Late-Breaking Clinical Trial and Clinical Science Special Reports Abstracts From the American Heart Association’s Scientific Sessions 2016; Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2016
This article has a correction. Please see:
2016 Late-Breaking Clinical Trial Abstracts
Late-Breaking Clinical Trial and Clinical Science Special Reports Abstracts From the American Heart Association’s Scientific Sessions 2016; Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2016
Big Trials for Big Questions
21170 Effects of Ticagrelor Compared With Clopidogrel in Patients With Peripheral Artery Disease (EUCLID)
Manesh R Patel1, F. Gerry R Fowkes2, Jeffrey S Berger3, Lars Norgren4, Gretchen Heizer5, Iris Baumgartner6, Kenneth W Mahaffey7, Brian G Katona8, Peter Held9, Juuso Blomster9, W. Schuyler Jones1, Craig Reist10, Marcus Millegard9, William R Hiatt11; 1Dept of Medicine, Div of Cardiology, Duke Clinical Rsch Institute, Duke Univ Med Cntr, Durham, NC, 2Cntr for Population Health Sciences, Univ of Edinburgh, Edinburgh, United Kingdom, 3Divs of Cardiology and Vascular Sugery, Depts of Medicine and Surgery, New York Univ Sch of Medicine, New York, NY, 4Faculty of Medicine and Health, Orebro Univ, Orebro, Sweden, 5Dept of Biostatistics, Duke Clinical Rsch Institute, Duke Univ Med Cntr, Durham, NC, 6Swiss Cardiovascular Cntr, Div of Angiology, Bern Univ Hosp, Bern, Switzerland, 7Dept of Medicine, Stanford Cntr for Clinical Rsch, Stanford Univ, Stanford, CA, 8Global Medicines Development, AstraZeneca, Gaithersburg, MD, 9Rsch and Development, AstraZeneca, Molndal, Sweden, 10Global Megatrials, Duke Clinical Rsch Institute, Duke Univ Med Cntr, Durham, NC, 11Div of Cardiology, Univ of Colorado Sch of Medicine and CPC Clinical Rsch, Aurora, CO.
Background: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis with a worldwide prevalence. The optimal antithrombotic management of patients with symptomatic but stable PAD is not known. Clopidogrel reduced cardiovascular events compared with ASA in a subgroup of PAD patients in the CAPRIE trial. The EUCLID trial (NCT01732822) was designed to test if long-term monotherapy treatment with ticagrelor would be superior to clopidogrel at preventing cardiovascular death, myocardial infarction, or ischemic stroke in patients with symptomatic PAD. Methods: EUCLID is a randomized, double-blind, double-dummy, event-driven trial performed in 28 countries and 821 sites. Investigators randomized patients to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients with symptomatic PAD were eligible based on an abnormal ankle-brachial index (ABI) ≤ 0.80 or a prior (>30 days) lower extremity revascularization for symptomatic PAD. Patients determined as poor metabolizers of clopidogrel (homozygous for 2C19 mutation) were excluded. All cardiovascular and acute limb ischemia events (included as a secondary endpoint) were adjudicated in a blinded fashion. The trial had 85% power to detect a hazard ratio of 0.85, which required accumulation of at least 1,364 primary events. Results: The trial randomized 13,885 patients with a mean age of 66 years, 72% were men, 57% were randomized based on a prior revascularization and 43% based on an abnormal ABI. In randomized patients, 12% had a prior history of stroke or TIA, 18% a prior myocardial infarction, and 23% a prior coronary revascularization. Primary and key secondary results will be available in October 2016. Conclusion: EUCLID represents the largest randomized outcome trial in patients with symptomatic PAD. The primary results of EUCLID will be available at the time of presentation.
Author Disclosures: M.R. Patel: Research Grant; Modest; Procyrion. Consultant/Advisory Board; Modest; AstraZeneca, Bayer, Jansen, Genzyme. Research Grant; Significant; AstraZeneca, Jansen, Bayer, NHLBI. F.R. Fowkes: Consultant/Advisory Board; Modest; AstraZeneca, Merck, Bayer. J.S. Berger: Research Grant; Significant; National Institutes of Health, American Heart Association, AstraZeneca, Janssen, Merck. Consultant/Advisory Board; Modest; Takeda. L. Norgren: Consultant/Advisory Board; Modest; AnGes, AstraZeneca, Bayer, Mitsubishi Takeda, Novartis, Pluristem. G. Heizer: None. I. Baumgartner: None. K.W. Mahaffey: Research Grant; Significant; Amgen, Daiichi, Johnson & Johnson, Medtronic, Merck, St. Jude, Tenax. Consultant/Advisory Board; Modest; AC, BAROnova, Bayer, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Elsevier, Epson, Forest, Johnson & Johnson, Medtronic, Mt. Sinai, Myokardia, Omthera, Portola, Purdue Pharma, Springer Publishing, Theravance, Vindico, WebMD. Consultant/Advisory Board; Significant; AstraZeneca, Cubist, GlaxoSmithKline, Merck, The Medicines Company. Other; Significant; BioPrint Fitness. B.G. Katona: Employment; Significant; AstraZeneca. P. Held: Employment; Significant; AstraZeneca. J. Blomster: Employment; Significant; AstraZeneca. W. Jones: None. C. Reist: None. M. Millegard: Employment; Significant; AstraZeneca. W.R. Hiatt: Research Grant; Significant; National Institutes of Health, AstraZeneca, Bayer, Pluristem, ReNeuron.
14436 Cardiovascular Outcomes With Celecoxib vs. Ibuprofen or Naproxen: The Precision Trial
Steven E Nissen, Precision Clinical Trial Executive Committee; Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH.
Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are amongst the most commonly used treatments in the world. Concerns arose regarding the cardiovascular (CV) safety of cyclooxygenase type 2 (COX-2) selective inhibitors as a result of withdrawal of rofecoxib in 2004. As consequence, the US Food and Drug Administration required a postmarketing CV safety trial comparing the only remaining COX-2 selective inhibitor, celecoxib, with traditional non-selective NSAIDs. Methods: The Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (PRECISION) Trial was a double-blind, triple-dummy, randomized, multicenter non-inferiority study, using a 3-arm parallel group design. Male and female subjects with a clinical diagnosis of osteoarthritis or rheumatoid arthritis with established CV disease or high risk for CV disease who required daily NSAIDs chronically were randomized to celecoxib 100–200 mg twice daily, ibuprofen 600–800 mg three times daily or naproxen 375–500 mg twice daily. Administration of aspirin 75–100 mg daily was allowed according to local guidelines. Patients were provided with daily esomeprazole (20 mg to 40 mg) for gastroprotection. The primary endpoint was the composite of CV death, nonfatal myocardial infarction or nonfatal stroke. The design required meeting 4 criteria to establish non-inferiority, a hazard ratio (HR) of ≤1.12 and a 97.5% upper confidence interval (CI) <1.33 for the intent-to-treat population, and a HR ≤1.12 with an upper CI ≤ 1.40 for the on-treatment population. Although CV safety was the primary objective, clinically significant gastrointestinal events were adjudicated along with additional safety assessments including renal events. Measures of arthritis status and disability were also collected. Results: The study randomized 24,081 patients at 924 sites in 13 countries. Mean age was 63±9.4 years, 74.3% were white, and 64.1% were female. Aspirin was administered at baseline to 51.1% of patients. The primary diagnosis was rheumatoid arthritis in 10.1% of patients and 89.9% had osteoarthritis. Conclusions: The PRECISION Trial is a very large global CV safety study comparing selective and non-selective NSAIDs. Results will be available in mid-September 2016.
Author Disclosures: S.E. Nissen: Research Grant; Significant; Pfizer.
21212 The Effect of Blood Pressure and Cholesterol Lowering on Cognition
Jackie Bosch, HOPE-3 Investigators; Population Health Rsch Institute, McMaster Univ, Hamilton, Canada.
Background: Cognitive impairment and dementia are major contributors to disability and no strategy has been shown to reliably prevent it. While vascular risk factors have been related to cognitive impairment, the role of statin therapy and blood pressure in preventing cognitive decline in individuals without vascular disease is unknown. In the Heart Outcomes Prevention Evaluation-3 (HOPE-3), which studied the effects of blood pressure lowering and lipid lowering medications to prevent major cardiovascular outcomes, we evaluated the effects of these interventions on changes in cognitive function in those over 70 years. Methods: The HOPE-3 study randomized moderate risk individuals from 228 centres in 21 countries, to receive either candesartan /hydrochlorothiazide or placebo and rosuvastatin or placebo. Cognitive data were collected at baseline and study end in those over 70 years old. Participants completed the Digit Symbol Substitution Test (DSST) (primary outcome for cognitive substudy), the 11-item Montreal Cognitive Assessment (MoCA), and the Trail Making Test - Part B (TMT-B). Data were also collected on functional status at study start and end (EQ5-D and the Standard Assessment of Global activities in the Elderly, SAGE). Results were analysed using data for those who completed questionnaires at both visits with sensitivity analysis that included imputation. Results: 3,086 men and women 70 years or older were recruited and studied for an average of 5.7 years. The mean age was 74 years and 59% were women. The mean baseline blood pressure was 129/74 mmHg. Study results will be presented. Conclusion: This study will provide information on the impact of blood pressure lowering, lipid lowering and their combination on cognitive and functional changes after 5.6 years of intervention.
Author Disclosures: J. Bosch: None.
23867 Short- and Long-Term Effect of Immediate Vasodilator Therapy in Acutely Decompensated Heart Failure: Results of the True-AHF Trial
Milton Packer, on behalf of the TRUE-AHF Executive Committee & Investigators; Baylor Heart and Vascular Institute, Baylor Univ Med Cntr, Dallas, TX.
Ularitide produces systemic vasodilation and natriuresis, and inhibits the renin-angiotensin system in heart failure (HF). Favorable effects on cardiac filling pressures, symptoms and mortality in phase II trials led to the hypothesis that ularitide (15 ng/kg/min IV given very early following admission for acute HF) could improve both the early clinical course of patients and decrease the risk of cardiovascular death. The TRUE-AHF study is the first randomized, double-blind, parallel-group, placebo-controlled, event-driven trial in acute HF to evaluate the long-term effect of IV treatment on mortality. Patients were men or women, aged 18–85 years and had (1) unplanned hospitalization or emergency department visit for acute HF; (2) dyspnea at rest, which worsened within the past week and persisted despite ≥40 mg of IV furosemide (or equivalent); (3) evidence of HF on chest X-ray; (4) B-type natriuretic peptide >500 pg/mL or N-terminal-pro B-type natriuretic peptide >2000 pg/mL; (5) systolic blood pressure ≥116 and ≤180 mmHg at randomization; and (7) ability to start infusion within 12 hours after initial assessment. A total of 2157 patients were randomized (1:1) in a double-blind manner to a continuous IV infusion of ularitide 15 ng/kg/min or placebo for 48 hours, to be adjusted if the patient developed hypotension. The median time from clinical presentation until the start of the infusion was 6 hours. The trial has two primary endpoints: (1) the clinical course of patients during the first 48 hours, as assessed by a hierarchical clinical composite endpoint (improved, in-hospital worsening or unchanged); and (2) the risk of cardiovascular death over the entire duration of the trial (median follow-up: 27 months). The trial has reached the target number of cardiovascular deaths, and is in the final phase of closeout. The results of this landmark trial is likely to change how we think about the pathophysiology and treatment of acute heart failure.
Author Disclosures: M. Packer: Consultant/Advisory Board; Significant; Cardiorentis, Novartis.
Intervention and Surgery
Pioneering the Future of Heart Interventions
21193 Randomized Comparison of Single Versus Bilateral Internal Mammary Artery Grafting in 3102 Patients: Effects on Major Cardiovascular Outcomes After Five Years Follow Up
David P Taggart1, Douglas Altman2, Stephen Gerry2, Alastair Gray3, Umberto Benedetto4, Belinda Lees1, Marcus D Flather5, Arterial Revascularisation Trial (ART) Investigators; 1Nuffield Dept of Surgery, Univ of Oxford, Oxford, United Kingdom, 2Cntr for Statistics in Medicine, Univ of Oxford, Oxford, United Kingdom, 3Health Economics Rsch Group, Univ of Oxford, Oxford, United Kingdom, 4Deaprtment of Cardiac Surgery, Univ of Bristol, Bristol, United Kingdom, 5Norwich Med Sch, Univ of East Anglia, Norwich, United Kingdom.
Introduction: In patients with multivessel coronary artery disease, surgical revascularization using a single internal mammary artery (SIMA) plus vein grafts has been shown to provide effective long term health improvements. There is growing evidence from observational studies that the use of a bilateral internal mammary artery (BIMA) approach may further improve long term outcomes. However, due to lack of firm evidence, the BIMA strategy remains underutilized. Methods: The Arterial Revascularisation Trial (ART) randomized patients scheduled for coronary artery bypass grafting on clinical criteria to SIMA (1554) or BIMA (1448) in 28 cardiac surgical centres in 7 countries. The primary outcome was death from any cause. Secondary outcomes included the composite of death, MI, stroke, and additional safety outcomes. Results: Mean age was 64 years, 24% women, 15% current smokers, 24% diabetes, 42% prior MI, 8% non-Caucasian and 65% NYHA II and III. Forty one percent of procedures were performed off pump with no imbalance between the two groups and 81% received 3 or more grafts. At 5 years follow up the death rate in the SIMA group was 8.4% compared to 8.7% in BIMA (HR 1.04 95%CI 0.82–1.33; p=0.7) and for the composite of death, MI, Stroke 12.7% versus 12.2% (HR 0.97 95%CI 0.79–1.18 - see Figure). Adjustment for age, gender and diabetes yielded essentially the same results. Major bleeds were documented in 2.6% SIMA and 3.1% BIMA (p=0.4), need for repeat revascularization 6.6% and 6.5% (p=0.9), sternal wound infection 1.9% and 3.5% (p=0.005) and reconstruction 0.6% and 1.9% (p=0.002) respectively. Conclusions: At five years follow-up BIMA surgery provides similar clinical outcomes to SIMA with some early excess of sternal wound complications. Follow up to ten years is ongoing to determine if BIMA provides longer term benefits as vein graft failure becomes more common after 5 years.
Author Disclosures: D.P. Taggart: None. D. Altman: None. S. Gerry: None. A. Gray: None. U. Benedetto: None. B. Lees: None. M.D. Flather: None.
21209 The FUnctional Testing Underlying Coronary Revascularization (FUTURE) Study: A “Real World” Comparison of Fractional Flow Reserve-guided Management versus Conventional Management in Multi Vessel Coronary Artery Disease Patients
Gilles Rioufol1, Nathan Mewton2, Muriel Rabilloud3, Bernadette Vaz4, Francois Roubille5, Thibault Perret6, Pascal Motreff7, Michel Ovize 8, Gérard Finet9, on behalf of the FUTURE Trial Investigators; 1Interventional Cardiology dpt, Hospices Civils de Lyon, Lyon, France, 2Cntr for Clinical Investigations dpt, Hospices Civils de lyon, Lyon, France, 3Biostatistic dpt, Hospices Civils de lyon, Lyon, France, 4Cntr for Clinical Investigations dpt, Hospices Civils de Lyon, Lyon, France, 5Cardiology dpt, CHRU Montpellier, Montpellier, France, 6Cardiology dpt, Cntr Hospier Saint Joseph et Saint Luc, Lyon, France, 7Cardiology dpt, CHU Gabriel-Montpied, Clermont Ferrand, France, 8centre for Clinical Investigations dpt, Hospices Civils de Lyon, Lyon, France, 9Cardiology dpt, Hospices Civils de Lyon, Lyon, France.
Background: Fractional flow-reserve (FFR)-guided revascularization by percutaneous coronary intervention (PCI) in selected patients has been shown to improve clinical outcomes in comparison to medical therapy alone or conventional PCI without FFR. There is however no hard evidence assessing the use of FFR in a “real-world” setting for therapeutic management of multivessel coronary artery disease patients. Trial design The objective of this investigator-initiated, multicenter, open, randomized clinical trial was to investigate whether FFR-guided therapeutic management including medical treatment only, PCI or coronary artery bypass graft (CABG) surgery is superior to conventional management in patients with multivessel disease. Eligible patients had ≥50% coronary stenosis in two or more major epicardial vessels including the left anterior descending (LAD) coronary artery. Acute coronary syndrome and stable coronary artery disease consecutive patients were randomized in a 1:1 fashion to either FFR-guided management or traditional management. In the traditional group, treatment strategy was decided based on the angiogram (with or without any preceding non invasive ischemia testing) excluding FFR. Patients assigned to FFR-guided management had FFR measured in each ≥50% coronary stenosis vessel and strategy was built only when FFR was ≤0.80. The primary end point was a composite of major adverse cardiovascular events, including all-cause death, non-fatal myocardial infarction (MI), stroke and repeat coronary revascularization at one year. Results: The trial was scheduled to include 1728 patients over 39 centers in France. On May 12th, the study independent data safety monitoring board recommended to stop study enrollment due to a significant greater mortality in the FFR-group. 941 patients (age: 65±10 years, 83% males, 56±11% of LVEF, 21% stable angina/ 46% ACS setting / 33% other clinical presentation) were included at this time. Presentation of the complete interim analysis will be ready in October 2016. Conclusion: The FUTURE study compares in a multicenter, controlled, randomized fashion FFR-guided therapeutic management to conventional therapeutic management in patients with multivessel coronary artery disease.
Author Disclosures: G. Rioufol: Other Research Support; Significant; Saint Jude medical, Vocano. Honoraria; Modest; saint Jude medical, Astra Zeneca. Consultant/Advisory Board; Modest; Saint jude medical, Boston Scientific. N. Mewton: None. M. Rabilloud: None. B. Vaz: None. F. Roubille: None. T. Perret: None. P. Motreff: None. M. Ovize: None. G. Finet: None.
21183 An Open-label, Randomized, Controlled, Multicenter Study ExplorIng Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention PIONEER AF-PCI
C Michael Gibson1, Roxana Mehran2, Christoph Bode3, Johnathan Halperin2, Freek W Verheugt4, Peter Wildgoose5, Martin van Eickels6, Gregory Y Lip7, Marc Cohen8, Steen Husted9, Eric Peterson10, Keith Fox11;1Medicine, Beth Israel Deaconess Med Cntr, Boston, MA, 2Cardiology, Mount Sinai Med Cntr, New York, NY, 3Heart Cntr, Cardiology and Angiology I, Univ of Freiburg, Freiburg, Germany, 4Medicine, Radboud Univ Med Cntr, Nijmegen, Netherlands, 5Janssen Scientific Affairs, LLC, Jansen Pharmaceuticals, Inc., Raritan, NJ, 6Janssen Scientific Affairs, LLC, Bayer Pharmaceuticals, Inc., Raritan, NJ, 7Medicine, Univ of Birmingham Cntr for Cardiovascular Sciences, Birmingham, United Kingdom, 8Cardiology, Newark Beth Israel Med Cntr, Newark, NJ, 9Medicine, Aarhus Univ Hosp, Herning, Denmark, 10Medicine, Duke Clinical Rsch Institute, Durham, NC, 11Cntr for Cardiovascular Science, Univ of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
Introduction: Patients with atrial fibrillation (AF) who undergo PCI are often treated with triple therapy using an oral anticoagulant plus DAPT, but the optimal combination and duration of therapy remain uncertain. Also, prior randomized studies suggested that a dual-pathway therapeutic approach using a factor Xa inhibitor and a single antiplatelet agent may be superior. Hypothesis: Among non-valvular AF patients who undergo PCI with stent placement, rivaroxaban plus either a thienopyridine or DAPT is not associated with an increase in bleeding rates as compared with standard of care triple therapy including a VKA. Methods: PIONEER AF-PCI is an exploratory, randomized, open-label 12-month fixed duration trial that enrolled patients with paroxysmal, persistent, or permanent non-valvular AF undergoing PCI with stent placement (n=2,124). Patients were randomized in a 1:1:1 ratio to receive either rivaroxaban 15 mg qd plus a thienopyridine for 12 months, rivaroxaban 2.5 mg bid (with stratification to a pre-specified duration of DAPT of 1, 6, or 12 months) or dose-adjusted VKA qd (with stratification to a pre-specified duration of DAPT of 1, 6, or 12 months). Results: The primary safety endpoint will be the percentage of clinically significant bleeding through 12 months (composite of TIMI major bleeding, TIMI minor bleeding, or bleeding requiring medical attention) from the first dose until 2 days of drug discontinuation. Major secondary endpoints will be the components of the primary safety endpoint. Adverse cardiovascular events, including the composite of CV death, MI, or stroke, as well as the components of the composite endpoint and stent thrombosis, will also be evaluated. Time-to-first event analysis using Cox proportional hazards models through 12 months will compare the hazard ratios of the primary safety endpoint, TIMI major bleeding, and adverse cardiovascular events between the rivaroxaban groups against the VKA group. Conclusion: PIONEER AF-PCI will test the hypothesis that among AF patients undergoing PCI, rivaroxaban with either a thienopyridine or DAPT is not associated with an increase in clinically significant bleeding as compared with standard of care triple therapy including a VKA. (ClinicalTrials.gov: NCT01830543).
Author Disclosures: C. Gibson: Research Grant; Significant; Angel Medical Corporation, Bayer Corp., CSL Behring, Ikaria, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, Portola Pharmaceuticals, Stealth Peptides, Inc., St. Jude Medical. Other Research Support; Modest; The Medicines Company. Consultant/Advisory Board; Modest; Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly and Company, Gilead Sciences, Inc., The Medicines Company, Novo Nordisk, Pfizer, St. Jude Medical, Web MD. R. Mehran: Research Grant; Significant; Medicines Company, Eli Lilly/DSI, Bristol Myers Squibb, AstraZeneca, OrbusNeich, Bayer, CSL Behring. Consultant/Advisory Board; Significant; Janssen Pharmaceuticals, Osprey Medical, Watermark Research Partners, Medscape, Abbott Laboratories. C. Bode: None. J. Halperin: None. F.W. Verheugt: None. P. Wildgoose: Employment; Significant; Janssen. M. van Eickels: Employment; Modest; Bayer HealthCare Pharmaceuticals. G.Y. Lip: None. M. Cohen: Other Research Support; Significant; sanofi. S. Husted: None. E. Peterson: Research Grant; Significant; Janssen Pharmaceutical Products. Consultant/Advisory Board; Modest; Janssen Pharmaceutical Products, Regeneron Pharmaceuticals Inc, Sanofi-Aventis. Consultant/Advisory Board; Significant; AstraZeneca, Bayer Corporation US, Boehringer Ingelheim, Merck & Co, Valeant. K. Fox: Research Grant; Modest; Lilly, Bayer, Johnson-Johnson, AstraZeneca. Speakers Bureau; Modest; Bayer, Johnson-Johnson, AstraZeneca, Sanofi-Aventis. Consultant/Advisory Board; Modest; Lilly, Bayer, Johnson-Johnson, AstraZeneca, Sanofi-Aventis, Boehringer Ingelheim, Eli Lilly.
Insights from New Therapeutic Trials for Lipids
21224 Inhibition of PCSK9 Synthesis via RNA Interference: 90 Day Data From Orion-1-a Multi-Centre Phase-2 Randomized Controlled Trial
Kausik K Ray1, Ulf Landmesser2, Lawrence A Leiter3, David Kallend4, Peter Wijngaard5, Robert Dufour6, Timothy Hall7, Mahir Karakas8, Traci Turner9, Frank L Visseren10, R S Wright11, John J Kastelein12; 1Primary Care and Public Health, Imperial College London, London, United Kingdom, 2Dept of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany, 3Medicine, Univ of Toronto, Toronto, Canada, 4Cardiovascular Innovation Group, The Medicines Company (Schweiz) GmbH, Zurich, Switzerland, 5Global Innovation Group, The Medicines Company (Schweiz) GmbH, Zurich, Switzerland, 6Medicine, Cardiovascular Prevention Clinic, Institut de recherches cliniques de Montréal, Montreal, Canada, 7Knowle House Surgery, Knowle House Surgery, Plymouth, United Kingdom, 8General and Interventional Cardiology, Univ Heart Cntr Hamburg, Hamburg, Germany, 9Metabolic and Atherosclerosis Rsch Cntr – Medpace, Metabolic and Atherosclerosis Rsch Cntr – Medpace, Cincinnati, OH, 10Dept of Vascular Medicine, Univ Med Cntr Utrecht, Utrecht, Netherlands, 11Dept of Cardiology, Mayo Clinic, Rochester, MN, 12Dept. of Vascular Medicine, Academic Med Cntr / Univ of Amsterdam, Amsterdam, Netherlands.
Background: Current therapies targeting PCSK9 use expensive monoclonal antibodies every 2–4 weeks. In contrast RNA interference using a synthetic double stranded oligonucleotide (PCSK9si) is a less expensive alternative, with the potential for sustained suppression of hepatic PCSK9 production with fewer injections. Methods: ORION-1 is a Phase 2 double blind randomized controlled trial comparing 6 different SC dosing regimens of PCSK9si to SC placebo (enrolment plan Table). Eligible patients aged ≥18y with atherosclerotic cardiovascular disease (ASCVD) or high ASCVD risk and in whom, LDL-C was >70mg/dl or 100mg/dl respectively, despite maximally tolerated statin therapy were enrolled. Results: In total 501 patients were randomized: mean age 63y, 65.1% male, 48.3% had ASCVD, 24% had diabetes, 27.7% were primary prevention and the rest had FH. At baseline 81% were on statins and 28.1% were on ezetimibe (baseline LDL-C 128mg/dl). This interim analysis reports the percentage change in LDL-C at 90 days for each treatment arm vs placebo. The principal endpoint being percentage change in LDL-C at day 180. PCSK9 reduction is a secondary endpoint. The time course (including other lipid parameters) of the entire study population following a single dose through to 90 days will be reported. Safety data will be reported through to 90 days in all subjects. In addition data for LDL-C, PCSK9 and other lipid parameter changes at 6 months will be reported on approximately 200 patients, including safety data. Interpretation: ORION-1 will provide long term information on the safety and efficacy of using RNA interference to target intracellular PCSK9 production as a means to lower LDL-C in a large patient cohort. These data will inform us about the potential clinical utility of PCSK9si when administered quarterly or bi-annually to provide sustained reductions in LDL-C. If safe and effective, PCSK9si will be assessed in Phase 3 cardiovascular lipid-lowering and outcomes studies.
Author Disclosures: K.K. Ray: Research Grant; Significant; Sanofi, Regeneron, Pfizer, MSD. Honoraria; Modest; Takeda, Boehringer Ingelheim, Cipla, Algorithm, Kowa, Sanofi, Amgen, Pfizer, AZ, Abbvie. Consultant/Advisory Board; Modest; Sanofi, Regeneron, Amgen, Medicines Company, AZ, Cerenis, Ionis, Abbvie, Resverlogix. U. Landmesser: Honoraria; Modest; Amgen, Pfizer, Sanofi, Medicines Company, MSD. Consultant/Advisory Board; Modest; Amgen, Pfizer, Sanofi, Medicines Company, MSD. L.A. Leiter: Research Grant; Significant; Amgen, Medicines Company, Merck, Pfizer, Sanofi/ Regeneron. Honoraria; Modest; Amgen, Sanofi, Regeneron. Honoraria; Significant; Merck. Consultant/Advisory Board; Modest; Aegerion, Amgen, Merck, Sanofi, Regeneron. D. Kallend: Employment; Significant; Medicines Company. P. Wijngaard: Employment; Significant; Medicines Company. R. Dufour: Research Grant; Significant; Amgen, Sanofi, Pfizer, Medicines Company, Ionis. Speakers Bureau; Modest; Amgen, Sanofi, Valeant. Consultant/Advisory Board; Modest; Amgen, Sanofi, Janssen, Aegerion. T. Hall: None. M. Karakas: Honoraria; Modest; Amgen, Sanofi. Consultant/Advisory Board; Modest; Amgen, Sanofi. T. Turner: None. F.L. Visseren: None. R.S. Wright: Consultant/Advisory Board; Modest; Sanofi, Regeneron, Pfizer, Medicines Company, Boehringer Ingelheim, Astra Zeneca. J.J. Kastelein: Consultant/Advisory Board; Modest; Sanofi, Amgen, Pfizer, Eli Lilly, The Medicines Company, Regeneron.
14387 Effect of Evolocumab on Progression of Coronary Atherosclerosis in Statin-Treated Patients: A Placebo-Controlled Intravascular Ultrasound Trial
Steven E Nissen1, Stephen J Nicholls2, Glagov Clinical Trial Executive Committee; 1Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 2Cardiovascular Medicine, South Australian Health & Med Rsch Institute, Adelaide, Australia.
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors markedly reduce levels of low-density lipoprotein cholesterol (LDL-C), but the effect of these drugs on the progression or regression of coronary atherosclerosis remains unknown. Methods: The GLobal Assessment of plaque reGression with a PCSK9 antibOdy as measured by intraVascular ultrasound (GLAGOV) study is a Phase 3 double-blind, placebo-controlled trial that randomized 968 statin-treated patients with established coronary heart disease at 226 sites in 32 countries to the PCSK9 inhibitor, evolocumab, or placebo. Key inclusion criteria required an LDL-C ≥80mg/dL or ≥60mg/dL with additional high-risk characteristics. Key exclusion criteria included prior use of a PCSK9 inhibitor, uncontrolled hypertension, or triglyceride level >400 mg/dL. Patients underwent an intravascular ultrasound (IVUS) examination of a single coronary artery during a clinically-indicated angiogram at baseline. Patients were randomized in a 1:1 ratio to evolocumab 420 mg monthly or placebo for 78 weeks, followed by a repeat IVUS examination of the initially-studied vessel. The primary efficacy endpoint is the nominal change in percent atheroma volume (PAV) from baseline to 78 weeks post randomization measured by IVUS. Secondary efficacy endpoints include the nominal change in normalized total atheroma volume (TAV) from baseline to 78 weeks post randomization and the percentage of patients demonstrating regression. The trial is 90% powered to detect a 0.71 change in PAV, assuming a common standard deviation of 2.9. Results: The baseline characteristics of randomized patients includes a mean age of 59.8±9.2 years, 72% were male, 24.3% were current smokers, and 20.6% were diabetic. Mean LDL-C was 92.6±27.2 mg/dL, HDL-C was 46.0±12.8 mg/dl, and median high sensitivity C-reactive protein was 1.61 (interquartile range [IQR] 0.79–3.38) mg/L. Median lipoprotein (a) was 32 nmol/L (IQR 12, 152) Analysis of IVUS endpoints will be available during the first half of September, 2016. Conclusions: The GLAGOV study is the first intravascular outcome trial testing the effects of a PCSK9 inhibitor on the regression or progression of coronary atherosclerosis as measured by intravascular ultrasound.
Author Disclosures: S.E. Nissen: Research Grant; Significant; Amgen, Pfizer. S.J. Nicholls: Research Grant; Significant; Amgen.
21180 The Safety and Tolerability of CSL112, a Reconstituted, Infusible, Human APOA-I, After Acute Myocardial Infarction - The APOA-I Event Reduction in Ischemic Syndromes I (AEGIS-I) Trial
C. Michael Gibson1, Serge Korjian1, Pierluigi Tricoci2, Yazan Daaboul1, John H Alexander3, Philippe G Steg4, A. M Lincoff5, John J Kastelein6, Roxana Mehran7, Denise D'Andrea8, Bela Merkely9, Maciej Zarebinski10, Ton Oude Ophius11, Robert A Harrington12;1Cardiology, Beth Israel Deaconess Med Cntr, Boston, MA, 2Medicine, Duke Clinical Rsch Institute, Durham, NC, 3Medicine, Duke Univ Med Cntr, Durham, NC, 4Cardiology, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Paris, France, 5Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 6Vascular Medicine, Academic Med Cntr, Univ of Amsterdam, Amsterdam, Netherlands, 7Cardiology, Mount Sinai Med Cntr, New York, NY, 8CSL Behring, LLC, CSL Behring, LLC, King of Prussia, PA, 9Cardiology, Semmelweis Univ Heart Cntr, Budapest, Hungary, 10Cardiology, Warsaw Med Univ, Warsaw, Poland, 11Cardiology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands, 12Medicine, Stanford Univ, Stanford, CA.
Introduction: CSL112, an infusible formulation of human apoA-I, increases HDL-mediated cholesterol efflux and has been demonstrated to reduce the size of atherosclerotic lesions in animal and clinical studies. The safety profile of CSL112 is uncertain among patients with recent MI and either normal renal function or mild renal impairment. Hypothesis: Infusion of CSL112 is safe and does not significantly alter liver or kidney function among patients with recent MI and either normal renal function or mild renal impairment. Methods: AEGIS-I (Apo-I Event Reduction in Ischemic Syndromes-I) was a multicenter, placebo-controlled, dose-ranging, randomized phase 2b trial that evaluated the safety profile of CSL112 and characterized its pharmacokinetic/pharmacodynamic properties among patients with recent MI. Patients were enrolled up to 7 days following a spontaneous MI and were stratified by renal function. Patients were then randomized in a 1:1:1 ratio to either one of two doses of CSL112 (2g or 6g) or placebo infused weekly for 4 consecutive doses. All MACE endpoint events were adjudicated by a blinded, independent clinical events committee. Results: A total of 1,258 patients were randomized. The co-primary safety endpoints were the incidence of either hepatotoxicity (either ALT >3x upper limit of normal (ULN) or total bilirubin >2x ULN) or renal toxicity (either serum creatinine ≥1.5x the baseline value or new requirement for renal replacement therapy) through the end of the active treatment period (ie, study day 29). A major secondary endpoint was the time-to-first occurrence of MACE (composite of CV death, MI, ischemic stroke, or hospitalization for unstable angina) from the beginning of the first infusion until the last treated subject had completed study day 112. Measures of cholesterol efflux capacity, and apoA-I pharmacokinetics were evaluated. Results will be available at AHA 2016. Conclusion: AEGIS-I trial will evaluate the hepatic and renal safety of CSL112, an infusible formulation of human apoA-I, in patients with recent MI and either normal renal function or mild renal impairment.
Author Disclosures: C. Gibson: Research Grant; Significant; Angel Medical Corporation, Bayer Corp., CSL Behring, Ikaria, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, Portola Pharmaceuticals, Stealth Peptides, Inc., St. Jude Medical. Other Research Support; Modest; The Medicines Company. Consultant/Advisory Board; Modest; Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly and Company, Gilead Sciences, Inc., The Medicines Company, Novo Nordisk, Pfizer, St. Jude Medical, Web MD. S. Korjian: None. P. Tricoci: None. Y. Daaboul: None. J.H. Alexander: Research Grant; Significant; Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, National Institutes of Health, Regado Biosciences, Tenax Therapeutics, Vivus Pharmaceuticals, Sanofi. Consultant/Advisory Board; Modest; Portola Pharmaceuticals, Sohmalution, VA Cooperative Studies Program. Consultant/Advisory Board; Significant; Bristol-Myers Squibb. P.G. Steg: None. A.M. Lincoff: Consultant/Advisory Board; Modest; Eli Lilly and Company. J.J. Kastelein: Consultant/Advisory Board; Modest; Sanofi, Amgen, Pfizer, Eli Lilly, The Medicines Company, Regeneron. R. Mehran: Research Grant; Significant; Medicines Company, Eli Lilly/DSI, Bristol Myers Squibb, AstraZeneca, OrbusNeich, Bayer, CSL Behring. Consultant/Advisory Board; Significant; Janssen Pharmaceuticals, Osprey Medical, Watermark Research Partners, Medscape, Abbott Laboratories. D. D’Andrea: Employment; Significant; CSL Behring. B. Merkely: None. M. Zarebinski: None. T. Oude Ophius: None. R.A. Harrington: Research Grant; Modest; Portola Pharmaceuticals, CSL Behring, AstraZeneca, GlaxoSmithKline, Merck, Regado, The Medicines Company, Sanofi Aventis. Consultant/Advisory Board; Modest; Merck, The Medicines Company, Amgen, Gilead Sciences, MyoKardia, WebMD. Other; Modest; Scanadu, SignalPath, Element Science, Vida Health, Adverse Events.
21186 Ionis-Angptl3-lRx, an Antisense Inhibitor to Angiopoietin-like Protein 3 [Angptl3] Reduces Plasma Angptl3 and Lipids in Healthy Volunteers With Elevated Triglycerides
Teresa Brandt1, Li-jung Tai1, Joseph L Witztum2, Steven G Hughes1, Eunju Hurh3, Brad McEvoy4, Rosie Yu5, Andres Digenio6, Richard Lee7, Mark Graham8, Rosanne Crooke9, Sotirios Tsimikas1; 1Clinical development, Ionis Pharmaceuticals, Carlsbad, CA, 2endocrinology, UCSD, La jolla, CA, 3Preclinical Develompent, Ionis Pharmaceuticals, Carlsbad, CA, 4Biometrics, Ionis Pharmaceuticals, Carlsbad, CA, 5Pre-clinical development, Ionis Pharmaceuticals, Carlsbad, CA, 6clinical development, Akcea Employee, a subsidiary of Ionis Pharmaceuticals, Cambridge, MA, 7CLINICAL DEVELOPMENT, Ionis Pharmaceuticals, Carlsbad, CA, 8Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA, 9Cardiovascular Disease, Ionis Pharmaceuticals, Carlsbad, CA.
Background: Loss-of-function variants in angiopoietin-like 3 [ANGPTL3] have been linked in genome-wide association studies to familial combined hypolipidemia, with marked reduction of all plasma lipoproteins, improved insulin sensitivity, absence of hepatic steatosis, and reduced risk of CVD. We hypothesize that suppressing ANGPTL3 can improve dyslipidemia. Previously, we demonstrated that a second generation antisense oligonucleotide (ASO) against ANGPTL3 produced dose-dependent reductions in plasma ANGPTL3, triglycerides (TG), and total cholesterol (TC) in normal healthy volunteers. In the current study, we examine the effect of ANGPTL3 suppression using a hepatocyte specific ASO in healthy volunteers with elevated triglycerides. Methods: Since ANGPTL3 mRNA is expressed in hepatocytes, we conjugated ANGPTL3 ASO with an N-acetyl galactosamine complex (GalNAc3) [IONIS-ANGPTL3-LRx] which specifically targets the ASO to the asialoglycoprotein receptor on hepatocytes and improves the potency in mouse liver by >10-fold. IONIS-ANGPTL3-LRx was evaluated in a randomized, placebo-controlled, phase 1 study for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics) in single ascending doses (SAD) from 20 to 80 mg and multiple ascending doses (MAD) at 20 and 40 mg subcutaneously once weekly for 6 weeks. Results: Treatment with IONIS-ANGPTL3-LRx was well-tolerated and demonstrated an acceptable safety profile. Evaluation of the PK profile demonstrated rapid absorption, dose-dependent increases in exposure, and a terminal elimination half-life of 4 weeks. IONIS-ANGPTL3-LRx produced mean percent reductions from baseline (SEM) as follows: Conclusion: IONIS-ANGPTL3-LRx represents a unique drug to reduce atherogenic lipoproteins and may show promise for treating elevated TG and LDL in hyperlipidemic patients.
Author Disclosures: T. Brandt: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. L. Tai: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. J.L. Witztum: Consultant/Advisory Board; Modest; Consultant Cymbay, Consultant Prometheus. Consultant/Advisory Board; Significant; Consultant at Ionis Pharmaceuticals. Other; Modest; Patents and Patent Applications for the use of Oxidation-Specific Epitopes held by the University of California, San Diego. S.G. Hughes: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. E. Hurh: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. B. McEvoy: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. R. Yu: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. A. Digenio: Employment; Significant; Akcea Therapeutics Employee. R. Lee: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. M. Graham: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. R. Crooke: Employment; Significant; Ionis Pharmaceuticals Employee. Other; Significant; Ionis Pharmaceuticals Share Holder. S. Tsimikas: Employment; Significant; Ionis Pharmaceuticals Employee, University California, San Diego. Other; Significant; Shareholder - Ionis Pharmaceuticals, Inc.
21216 Impact of Infusion of an ApoA-IMilano HDL Mimetic on Regression of Coronary Atherosclerosis in Acute Coronary Syndrome patients: the MILANO-PILOT Study
Stephen Nicholls1, Steven Nissen2, David Kallend3, Peter Winjgaard3, Marilyn Borgman2; 1Heart Health, South Australian Health and Med Rsch Institute, Adelaide, Australia, 2Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, 3Cardiology, The Medicines Company, Parsippany, NJ.
Background: A previous small study employing infusions of an HDL-mimetic containing apoA-IMilano (AIM) demonstrated rapid and substantial regression of coronary atherosclerosis in patients with acute coronary syndromes (ACS). However, difficulty producing AIM on a large scale precluded further studies. Recent efforts have enabled adequate production to enable further development of this novel agent. Methods: The MILANO-PILOT Trial (MDCO-216 Infusions Leading to changes in Atherosclerosis: a Novel therapy in development to improve cardiovascular Outcomes - Proof of concept IVUS, Lipids and Other surrogate biomarkers Trial is a phase 2, double-blind, placebo-controlled trial. 120 patients with a recent ACS will be randomized at 28 sites in 5 countries to five 20 mg/kg weekly infusions of MDCO-216 or placebo. Eligibility requires an ACS event within the previous 14 days. Patients undergo an intravascular ultrasound (IVUS) examination of a single coronary artery with a maximum stenosis of 20–50% during a clinically-indicated angiogram at baseline. Repeat IVUS imaging is performed within the same artery one week following the final infusion. The primary efficacy parameter is the nominal change in PAV from baseline to end of study. Secondary efficacy parameters include the nominal change in normalized total atheroma volume, changes within the 10-mm segment containing the greatest plaque burden, and the proportion of patients demonstrating regression. Effects on lipid parameters and ex vivo cholesterol efflux capacity will also be evaluated. The trial is powered to detect a 1.5% reduction in PAV, assuming a standard deviation of 3.0%. Results: Patient enrollment will be complete by September, 2016. Patients have a mean age of 61.3 years, 19% had diabetes and 47% were treated with a statin at presentation. A prespecified interim analysis is planned for the time at which 80 patients complete the study and will be performed in September, 2016. Conclusions: MILANO-PILOT will provide contemporary insights on the impact of infusing HDL containing AIM on regression of coronary atherosclerosis. This will be a pivotal determinant in the ultimate development of this novel therapeutic approach for treatment of patients with ACS.
Author Disclosures: S. Nicholls: Research Grant; Significant; Amgen, Anthera, Eli Lilly, The Medicines Company, Sanofi-Regeneron, Cerenis, Novartis, Resverlogix, AstraZeneca, InfraReDx. Consultant/Advisory Board; Modest; AstraZeneca, Amgen, Eli Lilly, Boehringer Ingelheim, CSL Behring, Roche, Takeda, Merck, Pfizer, Sanofi-Regeneron, Eli Lilly. S. Nissen: Research Grant; Modest; Amgen, Pfizer, Esperion, Lilly, AstraZeneca, The Medicines Company, Takeda, Orexigen, Novo Nordisk, Novartis. D. Kallend: Employment; Significant; The Medicines Company. P. Winjgaard: Employment; Significant; The Medicines Company. M. Borgman: None.
Guiding the Momentum to Effect HF Outcomes- Ironing out the Wrinkles
21222 Transcatheter Interatrial Shunt Device Provides Sustained Clinical Benefit at One Year in Patients With Preserved or Mildly Reduced Ejection Fraction: The REDUCE LAP Heart Failure Trial
David Kaye1, Gerd Hasenfuß2, Petr Neuzil3, Marco Post4, Rob Doughty5, Jean-Noel Trochu6, Adam Kolodziej7, Ralf Westenfeld8, Martin Penicka9, Mark Rosenberg10, Jörg Hausleiter11, Philip Raake12, Mark Petrie13, Martin Bergmann14, Guillaume Jondeau15, Frank Silvestry16, Chris Hayward17; 1Cardiovascular Medicine, Alfred Hosp, Melbourne, Australia, 2Cardiology, Universitätsmedizin Göttingen, Göttingen, Germany, 3Cardiovascular Medicine, Na Homolce Hosp, Prague, Czech Republic, 4Cardiology, St. Antonius Hosp, Nieuwegein, Netherlands, 5Cardiology, Auckland City Hosp, Auckland, New Zealand, 6Cardiology, CHU de Nantes, Nantes, France, 7Cardiology, 4th Military Hosp, Wroclaw, Poland, 8Cardiology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany, 9Cardiology, Onze-Lieve-Vrouwziekenhuis VZW, Aalst, Netherlands, 10Cardiology, Universitätsklinikum Schleswig-Holstein, Kiel, Germany, 11Cardiology, Ludwig-Maximilians-Universität München, Munich, Germany, 12Cardiology, UniversitätsKlinikum Heidelberg, Heidelberg, Germany, 13Cardiology, Golden Jubilee Hosp, Glasgow, United Kingdom, 14Cardiology, Cardiologicum Hamburg, Hamburg, Germany, 15Cardiology, Hôpital Bichat, Paris, France, 16Cardiovascular Div, Hosp of the Univ of Pennsylvania, Philadelphia, PA, 17Cardiology, St Vincents Hosp, Sydney, Australia.
Introduction: Heart failure with preserved ejection fraction (HFPEF) has a complex pathophysiology and remains a therapeutic challenge. Elevated left atrial pressure (LAP), particularly during exercise, is a near-universal finding and a key contributor to morbidity and mortality. Preliminary studies demonstrate that a novel inter-atrial septal shunt device (IASD) which allows shunting to reduce LAP provides both clinical and hemodynamic benefit at 6 months, including improved quality of life, functional capacity and reduced exercise related filling pressures. Given the chronicity of HFPEF, evidence of long-term benefit is required. Objective: To evaluate safety, device performance, and clinical outcomes 1 year post IASD placement. Methods: Patients with ejection fraction (EF) ≥40%, New York Heart Association (NYHA) class II-IV, elevated pulmonary capillary wedge pressure at rest (≥15 mmHg), or during supine bicycle exercise (≥25 mmHg) were included. We evaluated device patency, shunt direction, NYHA class, quality of life (MLWHFQ), 6 minute walk distance (6MWD), echocardiographic chamber volumes and function, and major adverse cardiac, cerebrovascular and systemic embolic events at 1 year. Results: (Table). IASD placement, performed in 64 patients, appeared safe and survival was 95.3% at 1 year. Device patency was confirmed and exercise capacity, NYHA class, and quality of life were significantly improved at 12 months. Echocardiography showed stable increases in right heart volumes. Invasive hemodynamics were optionally performed in 18 patients. Resting PCWP was unchanged, however the workload normalized PCWP was significantly lower at 12 months. PVR was unchanged. Conclusion: Implantation of an interatrial shunt device is feasible and appears safe. The 12 month results demonstrate sustained device performance and clinical benefit suggesting this device approach may represent a novel strategy for the management of HFPEF.
Author Disclosures: D. Kaye: Consultant/Advisory Board; Modest; Corvia Medical. G. Hasenfuß: Consultant/Advisory Board; Modest; Corvia Medical. P. Neuzil: None. M. Post: None. R. Doughty: None. J. Trochu: None. A. Kolodziej: None. R. Westenfeld: None. M. Penicka: None. M. Rosenberg: None. J. Hausleiter: None. P. Raake: None. M. Petrie: Consultant/Advisory Board; Modest; Corvia Medical. M. Bergmann: None. G. Jondeau: None. F. Silvestry: Consultant/Advisory Board; Modest; Corvia Medical. C. Hayward: None.
21206 Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure (ATHENA-HF) Trial
Javed Butler1, Marvin A Konstam2, Michael Felker3, Andreas P Kalogeropoulos4, Michael M Givertz5, Douglas L Mann6, Kenneth B Margulies7, Margaret M Redfield8, Marc J Semigran9, Wilson Tang10, David J Whellan11, Stephen E McNulty12, Kevin J Anstrom13, Patrice Desvigne-Nickens14, Adrian F Hernandez13, Eugene Braunwald5; 1Medicine, Stony Brook Univ, Atlanta, GA, 2Medicine, Tufts Univ, Boston, MA, 3Medicine, Duke Univ, Durham, NC, 4Medicine, Emory, Atlanta, GA, 5Medicine, Brigham and Womens Hosp, Boston, MA, 6Medicine, Washington Univ, St Louis, MO, 7Medicine, Univ of Pennsylvania, Philadelphia, PA, 8Medicine, Mayo Clinic, Rochester, MN, 9Medicine, Mass General Hosp, Boston, MA, 10Medicine, Cleveland Clinic, Cleveland, OH, 11Medicine, Thomas Jefferson Univ, Philadelphia, PA, 12DCRI, Duke, Durham, NC, 13Medicine, Duke, Durham, NC, 14NHLBI, NHLBI, Bethesda, MD.
Introduction: In patients with acute heart failure (AHF), mineralocorticoid receptor antagonists (MRA) at high doses may relieve congestion through their natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with AHF. Hypothesis: In AHF patients, high-dose spironolactone therapy in addition to standard care will lead to greater reductions in N-terminal pro-B-type natriuretic peptide (NTproBNP) levels from randomization to 96 hours compared to patients receiving standard care. Methods: The ATHENA-HF conducted by the NHLBI Heart Failure Network is a randomized, double blind, placebo-controlled trial of the efficacy and safety of 100 mg daily spironolactone vs. placebo. 360 patients with AHF irrespective of ejection fraction were randomized within 24 hours of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone compared to standard care will lead to greater reductions in NTproBNP levels between randomization and 96 hours. The secondary endpoints include changes in dyspnea relief, urine output, weight change, and in-hospital worsening HF. 30-day clinical outcomes will be assessed. Safety endpoints include hyperkalemia and renal dysfunction. Differences among patients with reduced versus preserved ejection fraction will be determined. Results: Enrollment in ATHENA-HF was completed in March 2016 and follow up and database finalization will be completed in July 2016. Baseline demographics include age 64.7 years; females 36%; and blacks 42%. Mean ejection fraction is 34.7%, 73.9% of patients have HF with reduced ejection fraction and estimated GFR is 61.5 ml/min. Conclusions: ATHENA-HF is the first double blind randomized multicenter trial assessing the efficacy and safety of high dose MRA therapy in patients with AHF.
Author Disclosures: J. Butler: None. M.A. Konstam: None. M. Felker: None. A.P. Kalogeropoulos: None. M.M. Givertz: None. D.L. Mann: None. K.B. Margulies: None. M.M. Redfield: None. M.J. Semigran: None. W. Tang: Research Grant; Significant; National Institutes of Health. D.J. Whellan: None. S.E. McNulty: None. K.J. Anstrom: None. P. Desvigne-Nickens: None. A.F. Hernandez: None. E. Braunwald: None.
21208 Oral Iron Repletion effects on Oxygen Uptake in Heart Failure (IRONOUT HF)
Gregory D Lewis1, Kevin J Anstrom2, Steven McNulty2, Adrian F Hernandez3, Eugene Braunwald4, NHLBI Heart Failure Network; 1Cardiology Div, Massachusetts General Hosp, Boston, MA, 2Cardiology Div, Duke Univ, Durham, NC, 3Cardiology Div, Duke Univ, Durham, MA, 4Cardiology Div, Harvard Med Sch, Boston, MA.
Background: Iron deficiency is present in ~50% of patients with heart failure with reduced ejection fraction (HFrEF) and is an independent predictor of mortality. Despite growing recognition of the functional and prognostic significance of iron deficiency in HF, the utility of inexpensive, readily available oral iron supplementation in HF is unknown. Methods: The Oral Iron Repletion effects ON Oxygen UpTake in Heart Failure (IRONOUT HF) Trial is an NIH-sponsored multi-center, randomized, double-blinded, placebo-controlled trial of oral iron polysaccharide (300 mg/day) compared to matching placebo. The trial enrolled 225 patients with HFrEF (LVEF <0.40) and iron deficiency, defined as a serum ferritin between 15–100 ng/ml or serum ferritin 100–299 ng/ml with transferrin saturation (Tsat) <20%. The primary endpoint is change in peak oxygen uptake (pkVO2) measured at baseline and at 16 weeks. Secondary endpoints include assessments of the impact of oral iron on submaximal exercise capacity; plasma NT-pro BNP levels; and health status: Kansas City Cardiomyopathy Questionnaire (KCCQ). Results: Enrollment in IRONOUT HF was completed in November 2015, last visit was in March 2016 and database lock was in May 2016. Baseline characteristics include: n=225, (median (25th, 75th) or %): Age 63 years (55, 70); Female 36%; Black 25%; NYHA II/III 66%/33%, and LVEF 25% (20, 34). The primary endpoint, change in pkVO2, did not differ between groups (+23ml (-84, 142) vs. -2ml (-110, 104), p=0.45). In ancillary analyses, oral iron only modestly improved iron measures (i.e. Tsat increased from 19 to 22% p=0.003). Baseline Tsat was related to pkVO2 and KCCQ and changes in Tsat correlated with changes in pVO2 over the course of the trial. Further analyses of biomarker samples are underway to understand the primary results (i.e. hepcidin levels in relation to responsiveness to oral iron). Conclusion: High-dose oral iron minimally repleted iron stores and did not improve exercise capacity in HFrEF raising questions about the ability of oral iron therapies to be sufficient in patients with HF. We will present the primary results and mechanistic insights into refractoriness of HF patients to the commonly used strategy of oral iron supplementation.
Author Disclosures: G.D. Lewis: Other Research Support; Significant; Abbott Vascular, Novartis, Stealth, Shape Systems. Consultant/Advisory Board; Significant; Sonivie. K.J. Anstrom: None. S. McNulty: None. A.F. Hernandez: Research Grant; Significant; Amgen, AstraZeneca, Merck, Novartis. Consultant/Advisory Board; Modest; Amgen; AstraZeneca;Luitpold; Merck, and Novartis. E. Braunwald: None.
21200 Multicenter Study of Maglev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With Heartmate 3 (MOMENTUM 3)- Primary Results of the Short Term (6 month) Cohort
Mandeep R Mehra; Heart and Vascular Cntr, Brigham and Women’s Hosp, Boston, MA.
Background: The HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) (St. Jude Medical, Inc.) contains a centrifugal, fully magnetically levitated, continuous-flow blood pump engineered to enhance hemocompatibility and reduce shear stress. MOMENTUM 3 is a pivotal prospective, randomized, controlled trial to evaluate the safety and effectiveness of the HM3 LVAS compared to the HeartMate II (HMII) LVAS. Methods: MOMENTUM 3 uses an innovative adaptive study design in adult patients who are candidates for LVAS with advanced heart failure (NYHA Class III with dyspnea on mild physical activity, or NYHA Class IV refractory to advanced heart failure management). The primary endpoint, evaluated for non-inferiority compared to the HMII, is a composite of survival to transplant, recovery or LVAD support free of debilitating stroke (MRS >3) or reoperation to replace the pump. Patients are enrolled and randomized 1:1 HM3:HMII irrespective of the intended use of the LVAS (bridge to transplantation or destination therapy) with primary outcomes evaluated at short term (ST, 6 months, n=294) and long term (LT, 2 years, n=366) time points (figure) (J Heart Lung Transplant. 2016 Apr;35(4):528–36). An additional 662 patients are being enrolled (for a total 1,028 patients) for evaluation of pump replacement at 2 years. Enrollment commenced on September 4, 2014, the ST cohort completed enrollment in October 2015 and 6 month follow-up on April 13th, 2016; the LT cohort completed enrollment in November 2015 and is in the follow-up phase with the remaining study cohort enrollment ongoing. Results: We will present the composite primary and secondary end points of the ST (6 month) cohort including survival, adverse events, quality of life, and functional status. Data will be finalized by September 2016. Conclusions: This will be the first presentation of results from the MOMENTUM 3 trial of the maglev HeartMate 3 LVAS. (Funded by St. Jude Medical, Inc; ClinicalTrials.gov number, NCT02224755).
Author Disclosures: M.R. Mehra: Consultant/Advisory Board; Modest; Medtronic, TEVA, St. Jude Medical, Stealth Therapeutics, J & J (Janssen).
24089 A Multi-sensor Algorithm Predicts Heart Failure Events in Patients with Implanted Devices: Results from the MULTISENSE Study
John P Boehmer1, Ramesh Hariharan2, Fausto G Devecchi3, Andrew L Smith4, Molon Giulio5, Alessandro Capucci6, Qi An7, Viktoria Averina7, Pramodsingh H Thakur7, Ramesh Wariar7, Yi Zhang7, Jagmeet Singh8; 1College of Medicine, Pennsylvania State Univ, Hershey, PA, 2Clinical cardiac electrophysiology, Univ of Texas Physicians, Houston, TX, 3Cardiac Arrhythmia Service, Lutheran Health Network, Fort Wayne, IN, 4Emory Univ, Emory Univ, Atlanta, GA, 5Cardiology, Sacro Cuore Hosp, Negrar, Italy, 6Cardiology and Arrhythmology Clinic, Università Politecnica delle March, Ancona, Italy, 7Boston Scientific, Boston Scientific, Marlborough, MA, 8Heart Cntr, Massachusetts General Hosp, Boston, MA.
Introduction: Heart Failure (HF), a growing health-care challenge globally, involves costly hospitalizations with adverse impact on patient outcomes. Reliable monitoring for early signs of worsening HF is needed to enable proactive interventions for prevention of acute decompensations. We hypothesize that an algorithm combining information from a diverse set of implanted device based sensors judiciously chosen to target different aspects of HF pathophysiology can effectively detect worsening HF. Method: MultiSENSE enrolled patients with HF and reduced EF (HFrEF) implanted with CRT-D, converted into an investigational device to enable chronic ambulatory data collection. HF events (HFEs) were defined as HF admissions or unscheduled visits with augmented intravenous HF treatment, and were independently adjudicated. Patients were assigned to Development or Test set cohorts in chronological order of enrollment. The development set was used to construct a composite index and alert algorithm (HeartLogicTM) combining Heart Sounds, Respiration, Thoracic Impedance, Heart Rate and Activity; whereas the test set was sequestered for its subsequent independent validation. Sensitivity was defined as the proportion of usable HFEs detected by HeartLogic alerts. Unexplained alert rate (UAR) was defined as the ratio of alerts not explained by HF to the total usable follow-up duration. The two co-primary endpoints: 1. Sensitivity performance goal (PG) of >40%; 2. UAR PG of <2 alerts per patient year were tested with a 2-sided 95% confidence interval (CI). Results: Overall, 900 (Development = 500, Test = 400) patients had sensor data collection enabled and followed for up to a year. Primary endpoints were evaluated using the 320 patient years of follow-up data and 50 adjudicated usable HFEs in the Test Set cohort (72% male; age 66.8±10.3 years; NYHA Class at enrollment I/II/III/IV/unknown: 5%/69%/25%/1%/1%; LVEF 30.0±11.4%). With an observed sensitivity of 70% (Lower 2-sided 95% CI: 55.4%) and UAR of 1.45 (Upper 2-sided 95% CI: 1.65), both endpoints were met. Conclusion: The HeartLogic multi-sensor HF diagnostic algorithm significantly exceeded its pre-specified endpoints demonstrating compelling performance for worsening HF detection.
Author Disclosures: J. Singh: Consultant/Advisory Board; Modest; BSC, SJM, MDT, BTRK, LIVANOVA, Impulse Dynamics. Consultant/Advisory Board; Significant; <10,000.
2016 Clinical Science Special Reports Abstracts
Cellular Biology and Function
Cell Therapy: Ready for Prime Time?
21236 Administration of Autologous Bone Marrow Cells for Limb Salvage in Patients With Critical Limb Ischemia: Results of the Multicenter Phase III MOBILE Trial
Michael P Murphy1, Charles Ross2, Milina R Kibbe3, Rebecca L Kelso4, Melhem J Sharafuddin5, Edith Tzeng6, John R Laird7, Mobile Working Group1;1Surgery, Indiana Univ Sch of Medicine, Indianapolis, IN, 2Surgery, Piedmont Heart Inst, Atlanta, GA, 3Surgery, UNC, Chapel Hill, NC, 4Surgery, Cleveland Clinic, Cleveland, IN, 5Surgery, Univ of Iowa Sch of Med, Iowa City, IA, 6Surgery, Univ of Pittsburgh Sch of Med, Pittsburgh, PA, 7Cardiology, UC Davis Sch of Med, Sacramento, CA.
Background: Critical limb ischemia (CLI) heralds a significant risk of amputation. A previous Phase I study suggests that a concentrated preparation of autologous bone marrow cells (cBMA) improved limb perfusion and decreased amputation rates. The purpose of this pivotal Phase III trial is to determine if (cBMA) improves amputation free survival in this cohort of CLI patients. Methods: The MOBILE trial was a double-blind, placebo-controlled trial that randomized poor option CLI patients to receive either autologous cBMA injected into the lower leg or placebo (sham procedure) in a 3:1 fashion. Randomization was stratified based on disease severity (Rutherford score) and diagnosis of diabetes. The primary efficacy endpoint was amputation free survival (AFS) defined as major amputation and/or all-cause mortality. Secondary endpoints were changes in ankle-brachial index (ABI), toe brachial index (TBI), transcutaneous oxygen pressure (TcPO2), 6 minute walk test (6MWT), and quality of life measures. Results: A total of 152 patients were randomized at 24 clinical sites (91 male, 64 female) 65± 12.1 years old. There were no significant differences in events (amputation and death) at 52 weeks between cBMA (20.17%) vs. the placebo group (30.56%), hazard ratio (HR) 0.64; 95% CI 0.31 - 1.31; p=0.224. Post-hoc analysis based on randomization stratification revealed that there was a significant improvement in AFS for non-diabetics treated with cBMA vs. placebo (HR 0.31; 95% CI 0.12 - 0.81; p= 0.016) though not for diabetics (HR 1.45; 95% CI 0.42- 5.05; p= 0.555). Further analysis revealed that Rutherford 5 non-diabetic patients treated with cBMA had a significant increase in AFS (HR 0.26; 95% CI 0.07–0.98; p = 0.046). No benefit with treatment was observed in the Rutherford 5 diabetic group. There were no significant findings for ABI, TBI, TcPO2, 6MWT, and quality of life measures. Conclusions: Posthoc analysis of enrollment stratum demonstrates that autologous cBMA significantly improves AFS in non-diabetic patients with poor option CLI. Further mechanistic analyses of the cBMA composition in diabetics may lead to more effective strategies in treating this challenging patient population. Trial Registration: clinical trials.gov Identifier: NCT01049919.
Author Disclosures: M.P. Murphy: None. C. Ross: None. M.R. Kibbe: None. R.L. Kelso: None. M.J. Sharafuddin: None. E. Tzeng: None. J.R. Laird: None. M. Group: None.
21201 Administration of ALDH Bright Cells to Patients With Intermittent Claudication: The NHLBI CCTRN Pace Trial
Emerson C Perin1, Michael Murphy2, Keith March2, Roberto Bolli3, Nicholas J Leeper4, Phillip C Yang5, Jason Alexander6, Timothy D Henry7, Jay H Traverse8, Carl J Pepine9, James T Willerson1, Omaida Velasquez10, Joshua M Hare11, Vijaykumar S Kasi12, Joao A Lima13, William R Hiatt14, Doris A Taylor15, Adrian P Gee16, Lem Moyé17, Ray F Ebert18, Robert D Simari19, Alan T Hirsch20; 1Cardiology, Texas Heart Institute, Houston, TX, 2Clinical Cell Therapy Cntr, Indiana Univ Sch of Medicine, Indianapolis, IN, 3Div of Cardiovascular Medicine, Univ of Louisville, Louisville, KY, 4Vascular Surgery and Medicine, Stanford Univ Sch of Medicine, Stanford, CA, 5Cardiovascular Medicine, Stanford Univ Sch of Medicine, Stanford, CA, 6Vascular and Endovascular Services, Minneapolis Heart Institute Foundation, Abbott Northwestern Hosp, Minneapolis, MN, 7Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA, 8Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hosp, Minneapolis, MN, 9Cardiology, Univ of Florida Sch of Medicine, Gainesville, FL, 10Vascular Surgery, Univ of Miami Miller Sch of Medicine, Miami, FL, 11Cardiology, Univ of Miami Miller Sch of Medicine, Miami, FL, 12Cardiology, Orlando Health Heart Institute, Orlando, FL, 13Cardiovascular Imaging, Johns Hopkins Univ, Baltimore, MD, 14Medicine, Univ of Colorado Sch of Medicine, Aurora, CO, 15Regenerative Medicine, Texas Heart Institute, Houston, TX, 16Cell and Gene Therapy, Baylor College of Medicine, Cntr for Cell and Gene Therapy, Houston, TX, 17Biostatistics, Univ of Texas Health Science Cntr Sch of Public Health, Houston, TX, 18Stem Cell and Gene Therapy - Cardiovascular, National Institute of Health, National Heart, Lung and Blood Institute, Bethesda, MD, 19Dean’s Office, Univ of Kansas Sch of Medicine, Kansas City, KS, 20Cardiovascular Div, Lillehei Heart Institute, Univ of Minnesota, Sch of Medicine, Minneapolis, MN.
Context: Peripheral artery disease (PAD) affects 8–12% of Americans over 65 and is associated with a decline in functional status due, in part, to the primary ischemic symptom, intermittent claudication (IC). All current IC treatments have limitations. We hypothesized that aldehyde dehydrogenase bright (ALDHbr) cell administration might promote angiogenesis and improve IC. Objectives: To evaluate the safety and efficacy of autologous bone marrowderived ALDHbr cells in PAD patients with IC and validate new novel magnetic resonance (MR) endpoints. Design, Setting, and Patients: In a randomized, double-blind, placebo-controlled, multicenter trial, 82 people (61 M, 21 F) were randomized between June 2013 and Dec 2015 at 9 sites. Participants had an average age 66±9 years, average baseline peak walking time (PWT) of 5±2.6 mins, and ABI 0.60±0.14. Intervention: All underwent bone marrow aspiration and were randomized 1:1 to receive either ALDHbr cells, enriched by cell sorting, or cell-free placebo via 10 (1 ml) intramuscular injections in the thigh adductors and gastrocnemius of the index leg. Results: There were no significant differences in change from baseline and 6 months between the cell and placebo group for the four co-primary endpoints: PWT (0.9±0.8 minutes; 95% CI -0.6 to 2.5; p=0.238), collateral count (0.9±0.6 arteries; 95% CI-0.23 to 2.1; p=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/sec; 95% CI -0.8 to 0.8; p=0.978), and capillary perfusion (-0.17±0.55; 95% CI -1.26 to 0.91; p=0.752). Additionally, there were no significant improvements for quality of life secondary endpoints, nor correlative relationships between changes in MR outcomes and PWT. Post-hoc exploratory analysis revealed ALDH bright cells were associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI 0.1 to 2.9; p=0.047) in participants with completely occluded femoral arteries. Conclusion: ALDHbr cell administration did not change PWT or MR anatomic or physiologic outcomes. Furthermore, changes in PWT were not associated with improvements in the MR anatomic nor perfusion endpoints. Collateral count improvements in participants with occluded femoral arteries must be investigated and confirmed in future PAD clinical research.
Author Disclosures: E.C. Perin: Research Grant; Significant; National Heart, Lung and Blood Institute. M. Murphy: Research Grant; Significant; National Heart, Lung and Blood Institute. K. March: Research Grant; Significant; National Heart, Lung and Blood Institute. R. Bolli: Research Grant; Significant; National Heart, Lung and Blood Institute. N.J. Leeper: Research Grant; Significant; National Heart, Lung and Blood Institute. P.C. Yang: Research Grant; Significant; National Heart, Lung and Blood Institute. J. Alexander: Research Grant; Significant; National Heart, Lung and Blood Institute. T.D. Henry: Research Grant; Significant; National Heart, Lung and Blood Institute. J.H. Traverse: Research Grant; Significant; National Heart, Lung and Blood Institute. C.J. Pepine: Other Research Support; Modest; Boehringer Ingelheim (VBWG), Gilead (VBWG), United Therapeutics (VBWG)). Consultant/Advisory Board; Modest; AMGEN, AstraZeneca, Bayer HealthCare, FACT (Foundation of the Accreditation of Cellular Therapy), Gilead, Merck, SLACK Inc.. Research Grant; Significant; Bayer Healthcare (FINESSE HF), Baxter Healthcare (CMIRENEW), Capricor Inc. (ALLSTAR), Cytori Theraputics (ATHENA & ATHENA Ancillary), Florida Health Equity Research Inst. (HERI), Gilead Sci Inc (RWISE), inVentive Health Clinical LLC (TEVA), NHLBI (SEVERAL GRANTS), Sanofi-Aventis (ODYSSEY). Other Research Support; Significant; AMGEN (VBWG), AstraZeneca (VBWG), Bayer Healthcare (VBWG), Daiichi Sankyo (VBWG), Gilead Sci Inc (VBWG), Pfizer (VBWG), United Therapeutics (VBWG). J.T. Willerson: Research Grant; Significant; National Heart, Lung and Blood Institute. O. Velasquez: Research Grant; Significant; National Heart, Lung and Blood Institute. J.M. Hare: Research Grant; Significant; National Heart, Lung and Blood Institute. V.S. Kasi: Research Grant; Significant; National Heart, Lung and Blood Institute. J.A. Lima: Research Grant; Modest; Biomet, CAPRICOR. W.R. Hiatt: None. D.A. Taylor: Research Grant; Significant; National Heart, Lung and Blood Institute. A.P. Gee: Research Grant; Significant; National Heart, Lung and Blood Institute. L. Moyé: Research Grant; Significant; National Heart, Lung and Blood Institute. R.F. Ebert: None. R.D. Simari: Research Grant; Significant; National Heart, Lung and Blood Institute. A.T. Hirsch: Research Grant; Significant; National Heart, Lung and Blood Institute, AstraZeneca, Pluristem, Merck. Speakers Bureau; Significant; Merck. Consultant/Advisory Board; Significant; Bayer.
21230 Randomized Comparison of Allogeneic vs Autologous Mesenchymal Stem Cells in Patients With Non-Ischemic Dilated Cardiomyopathy-The POSEIDON-DCM Trial
Joshua M Hare1, Darcy L DiFede2, Raul Mitrani1, Muzammil Mushtaq1, Maureen H Lowery1, John J Byrnes1, Robert C Hendel3, Mauricio G Cohen1, Carlos Alfonso1, Angela M Castellanos1, Ana M Landin1, Victoria Florea1, Aisha Khan1, Krystalenia Valasaki1, Marietsy V Pujol1, Samirah Gomes1, Joel E Fishman1, Eduard Ghersin1, Pradip Pattany1, Samuel Golpanian1, Cindy Delgado1, Fouad Abuzeid1, Mayra Vidro-Casiano1, Courtney Premer1, Audrey Medina1, Valeria Porras1, Konstantinos Chatzistergos1, Erica Anderson4, Adam Mendizabal4, Jill El-Khorazaty4, Alan W Heldman5;1Medicine, Univ of Miami, Miami, FL, 2Interdisciplinary Stem Cell Insitute, Univ of Miami, Miami, FL, 3Cardiovascular Surgery, Univ of Miami, Miami, FL, 4Biostatistics, Emmes Corp, Rockville, MD, 5Non Affiliated, Non Affiliated, Miami, FL.
Whereas the majority of clinical trials to date have focused on testing the safety and efficacy of human mesenchymal stem cells (hMSCs) for ischemic cardiomyopathy, only limited data is available regarding cell-based therapy for patients with non-ischemic dilated cardiomyopathy (NIDCM). In order to address this, we conducted the POSEIDON-DCM trial, an NIH-funded, randomized, comparison of identically prepared autologous (auto) vs allogeneic (allo) bone marrow-derived hMSCs. A dose of 100 million hMSCs was delivered by transendocardial stem cell injection (TESI) in patients with NIDCM. Patients (n=37; age: 55.8 ±11.2; 32% female) received hMSCs TESI in 10 left ventricular (LV) sites using NOGA Infusion Catheter and were followed for 12-months for safety: serious adverse events (SAE) and efficacy endpoints: Ejection Fraction (EF), Minnesota Living with Heart Failure Questionnaire (MLHFQ), 6 Minute Walk Test (6MWT), MACE and immunebiomarkers. No 30-day treatment-emergent (TE)-SAEs occurred; 12-month SAE incidence was: allo: 27.8% (95% CI: 9.7, 53.5), auto: 62.5% (95% CI: 35.4, 84.8), (p=0.1003). No immune rejection occurred. EF increased in allo: 8.0 units (95% Cl: 2.8, 13.2, p=0.004), but not auto: 5.4 units (95% Cl: -1.4, 12.1, p=0.116, auto vs allo p=0.4887). 6MWT increased for allo: 37.0 meters (95% Cl: 2.0 to 72.0, p=0.04), but not auto: 7.3 meters (95% Cl: -47.8, 33.3, p=0.71, auto vs allo p=0.0168). The MLHFQ score decreased in allo (p=0.0022) and auto (p=0.463-p=0.172) over time. MACE and hospitalizations were significantly lower in allo vs. auto (p<0.05). TNF-α decreased (p=0.0001 for each) but to a greater extent in allo vs. auto at 6-months (p=0.05). Together these findings demonstrate safety and support greater and clinically meaningful efficacy of allo-hMSC compared to auto-hMSC in patients with NIDCM. These findings provide the basis for future pivotal trials of cell-based therapy for NIDCM.
Author Disclosures: J.M. Hare: Ownership Interest; Significant; Vestion Inc.. Consultant/Advisory Board; Modest; Vestion Inc. D.L. DiFede: Consultant/Advisory Board; Modest; BDS. R. Mitrani: None. M. Mushtaq: None. M.H. Lowery: None. J.J. Byrnes: None. R.C. Hendel: None. M.G. Cohen: Speakers Bureau; Modest; Terumo Medical, Medtronic. Honoraria; Modest; Medtronic, Abiomed, Merit Medical.. Consultant/Advisory Board; Modest; The Medicines Company. C. Alfonso: None. A.M. Castellanos: None. A.M. Landin: Consultant/Advisory Board; Modest; Longeveron. V. Florea: None. A. Khan: None. K. Valasaki: None. M.V. Pujol: None. S. Gomes: None. J.E. Fishman: None. E. Ghersin: None. P. Pattany: None. S. Golpanian: None. C. Delgado: None. F. Abuzeid: None. M. Vidro-Casiano: None. C. Premer: None. A. Medina: None. V. Porras: None. K. Chatzistergos: None. E. Anderson: None. A. Mendizabal: None. J. El-Khorazaty: None. A.W. Heldman: Ownership Interest; Significant; Vestion.
18019 The NHLBI TIME Trial: Role of Microvascular Obstruction in 2-Year Clinical and MRI Follow-up
Jay H Traverse1, Timothy D Henry2, Carl J Pepine3, James T Willerson4, Emerson C Perin4, Doris A Taylor5, Atul R Chugh6, Phillip C Yang7, Stephen G Ellis8, David X Zhao9, Marc S Penn10, John R Forder11, Ray F Ebert12, Lem A Moye13, Robert J Simari14; 1Dept of Medicine, Minneapolis Heart Institute Foundation Abbott Northwestern Hosp, Minneapolis, MN, 2Dept of Cardiology, Cedars Sinai Med Cntr, Los Angeles, CA, 3Dept of Cardiology, Univ of Florida, Gainesville, FL, 4Dept of Cardiology, Texas Heart Institute, Houston, TX, 5Stem Cell Institute, Texas Heart Institute, Houston, TX, 6Cardiology, Saint Francis Heart Cntr, Indianapolis, IN, 7Dept of Medicine, Stanford Univ, Stanford, CA, 8Dept of Cardiology, Cleveland Clinic Foundation, Cleveland, OH, 9Dept of Cardiology, Wake Forest Sch of Medicine, Winston Salem, NC, 10Dept of Cardiology, Summa Physicians, Akron, OH, 11Dept of Radiology, Univ of Florida, Gainesville, FL, 12Clinical Trials, National Heart Lung and Blood Institute, Rockville, MD, 13Sch of Public Health, UT Health, Houston, TX, 14Dean, Univ of Kansas Med Sch, Kansas City, KS.
Background: TIME was a randomized, double-blind, placebo-controlled trial by the NHLBI-sponsored Cardiovascular Cell Therapy Research Network of 120 anterior STEMI patients with moderate to severe LV dysfunction randomized to 150 million autologous bone marrow mononuclear cells (BMCs) or placebo with intracoronary delivery on Day 3 or Day 7 following reperfusion with PCI. The primary endpoints were changes in global (LVEF) and regional LV function between baseline and 6 months as determined by cardiac MRI. No benefit of cell therapy was observed on the recovery of LV function at 6 months or 2-years vs. placebo. The presence of microvascular obstruction (MVO) on MRI following STEMI is associated with adverse LV remodeling, however, its long-term effects out to 2-years has not been previously reported. Because MVO was present in nearly 50% of the cohort at baseline (Day3), we analyzed its long-term effects on LV function and remodeling. Methods and Results: Data is presented as the aggregate of the combined BMC and placebo Day 3 and Day 7 groups (means) and stratified by the presence or absence of MVO. A total of 112 patients had analyzable MRIs at Day 3 and 47 patients had MVO. Only 1 / 15 patients with MVO were female compared to nearly 50% of the males (p = 0.001). MVO was associated with greater infarct size at baseline, marked reductions in the recovery of LVEF at 6-months (-0.1 versus 6.1%), and significantly greater adverse remodeling. At 2 years, 83 patients had follow-up MRI and 34 had MVO representing the longest longitudinal MRI analyses of MVO in STEMI patients. The differences in infarct size, LV function and volumes between patients with and without MVO lessened over time as patients with MVO and severe LV dysfunction were lost to follow-up due to ICD placement. Conclusions: MVO portends an adverse prognosis on the recovery of LV function and MACE rates in patients who receive BMCs. The treatment effect of BMCs on LV function was not influenced by the presence or absence of MVO.
Author Disclosures: J.H. Traverse: Research Grant; Significant; NHLBI. T.D. Henry: Research Grant; Significant; NHLBI. C.J. Pepine: Research Grant; Significant; NHLBI. J.T. Willerson: Research Grant; Significant; NHLBI. E.C. Perin: Research Grant; Significant; NHLBI. D.A. Taylor: Research Grant; Significant; NHLBI. A.R. Chugh: None. P.C. Yang: Research Grant; Significant; NHLBI. S.G. Ellis: None. D.X. Zhao: None. M.S. Penn: None. J.R. Forder: Research Grant; Significant; NHLBI. R.F. Ebert: None. L.A. Moye: Research Grant; Significant; NHLBI. R.J. Simari: Research Grant; Significant; NHLBI.
Precision Medicine on the Front Lines
21204 A Genome-wide Association Study (GWAS) Identifies Novel Loci Associated With Clinically Defined Statin-Associated Muscle Symptoms in a Double-Blind Cross-Over Re-challenge Trial
Erik Stroes1, Ricardo Dent2, Robert S Rosenson3, Paul D Thompson4, Christie M Ballantyne5, Ioanna Gouni-Berthold6, Yi-Hsiang Hsu7, Michael Davis8, Scott M Wasserman9, Steven E Nissen10; 1Vascular Medicine, Academic Med Cntr, Amsterdam, Netherlands, 2Clinical Development, Amgen, Zug, Switzerland, 3The Cardiometabolic Disorders Unit, Icahn Sch of Medicine at Mount Sinai, New York, NY, 4Cardiology, Hartford Hosp, Hartford, CT, 5Dept of Medicine, Baylor College of Medicine and the Methodist DeBakey Heart and Vascular Cntr, Houston, TX, 6Cntr for Endocrinology, Diabetes and Preventive Medicine, Univ of Cologne, Cologne, Germany, 7Clinical Biomarkers, Amgen, Cambridge, MA, 8Clinical Biomarkers, Amgen, Thousand Oaks, CA, 9Cardiovascular, Amgen, Thousand Oaks, CA, 10Dept of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH.
Introduction: Genetic factors may influence statin-associated muscle symptoms (SAMS). The GAUSS-3 study, which included a unique, double-blind, placebo-controlled atorvastatin re-challenge to identify SAMS provides an ideal dataset to describe the SAMS phenotype. A robust, discovery-based GWAS was conducted in subjects enrolled in GAUSS-3 and other evolocumab trials (RUTHERFORD-1/2 and LAPLACE-1) to identify associated genes. Methods: Genotypes from 771 adult Caucasians were obtained (Illumina SNP chips, 730K common + 228K mis/nonsense variants with imputation against ~40M un-genotyped SNPs from ~32K whole genome sequences, Haplotype Reference Consortium). SAMS was established in 149 subjects (cases) by correct reporting of muscle symptoms during the statin re-challenge period (132) or by documented CK greater than 10 times the upper limit of normal with muscle symptoms while on statins (17). Subjects tolerating high-dose statins in combination trials and those without established SAMS in the GAUSS-3 screening period served as controls (622). Models were adjusted for age, sex, BMI, and ancestral genetic background (principal components); additive and recessive models were applied. Variants with minor allele count ≥ 5 were assessed by Fisher’s exact or multiple logistic regressions (R packages). Rare variants (MAF < 1%) were assessed with the Optimal Sequence Kernel Association Test (SKAT-O). Results: Cases and controls were balanced in age, sex, and BMI profiles. Several genome-wide significant associations (p < 5x10–8) were discovered, i.e. common SNPs located in chr2q21, chr17q24, and chr21q22. Using an additive effect model, carriers of a risk allele for genome-wide significant SNPs in chr2q21 and chr17q24 GWAS loci had an increased risk (OR=2.3~4.8) of SAMS. Conversely, carriers of the risk alleles in chr21 had a decreased risk (OR=0.5) of SAMS. Suggestive associations (p < 10–6) were also identified. Conclusion: A GWAS of patients from GAUSS-3, the most objectively identified SAMS phenotype identified to date, suggests polygenic inheritance of SAMS. These novel SNPs, not previously described in the statin intolerance literature, may provide insight into the pathogenesis of SAMS and help identify definitive biomarkers.
Author Disclosures: E. Stroes: Consultant/Advisory Board; Modest; Amgen, Sanofi, Novartis, Merck, Regeneron, Santaris, ISIS Pharmaceuticals. R. Dent: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. R.S. Rosenson: Research Grant; Modest; Amgen, Sanofi, Regeneron. Ownership Interest; Modest; LipoScience. Consultant/Advisory Board; Modest; Amgen, Sanofi, Regeneron, Abbott, LipoScience, Novartis, Sticares, InterACT. P.D. Thompson: Research Grant; Modest; Regeneron, Sanofi, Esperion, Amarin, Pfizer. Honoraria; Modest; Merck, Amarin, Sanofi, Regeneron, Amgen. Consultant/Advisory Board; Modest; Amgen, Genomas, Sanofi, Merck, Esperion, Amarin, Regeneron, AstraZeneca. C.M. Ballantyne: Consultant/Advisory Board; Modest; Abbott Diagnostics, Amarin, Amgen, Eli Lilly, Esperion, Ionis, Matinas BioPharma Inc, Novartis, Regeneron, Roche Diagnostic. Research Grant; Significant; NIH, AHA, ADA. Other Research Support; Significant; Abbott Diagnostic, Amarin, Amgen, Eli Lilly, Esperion, Ionis, Novartis, Pfizer, Regeneron, Roche Diagnostic, Sanofi-Synthelabo. Consultant/Advisory Board; Significant; Astra Zeneca, Merck, Pfizer, Sanofi-Synthelabo. I. Gouni-Berthold: Research Grant; Modest; Bayer Health Care. Honoraria; Modest; Genzyme, Novartis, Pfizer, Ipsen, Bristol-Meyers Squibb, Amgen, Sanofi, Otsuka, Novo Nordisk. Consultant/Advisory Board; Modest; Sanofi, Amgen, AstraZeneca, Bristol-Myers Squibb, Lilly. Y. Hsu: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. M. Davis: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. S.M. Wasserman: Employment; Significant; Amgen. Ownership Interest; Significant; Amgen. S.E. Nissen: Research Grant; Modest; Amgen, Pfizer, Esperion, Lilly, AstraZeneca, The Medicines Company, Takeda, Orexigen, Novo Nordisk, Novartis.
21140 Incidence of Acute Myocardial Infarction in Patients With Genotyped Familial Hypercholesterolemia in Norway During 2001–2009
Liv J Mundal1, Jannicke Igland2, Grete S Tell3, Marit B Veierød4, Kirsten B Holven5, Randi Selmer6, Torbjørn Wisløff7, Ivar S Kristiansen8, Trond P Leren9, Kjetil Retterstøl1; 1Nutrition and Lipid Clinic, Univ of Oslo and Oslo Univ Hosp, Oslo, Norway, 2Dept of global public health and primary care, Univ of Bergen, Bergen, Norway, 3Global Public Health and Primary Care, Univ of Bergen, Bergen, Norway, 4Dept of Biostatistics, Univ of Oslo, Oslo, Norway, 5Nutrition and National Advisory unit on Familial Hypercholesterolemia, Univ of Oslo and Oslo Univ Hosp, Oslo, Norway, 6Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway, 7Pharmacoepidemiology, Norwegian Institute of Public Health and Univ of Oslo, Oslo, Norway, 8Dept of Health Management and Health Economics, Univ of Oslo, Oslo, Norway, 9Oslo Univ Hosp, Oslo Univ Hosp, Oslo, Norway.
Aims: It is not known to which extent familial hypercholesterolemia (FH) increases the risk for cardiovascular disease in a population were statin treatment is common. The primary aim of this study was to investigate incidence of acute myocardial infarction (AMI) and cerebro vascular disease relative to the total Norwegian population of about 5 million people in the period 2001–2009 in a large sample of genotyped FH patients stratified by sex and age groups. Methods and Results: The complete cohort of genotyped FH patients without previous AMI in Norway (n=4164) were included in the analyses during an observation periode of 17,720 patient-years in total. All AMI hospitalizations (ICD9 410; ICD10 I21, I22) and coronary out-of-hospital deaths (ICD9 410–414; ICD10 I20-I25) and stroke (I60, I61, I63, I64 and cerebro vascular disease I60-I69, G45 in all Norwegian genotyped FH patients were obtained from the Cardiovascular Disease in Norway project. An incident AMI was defined as a hospitalization or out-of-hospital death due to AMI with no prior hospitalization for AMI. Standardized incidence ratios (SIRs) with 95% confidence intervals (95% CIs) were calculated by indirect standardization with AMI incidence rates for the total Norwegian population during 2001–2009 stratified by sex, calendar year and one-year age groups as reference rates. In FH women total SIR (95% CI) was 2.27 (1.62–3.18), in young women 25–39 years SIR (95% CI) was 13.58 (5.10–36.20). In FH men total SIR (95% CI) was 2.35 (1.84–2.99), and in young men 25–39 years SIR (95% CI) was 7.46 (3.73–14.93). Conclusion: Women and men with genetically verified FH have significantly higher incidence of AMI compared to the general Norwegian population. Highest incidences were found in young age groups 25–39 years where the incidence was more than 13-fold and 7-fold increased respectively. Cerebro vascular disease was statistically significantly increased in FH men 40-40 years only.
Author Disclosures: L.J. Mundal: None. J. Igland: None. G.S. Tell: None. M.B. Veierød: None. K.B. Holven: Research Grant; Significant; Tine, Mills, Olympic Seafood. Other Research Support; Significant; Sanofi, Amgen. Consultant/Advisory Board; Modest; Pronova and Amgen. R. Selmer: None. T. Wisløff: None. I.S. Kristiansen: None. T.P. Leren: None. K. Retterstøl: Research Grant; Significant; Oslo Economics. Honoraria; Modest; MSD (Norway), Amgen, Sanofi, Norwegian Medical Association, Mills DA.
21273 A Loss-of-Function Variant in CETP Is Associated With Altered Lipid Metabolism but Not With Cardiovascular Disease Incidence in Chinese Adults
Zhengming Chen1, Iona Y Millwood2, Derrick A Bennett1, Ruth Boxall2, Robert Clarke1, Richard Peto1, Robin G Walters1, Michael V Holmes2, Rory Collins1, China Kadoorie Biobank Collaborative Group; 1Nuffield Dept of Population Health, Univ of Oxford, Oxford, United Kingdom, 2MRC Population Health Rsch Unit, Univ of Oxford, Oxford, United Kingdom.
Introduction: Raising HDL-C through cholesteryl ester transfer protein (CETP) inhibition may represent an important strategy for cardiovascular disease (CVD) prevention and treatment. However, recent phase III trials of CETP inhibitors have reported no apparent beneficial effects on CVD risk. In East Asians, a loss-of-function variant rs2303790 (c.1376A>G, p.D459G) in the CETP gene can help assess the effects of lifelong lower CETP activity. Hypothesis: A loss-of-function variant in CETP, mimicking pharmacological inhibition of CETP, may associate with lower risk of CVD. Methods: The China Kadoorie Biobank recruited 512,891 adults aged 30–79 years in 2004–08 from 10 areas in China, with follow-up through linkage to registries and electronic health records. rs2303790 was genotyped in 91,850 individuals (75,200 population-based and 16,650 CVD case-control samples) of whom 17,850 had conventional lipid measurements and 4,650 had lipoprotein subtypes measured by NMR-metabolomics. Linear and logistic regression models yielded adjusted per allele effects for continuous traits and for 11,650 occlusive CVD events (comprising 75% ischaemic strokes and 25% major coronary events). Results: The CETP loss-of-function variant (frequency 2.2%) was associated with an increase of 0.53 standard deviations per allele (95% CI 0.45–0.60) in HDL-C (equivalent to 6.1 mg/dL), but had little effect on LDL-C concentration. Significant effects of the CETP loss-of-function variant on circulating metabolites included larger HDL particle size, smaller LDL particle size, and within HDL particles, increased cholesterol esters and reduced triglycerides relative to total lipids. However, the CETP loss-of-function variant was not associated with lower risk of occlusive CVD (per allele odds ratio 1.02, 95% CI 0.91–1.14) or with the individual outcomes ischaemic stroke or major coronary events. Conclusions: A loss-of-function variant in CETP was associated with major changes in HDL metabolism, consistent with inhibition of CETP function, but had no significant effects on risk of CVD. These results do not support the hypothesis that increasing HDL-C by CETP inhibition confers protection against CVD in East Asians.
Author Disclosures: Z. Chen: Research Grant; Significant; This study was part-funded by a research grant from Merck. I.Y. Millwood: None. D.A. Bennett: None. R. Boxall: None. R. Clarke: None. R. Peto: None. R.G. Walters: None. M.V. Holmes: None. R. Collins: Research Grant; Significant; This study was part-funded by a research grant from Merck.
21050 Prospective Clinical Implementation of CYP2C19-Genotype Guided Antiplatelet Therapy After PCI: a Multi-Site Investigation of MACE Outcomes in a Real-World Setting
Larisa H Cavallari1, Joshua C Denny2, Craig R Lee3, Amber L Beitelshees4, Julio D Duarte5, Steve E Kimmel6, Deepak Voora7, Caitrin W McDonough1, Yan Gong1, Wei-Qi Wei2, Victoria M Pratt8, Supatat Chumnumwat5, James C Coons9, Rhonda M Cooper-DeHoff1, Chintan V Dave10, Chrisly Dillon11, Issam S Hamadeh1, Lindsay Hines12, Lucius A Howell13, Linda J Jeng4, Yee M Lee5, Todd C Skaar14, Vindhya B Sriramoju13, James M Stevenson15, Mark R Vesely4, Dyson Wake1, Rolf P Kreutz16, George A Stouffer13, Russell A Wilke17, Philip E Empey18, Nita A Limdi19, Dan M Roden20, Alan R Shuldiner4, Julie A Johnson21, Josh F Peterson2; 1Pharmacotherapy and Translational Rsch and Cntr for Pharmacogenomics, Univ of Florida, Gainesville, FL, 2Biomedical Informatics and Medicine, Vanderbilt Univ Med Cntr, Nashville, TN, 3Pharmacotherapy and Experimental Therapeutics, Univ of North Carolina at Chapel Hill, Chapel Hill, NC, 4Medicine, Univ of Maryland, Baltimore, MD, 5Pharmacy Practice, Univ of Illinois at Chicago, Chicago, IL, 6Medicine, Univ of Pennsylvania, Philadelphia, PA, 7Medicine, Duke Univ, Durham, NC, 8Med and Molecular Genetics, Indiana Univ, Indianapolis, IN, 9Pharmacy and Therapeutics, Univ of Pittsburgh Sch of Pharmacy, Pittsburgh, PA, 10Pharmaceutical Outcomes and Policy, Univ of Florida, Gainesville, FL, 11Neurology, Sch of Medicine, Univ of Alabama at Birmingham, Birmingham, AL, 12Neuropsychology, Univ of North Dakota, Fargo, ND, 13Div of Cardiology, Univ of North Carolina at Chapel Hill, Chapel Hill, NC, 14Medicine, Indiana Univ of Medicine, Indianapolis, IN, 15Pharmacy and Therapeutics, Cntr for Clinical Pharmacuetical Sciences, Univ of Pittsburgh Sch of Pharmacy, Pittsburgh, PA, 16Clinical Medicine, Indiana Univ, Indianapolis, IN, 17Internal Medicine, Univ of South Dakota, Sioux Falls, SD, 18Pharmacy and Therapeutics, Cntr for Clinical Pharmacuetical Sciences, Univ of Pittsburgh, Pittsburgh, PA, 19Neurology and Hugh Kaul Persoanlized Medicine Institute, Sch of Medicine, Univ of Alabama at Birmingham, Birmingham, AL, 20Depts of Biomedical Informatics and Medicine, Vanderbilt Univ Med Cntr, Nashville, TN, 21College of Pharmacy, Univ of Florida, Gainesville, FL.
Introduction: CYP2C19 loss-of-function (LOF) alleles impair clopidogrel (clop) effectiveness after percutaneous coronary intervention (PCI), but the impact on clinical outcomes of a genotype-guided antiplatelet therapy (APT) approach is unknown. A collaboration across 9 U.S. institutions examined outcomes after prospective clinical implementation of CYP2C19 genotype-guided APT in a real-world setting. Methods: Each site conducted CYP2C19 clinical genotyping and recommended alternative APT in LOF allele carriers post PCI. Major adverse cardiovascular events (MACE) within 12 months post PCI were quantified in 7 sites via manual electronic medical record (mEMR) abstraction, and are being validated using data from 2 sites with automated (aEMR) extraction. Time to MACE, defined as death, MI, or stroke with mEMR abstraction, was compared in LOF allele carriers receiving clop (LOF-clop) versus LOF allele carriers receiving alternative APT (LOF-alt). Kaplan Meier survival and Cox regression analyses were performed. Results: In the 7 sites with mEMR abstraction (n=1815), mean age was 63±12 years, 78% were White, and 572 (31.5%) had a LOF allele. MACE risk was significantly higher in LOF-clop patients compared with LOF-alt patients (HR: 2.3, 95% CI: 1.2-4.5; p=0.0154, Figure). Adjusting for clinical covariates did not affect results. Validation of findings at 2 sites with aEMR extraction is underway. Conclusions: In data collected in a real-world setting with CYP2C19 genotyping as part of clinical care after PCI, there was a higher risk for MACE in CYP2C19 LOF patients who were prescribed clopidogrel versus alternative antiplatelet therapy.
Author Disclosures: L.H. Cavallari: None. J.C. Denny: None. C.R. Lee: None. A.L. Beitelshees: None. J.D. Duarte: None. S.E. Kimmel: None. D. Voora: None. C.W. McDonough: None. Y. Gong: None. W. Wei: None. V.M. Pratt: None. S. Chumnumwat: None. J.C. Coons: None. R.M. Cooper-DeHoff: None. C.V. Dave: None. C. Dillon: None. I.S. Hamadeh: None. L. Hines: None. L.A. Howell: None. L.J. Jeng: None. Y.M. Lee: None. T.C. Skaar: None. V.B. Sriramoju: None. J.M. Stevenson: None. M.R. Vesely: None. D. Wake: None. R.P. Kreutz: None. G.A. Stouffer: None. R.A. Wilke: None. P.E. Empey: None. N.A. Limdi: None. D.M. Roden: Research Grant; Modest; NIH. A.R. Shuldiner: None. J.A. Johnson: None. J.F. Peterson: None.
Risk Reduction Strategies on a Global Stage
21002 A Comprehensive Lifestyle Intervention in Patients With Coronary Artery Disease: Main Results of the Randomized Multicenter Response 2 Trial
Ron Peters1, Madelon Minneboo1, Sangeeta Lachman1, Marjolein Snaterse2, Harald Jorstad1, Gerben ter Riet3, Matthijs Boekholdt1, Wilma Scholte op Reimer2; 1Cardiology, Academic Med Cntr, Amsterdam, Netherlands, 2Faculty of Health, Amsterdam Univ of Applied Sciences, Amsterdam, Netherlands, 3General Medicine, Academic Med Cntr, Amsterdam, Netherlands.
Background: In patients with coronary artery disease (CAD) targets for smoking cessation, weight reduction and adequate physical activity are rarely met. New approaches are needed to improve these lifestyle related risk factors (LRRFs). Objective: The Randomized Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists (RESPONSE) 2 trial evaluates the effect of referral of patients with CAD to a set of comprehensive lifestyle programs, using three established, community-based interventions, on top of usual care. Methods: The RESPONSE 2 trial is a multicenter, randomized clinical trial in 15 medical centers in the Netherlands. Patients (≥18 years) hospitalized for CAD, with at least one LRRF, were included. All patients received guideline-based usual care, including outpatient care by cardiologists and specialized nurses, and cardiac rehabilitation. Patients in the intervention group (and their partners, if appropriate) were referred to one, two or three widely available programs targeting 1) weight reduction (Weight WatchersTM) 2) improvement of physical activity (Philips DirectLifeTM) and 3) smoking cessation (telephone coaching: LuchtsignaalTM). The primary outcome is the proportion of patients who improved on at least one LRRF without deterioration in the other two at 12 months. We consider a 30% relative increase in the proportion of successful patients in the intervention group compared with the control group clinically relevant. Results: 824 patients were randomized between April 2013 and July 2015. Mean age was 58.8 (SD±9.1) years, 48% were smokers, 87% had a BMI>25, and 62% had inadequate levels of physical activity. With 93% of follow-up complete (June 23, 2016), the proportion of successful patients in the intervention group is 36% (n=128) compared with 26% (n=88) in the control group (p=0.003), a relative increase of 38%. Final results will be available by July 7, 2016. Clinical importance: The RESPONSE 2 trial shows that referral to a comprehensive set of community-based lifestyle interventions can lead to important improvements of lifestyle-related risk factors in patients with CAD. As these lifestyle interventions are widely available, these interventions can readily be implemented into daily practice.
Author Disclosures: R. Peters: Research Grant; Significant; Philips, Weight Watchers, Möller Foundation. M. Minneboo: None. S. Lachman: None. M. Snaterse: None. H. Jorstad: None. G. ter Riet: None. M. Boekholdt: None. W. Scholte op Reimer: None.
21187 A Cluster Randomized Trial of a Comprehensive Approach for Hypertension Control in Low-income Patients in Argentina
Jiang He1, Vilma Irazola2, Katherine T Mills1, Rosana Poggio2, Andrea Beratarrechea2, Jacquelyn Dolan1, Chung-Shiuan Chen1, Luz Gibbons2, Marie Krousel-Wood3, Lydia A Bazzano1, Jing Chen3, Adolfo Rubinstein2, HCPIA Investigators; 1Dept of Epidemiology, Tulane Univ, New Orleans, LA, 2Southern Cone American Cntr of Excellence for Cardiovascular Health, Institute for Clinical Effectiveness and Health Policy, Buenos Aires, Argentina, 3Dept of Medicine, Tulane Univ, New Orleans, LA.
Although clinical trials have demonstrated that antihypertensive treatment lowers the risk of cardiovascular disease and mortality, uncontrolled hypertension is highly prevalent in low-income communities. We conducted a cluster randomized trial to test whether implementation of a comprehensive intervention program in a national public primary care network will improve hypertension control among uninsured hypertensive patients. We recruited 1,954 eligible participants from 18 clinics of the Remediar+Redes Program in Argentina. Nine clinics were randomly assigned to the intervention and 9 to usual care. The comprehensive intervention program includes health care provider education, blood pressure (BP) audit and feedback, BP self-monitoring, community health worker-led health education and counseling, and a mobile phone-based health message intervention over 18-months. The primary outcome, net change in systolic BP from baseline to month 18, was significantly reduced in the intervention group compared to the control group (see table). In addition, for the secondary outcomes, net change in diastolic BP was significantly reduced and the proportion of controlled hypertension at 18 months was significantly increased in the intervention group compared to the control group. Furthermore, high adherence to antihypertensive medications (Morisky Score =8) and intensification of antihypertensive medications over the 18-month intervention were significantly higher in the intervention group. In conclusion, our study indicates that this multilevel comprehensive intervention program is effective for BP control among low-income hypertensive patients.
Author Disclosures: J. He: None. V. Irazola: None. K.T. Mills: None. R. Poggio: None. A. Beratarrechea: None. J. Dolan: None. C. Chen: None. L. Gibbons: None. M. Krousel-Wood: None. L.A. Bazzano: None. J. Chen: None. A. Rubinstein: None.
21264 A Randomized Trial of Community Health Action to Encourage healthy Behaviors: The Grenada Heart Project-Change Trial
Sameer Bansilal1, Jacqueline Latina1, Francis Martin2, Rajesh Vedanthan1, Samantha Sartori1, Michael Farkouh1, Claire Kofler1, Marcelle Lewis3, Marilyn Hunn1, Valentin Fuster1; 1The Cardiovascular Institute, Icahn Sch of Medicine at Mount Sinai, New York, NY, 2Primary Health Care, St. George’s Univ and Ministry of Health, St. George, Grenada, 3Health Services Rsch, The Grenada Heart Project, St. George, Grenada.
Introduction: Cardiovascular diseases stem from modifiable risk factors. Peer support is a proven strategy for many chronic illnesses. Randomized trials assessing the efficacy of this strategy for global CV risk factor modification in low resource settings are lacking. Hypothesis: We assessed the hypothesis that a peer-group strategy helps improve healthy behaviors in individuals with CV risk factors in the Caribbean Islands of Grenada. Methods: We recruited 402 adults from the Grenada Heart Project (GHP) Cohort Study of 2827 subjects with at least two risk factors: diabetes (19.5%), hypertension (34%), overweight (65%), smoking (4.5%), low fruit/vegetable intake (56.5%) or physical inactivity (51%). Subjects were randomized 1:1 to a peer-group based intervention group (IG) or a self-management control group (CG) for 12 months. Peer-elected leaders moderated monthly meetings involving role-play, brainstorming and activities to address emotions, diet and exercise. The primary outcome was mean change in a composite score related to Blood pressure, Exercise, Weight, Alimentation, Tobacco and Quality of Life (Fuster-BEWAT plus score, scale of 0–21). Multilevel models with the parish as cluster variable were applied to assess differences between groups. Results: Participants’ mean age was 51 ± 14 years, 66% female, with mean baseline Fuster-BEWAT plus score of 9.4 ± 2.7. The 12-month primary outcome assessment for all subjects will be complete on Jun 30, 2016. If accepted, we will present the detailed primary results of this community-based trial conducted in a low resource setting (Primary results Table/Figure shell underneath). Conclusion: The GHP-CHANGE will evaluate the impact of a peer-group intervention on CV risk factors in a low resource setting for a cohort with multiple risk factors.
Author Disclosures: S. Bansilal: None. J. Latina: None. F. Martin: None. R. Vedanthan: None. S. Sartori: None. M. Farkouh: None. C. Kofler: None. M. Lewis: None. M. Hunn: None. V. Fuster: None.
21272 Large Scale Analysis of Lifetime Risk of Cardiovascular Disease in Europe and Population Attributable Risk of Cardiovascular Risk Factors for the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Investigators
Stefan Blankenberg, BiomarCaRE Consortium; General and Interventional Cardiology, Univ Heart Cntr Hamburg, Hamburg, Germany.
The lifetime risk of cardiovascular diseases (CVDs) has not been reported on a European level. Europe needs a better defined and adjusted cardiovascular risk score for CVD. We tested the single and aggregate effect of cardiovascular risk factors on CVD outcome in Europe and identified the population attributable risk of traditional and novel cardiovascular risk factors. We conducted a meta-analysis at the individual level using the European BiomaCaRE project (Biomarkers for Cardiovascular Risk Assessment in Europe) involving >250,000 participants with 22,144 incident cardiovascular events during a maximum follow up of 29 years. We calculated prevalence of risk factors (smoking, hypertension, total cholesterol, diabetes and body-mass-index) according to age groups for men and women. We estimated the population attributable risks (PARs) of above mentioned risk factors for the 10-year incidence and lifetime risk of cardiovascular outcome. Of the 22,144 individuals suffering from incident CVD in Europe only 958 (4.3 %) were free of cardiovascular risk factors at baseline, 4,707 (21.3 %) had at least one risk factor, 39.7% had 2 and 34.8% 3 or more cardiovascular risk factors at baseline examination. Diabetes (hazard ratio (HR) (2.17, PAR 12.6%), smoking 1.90, PAR 5.4%) and hypertension (1.69, PAR 5.6%) accounted for the highest PAR followed by total cholesterol (1.45, PAR 3.6 %) and BMI (1.28, PAR 2.8%). All risk factors were significantly related to incident CVD, were noted in men and women, with moderated differences between European regions. The figure denotes the magnitude of PAR according to each risk factor (Figure 1 PARs according to age groups). The present study represents the largest analysis of lifetime risk of CVD in Europe. Smoking, diabetes, abnormal lipids, hypertension, and abdominal obesity, account for 30% of cardiovascular disease risk in Europe and is differentially weighted according to age groups, gender and European regions.
Author Disclosures: S. Blankenberg: None.
Hi Impact EP Registries and Clinical Trials
21098 Atrial Substrate Modification With Aggressive Blood Pressure Control to Prevent Atrial Fibrillation (SMAC AF)
Ratika Parkash1, George Wells2, John Sapp1, Jeffrey Healey3, Jean-Claude Tardif4, Isabelle Greiss5, Lena Rivard6, Jean-Francois Roux7, David Birnie8, Andrew Ha9, Stephen Wilton10, Iqwal Mangat11, Christopher Gray1, Evan Lockwood12, Isabelle Nault13, Martin Gardner1, Anthony Tang14; 1Medicine, QEII Health Sciences Cntr, Halifax, Canada, 2Epidemiology and Biostatistics, Univ of Ottawa Cardiovascular Rsch Methods Cntr, Ottawa, Canada, 3Medicine, Population Health Rsch Institute, Hamilton, Canada, 4Cardiology, Montreal Heart Institute, 5000, rue Belanger, Canada, 5Medicine, Cntr Hospier de l’Universite de Montreal, Montreal, Canada, 6Cardiology, Montreal Heart Institute, Montreal, Canada, 7Medicine, Cntr Hospier de Universite de Sherbrooke, Sherbrooke, Canada, 8Medicine, Univ of Ottawa Heart Institute, Ottawa, Canada, 9Medicine, Peter Munk Cardiac Cntr, Univ Health Network, Toronto, Canada, 10Medicine, Univ of Calgary, Calgary, Canada, 11Medicine, St. Michael’s Hosp, Toronto, Canada, 12Medicine, CK Hui Heart Cntr, Edmonton, Canada, 13Medicine, Universite de Laval, Quebec City, Canada, 14Medicine, London Health Sciences Cntr, London, Canada.
Background: Hypertension is a known risk factor for atrial fibrillation (AF) and results in 20% of the attributable risk for AF. Hypertension has been shown to aggravate both triggers and the atrial substrate necessary for initiation and maintenance of AF. Aggressive blood pressure lowering may prevent and reverse this. Recent evidence supports aggressive blood pressure lowering reduces cardiovascular risk, yet there is no evidence that this therapy will prevent recurrent AF in any population. We designed a randomized clinical trial to determine whether aggressive blood pressure lowering prevents recurrent AF. Study Design: This is a randomized, open-label trial with blinded endpoint evaluation in patients who underwent catheter ablation for paroxysmal and persistent AF. Patients were randomized in a 1:1 ratio to either aggressive blood pressure lowering or standard treatment prior to and following the ablation procedure. The primary outcome was time to symptomatic recurrence of AF lasting greater than 30 seconds after a 3 month blanking period post-ablation. The secondary outcomes were any recurrence of AF post-randomization, visits to the emergency department, AF hospitalizations, thromboembolic events and quality of life (measured by the CCS-SAF scale, SF-36 and AF severity scales). Sample Size: The study was designed to achieve 80% power to detect a 30% relative risk reduction in the primary outcome with a median follow-up of 18 months, accounting for a 1% loss to follow up, 0% crossover and 1% dropout rate, with a projected overall number of patients with primary outcome number of events to be 99 (53.8%). Study population: There were 173 patients enrolled into the study from July, 2011 and October, 2015 who underwent catheter ablation. At baseline, the mean age was 59.7± 8.7 years; 128 (74 %) were male; 130 (75.1% had a history of hypertension, mean SBP was 142.8±11.9 mmHg; 99 (57.2 %) had paroxysmal AF, and mean LA diameter was 41.6±6.6 mm. Results: The primary endpoint has thus far been reached in 104 (60.1%) patients with a median follow-up of 9.8 (IQR: 4.9 to 19.6) months. The final data analysis with the intention-to-treat principle of primary and major secondary endpoint will be completed in October and will be available for the AHA presentation.
Author Disclosures: R. Parkash: Research Grant; Significant; St. Jude Medical, Medtronic. Other Research Support; Significant; Canadian Insitute of Health Research, Heart and Stroke Foundation of Canada. Honoraria; Modest; Pfizer. G. Wells: None. J. Sapp: Research Grant; Significant; St. Jude, Johnson and Johnson, Heart and Stroke Foundation of Canada, Canadian Institute of Health Research. J. Healey: None. J. Tardif: None. I. Greiss: None. L. Rivard: Research Grant; Significant; Bayer, Canadian Stroke Prevention Intervention Network. J. Roux: Speakers Bureau; Modest; BMS-Pfizer, Boehringer-Inhelheim, Bayer. Consultant/Advisory Board; Modest; BMS-Pfizer, Boehringer-Inhelheim, Bayer. D. Birnie: None. A. Ha: None. S. Wilton: Research Grant; Significant; St. Jude Medical. Honoraria; Modest; Boehringer-Ingelheim. Consultant/Advisory Board; Modest; Arca Biopharma. I. Mangat: None. C. Gray: None. E. Lockwood: Research Grant; Modest; Bayer, Boehringer-Ingelheim, Medtronic. Speakers Bureau; Modest; Bayer, Boehringer-Ingelheim, BMS/Pfizer. Consultant/Advisory Board; Modest; Bayer, Boehringer-Ingelheim. I. Nault: None. M. Gardner: None. A. Tang: None.
21099 Prevalence of Sub-Clinical Atrial Fibrillation Using an Implantable Cardiac Monitor in Patients With Cardiovascular Risk Factors: ASSERT II
Jeff S Healey1, Marco Alings2, Peter Leong-Sit3, Jacob J de Graaf4, David H Birnie5, Michel Freericks6, Andrew Ha7, Atul Verma8, Darryl Leong9, Hisham Dokainish10, Francois Philippon11, Walid Barake12, Kim Simek13, Michael D Hill14, Jia Wang13, Mark Carlson15, William F McIntyre1, Stuart J Connolly1; 1Arrhythmia, McMaster Univ, Hamilton, Canada, 2Arrhythmia, Amphia Ziekenhuis & Julius Clinical, Breda, Netherlands, 3Arrhythmia, London Health Sciences Cntr Univ Hosp, London, Canada, 4Arrhythmia, Nij Smellinghe Ziekenhuis, Drachten, Netherlands, 5Cardiology, Univ of Ottawa Heart Institute, Ottawa, Canada, 6Arrhythmia, Montessoriweg, AN, Netherlands, 7Electrophysiology, Peter Munk Cardiac Cntr, Univ Health Network, Toronto, Canada, 8Arrhythmia, Southlake Regional Health Cntr, Newmarket, Canada, 9Arrhythmia, PHRI, McMaster Univ and Hamilton Health Sciences, Hamilton, Canada, 10Cardiology, McMaster Univ, Hamilton, Canada, 11Cardiology, Quebec Heart and Lung Institute, Quebec, Canada, 12Cardiology, Univ of Alberta, Mazankowski Alberta Heart Institute, Edmonton, Canada, 13Arrhythmia, Population Health Rsch Institute, Hamilton, Canada, 14Clinical Neurosciences, Univ of Calgary, Calgary, Canada, 15Arrhythmia, St. Jude Med, Sylmar, CA.
Background: Atrial fibrillation (AF)-associated strokes are common, severe and are highly preventable with the oral anticoagulation (OAC). The TRENDS and ASSERT studies demonstrated that short-lasting, typically asymptomatic episodes of sub-clinical AF are common in individuals with pacemakers; and associated with an increased risk of stroke. The prevalence of sub-clinical AF among older individuals without pacemakers is not known. Implantable, sub-cutaneous devices now permit long-term, continuous cardiac rhythm monitoring and automatic detection of AF. Methods: At 26 sites in Canada and the Netherlands, we conducted a prospective cohort study to determine the incidence of sub-clinical AF lasting ≥ 5 minutes. Patients ≥ 65 years old were enrolled if they had a CHA2DS2-VASc score of ≥ 2, or a history of obstructive sleep apnea, or had a BMI > 30. Subjects ALSO had to have evidence of left atrial enlargement (diameter ≥ 4.4 cm or volume ≥ 58 mL), or a serum NT-ProBNP ≥ 290 pg/mL. Patients were excluded if they had previously documented AF or flutter, had an implanted pacemaker or defibrillator, were receiving chronic OAC therapy, or had scheduled plans for cardiac surgery in the next 6 months. Consenting patients received a St. Jude Confirm® implantable loop recorder. Results: A total of 273 eligible patients were enrolled, of whom 256 received the Confirm loop recorder. The avg. age of participants was 73.9 ± 6.2 years, and 34% were female. Their average CHA2DS2-VASc score was 4.1 ± 1.4; 73% had a history of hypertension, 25% had diabetes mellitus, 32% had vascular disease, 11% had documented sleep apnea, and 20% had a prior history of stroke. The average NT-ProBNP at baseline was 417 ± 1041 pg/mL, left atrial diameter was 4.7 ± 0.8 cm and left atrial volume was 76.5 ± 20.6 mL. Patients have been followed for an avg. of 14.6 ± 5.0 months, and follow-up will be complete in July 2016. All device-detected AF will be adjudicated by committee. Conclusion: The ASSERT-II trial will report the incidence of sub-clinical AF among individuals 65 years and older who do not have pacemakers, and will determine if any clinical, biochemical or echocardiographic variables predict sub-clinical AF. ASSERT-II will help determine if monitoring for sub-clinical AF is an attractive screening strategy.
Author Disclosures: J.S. Healey: None. M. Alings: None. P. Leong-Sit: Consultant/Advisory Board; Modest; St. Jude Medical. J.J. de Graaf: None. D.H. Birnie: None. M. Freericks: None. A. Ha: None. A. Verma: None. D. Leong: None. H. Dokainish: None. F. Philippon: None. W. Barake: None. K. Simek: None. M.D. Hill: None. J. Wang: None. M. Carlson: Employment; Significant; St. Jude Medical. W.F. McIntyre: None. S.J. Connolly: None.
21232 The San Francisco POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study
Zian H Tseng1, Jeffrey Olgin1, Philip Ursell2, Eric Vittinghoff3, Anthony S Kim4, Amy P Hart5, Ellen Moffatt5; 1Medicine, Div of Cardiology, Section of Cardiac Electrophysiology, UC San Francisco, San Francisco, CA, 2Pathology, UC San Francisco, San Francisco, CA, 3Epidemiology and Biostatistics, UC San Francisco, San Francisco, CA, 4Neurology, UC San Francisco, San Francisco, CA, 5Pathology, Office of Chief Med Examiner, San Francisco, San Francisco, CA.
Introduction: Sudden cardiac death (SCD) is a leading cause of mortality worldwide, yet prior studies have used retrospective death certificate (DC) methods or epidemiologic definitions (WHO, Hinkle-Thaler) that infer cardiac cause of death (COD) from paramedic records thus its true incidence is unknown. > 90% of SCDs occur out of hospital (OOH); investigation after such natural deaths is not routine coroner/medical examiner (ME) practice, thus autopsies are rarely performed and underlying COD are unknown. We performed active surveillance of all OOH deaths reported to the ME to identify and autopsy all incident WHO-defined SCDs to precisely define its burden and COD. Methods: Between 2/1/2011 and 3/1/2014, we identified incident WHO SCDs ages 18–90 for detailed autopsy, toxicology, and histology via surveillance of consecutive OOH deaths, which must be reported to the ME by law. All county DC were reviewed to cross-check for missed SCDs. A multidisciplinary committee adjudicated final COD. Sudden arrhythmic deaths (SAD) had no extra-cardiac COD (eg, tamponade, PE, hemorrhage) or acute HF. Results: Of 3,658 OOH deaths, we identified 541 SCDs over 37 months (mean 62.8 y, 69% male); 525 (97%) were autopsied. An additional 89 SCDs were within 3 weeks of immediate medical care with DC signed by MD, therefore were ineligible for autopsy but included in citywide incidence of 28.9/100,000 person-y, with differences by sex and race (P<0.0005). 342 of 525 SCDs (65%) had no cardiac history. Leading COD were coronary disease (32%), occult overdose (14%), cardiomyopathy (10%), hypertrophy (9%), and neurologic (5%, Fig). SADs were 56% of overall (294/525), 65% (78/120) of witnessed, and 53% (216/405) of unwitnessed SCDs (P=NS). Among witnessed SCDs, VT/VF predicted SAD (91%) and PEA non-SAD (87%, p<0.0001). Conclusion: In the autopsy-defined POST SCD study, capturing nearly all OOH SCDs in an entire ethnically diverse metropolitan area, just over half of presumed SCDs were actually SAD.
Author Disclosures: Z.H. Tseng: Research Grant; Significant; NIH/NHLBI R01HL102090, NIH/NHLBI R01HL12655, CDC DP14-1403, NIH. J. Olgin: None. P. Ursell: None. E. Vittinghoff: None. A.S. Kim: None. A.P. Hart: None. E. Moffatt: None.
21092 Idarucizumab For Dabigatran Reversal: Updated Results Of The Re-verse Ad Study
Charles V Pollack1, Paul A Reilly2, Joanne van Ryn3, John Eikelboom4, Stephan Glund5, Richard A Bernstein6, Robert Dubiel2, Menno V Huisman7, Elaine M Hylek8, Pieter W Kamphuisen9, Joerg Kreuzer10, Jerrold H Levy11, Frank W Sellke12, Joachim Stangier13, Thorsten Steiner14, Bushi Wang2, Chak-Wah Kam15, Jeffrey I Weitz16; 1Emergency Medicine, Thomas Jefferson Univ, Philadelphia, PA, 2CV, Boehringer Ingelheim, Ridgefield, CT, 3CV, Boehringer Ingelheim, Biberach, Germany, 4Hematology, McMaster Univ, Hamilton, Canada, 5CV, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, 6Neurology, Feinberg Sch of Medicine of Northwestern Univ, Chicago, IL, 7Hematology, Leiden Univ Med Cntr, Leiden, Netherlands, 8Medicine, Boston Univ Sch of Medicine, Boston, MA, 9Medicine, Tergooi Hosp, Hilversum, Netherlands, 10CV, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany, 11Anesthesiology & Critical Care, Duke Univ Sch of Medicine, Durham, NC, 12Surgery, Brown Med Sch and Rhode Island Hosp, Providence, RI, 13CV, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany, 14Neurology, Klinikum Frankfurt Höchst, Frankfurt, Germany, 15Emergency Medicine, Tuen Mun Hosp, Tuen Mun, Hong Kong, 16Hematology, McMaster Univ and Thrombosis and Atherosclerosis Rsch Institute, Hamilton, Canada.
Background: Dabigatran is a widely used oral thrombin inhibitor. Idarucizumab, a humanized antibody Fab fragment directed against dabigatran, was recently licensed for reversal of the anticoagulant effects of dabigatran. In the first 90 patients enrolled in this prospective cohort study (N Eng J Med 2015;373:511), idarucizumab rapidly and completely reversed dabigatran’s effect. No safety concerns were identified. Aims: To evaluate further the efficacy and safety of idarucizumab in dabigatran-treated patients whose clinical status warrants urgent anticoagulation reversal. Methods: RE-VERSE AD is a multinational, open-label study with a target sample size of approximately 500 patients presenting with life-threatening or uncontrolled bleeding (Group A) or requirement for urgent surgery or intervention that cannot be delayed (Group B). Patients are given 5 g (2x2.5g vials) of idarucizumab by IV bolus injection. The primary endpoint is maximum reversal of the anticoagulant effect of dabigatran within 4 hours after idarucizumab administration, based on central lab determination of the diluted thrombin time (dTT) and ecarin clotting time (ECT). Dabigatran and idarucizumab levels are also determined. Clinical outcomes, including time to cessation of bleeding (when possible to determine), hemostasis at surgery, post-reversal thrombotic events, mortality, and other safety indicators are assessed. Results: As of submission, 494 patients have been enrolled; 60% in Group A and 40% in Group B. We will report efficacy and safety, and the numbers of patients with intracranial bleeding, with gastrointestinal bleeding, with traumatic injuries, and those requiring urgent procedures. Consistent with initial results, idarucizumab rapidly normalized the dTT and ECT with sustained reversal in the majority of patients. Cases of recurrent bleeding, repeat doses of idarucizumab, post-reversal thrombotic events, other safety outcomes, and 3 month follow-up will be reported. Conclusion: Idarucizumab is a specific reversal agent for dabigatran that rapidly, safely, and durably reverses its anticoagulant effects in the emergency setting.
Author Disclosures: C.V. Pollack: Research Grant; Significant; AstraZeneca. Honoraria; Modest; Daiichi-Sankyo. Honoraria; Significant; Boehringer Ingelheim, Janssen Pharma, BMS/Pfizer. P.A. Reilly: Employment; Significant; Boehringer Ingelheim. J. van Ryn: Employment; Significant; Boehringer Ingelheim. J. Eikelboom: Honoraria; Significant; Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Janssen, Pfizer. S. Glund: Employment; Significant; Boehringer Ingelheim. R.A. Bernstein: Honoraria; Significant; Boehringer Ingelheim, Medtronic. R. Dubiel: Employment; Significant; Boehringer Ingelheim. M.V. Huisman: Honoraria; Significant; Boehringer Ingelheim. E.M. Hylek: Honoraria; Modest; Bayer, Daiichi Sankyo, Janssen, Medtronic, Pfizer, Portola, Armetheon. Honoraria; Significant; Boehringer Ingelheim, BMS. P.W. Kamphuisen: Honoraria; Significant; Boehringer Ingelheim. J. Kreuzer: Employment; Significant; Boehringer Ingelheim. J.H. Levy: Honoraria; Modest; Daiichi Sankyo, Grifols, CSL Behring, Instrumentation labs, Janssen. Honoraria; Significant; Boehringer Ingelheim. F.W. Sellke: Honoraria; Modest; Boehringer Ingelheim. J. Stangier: Employment; Significant; Boehringer Ingelheim. T. Steiner: Research Grant; Significant; Octapharma. Honoraria; Modest; Bayer, BMS/Pfizer, Daiichi-Sankyo, Octapharma. Honoraria; Significant; Boehringer Ingelheim. B. Wang: Employment; Significant; Boehringer Ingelheim. C. Kam: None. J.I. Weitz: Honoraria; Modest; Merck, Johnson & Johnson, Ionis. Honoraria; Significant; Boehringer Ingelheim, Bayer, Janssen, BMS, Pfizer, Daiichi-Sankyo.
2016 Late-Breaking Resuscitation Science Abstracts
Resuscitation Science Symposium
Late-Breaking Resuscitation Science Session
23290 The Impact of Innovative Early Warning Electronic Information System on Reducing In-Hospital Cardiac Arrest
Shu-Hung Kuo1, Wei-Chun Huang2, Wang-Chuan Juan1, Kun-Chang Lin1, Wang-Ting Hung1, Meng-Wei Ke1, Cheng-Hung Chiang1, Sheng-Che Lin1, Chin-Chang Cheng1, Po Hsiang Lin1, Kai-Yu Fong1, De-sheng Hou1, Shue-Ren Wann1, Yao-shen Chen1, Guang-Yuan Mar1, Chun-Peng Liu1; 1Kaohsiung Veterans General Hosp, Kaohsiung City, Taiwan, 2Section of Critical care medicine, Kaohsiung Veterans General Hosp, Fooyin Uni. & Yang Ming Uni., Kaohsiung City, Taiwan.
Backgrounds: Despite improvement of outcomes after in-hospital cardiac arrest (IHCA), the rate of survival to discharge is still less than 25%. American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care add surveillance and prevention into new IHCA chains of survival, which means early warning system is critical for IHCA patients. The aim of this study is to investigate the impact innovative early warning electronic information system on reducing in-hospital cardiac arrest in a tertiary medical center. Methods: Since 2015, we organized a multidisciplinary team, including cardiologists, intensivists, emergency physicians, and nursing staffs. The key interventions in this program include electronic national early warning score information system, real time early warning screen saver and electric board, nurses and physicians computer-based reminding alarm if NEWS ≥7 or more than highest scores among previous 3 measurements, in service education and early warning monitor team. Total 143,450 patients admitted between January 2013 and January 2016 were divided into 3 groups: pre-interventional group (Jan 2013 to April 2015; n=707,957 patient-day), Interventional group (May to June 2015; n=52,687 patient-day) and post-interventional group (July 2015 to Jan 2016; n=184,636 patient-day). Results: The incidence of In-hospital cardiac arrest improved from 0.38% in pre-interventional group, to 0.32% in interventional group and to 0.20% in post-interventional group (p<0.05). The 48 hours survival rate in IHCA patients increased from 34.4% in pre-interventional group, to 41.2% in interventional group and to 45.4% in post-interventional group (p<0.05). The rate of survival to discharge in IHCA patients with pulseless ventricular tachycardia/fibrillation (VT/Vf) increased from 15.6%, to 37.5% and 50% in post-interventional group (p<0.05).The rate of survival to discharge in IHCA patients increased from 15.6%, to 29.4% and 36.4% in post-interventional group (p<0.05). Conclusion: The study demonstrated that innovative early warning electronic information system could improve the rate of IHCA, 48 hours survival rate and discharge survival rate in IHCA patients with or without pulseless VT/Vf.
Author Disclosures: S. Kuo: None. W. Huang: None. W. Juan: None. K. Lin: None. W. Hung: None. M. Ke: None. C. Chiang: None. S. Lin: None. C. Cheng: None. P. Lin: None. K. Fong: None. D. Hou: None. S. Wann: None. Y. Chen: None. G. Mar: None. C. Liu: None.
23382 Impact of Bystander AED Use on Survival And Functional Outcomes in Shockable Observed Public Cardiac Arrest
Ross A Pollack1, Siobhan Brown2, Tom Rea2, Tom Aufderheide3, Jason Buick4, Jim Christenson5, Ahamed Idris6, Jamie Jasti3, Mike Kampp7, Peter Kudenchuk2, Susanne May2, Laurie Morrison4, Marc Muhr8, Graham Nichol2, Joseph P Ornato9, George Sopko10, Christian Vaillancourt11, Myron Weisfeldt12; 1MD Program, Johns Hopkins Sch of Medicine, Baltimore, MD, 2Univ of Washington, Seattle, WA, 3Med College of Wisconsin, Milwaukee, WI, 4Univ of Toronto, Toronto, Canada, 5Univ of British Columbia, Vancouver, Canada, 6UT Southwestern, Dallas, TX, 7Oregon Health and Science Univ, Portland, OR, 8Clark County EMS, Vancouver, WA, 9Virginia Commonwealth Univ Health System, Richmond, VA, 10NIH/ NHLBI, Bethesda, MD, 11Univ of Ottawa, Ottawa, Canada, 12Johns Hopkins Sch of Medicine, Baltimore, MD.
Introduction: Survival following out of hospital cardiac arrest (OHCA) with a shockable rhythm can be improved with rapid defibrillation. Shockable cardiac arrest accounts for only 25% of total OHCA, but 60% are shockable when the arrest is public and witnessed. Bystander AED shock compared to EMS may reduce time to defibrillation and improve outcomes. Hypothesis: In shockable observed public (SOP) OHCA, bystander shock leads to improved survival and functional neurologic outcome compared to EMS shock. Methods: The Resuscitations Outcomes Consortium (ROC) assessed OHCA outcomes at 9 sites from 2005–2015. Data were from the ROC EPISTRY. Neurologic status was assessed from medical records by trained ROC staff. Favorable outcome was defined as modified Rankin score (mRS) of ≤2. Odds ratios were adjusted for age, sex and bystander CPR. Results: Of the total 50995 OHCA (2011–2015), 2540 were SOP OHCA. A bystander shocked 19% of these patients, compared to ~10% from 2005–2006. For the 2011–2015 cohort, compared to those with initial shock by EMS, SOP OHCA patients receiving shock by bystander were significantly more likely to survive to hospital discharge (67.4% vs 43.2%, adjusted OR 2.69 [2.13–3.41 p<0.001]) despite rapid EMS response times. In SOP OHCA for which neurological outcome is currently available (Table*), favorable neurological status was more common among those treated with a bystander compared to EMS shock (54.6% vs 32.2%, unadjusted OR 2.54 [2.05–3.13 p<0.0001]). Conclusion: Bystander AED use has been significant over the last ten years in SOP OHCA at ROC sites. Bystander shock is associated with a greater likelihood of survival to discharge and better functional status.
*Additional by presentation
Author Disclosures: R.A. Pollack: None. S. Brown: None. T. Rea: None. T. Aufderheide: None. J. Buick: None. J. Christenson: None. A. Idris: Research Grant; Modest; HeartSine, Inc. (AED manufacturer). Consultant/Advisory Board; Modest; HeartSine, Inc. (AED manufacturer). J. Jasti: None. M. Kampp: None. P. Kudenchuk: None. S. May: None. L. Morrison: None. M. Muhr: None. G. Nichol: None. J.P. Ornato: None. G. Sopko: None. C. Vaillancourt: None. M. Weisfeldt: None.
23375 Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest, a Randomized Controlled Trial
Sebastian Wiberg1, Christian Hassager2, Henrik Schmidt3, Jakob Hartvig Thomsen2, Martin Frydland2, Matias Greve Lindholm2, Dan Eik Høfsten2, Thomas Engstrøm2, Lars Køber2, Jacob Eifer Møller3, Jesper Kjaergaard2; 1Dept of Cardiology, Rigshospitalet - Copenhagen Univ Hosp, Copenhagen, Denmark, 2Rigshospitalet - Copenhagen Univ Hosp, Copenhagen, Denmark, 3Odense Univ Hosp, Odense, Denmark.
Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is approximately 50%. The leading cause of death is neurologic injury. Glucagon-like peptide-1 (GLP-1) analogs are approved for type 2 diabetes and pre-clinical and clinical data have suggested organ protective effects in patients undergoing ischemia and reperfusion. The aim of this trial was to investigate the neuroprotective effects of exenatide in resuscitated OHCA patients. Methods: We conducted a two-centre, double-blind trial randomizing 120 consecutive comatose OHCA patients to a 6 hour and 15 minutes infusion of 17.4 μg of exenatide (Byetta®) or placebo in addition to standardized intensive care. The co-primary endpoint was feasibility and efficacy; the latter defined as the geometrical area under the biomarker neuron-specific enolase (NSE) curve from 24 to 72 hours after admission. Secondary endpoints included 180-day mortality and a composite endpoint of death and poor neurologic function, defined as a cerebral performance category of three to five at 30 and 180 days. Results: Study drug was initiated within 240 minutes from return of spontaneous circulation in 96% of patients. Median blood glucose 8 hours after admission was lower in patients receiving exenatide versus placebo (5.8 (5.2–6.7) mmol/L versus 7.3 (6.2–8.7) mmol/L, p<0.0001). There was no significant difference in the area under the NSE-curve between the groups (Figure 1.a). The 180-day mortality in patients receiving exenatide was 28% compared to 38% in patients receiving placebo (pLog-Rank = 0.31, Figure 1.b). There was no significant difference in mortality or poor neurologic function. Adverse events were rare with no difference between groups. Conclusions: Acute administration of exenatide to comatose patients after OHCA is feasible and appears safe. Exenatide did not reduce NSE levels nor a composite endpoint of death or poor neurologic function after 180 days.
Author Disclosures: S. Wiberg: None. C. Hassager: None. H. Schmidt: None. J. Thomsen: None. M. Frydland: None. M. Lindholm: None. D. Høfsten: None. T. Engstrøm: None. L. Køber: None. J. Møller: None. J. Kjaergaard: None.
24094 A Pilot Multicenter Randomized Trial on the Effectiveness of Different Levels of Cooling in Comatose Survivors of Out-of-hospital Cardiac Arrest. FROST-I trial
Esteban Lopez-de-Sa1, Miriam Juarez2, Eduardo Armada3, Jose C Sanchez-Salado4, Pedro L Sanchez5, Pablo Loma-Osorio6, Alessandro Sionis7, Maria C Monedero3, Manuel Martinez-Selles2, Miguel Sanchez-Gracia8, Albert Ariza4, Aitor Uribarri5, Jose M Garcia-Acuna9, Patricia Villa10, Pablo J Perez11, Christian Storm12, Jose L Lopez-Sendon3; 1Cardiology, Hosp Universitario La Paz, Madrid, Spain, 2Hosp Universitario Gregorio Maranon, Madrid, Spain, 3Hosp Universitario La Paz, Madrid, Spain, 4Hosp Universitario de Bellvitge, L’Hospet de Llobregat., Spain, 5Hosp Universitario de Salamanca, Salamanca, Spain, 6Hosp Universitario Josep Trueta, Girona, Spain, 7Hosp de la Santa Creu i Sant Pau, Barcelona, Spain, 8Hosp Clinico San Carlos, Madrid, Spain, 9Complejo Hospario Universitario de Santiago, Santiago de Compostela, Spain, 10Hosp Universitario Principe de Asturias, Alcala de Henares, Spain, 11Hosp Universitario de Canarias, San Cristóbal de La Laguna, Spain, 12Charité – Universitätsmedizin Berlin, Berlin, Germany.
Background: The application of Target Temperature Management (TTM) has been associated with decreased mortality and improved neurological function in patients with return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA). But, there are still many unknown issues regarding this therapy, such as optimum cooling level, cooling duration, etc. There are only 2 previous trials in humans trying to offer some light about the best level of cooling with contradictory results. The aim of the present clinical trial is to obtain initial reliable data on the effect of different levels of TTM in comatose survivors of OHCA as a basis for future research, trying to minimize multiple confounding factors related to prognosis in this scenario. We hypothesized that cooling at colder temperatures would be associated with better outcome. Methods: FROST I trial is a prospective, multicenter, international, controlled, open-label, randomized interventional pilot trial with 1:1:1 concealed allocation of OHCA patients to TTM to 32°, 33° or 34°C for 24 h with the intravascular Thermogard XP Temperature Management System, and blinded outcome evaluation. The trial is being conducted in 16 centers in Spain and Germany and is sponsored by ZOLL Circulation, Inc., USA. A total of 150 subjects were enrolled in the study from June 5th, 2014 to April 19th, 2016. The primary objective is to assess the fraction of subjects surviving with good neurologic outcome at 90 days considered as a Modified Rankin Scale ≤3. The 90 days follow-up of the last patient enrolled will occur July 18th, 2016. Patients will be followed for one year. The study population includes comatose survivors age between 18 and 80 years, with witnessed OHCA of presumed cardiac cause, initial shockable cardiac rhythm, sustained ROSC, interval from collapse to advance life support <20 minutes, interval from collapse to ROSC <60 minutes, hemodynamically stable and interval from ROSC to randomization <240 minutes. The main exclusion criteria included traumatic or toxic cardiac arrest, pregnancy, unwitnessed arrest, in-hospital arrest and body core temperature <34°C at randomization. ClinicalTrials.gov Identifier: NCT02035839.
Author Disclosures: E. Lopez-de-Sa: Research Grant; Modest; ZOLL Circulation, Inc., USA., GlaxoSmithKline plc, Astra Zeneca, PFIZER S.L.U., MSD. Research Grant; Significant; Servier. Speakers Bureau; Modest; Daiichi Sankyo, Rovi, MSD, Servier. Consultant/Advisory Board; Modest; Daiichi Sankyo. M. Juarez: Research Grant; Modest; Zoll Circulation, Inc., USA. E. Armada: Research Grant; Modest; ZOLL Circulation, Inc., USA.. J.C. Sanchez-Salado: None. P.L. Sanchez: None. P. Loma-Osorio: Research Grant; Modest; Zoll Circulation, Inc., USA., Sanofi. Honoraria; Modest; Sanofi, Daiichi Sankyo, AstraZeneca, Pfizer. A. Sionis: None. M.C. Monedero: Research Grant; Modest; Zoll Circulation, Inc., USA., Lilly. M. Martinez-Selles: Research Grant; Modest; Zoll Circulation, Inc., USA.. M. Sanchez-Gracia: None. A. Ariza: Research Grant; Modest; Zoll Circulation, Inc., USA. A. Uribarri: Research Grant; Modest; Zoll Circulation, Inc., USA.. J.M. Garcia-Acuna: None. P. Villa: None. P.J. Perez: Research Grant; Modest; Zoll Circulation, Inc., USA. C. Storm: Research Grant; Significant; Fresenius Deutschland. Speakers Bureau; Modest; Philips, C.R.BARD, Zoll, Medivance, COVIDIEN, Nonin Medical, German Heart Foundation. J.L. Lopez-Sendon: Research Grant; Modest; Sanofi, Servier, AstraZeneca, GlaxoSmithKline, Menarini, Novartis. Consultant/Advisory Board; Modest; Boehringer-Ingelheim (lecture fees), Daiichi Sankyo (lecture fees). Other; Modest; Servier.
ReSS Poster Session-Day 1 Section 00
23667 Adherence to Cardiopulmonary Resuscitation Guidelines for the Entire Cardiac Arrest Duration on Patient Survival
Ahmed Taher1, Ian R Drennan2, Adam Byers3, Sheldon Cheskes4, Paul Dorian3, Michael Feldman5, Laurie J Morrison3, Cathy Zhan3, Steve Lin3; 1Rescu, Li Ka Shing Knowledge Inst, St Michael’s Hosp, Toronto, Canada, 2Rescu, Li Ka Shing Knowledge Inst, Rescu, Li Ka Shing Knowledge Inst, St Michael’s Hosp; Inst of Med Sciences, Faculty of Med, Univ of Toronto, Toronto, Canada, 3Rescu, Li Ka Shing Knowledge Inst, St Michael’s Hosp; Univ of Toronto, Toronto, Canada, 4Rescu, Li Ka Shing Knowledge Inst, St Michael’s Hosp; Sunnybrook Cntr for Prehospital Medicine, Toronto, Canada, 5Sunnybrook Cntr for Prehospital Medicine, Sunnybrook Health Sciences Cntr, Toronto, Canada.
Introduction: High-quality cardiopulmonary resuscitation (CPR) is essential for patient survival. There is limited research examining the impact of CPR quality over the entire duration of resuscitation. Objective: To examine CPR quality over the entire duration of resuscitation and its associations with out-of-hospital cardiac arrest (OHCA) survival. Methods: This was a retrospective observational study using data from the Toronto RescuNET Epistry-Cardiac Arrest database. We included consecutive, adult (>18) OHCA treated by EMS between January 1, 2014 and September 30, 2015. High-quality CPR was defined, in accordance with 2015 AHA Guidelines, as chest compression rate of 100–120/min, depth of 5.0–6.0cm and compression fraction (CCF) of >0.80. We further categorized adherence to these benchmarks as high (>80% of the time), moderate (50–80%) and low (<50%). We used multivariable logistic regression to determine associations between CPR quality and survival to hospital discharge. Results: A total of 5,208 OHCA met our inclusion criteria with an overall survival rate of 8%. The median (IQR) duration of resuscitation was 23.0 min (14.0,32.2). Overall adherence was moderate to high in 97% of cases for CCF, 77% for rate, and 25% for depth. Patients who survived to discharge compared to those who died had high adherence rates of 61% vs 83% for CCF (p<0.001), 15% vs 6% for depth (p<0.001), and 41% vs 42% for rate (p=0.66). After controlling for Utstein variables, high adherence of chest compression depth showed a non-significant statistical trend towards improved survival (OR 1.68, 95% CI 0.96, 2.92). Other variables associated with increased survival were public location, initial CPR by EMS providers or bystanders, witnessed cardiac arrest (EMS or bystander), and initial shockable rhythm. Increasing age and longer duration of resuscitation were associated with decreased survival. Conclusion: Overall, EMS providers were not able to adhere to guideline recommendations of chest compression rate and depth for the entire duration resuscitation for the majority of OHCAs. Maintaining chest compression depth between 5-6cm for >80% of the entire resuscitation was associated with a trend towards increased survival.
Author Disclosures: A. Taher: None. I.R. Drennan: Other Research Support; Modest; Canadian Institutes of Health Research Banting and Best Doctoral Research Award. Consultant/Advisory Board; Modest; Evidence Reviewer for the C2015 International Liaison Committee on Resuscitation. A. Byers: None. S. Cheskes: Honoraria; Modest; Speaker Honorarium Zoll Medical and Physio Control. Other; Modest; Investigator of the Toronto ROC regional coordinating centre. P. Dorian: None. M. Feldman: None. L.J. Morrison: Research Grant; Significant; Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada. Other; Modest; Principal Investigator of the Toronto ROC regional coordinating centre. Other; Significant; Salary support from NIH, Li Ka Shing Knowledge Institute and the St. Michael’s Foundation. C. Zhan: None. S. Lin: Research Grant; Modest; This study was funded by the Canadian Association of Emergency Physicians. Research Grant; Significant; Heart and Stroke Foundation of Canada and ZOLL Foundation. Consultant/Advisory Board; Modest; Evidence Reviewer for the C2015 International Liaison Committee on Resuscitation.
23510 Antiarrhythmic Drugs for Shock Refractory Secondary Ventricular Fibrillation Following Initial Nonshockable Out-of-Hospital Cardiac Arrest: The Resuscitation Outcomes Consortium Amiodarone, Lidocaine or Placebo Study
Peter J Kudenchuk1, Mohamud Daya2, Brian Leroux3, Tom Rea3, Graham Nichol3, Laurie J Morrison4, Christian Vaillancourt5, Lynn Wittwer6, Clifton W Callaway7, James Christenson8, Debra Egan9, Joe P Ornato10, Myron L Weisfeldt11, Ian G Stiell5, Ahamed G Idris12, Tom P Aufderheide13, James V Dunford14, M R Colella13, Gary M Vilke14, Ashley M Brienza7, Patrice Desvigne-Nickens9, Pamela Gray15, Randal Gray15, Norman Seals16, Ron Strait17, Paul Dorian4; 1Medicine/Cardiology, Univ Of Washington, Seattle, WA, 2Oregon Health & Sciences Univ, Portland, OR, 3Univ Of Washington, Seattle, WA, 4Univ of Toronto, Toronto, Canada, 5Univ of Ottawa, Ottawa, Canada, 6Clark County Emergency Med Services, Vancouver, WA, 7Univ of Pittsburgh, Pittsburgh, PA, 8Univ of British Columbia, Vancouver, Canada, 9National Heart Lung and Blood Institute, Washington, DC, 10Virginia Commonwealth Univ, Richmond, VA, 11Johns Hopkins Univ, Baltimore, MD, 12Univ of Texas Southwestern, Dallas, TX, 13Med College of Wisconsin, Milwaukee, WI, 14Univ of California San Diego, San Diego, CA, 15Univ of Alabama, Birmingham, AL, 16Dallas Fire-Rescue, Dallas, TX, 17British Columbia Emergency Med Services, Vancouver, Canada.
Background: Out of hospital cardiac arrest often presents with nonshockable rhythms (NS OHCA). It is not known if antiarrhythmic drugs are beneficial when shock refractory ventricular fibrillation or pulseless ventricular tachycardia (SR VF/VT) follows initial NS OHCA. Methods: Adults with non-traumatic OHCA and vascular access who had SR VF/VT to ≥1 shock anytime during resuscitation were randomized double blind to amiodarone (≤ 450 mg), lidocaine (≤180 mg) or saline placebo along with standard care by Emergency Medical Services (EMS) at 10 North American sites. Two groups were concurrently randomized: those with initial VF/VT OHCA (reported earlier) and with initial NS OHCA evolving to SR VF/VT (this report). The trial was powered for hospital discharge survival after initial VF/VT OHCA; Modified Rankin Score (MRS) ≤ 3 and adverse drug events (AE) were secondary outcomes. No differences in these outcomes were hypothesized for SR VF/VT after NS OHCA regardless of treatment. Results: Of 37,889 patients with OHCA, 29,986 had NS OHCA, 1063 of whom evolved to SR VF/VT and were study eligible. Of these, 316 (29.7%) received placebo, 358 (33.6%) lidocaine and 389 (36.5%) amiodarone. Patients in the 3 arms differed in age (mean 64.5, 63.9 and 65.4 yrs), male gender (65.2%, 69.3% and 75.1%), arrest in public (14.6%, 14.2%, 15.3%) but not witnessed arrest (45%, 44.8%, 44.4%), or in mean time from EMS call to study drug (27.1, 26.7, and 26.8 min). Of patients treated with placebo, lidocaine or amiodarone 65 (20.6%), 74 (20.7%) and 64 (16.5%) were admitted to hospital; 6 (1.9%), 11 (3.1%) and 16 (4.1%) survived to hospital discharge; and 3 (1.0%), 6 (1.7%), and 8 (2.1%) survived with MRS ≤ 3. AEs were infrequent and similar between treatment arms. The unadjusted absolute survival difference (95% CI) for amiodarone vs placebo was 2.2% (-0.3%, 4.7%) and for lidocaine vs placebo 1.2% (-1.2%, 3.5%). When adjusted for pre-randomization features these were 2.4% (-0.2%, 5.1%) and 1% (-1.3%, 3.4%). There was no significant interaction between the specific NS OHCA rhythm and treatment arm with survival. Conclusions: Outcome is poor when SR VF/VT follows NS OHCA. A trial of 3000 patients would be required to confirm both the safety and possible survival benefit from these antiarrhythmic drugs.
Author Disclosures: P.J. Kudenchuk: None. M. Daya: None. B. Leroux: None. T. Rea: None. G. Nichol: None. L.J. Morrison: None. C. Vaillancourt: None. L. Wittwer: None. C.W. Callaway: None. J. Christenson: None. D. Egan: None. J.P. Ornato: None. M.L. Weisfeldt: None. I.G. Stiell: None. A.G. Idris: None. T.P. Aufderheide: None. J.V. Dunford: None. M.R. Colella: None. G.M. Vilke: None. A.M. Brienza: None. P. Desvigne-Nickens: None. P. Gray: None. R. Gray: None. N. Seals: None. R. Strait: None. P. Dorian: None.
24096 A Cluster Randomized Trial of the Duration of Cooling in Therapeutic Hypothermia After Resuscitation for Cardiac Arrest
Yoshio Tahara1, Naohiro Yonemoto2, Migaku Kikuchi3, Katsutaka Hashiba4, Hideki Arimoto5, Kenji Nishioka6, Nobuaki Kokubu7, Satoshi Yasuda8, Takahiro Atsumi9, Kazunori Kashiwase10, Shunji Kasaoka11, Yasuhiro Kuroda12, Akiko Kada13, Hiroyuki Yokoyama8, Hiroshi Nonogi14, J-PULSE-Hypo-DC Trial Study Group; 1Dept of Cardiovascular Medicine, National Cerebral and Cardiovascular Cntr, Osaka, Japan, 2Kyoto Univ Sch of Public Health, Kyoto, Japan, 3Dokkyo Med Univ, Tochigi, Japan, 4Yokohama City Univ Med Cntr, Yokohama, Japan, 5Osaka City General Hosp, Osaka, Japan, 6Hiroshima City Hiroshima Citizens Hosp, Hiroshima, Japan, 7Sapporo Med Univ, Sapporo, Japan, 8National Cerebral and Cardiovascular Cntr, Osaka, Japan, 9Seirei Hamamatsu General Hosp, Hamamatsu, Japan, 10Osaka Police Hosp, Osaka, Japan, 11Kumamoto Univ Hosp, Kumamoto, Japan, 12Kagawa Univ Hosp, Kagawa, Japan, 13National Hosp Organization Nagoya Med Cntr, Nagoya, Japan, 14Shizuoka General Hosp, Shizuoka, Japan.
Objective: This study was designed to evaluate the appropriate duration of cooling (12–24 hours vs. 36 hours) in patients with cardiac arrest who receive therapeutic hypothermia after resuscitation. Methods: This was a cluster randomized trial performed in 10 hospitals. The primary outcome was the incidence of complications within 1 month. Complications included infection, hemorrhage, arrhythmias, decreasing blood pressure, shivering, convulsions and major adverse cardiovascular events (MACE), evaluated by an independent committee blinded to the assigned groups. Secondary outcomes were mortality and favorable neurological outcome (Cerebral Performance Categories, CPC: 1–2) within 24 hours, 7 days, 1 month, 3 months, and at discharge. We used random-effects models with clustered effects to calculate risk ratios (RR). Results: Data on 185 patients were analyzed according to intention-to-treat principle (12–24 hours group, n=100 in 5 hospitals; 36 hours group, n=85 in 5 hospitals). The primary outcome (incidence of complications within 1 month) did not differ significantly between groups (RR 1.04, 95% CI: 0.67 to 1.61, P=0.86). Mortality was lower in the 36 hours group than in the 12–24 hours group at 24 hours (RR 0.53, 95% CI: 0.39 to 0.37, P<0.0001) and at 7 days (RR 0.76, 95% CI: 0.62 to 0.93, P=0.007), but did not differ significantly after adjustment for baseline imbalance. Also, favorable neurological outcome was higher in the 36 hours group than in the 12–24 hours group at 7 days (RR 1.34, 95% CI: 1.04 to 1.73, P=0.0217) after adjustments for baseline imbalance and missing data. Other long-term secondary outcomes did not clearly differ between the groups. Conclusion: Differences in the duration of cooling were not associated with clear benefits except for lower short-term outcomes in patients with cardiac arrest who received therapeutic hypothermia after resuscitation.
Author Disclosures: Y. Tahara: None. N. Yonemoto: None. M. Kikuchi: None. K. Hashiba: None. H. Arimoto: None. K. Nishioka: None. N. Kokubu: None. S. Yasuda: None. T. Atsumi: None. K. Kashiwase: None. S. Kasaoka: None. Y. Kuroda: None. A. Kada: None. H. Yokoyama: None. H. Nonogi: None.
23408 Time to Defibrillation in Pediatric In-Hospital Cardiac Arrest and First Documented Shockable Rhythm
Elizabeth A Hunt1, Jordan M Duval-Arnould2, Melania M Bembea2, Tia T Raymond3, Aaron W Calhoun4, Robert A Berg5, Vinay M Nadkarni5, Michael W Donnino6, Lars W Andersen7; 1Anesthesiology and Critical Care Medicine, Johns Hopkins Univ Sch of Medicine, Baltimore, MD, 2Johns Hopkins Univ Sch of Medicine, Baltimore, MD, 3Med City Children’s Hosp, Dallas, TX, 4Univ of Louisville Sch.of Medicine, Louisville, KY, 5The Children’s Hosp of Philadelphia and Univ of Pennsylvania, Philadelphia, PA, 6Beth Israel Deaconess Med Cntr, Boston, MA, 7Aarhus Univ, Aarhus, Denmark.
Objective: Little is known about whether earlier defibrillation is associated with improved outcomes in children, as with adults. Our primary objective was to explore the relationship between time to defibrillation for in-hospital cardiac arrest (IHCA) in children with a first documented rhythm of ventricular fibrillation or pulseless ventricular tachycardia (VF/pVT) and survival. Methods: Data was obtained from the Get With The Guidelines® - Resuscitation (GWTG-R) registry from 2000 to 2015, for pulseless children <18 years old with a first documented rhythm of VF/pVT. The primary outcome was survival to hospital discharge and exposure variable was time from recognition of loss of pulse to first defibrillation. We applied a multivariable modified Poisson regression model with generalized estimating equations adjusting for multiple hospital, patient and event characteristics. In predefined sensitivity analysis, we treated time to defibrillation as a categorical variable (≤ 2 vs. > 2 minutes). Results: Of 17,771 pediatric IHCA events, 997 had a first documented rhythm of VF/pVT, 745 received at least one defibrillation and 477 were index events with complete data. Amongst these, 179 patients (38%) survived to hospital discharge. On bivariate analysis, children with medical cardiac disease had higher survival to discharge than other categories: [52%(68/131) vs. 32%(111/346); p<0.001]. The median time to defibrillation was 1 minute (InterQuartile Range: 1, 3). Time to defibrillation was not associated with survival in unadjusted analysis, (RR per minute increase: 0.96 [95%: 0.92, 1.01], p = 0.15) nor in multivariable analysis (adjusted RR: 0.99 [95%CI: 0.94, 1.06], p = 0.86), nor with return of spontaneous circulation or neurologic outcome. When treated as a categorical variable, 338 patients (71%) were defibrillated in ≤2 minutes with no association with survival. Conclusion: Despite current emphasis on rapid defibrillation, we found no association between time to defibrillation and survival in pediatric IHCA. These findings are in contrast to adult literature which may be due to physiological differences, patient heterogeneity, lack of statistical power, or potentially unrecognized confounders and warrants further investigation.
Author Disclosures: E.A. Hunt: None. J.M. Duval-Arnould: None. M.M. Bembea: Research Grant; Modest; Grant NIH/NINDS K23NS076674. T.T. Raymond: None. A.W. Calhoun: None. R.A. Berg: None. V.M. Nadkarni: None. M.W. Donnino: Consultant/Advisory Board; Modest; Paid Consultant for American Heart Association. L.W. Andersen: None.
23635 Does Early Prehospital Epinephrine Administration After Basic Life Support Improve the Outcomes of Emergency Medical Service-witnessed Out-of-hospital Cardiac Arrests?
Hideo Inaba1, Akira Yamashita2, Tetsuo Maeda2, Yukihiro Wato3, Yasuhiro Myojo4; 1Emergency Med Science, Kanazawa Univ Graduate Sch of Medicine, Kanazawa, Japan, 2Kanazawa Univ Graduate Sch of Medicine, Kanazawa, Japan, 3Kanazawa Med Univ, Uchinada, Japan, 4Ishikawa Prefectural Central Hosp, Kanazawa, Japan.
Backgrounds: Japanese paramedics are allowed to administer epinephrine only after confirming cardiac arrest but no drugs after ROSC. The administration was initiated in patients who did not respond to BLS. Early ROSC is known to be associated with better outcomes. High-quality of BLS is immediately started in EMS-witnessed OHCAs. It is extremely rare that resuscitation is terminated after arrival at hospital. Methods: We extracted 31,512 EMS-witnessed OHCAs without prehospital involvement of physicians from all-Japan registry for OHCA between 2011 and 2014. We first examine the time-dependent incidences of prehospital ROSC with and without epinephrine administration. Then, we analyze the effects on survival of two components: prehospital or in-hospital administration, early (<12 min) or late administration. Results: The rate of 1-M neurologically favourable survival was much higher when prehospital ROSC was achieved without epinephrine; 44.0% vs 6.4%. However, ROSC without epinephrine occurred much earlier than ROSC with epinephrine: median; IQR, 3; 2–7 min, 16; 11–21 min, respectively. Furthermore, backgrounds of OHCA including initial rhythm (shockable or not) largely differed between the 2 groups. Thus, we excluded the cases having prehospital ROSC without epinephrine and then performed the component analysis (Fig.1).The component analysis disclosed that only early administration component was associated with 1-M neurologically favourable survival (Fig.2): Adjusted OR; 95% CI, 2.38; 1.85–3.06. Conclusion: Early (<12 min) prehospital epinephrine administrations after BLS (5 min period) produce better outcomes than late in-hospital administrations.
Author Disclosures: H. Inaba: None. A. Yamashita: None. T. Maeda: None. Y. Wato: None. Y. Myojo: None.
23311 Dichloroacetic Acid Improves Neurological Outcomes by Increasing Mitochondrial ATP in a Rat Model of Cardiac Arrest
Peng Wang1, Ming di Chen2, Zhengfei Yang2, Jiali Lin2, Zitong Huang2, Wanchun Tang3; 1Dept of Emergency Medicine, Sun Yat-sen Memorial Hosp of Sun Yat-sen Univ, Guangzhou, China, 2Sun Yat-sen Memorial Hosp of Sun Yat-sen Univ, Guangzhou, China, 3Virginia Commonwealth Univ, Richmond, VA.
Introduction: Dichloroacetate acid (DCA) is a pyruvate dehydrogenase kinaseinhibitor, which activates pyruvate dehydrogenase, and increases cell ATP production by promoting influx of pyruvate into the Krebs cycle. In this study, we investigated the effects of DCA on post-resuscitation neurological injury in a rat model of asphyxia cardiac arrest (ACA). Hypothesis: We hypothesize that DCA increases the level of ATP in brain and then improves neurological outcome after resuscitation. Methods: ACA was induced by endotracheal tube clamping and untreated for 11 min. The animals were randomly divided into three groups: cardiac arrest and resuscitation group (n = 30), cardiac arrest and resuscitation plus DCA intervention group (n = 30) and sham control group (n = 6). DCA (80 mg/kg) was administrated by intraperitoneal injection at 30 min after the return of spontaneous circulation (ROSC). The neurologic deficit scores (NDS) were measured at 24 h, 48 h and 72 h. The brain ATP level was measured at 6 h, 12 h and 24 h. The 3-day survival analysis after ROSC was performed to compare the survival rates of three groups. The TUNEL assay was performed at 24 h after ROSC to detect damage neurons. Results: The NDS and ATP levels were significantly decreased after ROSC, but DCA treatment significantly improved NDS, ATP levels and 3-day survival rates of the rats after ROSC. DCA treatment also decreased the damaged neurons of the hippocampus CA1 area after ROSC. Conclusions: DCA treatment substantially improved survival and neurologic outcome after ROSC in the rats. The salutary effects of DCA were associated with increase of ATP production, suppression of neuronal apoptosis and inflammation in the brain.
Author Disclosures: P. Wang: None. M. Chen: None. Z. Yang: None. J. Lin: None. Z. Huang: None. W. Tang: None.
23662 The Mechanism of Chest Compression Generated Blood Flow Transitions from Cardiac Pump to Thoracic Pump Over Time in a Swine Model of Chest Compression
Joshua W Lampe1, Tai Yin2, George Bratinov3, Christopher L Kaufman4, Henry Halperin5, Lance B Becker2; 1Emergency Medicine, Northwell Health, Manhassett, NY, 2Northwell Health, Manhassett, NY, 3Children’s Hosp of Philadelphia, Philadelphia, PA, 4ZOLL Med, Chelmsford, MA, 5Johns Hopkins Sch of Medicine, Baltimore, MD.
Introduction: Two mechanisms, the cardiac pump and the thoracic pump, have been proposed to explain how a chest compression generates blood flow. These two mechanisms will exhibit different hemodynamic responses to variations in chest compression rate. We set out to determine which mechanism best described blood flow generated by mechanical chest compressions (CC) over 20 minutes of continuous CC. Materials and Methods: CPR was performed on nine domestic swine (~30 kg) using standard physiological monitoring. Flow was measured in the right common carotid and abdominal aorta. Ventricular fibrillation was electrically induced. Mechanical CC were started after ten minutes of untreated VF. CC were delivered at a rate of 50, 75, 100, 125, or 150 compressions per minute (cpm) and at a depth of 2” for a total of 20 min. CC rates were changed every 2 min and were randomized. Data were compared to predictions from previously published modeling of the two pump mechanisms. Results: Experimental and computational results are shown in the figure below. In minutes 0–10, aortic and carotid blood flow exhibited an almost linear dependence on chest compression rate, which is predicted by the cardiac pump model. Blood flow was greatest in the aorta with a rate of 150 CPM and greatest in the carotid artery with a rate of 125 CPM during the first 10 minutes of CPR. In minutes 10–20, aortic and carotid blood flow exhibited little dependence on chest compression rate, which is predicted by the thoracic pump model. Blood flow was greatest in both arteries with a rate of 100 CPM during the second 10 minutes of CPR. Conclusions: The data from this model of cardiac arrest suggest that the mechanism through which CC generate forward blood flow changes over time. This observation has significant implications for how to optimize chest compression delivery in order to obtain the best hemodynamic response.
Author Disclosures: J.W. Lampe: Employment; Significant; Northwell Health. Research Grant; Significant; NHLBI. Other Research Support; Significant; ZOLL Medical, Philips Healthcare, Nihon Kohden. Ownership Interest; Significant; IP in resuscitation devices. T. Yin: Employment; Significant; Northwell Health. G. Bratinov: Employment; Significant; Children’s Hospital of Philadelphia. C.L. Kaufman: Employment; Significant; ZOLL Medical. H. Halperin: Research Grant; Significant; NHLBI. Consultant/Advisory Board; Significant; Zoll, Taser. L.B. Becker: Employment; Significant; Northwell Health. Research Grant; Significant; NHLBI. Other Research Support; Significant; ZOLL Medical, Philips Healthcare, Nihon Kohden. Ownership Interest; Significant; IP in resuscitation Devices. Consultant/Advisory Board; Modest; Nihon Kohden.
24097 Antiplatelet Effects of Ticagrelor versus Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest Undergoing Percutaneous Coronary Intervention and Hypothermia: A Randomized Study
Klemen Steblovnik1, Ales Blinc2, Mojca Bozic-Mijovski2, Misa Fister2, Ursa Mikuz2, Marko Noc2; 1Cntr for Intensive Internal Medicine, Univ Med Cntr Ljubljana, Ljubljana, Slovenia, 2Univ Med Cntr Ljubljana, Ljubljana, Slovenia.
Background: Comatose survivors of out-of-hospital cardiac arrest (OHCA) frequently undergo immediate percutaneous coronary intervention (PCI) and stenting which is associated with the need for administration of P2Y12 inhibitor. In the present study we hypothesized that ticagrelor, given as crushed and dissolved tablets via nasogastric tube, results in faster and stronger platelet inhibition than clopidogrel. Methods: Consecutive comatose survivors of OHCA undergoing PCI and hypothermia (32–34 C) were randomized to ticagrelor 180 mg loading followed by 90 mg/12 hours or clopidogrel 600 mg loading followed by 75 mg/day. Platelet inhibition was measured by VerifyNow® P2Y12 Test and Multiplate® ADPtest at baseline and 2, 4, 12, 22 and 48 hours after the loading dose. High on treatment platelet reactivity (HPR) was defined for VerifyNow® as >208 PRU and <11% inhibition, and for Multiplate® as >46 U. Results: Between August 2014 and June 2016, 20 patients were randomized to ticagrelor and 17 to clopidogrel. The groups were comparable in terms of comorbidities, prehospital resuscitation, initial angiography and PCI features. Ticagrelor resulted in significantly decreased platelet reactivity which started 2 hours after the loading dose and persisted after additional maintenance doses during the 48 hours. At 12 hours, platelet reactivity measured by VerifyNow® was 101±75 PRU versus 238±67 PRU (p<0.001), % inhibition 55% versus 4% (p<0.001) and platelet reactivity by Multiplate® 15±10 U versus 28±17 (p=0.018) with ticagrelor and clopidogrel, respectively (Figure). At the same time, HPR by VerifyNow® was 11% versus 53% according to PRU (p=0.01), 5% versus 87% according to % inhibition (p<0.001) and 0% versus 20% by Multiplate® (p=0.047). Conclusions: In comatose survivors of OHCA undergoing PCI and hypothermia, ticagrelor provides significantly faster and more intense platelet inhibition than clopidogrel and may be the preferred P2Y12 inhibitor in these setting.
Author Disclosures: K. Steblovnik: None. A. Blinc: None. M. Bozic-Mijovski: None. M. Fister: None. U. Mikuz: None. M. Noc: Speakers Bureau; Modest; AstraZeneca, Eli Lilly. Speakers Bureau; Significant; Modest.
- © 2016 American Heart Association, Inc.