishikawa Prefecture
Hideo Inaba1, Tetsuo Maeda1, Taiki Nishi1, Keiko Takase1, Junro Taniguchi2, Satoru Sakagami3, Masaaki Hashimoto4 1Kanazawa Univ. Graduate Sch. Med, Kanazawa, Japan 2Ishikawa Prefecture Central Hosp, Kanazawa, Japan 3Kanazawa Med Cntr, Kanazawa, Japan 4Noto General Hosp, Kanazawa, Japan
Backgrounds and Aims: An AED has been designed to be used by laypersons that ideally have been well trained for basic life support. This survey was aimed to study whether the BLS response and the CPR quality may differ between healthcare providers (HCPs) and others (non-HCPs) as an AED user. Methods: In the period of April, 2006 to March, 2012, an AED was attached to 191 cases of out-of-hospital cardiac arrest (OHCA) and 5 cases of impending cardiac arrest. The backgrounds, BLS responseand CPR quality were compared between HCP and non-HCP groups. Results: There was no case of home-AED use. HCPs used an AED mainly in care facilities (151/159) and other citizens used only in other public places (32/32). In 6 cases (4 in HCP and 2 in non-HCP group), AED was attached but CPR was not performed. Shock was less frequently delivered in HCP group than in non-HCP group (16/159 vs. 10/32, P=0.0037). In 12 out of 26 shock-delivered cases survived at one year. Among the time factors relating to BLS response, the initiation of CPR was significantly delayed in non-HCP group. In 35 cases (31 in HCP and 4 in non-HCP group), AED had been set on patients before making emergency call. Analysis of CPR quality in 92 ECG record-obtained cases revealed that rate of compressions delivered per minute was significantly lower, and no flow time per one-minute segment and proportion of BLS pause were significantly larger in non-HCP group. The interval of power-on to the first ECG analysis varied widely in both groups; median value (10–90%) was 41 (4–69) sec in HCP and 57 (5–166) sec in non-HCP group. Conclusions: Improper BLS responses were common in OHCAs managed with public use of AED. Some citizens may give a priority to application of AED among BLS actions. High-quality CPR was rarely conducted in OHCAs managed by non-HCPs. To minimize these unfavorable effects of public AED use on OHCAs without shockable rhythms, a periodical training for BLS would be necessary in both HCPs and non-HCPs.
Author Disclosures: H. Inaba: None. T. Maeda: None. T. Nishi: None. K. Takase: None. J. Taniguchi: None. S. Sakagami: None. M. Hashimoto: None.
Key Words: Cardiac arrest, Device, Resuscitation
Friend Or Foe? Epinephrine Does Not Impact Survival and May Worsen Neurological Outcomes in Out-of-Hospital Cardiac Arrest: A Multi-Step Meta-Analysis of Randomized Control Trials
Alexandre Benjo1, Shashi Kumar2, Christos Maniotis3, Klio Chantziara4, Wallacy Garcia5, Erdal Gursoy5, Walter Pierce5, Emad Aziz5, Eyal Herzog5 1St.Luke's-Roosevelt Hosp Cntr, New york, NY, 2St.Luke's-Roosevelt Hosp Cntr/Columbia College of Physicians, New York, NY, 3St.Luke's-Roosevelt Hosp Cntr/Columbia College of Physicians and Hellenic Red Cross Hosp, Athens, Greece, New York and Athens (Greece), NY, 4St.Luke's-Roosevelt Hosp Cntr/Columbia College of Physicians and Evengelismos Hosp, Athens, Greece, New York and Athens (Greece), NY, 5St.Luke's-Roosevelt Hosp Cntr/Columbia College of Physicians, New york, NY
Background: Advanced cardiac life support is a corner stone in the management of cardiac arrest and epinephrine is an important part of its armamentarium. Randomized controlled trials and observational studies have demonstrated inconsistent results regarding the benefits of epinephrine in out-of-hospital cardiac arrest. We conducted a meta-analysis to evaluate mortality and neurological outcomes. Methods: All randomized controlled trials regarding out of hospital cardiac resuscitation were sought using PubMed, and Scopus databases during July 2012. We calculated the chances of patients surviving to hospital admission and through discharge and as well as having a good neurological outcome. When possible, we also stratified the data by the type of arrest, VT/VF or PEA/Assystole. Data was independently extracted by 4 reviewers and analyzed with RevMan 5.1 software. Results: As shown in Figure 1, epinephrine is associated with a higher rate of hospital arrival but not survival to discharge (A and B). Holds true in both VT/VF and PEA/Asystole arrests (C, D, E and F). Epinephrine usage was associated to worse neurological outcomes trend when analyzing both the patients that arrived to hospital and those surviving to discharge (G and H). Conclusions: There is no optimal data to support the use of epinephrine in out-of-hospital cardiac arrest. The available data points to a probable worse neurological outcome in survivors. Larger randomized controlled trials are needed.
Author Disclosures: A. Benjo: None. S. Kumar: None. C. Maniotis: None. K. Chantziara: None. W. Garcia: None. E. Gursoy: None. W. Pierce: None. E. Aziz: None. E. Herzog: None.
Key Words: Cardiac arrest, Resuscitation, Brain
The Common Sodium Channel Promoter Haplotype in Thai Symptomatic Brugada Syndrome Patients
Pattarapong Makarawate1, Narumol Chaosuwannakit1, Suda Vannaprasaht1, Koo Seok Hwee2, Edmund Jon Deoon Lee2, Wichittra Tassaneeyakul1 1Khon Kaen Univ, Khon Kaen, Thailand 2National Univ of Singpore, Singapore, Singapore
Background: Brugada Syndrome (BrS) is endemic in Asia and loss of function mutations in SCN5A encoded sodium channels are one cause of BrS. SCN5A Haplotype B (HapB) is common in Asians and absent in Caucasians which can cause loss of sodium channel function resulting in slow conduction in cardiac myocytes. We sought to discover the common SCN5A promoter of polymorphism in Thai BrS patients. Methods and Results: We included 48 symptomatic (syncope and survival from cardiac arrest) BrS Thai male patients. The genomic DNA samples were isolated from peripheral leukocytes and used as the template to amplify the coding region of the SCN5A gene. The coding and promoter regions of the cluster genes associated with BrS were sequenced in the attempt to identify mutations associated with the disease. SCN5A missense mutations (1673A>G) were found in 22% of Thai symptomatic BrS patients. Moreover, SCN5A HapB mutations were found more common among these patients (49%) than those previously reported in healthy Asian populations (24%). Conclusion: These data demonstrated that SCN5A HapB is a common SCN5A promoter variant seen in Thai Symptomatic BrS patients.
Author Disclosures: P. Makarawate: None. N. Chaosuwannakit: None. S. Vannaprasaht: None. K. Seok Hwee: None. E. Deoon Lee: None. W. Tassaneeyakul: None.
Key Words: Gene mutations, Sodium channel, Sudden cardiac death
Novel, Color-Coded Prefilled Syringe Significantly Decreases Time to Medication Administration, Preparation for Endotracheal Intubation, And Eliminates Critical Dosing Errors in Simulated Pediatric Resuscitations
Maria E. Moreira1, Allen D. Stevens2, Caleb S. Hernandez3, Katherine A. Bakes4, Seth C. Jones5, Jason Blumen6, Margaret K. Sande1, Jason S. Haukoos1 1Denver Health Med Cntr, Dept of Emergency Medicine, Denver, CO, 2National Jewish Health-Dept of Medicine, Denver, CO, 3North Colorado Med Cntr-Dept of Emergency Medicine, Greely, CO, 4Denver Health Med Cntr, Dept of Pediatric Emergency Medicine, Denver, CO, 5Univ of Phoenix, Society for Simulation in Healthcare, Denver, CO, 6Denver Health Med Cntr, Paramedic Devision, Denver, CO
Background: Pediatric resuscitations are stressful and require calculation of medication doses. This may lead to delay or error in medication administration. The purpose of this study was to assess the effect of a novel multi-color, prefilled syringe coded to the Broselow Tape on time to medication administration and dosing errors. Methods: Randomized cross-over trial. 10 Emergency Room (ER) teams (physician, and nurse), and 10 Pre-Hospital (paramedic, 2 EMTs). Each team participated in 2 high-fidelity simulations of pediatric arrest. Intervention: Color-coded, prefilled syringes. Control: Manually prepared dosing. Teams were randomized to the intervention or control for the 1st scenario and used the opposite method for the 2nd scenario. Teams repeated scenarios with the opposite method after a 4–16 week washout. Data Collection: Outcomes were confirmed by blinded, independent review of video recordings. Outcomes: Elapsed time of each medication preparation to administration, critical dosing errors (defined as >10% deviation beyond doses for weights within the Broselow color range) and preparation time for endotracheal intubation. ER Results: Median time to delivery of all medications for intervention and control groups was 18.5 (15.5–22.5) and 46.5 (29.0–63.5) seconds, (difference = 26 sec, 95% [CI]: 20–32 sec, P<0.001). Median preparation time for intubation was 34.8 (29.0–41.0) and 94.5 (87.0–123.5) seconds, respectively (difference = 59.7 sec, P=0.0004). 125 and 119 doses were given for the intervention and control groups, respectively. There were 0 (0%) and 20 (17%) critical dosing errors (difference = 17%, 95% [CI]: 10%–25%, P<0.001). Pre-hospital Results: Median time to delivery of all doses for the intervention and control groups was 33.8 (27.0–40.5) and 42.3 (IQR: 34.0–53.5) seconds, respectively (difference = 9 sec, 95% [CI]: 4–15 seconds, P<0.001). 60 and 65 doses were administered. There were 0 (0%) and 24 (37%) critical dosing errors (difference = 37%, 95% [CI]: 25%–49%, P<0.001). Conclusions: A novel, color-coded prefilled syringe eliminated critical dosing errors and significantly decreased time to medication administration and preparation for endotracheal intubation in simulated pediatric resuscitations.
Author Disclosures: M.E. Moreira: None. A.D. Stevens: None. C.S. Hernandez: Ownership Interest; Significant; Patent holder. K.A. Bakes: None. S.C. Jones: None. J. Blumen: None. M.K. Sande: None. J.S. Haukoos: None.
Key Words: Cardiopulmonary resuscitation, Pediatric cardiac intensive care, Emergency care
Why Traditional Chest Compression Is Not Adequate For Most Lone-Rescuer CPR Situations, and Whether There Is A Method That Is
Fernando J. Perez1, Robert H. Trenkamp, Jr,2 1Georgia Emergency Associates, Savannah, GA, 2Saving Lives In Chatham County, Savannah, GA
The study objectives were to discover the incidence of solo-rescuer out of hospital sudden cardiac arrests (“OHCA”), to quantify probable ambulance response time, to determine the proportion of the United States population that is capable of performing manual chest compressions from the time of the arrest to the “hands on” arrival of the ambulance crew, and if the traditional manual chest compression technique were found wanting, to find at least one method of chest compression which the general bystander population is capable of performing for that period. Our findings were that approximately 300,000 OHCA's occur in the United States per year, that approximately 200,000 of these arrests occur in the home, and that the survival rate for OHCA's in the home is 2%, or one quarter of the national average. The 'solo rescuer' problem exists in homes where there are exactly two people. Such homes comprise 33.6% of all homes. The response time - measured from the time of the arrest to the time the arriving ambulance's crew is “hands-on” with the victim is estimated to typically range between 3.8 and 17.3 minutes, with a typical average of 9.5 minutes. A test cohort of 100 people was randomly selected into gender/age strata, specified to approximate the relevant at-risk distribution of the population 35 years and older. Each test subject was interviewed. Each subject was taught traditional compression-only CPR. It became apparent during the informal testing we conducted before beginning the study that it was unusual to see a test subject who could perform ILCOR 2010 compliant chest compressions (greater than or equal to 2 inches deep at a rate of 100 per minute or higher) for 3.8 minutes. Accordingly, we added a test of the subject's ability to provide adequate compressions using the shoeless heel of their foot, rather than their hands, to compress the chest. The majority of the test subjects were able to provide compliant chest compressions for more than ten minutes using the 'heel CPR' method. Our conclusions are that this alternative method of performing chest compressions is superior to the traditional (manual) method, and that the curricula for bystander CPR courses should be modified to teach this alternative method of chest compression.
Author Disclosures: F.J. Perez: None. R.H. Trenkamp: None.
Key Words: Cardiopulmonary resuscitation, Cardiac arrest
Reevaluating Epinephrine in Out-of-Hospital Cardiac Arrest: A Systematic Review and Meta-Analysis
Steve Lin1, Clifton W. Callaway2, Prakeshkumar S. Shah3, Justin D. Wagner4, Joseph Beyene5, Laurie J. Morrison1 1Rescu, Li Ka Shing Knowledge Institute, St. Michael's Hosp, Univ of Toronto, Toronto, Canada 2Dept of Emergency Medicine, Univ of Pittsburgh Sch of Medicine, Pittsburgh, PA, 3Dept of Pediatrics, Univ of Toronto, Toronto, Canada 4Dept of Biology, Univ of Western Ontario, London, Canada 5Population Genomics Program, Dept of Clinical Epidemiology and Biostatistics, McMaster Univ, Hamilton, Canada
Introduction: International resuscitation guidelines support the routine administration of epinephrine during out-of-hospital cardiac arrest (OHCA). However, the evidence is not clear for the efficacy of epinephrine in long and short-term survival.Objective: To evaluate the efficacy of epinephrine (all doses and combinations) in adult OHCA patients on long-term (survival to discharge) and short-term outcomes (survival to admission or return of spontaneous circulation (ROSC)). Methods: The search included MEDLINE, EMBASE, and the Cochrane Library up to March 1, 2012, and hand searches of bibliographies and electronic resources to identify eligible published and unpublished randomized controlled trials (RCTs). Eligible trials compared epinephrine to vasopressin or placebo in adult OHCA patients. Two independent reviewers conducted the hierarchical selection, abstracted data, and assessed quality. Disagreement was resolved by consensus. The Mantel-Haenszel random effects method was used to test for differences. A subgroup analysis was performed using stratification by location (prehospital or emergency department). Results: Fourteen RCTs (N=12,246) met inclusion criteria: 6 compared standard dose epinephrine (SDE) to ≥5 times higher dose epinephrine (HDE) (n=6174), 6 compared SDE to epinephrine vasopressin combination (n=5202), 1 compared SDE to vasopressin alone (n=336), and 1 compared SDE to placebo (n=534). There was no survival to discharge advantage. HDE showed improved survival to admission [RR 1.15 (95% CI: 1.00–1.32), P=0.05] and ROSC [RR 1.17 (95% CI: 1.03–1.34), P=0.02] over SDE. SDE showed improved survival to admission [RR 1.95 (95% CI: 1.34–2.84), P<0.001] and ROSC [RR 2.80 (95% CI: 1.78–4.41), P<0.001] over placebo in the single RCT. HDE and epinephrine vasopressin combination improved survival to admission when stratified by prehospital setting [RR 1.15 (95% CI: 1.00–1.32), P=0.05] and emergency department [RR 1.20 (95% CI: 1.04–1.38), P=0.01], respectively. Conclusions: There was no clear advantage of any vasopressor in long-term survival. Similar short-term benefit was seen with HDE over SDE and SDE over placebo, suggesting HDE should be a treatment option in current resuscitation guidelines.
Author Disclosures: S. Lin: None. C.W. Callaway: None. P.S. Shah: None. J.D. Wagner: None. J. Beyene: None. L.J. Morrison: None.
Key Words: Cardiac arrest, Drugs
- © 2012 American Heart Association, Inc.