Late-Breaking Clinical Trial Abstracts
2014 Late-Breaking Clinical Trial Abstracts
Late-Breaking Clinical Trials: Risk and Benefit of Dual Antiplatelet Therapy
Increased Risk of Ischemic Events Upon Discontinuation of Prasugrel After 12 or 30 Months of Therapy Following Placement of the Taxus Liberté Paclitaxel-Eluting Coronary Stent
Kirk N Garratt1, Ronald D Jenkins2, Thomas K Pow3, W. Douglas Weaver4, Laura Mauri5, De J Kereiakes6, Kenneth J Winters7, Thomas Christen8, Dominic J Allocco8, David P Lee9; 1Cardiac Interventions, Lenox Hill Heart and Vascular Institute, New York, NY; 2Cardiac Interventions, Heart Clinics Northwest, Coeur d'Alene, ID; 3Cardiac Interventions, Great Lakes Heart Institute, St Joseph, MI; 4Cardiology, Henry Ford Hosp, Detroit, MI; 5Div of Cardiovascular Medicine, Brigham and Women's Hosp, Boston, MA; 6Cardiology, The Christ Hosp Heart and Vascular Cntr/The Lindner Rsch Cntr, Cincinnati, OH; 7Lilly Rsch Laboratories, Eli Lily and Company, Indianapolis, IN; 8Clinical Sciences, Boston Scientific, Marlborough, MA; 9Cardiovascular Medicine Clinic, Standford, Stanford, CA
Introduction: The TAXUS Liberté Post-approval Study (TL-PAS) studied long-term clinical outcomes for the TL stent in conjunction with the use of prasugrel and aspirin. A portion of patients from TL-PAS contributed to the Dual Anti-Platelet Therapy (DAPT) trial. Methods: Eligible and consecutive patients in the United States treated with TL stents were enrolled into TL-PAS (N=4199). Those meeting inclusion and exclusion criteria were recruited for participation in the DAPT trial (N=3904). Patients received open-label prasugrel plus aspirin for 12 months after stent placement. At 12 months, patients without ischemic or bleeding events continued aspirin therapy and were randomized 1:1 to continued blinded treatment with either prasugrel or placebo for an additional 18 months (N=2202). At 30 months, study drugs were discontinued, and aspirin was continued through at least 33 months after stent placement. Events were adjudicated by a clinical events committee and monitored by the TL-PAS Data Monitoring Committee (DMC). Results: Nearly 3 years following randomization, the DMC noted a significant increase in spontaneous ischemic events following withdrawal of prasugrel therapy in randomized patients. This risk was observed in both randomized arms: patients who switched to placebo after the first 12 months of unblinded DAPT and in patients randomized to blinded prasugrel who had completed an additional 18 months of drug therapy. In response, the DMC recommended that treatment be unblinded for TL-PAS patients when they completed 18 months of randomized drug treatment, to allow discussion of continuing prasugrel in those patients randomized to the active drug arm. Completed patient follow-up and the adjudicated death, unplanned revasularization, myocardial infarction, stroke and bleeding events will be available for presentation. Conclusion: An increased risk of ischemic events was observed after prasugrel cessation in patients randomized to either 12 months or 30 months of DAPT following placement of a TAXUS Liberté paclitaxel-eluting coronary stent and prompted the recommendation for unblinding of therapy by the DMC. A complete analysis of ischemic and bleeding events with the results of 12 versus 30 month treatment comparisons will be presented.
Author Disclosures: K.N. Garratt: None. R.D. Jenkins: None. T.K. Pow: Speakers Bureau; Modest; Lilly and Daiichi-Sankyo. Other; Modest; peripheral vascular trainer for Boston Scientific. W. Weaver: Other; Modest; Data and Safety Monitoring Board Boston Scientific. L. Mauri: Research Grant; Significant; Grants to Institution: Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daichii Sankyo, Bristol Myers Sqibb and sanofi-aventis. Consultant/Advisory Board; Modest; Biotronik, St. Jude, Medtronic. D.J. Kereiakes: Consultant/Advisory Board; Modest; Medpace, HCRI, Ablative Solution, Inc. Consultant/Advisory Board; Significant; Boston Scientific, Abbott Vascular, REVA Medical Inc. K.J. Winters: Employment; Significant; Eli Lilly. T. Christen: Employment; Significant; Boston Scientific. D.J. Allocco: Employment; Significant; Boston Scientific. D.P. Lee: None.
Key Words: Drug eluting stents, Antiplatelet drugs, Clinical trials, Prasugrel
Randomized, Double Blind Trial of 6 Versus 12 Months Of Dual Antiplatelet Therapy After DES-Implantation (ISAR-SAFE)
Stefanie Schüpke (nee Schulz)1, Julinda Mehilli2, Karl-Ludwig Laugwitz3, Franz-Josef Neumann4, Jurrien M ten Berg5, Tom Adriaenssens6, Yaling Han7, Barbara von Merzljak1, Gert Richardt8, Melchior Seyfarth9, Klaus Tiroch9, Tanja Morath1, Michael Maeng10, Bernhard Zrenner11, Nonlag Rifatov1, Claudius Jacobshagen12, Harald Mudra13, Eberhard Freiherr von Hodenberg14, Jochen Wöhrle15, Sebastian Kufner1, Christian Hengstenberg1, Marcus Fischer16, Martin Schmidt17, Franz Dotzer18, Tareq Ibrahim3, Peter Sick19, Christoph A Nienaber20, Arnoud W van 't Hof21, Takeshi Kimura22, Bernhard Witzenbichler23, Stephan Windecker24, Heribert Schunkert1, Adnan Kastrati1; 1Erwachsenenkardiologie, Deutsches Herzzentrum München, Muenchen, Germany; 2Medizinische Klinik und Poliklinik I, Klinikum der Universitaet München, München, Germany; 31. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Muenchen, Germany; 4Klinik für Kardiologie und Angiologie II, Universitäts-Herzzentrum Freiburg – Bad Krozingen, Bad Krozingen, Germany; 5Dept of Cardiology, St. Antonius Hosp, Nieuwegein, Netherlands; 6Dept of Cardiovascular Medicine, Univ Hosps Leuven, Leuven, Belgium; 7Cardiology, Shenyang Northern Hosp, Shenyang, China; 8Kardiologie und Angiologie, Herzzentrum der Segeberger Kliniken Gruppe, Bad Segeberg, Germany; 9Klinik für Kardiologie und Angiologie II, Helios Klinik Wuppertal, Wuppertal, Germany; 10Cardiology, Aarhus Univ Hosp, Aarhus N, Denmark; 11Kardiologie und Angiologie, Krankenhaus Landshut-Achdorf, Landshut, Germany; 12Klinik für Kardiologie und Pneumologie, Universitaetsmedizin Goettingen, Goettingen, Germany; 13Kardiologie und Angiologie, Klinikum Neuperlach, Muenchen, Germany; 14Kardiologie, MediClin Herzzentrum Lahr/Baden, Lahr, Germany; 15Klinik für Innere Medizin II, Universitätsklinikum Ulm, Ulm, Germany; 16Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany; 17Cardiology, Klinikum Bogenhausen, Muenchen, Germany; 18Cardiology, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany; 19Cardiology, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany; 20Cardiology, Universitätsklinik Rostock, Rostock, Germany; 21Cardiology, Isala Klinieken Zwolle, Locatie Weezenlanden, Zwolle, Netherlands; 22Dept of Cardiovascular Medicine, Kyoto Univ Hosp, Kyoto, Japan; 23Cardiology, Amper Kliniken Dachau, Dachau, Germany; 24Cardiology, Inselspital, Universitätsspital Bern, Bern, Switzerland
Introduction: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is still a question of debate. Hypothesis: We hypothesized that in patients with DES implantation a 6 month duration is not inferior to a 12 month duration of DAPT with aspirin and clopidogrel in terms of clinical outcomes. Methods: ISAR-SAFE is a randomized, double-blind, multicenter trial comparing 6 versus 12 months of clopidogrel therapy duration in patients with DES implantation. Patients were enrolled at 6 months after DES implantation and randomly assigned to either 6 further months of clopidogrel therapy or placebo. Based on sample size calculations the planned total number of patients was 6,000. A blinded overall analysis showed lower than expected event rates. This along with slow recruitment induced the DSMB to recommend stopping the trial after inclusion of 4,000 patients. A total of 4,005 patients have been enrolled. Primary endpoint is the composite of death, myocardial infarction, stent thrombosis, stroke and major bleeding at 9 months after randomization. Results: Results for clinical endpoints will be available in November 2014. Conclusions: ISAR-SAFE is the largest and the only double-blind, randomized clinical trial assessing the value of shortening DAPT duration from 12 to 6 months in patients with DES implantation. Although the trial was stopped prematurely after inclusion of two thirds of patients it has the potential to provide major insights into the optimal DAPT duration after DES implantation. The trial was supported by the BMBF (FKZ 01KG0901) and Abbott Vascular.
Author Disclosures: S. Schüpke (nee Schulz): None. J. Mehilli: Honoraria; Modest; Abbott Vascular, Terumo, Lilly/Daichii Sankyo. Consultant/Advisory Board; Modest; Abbott Vascular, Terumo, Lilly/Daichii Sankyo. K. Laugwitz: None. F. Neumann: None. J.M. ten Berg: None. T. Adriaenssens: None. Y. Han: None. B. von Merzljak: None. G. Richardt: Consultant/Advisory Board; Modest; Abbott, Boston, Biotronik. M. Seyfarth: None. K. Tiroch: None. T. Morath: None. M. Maeng: None. B. Zrenner: None. N. Rifatov: None. C. Jacobshagen: None. H. Mudra: None. E. Freiherr von Hodenberg: None. J. Wöhrle: None. S. Kufner: None. C. Hengstenberg: Speakers Bureau; Modest; Edwards, Transcatheter Technologies, Symetis, Novartis, BMS. M. Fischer: None. M. Schmidt: None. F. Dotzer: None. T. Ibrahim: None. P. Sick: None. C.A. Nienaber: None. A.W. van 't Hof: None. T. Kimura: None. B. Witzenbichler: None. S. Windecker: Research Grant; Significant; Biotronik, St. Jude. H. Schunkert: None. A. Kastrati: Consultant/Advisory Board; Modest; AstraZeneca, MSD.
Key Words: Clopidogrel, Drug eluting stents, Antiplatelet drugs
Is 6 Months DAPT Post Coronary Stenting Non Inferior To 24 Months? The Italic/Italic+ Randomized Trial. Results of the One Year Primary Endpoint
Martine Gilard1, Paul Barragan2, Arif Al Noryani3, Hussam Noor4, Talib Majwal5, Thomas Hovasse6, Philippe Castellant7, Michel Schneeberger8, Luc Maillard9, Laurent Ledain10, Marie-Claude Morice11; 1Interventional cardiology, Univ of Brest, Brest Cedex, France; 2Interventional Cardiology, Polyclinique Les Fleurs, Ollioules, France; 3Interventional Cardiology, Al Quassimi Hosp, Sharjah, United Arab Emirates; 4Interventional Cardiology, Bahrain Defence Force Royal Med Services, Bahrain, Bahrain; 5Interventional Cardiology, Dubai Hosp, Dubai, United Arab Emirates; 6Interventional Cardiology, Institut Cardiovasculaire Paris Sud, Générale de Santé, Massu, France; 7Interventional Cardiology, Hôpital La Cavale, Brest, France; 8Interventional Cardiology, Hôpital Albert Schweitzer, Colmar, France; 9Interventional Cardiology, Clinique Axium, Aix en Provence, France; 10interventional cardiology, Hôpital Saint-Louis, La Rochelle, France; 11interventional cardiology, Institut Cardiovasculaire Paris Sud, Massy, France
Background: The currently recommended duration of DAPT in DES recipients is 12 months to reduce the risk of late stent thrombosis. However, DAPT is associated with increased bleeding which may affect the outcome of patients especially those with co-morbidities or requiring surgical treatment. It was hypothesized that antiplatelet treatment with aspirin alone 6 months after DES implantation may be non-inferior to DAPT in aspirin non resistant pts Methods. A multicenter, all comer randomized study was set up to assess the non-inferiority of aspirin as a single treatment vs. DAPT with clopidogrel and aspirin after 6 months and for 24 months after DES in pts tested for non resistance to aspirin. The primary end-point is a composite of death, MI, TLR, stroke and major bleeding at 12 months post PCI. Secondary endpoints are the components of the primary endpoint and minor bleeding at 24 months. Results: From Nov 2008 to Dec 2010 (ITALIC Trial) and from Jan 2012 to Nov 2013 (ITALIC PLUS Trial), 2031 pts were enrolled in 70 centers in Europe and the Middle East. 80.1% were men, mean age: 61.6±11.0 yrs. 941 pts were randomized to DAPT for 24 months followed by aspirin and 953 pts to DAPT for 6 months followed by aspirin alone, 137 pts were resistant to aspirin (treatment left to the physicians' discretion) Risk factors: hypertension (64.9%) dyslipidemia (67.0%) diabetes (37.2%), family history (35.3%), current smoker (23.0%), all well balanced between the 2 groups. Procedural results: Pts had 1.04 procedures and mean no. of stents implanted per procedure was 1.9±0.16. Procedural success was obtained in 98.6%. In hospital, 10 pts experienced at least 1 of the composite endpoint including no death, 2 MI (0.05%), no CABG, 4 repeat PCI (0.2%), 1 stroke (0.05%) and 4 major bleeding(0.2%). 6-month follow-up was obtained in (95.8 %) of pts 109 (5.4%) pts experienced at least 1 of the composite endpoint events including 13 deaths (0.7%) 6 MI (0.3%), 2 CABG (0.1%), 76 repeat PCI for restenosis (4.0%) and 7(0.4%) major bleeding. Conclusion: The risk benefit ratio (bleeding/stent thrombosis) of short/long DAPT requires randomized trials. The primary endpoint of the ITALIC trial will be available at the meeting. ITALIC is the 1st randomized trial comparing 2 DAPT regimens in pts non resistant to aspirin.
Author Disclosures: M. Gilard: None. P. Barragan: None. A. Al Noryani: None. H. Noor: None. T. Majwal: None. T. Hovasse: None. P. Castellant: None. M. Schneeberger: None. L. Maillard: None. L. Ledain: None. M. Morice: None.
Key Words: Coronary artery disease, Antiplatelet drugs, Thrombosis, Patient safety
Risk and Benefit of Prolonged Dual Antiplatelet Therapy After Drug-eluting Coronary Stents: Primary Endpoint Results from the Dual Antiplatelet Therapy Study
Laura Mauri1, Dean J Kereiakes2, Robert W Yeh3, Priscilla Driscoll-Shempp4, Donald E Cutlip5, Philippe G Steg6, Eugene Braunwald7, Stephen D Wiviott1, David J Cohen8, David R Holmes, Jr.9, Mitchell W Krucoff10, James B Hermiller11, Harold L Dauerman12, Daniel I Simon13, David E Kandzari14, Kirk N Garratt15, David P Lee16, Thomas K Pow17, Peter N Ver Lee18, Michael J Rinaldi19, Joseph M Massaro20; 1Div of Cardiovascular Medicine, Brigham & Womens Hosp, Boston, MA; 2Lindner Rsch Cntr, The Christ Hosp Heart and Vascular Cntr/The Lindner Rsch Cntr, Cincinnati, OH; 3Medicine, Cardiology Div, Massachusetts General Hosp, Boston, MA; 4Program Development and Sponsored Studies, Harvard Clinical Rsch Institute, Boston, MA; 5Cardiology, Beth Israel Deaconess Med Cntr, Boston, MA; 6Cardiologie, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Paris, France; 7Medicine, TIMI Study Group, Brigham and Women's Hosp, Boston, MA; 8Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, MO; 9Cardiovascular Diseases, Mayo Clinic, Rochester, MN; 10Medicine/Cardiology, Duke Univ Med Cntr, Durham, NC; 11Cardiology, St.Vincent Heart Cntr, Indianaoplis, IN; 12Medicine, Fletcher Allen Health Care, Burlington, VT; 13Cardiovascular Medicine, Harrington Heart & Vascular Institute, Univ Hosps Case Med Cntr, Cleveland, OH; 14Cardiology, Piedmont Heart Institute, Atlanta, GA; 15Cardiology, Lenox Hill Hosp, New York, NY; 16Interventional Cardiology, Stanford Univ, Stanford, CA; 17Cadiology, Great Lakes Heart & Vascular Institute, St. Joseph, MI; 18Cardiology, Eastern Maine Med Cntr, Bangor, ME; 19Cardiology, The Sanger Heart & Vascular Institute, Carolinas Healthcare System, Charlotte, NC; 20Biostatistics, Harvard Clinical Rsch Institute, Boston, MA
Introduction: Patients undergoing coronary intervention with drug-eluting stents (DES) face late risks of ischemia and bleeding, yet the balance of these risks with prolonged antiplatelet therapy is unknown. We compared 30 vs 12 months of dual antiplatelet therapy (DAPT) with a thienopyridine plus aspirin in a broadly inclusive trial powered for stent thrombosis (ST), cardiovascular events, and bleeding. Methods: We conducted an international, randomized, double-blind, placebo-controlled trial that enrolled subjects treated with coronary stents. Subjects received aspirin plus open-label thienopyridine (clopidogrel or prasugrel) for 12 months after the index procedure. At 12 months, subjects without major bleeding or recurrent cardiovascular events were randomized 1:1 to either continued thienopyridine or placebo for 18 months while continuing aspirin, and were then followed for an additional 3 months after study drug discontinuation. The primary analysis cohort consisted of all randomized DES-treated subjects, according to ITT. The co-primary effectiveness endpoints of ST and MACCE (composite of death, MI or stroke) over the 12-30 month period after the index procedure were compared between treatments using the log-rank test and the Benjamini-Hochberg approach to control for Type I error at the 0.05 level across the two endpoints. The primary safety endpoint was the incidence of major bleeding (GUSTO moderate or severe). Results: Of 25,682 eligible subjects enrolled into the DAPT Study, 22,866 received DES, and 9,961 were randomized. Among randomized subjects, mean age was 62 years; 25% were female, 31% had diabetes mellitus, and 51% had at least one risk factor for ST at index procedure (e.g. 26% with acute coronary syndromes, 11% with acute STEMI, and 12% with a thrombus-containing lesion), 47% received everolimus-eluting stents, 27%, paclitaxel; 13%, zotarolimus; 11%, sirolimus; and 65% received clopidogrel, and 35%, prasugrel. Cony in pts with diabetes mellitus (DM). It is proposed that 64-slice coronary CT angiography (CCTA) may provide early CAD information on both myocardial ischemia and plaque burden, which could guide preventative therapy and reduce future cardiovascular events in high-risk otherwise asymptomatic DM patients. Methods: A total of 900 participants with high risk DM (males ≥50 yrs / females ≥55 yrs with DM ≥3 years on DM medication ≥1 yr, or males ≥40 yrs / females ≥45 yrs with DM ≥5 yrs on medication ≥1 yr) and no symptoms of CAD were randomly assigned to be assessed by CCTA or not. Pts randomized to CCTA (n=452) were managed by their physicians according to pre-specified trial recommendations based on the results of CCTA screening. Those randomized to the control arm (n=448) received standard medical therapy. Participants were monitored for procedures performed and changes in medical therapy accomplished at one year, and prospectively followed up for 4.0±1.7 years for the combined primary clinical endpoint of death, MI and unstable angina. Results: Major baseline characteristics included age = 61±8 years, males = 52%, DM duration = 13±10 years, Type I DM = 12%, Insulin requiring = 43%, systolic BP = 130±12 mm Hg, HgA1C = 7.5±1.4% and LDL cholesterol = 87±32 mg/dL. Of those randomized to the screening arm 285(63%) had at least some degree of atherosclerosis and 21 (4.7%) had severe (>70% stenosis) proximal vessel CAD. This resulted in 26 (5.8%) protocol coronary revascularization procedures, more use of statin therapy (83.1% versus 75.7%; p=0.008) and a significant reduction in blood pressure and LDL levels at one year compared to those randomized to control. The primary event rate was 7.6% and 6.2% for non-screened and screened groups respectively (Hazard ratio (HR) = 0.80, p=0.38). Conclusions: In this contemporary study population of patients with high risk, but well medically managed, asymptomatic diabetes, randomization to screening with CCTA resulted in a modest number of protocol recommended coronary revascularization procedures and a significant increase in the use of statin therapy. However, it did not result in a significant reduction in the primary clinical endpoint by 4.0 years.
Author Disclosures: J.B. Muhlestein: None. D.L. Lappé: None. J.A. Lima: Research Grant; Significant; Toshiba Medical Systems. H.T. May: None. T.L. Bair: None. V.T. Le: None. J.L. Anderson: None.
Key Words: Cardiac CT, Diabetes mellitus, Coronary artery disease, Prevention
ODYSSEY ALTERNATIVE: Efficacy And Safety of the Proprotein Convertase Subtilisin/kexin Type 9 Monoclonal Antibody, Alirocumab, versus Ezetimibe, in Patients With Statin Intolerance as Defined by a Placebo Run-in and Statin Rechallenge Arm
Patrick M Moriarty1, Paul D Thompson2, Christopher P Cannon3, John R Guyton4, Jean Bergeron5, Franklin J Zieve6, Eric Bruckert7, Terry A Jacobson8, Marie T Baccara-Dinet9, Jian Zhao10, Robert Pordy11, Daniel Gipe12; 1Dept of Internal Medicine, Div of Clinical Pharmacology, Univ of Kansas Med Cntr, Kansas City, KS; 2Cardiology, Hartford Hosp, JB722 Hartford, CT; 3none, Harvard Clinical Rsch Institute, Boston, MA; 4Dept of Medicine, Duke Univ Med Cntr, Durham, NC; 5Dept of Medicine (Service of Lipidology), Laval Univ Hosp, Quebec, Canada; 6Rsch Service, McGuire VA Med Cntr, Richmond, VA; 7Endocrinologie et prévention des maladies cardiovasculaires, Groupe Hospier Pitié-Salpêtrière, Paris, France; 8Dept of Medicine, Emory Univ, Atlanta, GA; 9PCSK-9 development and Launch Unit, Sanofi, Montpellier, France; 10Biostatistics & Data Management, Regeneron Pharmaceuticals, Inc, Tarrytown, NY; 11Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc, Tarrytown, NY; 12Clinical Sciences, Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc, Tarrytown, NY
Background: Statin intolerance (SI) limits many patients (pts) from taking statins and achieving LDL-C goals. Ezetimibe (EZE) is a recommended option for SI pts. ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab (ALI) vs. EZE in pts with history of SI due to muscle symptoms (inability to tolerate ≥2 statins, 1 at lowest approved starting dose). The novel study design included a placebo (PBO) run-in period and statin rechallenge arm to document SI.
Methods: SI pts (with CHD/other CV risk factors) first received single-blind subcutaneous and oral PBO for 4 weeks (W), and were excluded if muscle-related adverse events (AEs) were reported with PBOs. Continuing pts were randomized (2:2:1 ratio) to ALI 75 mg self-administered via 1-mL pre-filled pen every 2 weeks (Q2W) or EZE 10 mg/day or atorvastatin (ATV) 20 mg/day for 24 W. ALI dose was increased to 150 mg Q2W (also 1-mL) at W12 depending on CV risk and W8 LDL-C level. Primary endpoint was % change in LDL-C from baseline to W24 (intent-to-treat analysis). Pts could enter an open-label extension (OLE) and receive ALI 75/150 mg Q2W.
Results: PBO run-in was completed by 87.0% (314/361) pts, 6.9% (25) discontinued due to muscle AE. Baseline mean LDL-C levels were 191–194 mg/dL (Table), 15% of pts had HeFH. ALI produced significant LDL-C reductions vs. EZE at W24 (Table). Although treatment-emergent adverse events (TEAEs) were generally comparable between groups, the rate of skeletal muscle related TEAEs was significantly lower for ALI vs. ATV (P<0.05) (Table). Myalgia was the most common TEAE in all groups (Table). In total, 89.5% of randomized pts entered the OLE (Table).
Conclusions: ALI demonstrated significantly greater LDL-C lowering vs. EZE after 24 W in an SI population with very high baseline LDL-C levels and was well-tolerated, with significantly lower rates of musculoskeletal TEAEs than ATV. ALI may be considered a good alternative therapy in patients with a history of SI.
Author Disclosures: P.M. Moriarty: Research Grant; Modest; Amgen Amgen, Kowa, Lilly, Novartis, Sanofi, Regeneron, Genzyme, Pfizer, Catabasis, Espirion, B. Braun, Kaneka. Honoraria; Modest; Amarin, Kowa. Consultant/Advisory Board; Modest; Regeneron, Duke Clinical Research Institute, Lilly, Catabasis, B. Braun, Kaneka. P.D. Thompson: Employment; Significant; Hartford Hospital, Hartford, CT. Research Grant; Significant; National Institutes of Health, Genomas Pharmaceuticals, Roche, Sanofi, Regeneron, Esperion, Amarin, Pfizer. Honoraria; Modest; Merck, AstraZeneca, Kowa, Amarin. Expert Witness; Modest; Cases on Cardiac Complications of exercise, Cases of Statin Myopathy. Ownership Interest; Significant; Abbvie, Abbott Labs, General Electric, J&J. Consultant/Advisory Board; Modest; Amgen, AstraZeneca, Regeneron, Merck, Genomas, Runners World, Sanofi, Esperion, Amarin. C.P. Cannon: Research Grant; Modest; Accumetrics, CSL Behring, Essentialis, Regeneron, Sanofi, Takeda. Research Grant; Significant; Arisaph, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janssen, Merck. Consultant/Advisory Board; Modest; Bristol-Myers Squibb, Pfizer. Consultant/Advisory Board; Significant; Lipimedix. J.R. Guyton: Research Grant; Significant; Regeneron/Sanofi, Abbott, Genzyme/Sanofi, GlaxoSmithKline, Amarin Pharma, Amgen. Honoraria; Modest; Merck. Ownership Interest; Modest; Eli Lilly. Consultant/Advisory Board; Modest; Regeneron/Sanofi, Novella, Merck. J. Bergeron: Consultant/Advisory Board; Modest; Amgen (Canada), Sanofi (Canada). Other; Modest; Educational lecture to GPs for Merck (Canada), Valeant. F.J. Zieve: None. E. Bruckert: Research Grant; Modest; Amgen, Danone. Honoraria; Modest; Genfit, AstraZeneca. Consultant/Advisory Board; Modest; Aegerion, AMGEN, MSD, Unilever, Danone, Sanofi/Regeneron. T.A. Jacobson: Consultant/Advisory Board; Modest; Amarin, AstraZeneca, Merck, Regeneron, Sanofi. M.T. Baccara-Dinet: Employment; Significant; Sanofi. J. Zhao: Employment; Significant; Regeneron (contractor). R. Pordy: Employment; Significant; Regeneron Pharmaceuticals, Inc. D. Gipe: Employment; Significant; Regeneron Pharmaceuticals, Inc.
Key Words: PCSK9, Statins, Cholesterol-lowering drugs, Clinical trials, Lipoproteins
IMPROVE-IT Trial: A Comparison of Ezetimibe/Simvastatin versus Simvastatin Monotherapy on Cardiovascular Outcomes After Acute Coronary Syndromes
Christopher P Cannon on behalf of the IMPROVE IT Investigators1, 1Cardiovascular Div, Brigham and Women’s Hosp, Boston, MA
Background: LDL-C reduction with statin therapy has been shown to improve cardiovascular outcomes in patients with coronary artery disease, whether initiated during the chronic, stable phase or at the time of acute coronary syndromes (ACS). Whether the addition of ezetimibe to statin therapy can reduce cardiovascular events further has not been demonstrated. IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; NCT00202878) is a multicenter, randomized, double blind trial designed to test the hypothesis that the addition of ezetimibe to a statin improves cardiovascular outcomes relative to statin monotherapy in patients after ACS.Study design: From October 26, 2005 to July 8, 2010, 18,144 moderate-high risk patients stabilized following ACS with LDL-C levels <125 mg/dL (statin naïve) or and 79 mg/dL, the S dose was increased to 80 mg in a double-blind fashion in both treatment groups. The primary endpoint was first occurrence of cardiovascular death, nonfatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (≥30 days following randomization) or stroke, as adjudicated by a blinded clinical events committee. Patients were followed for ≥ 2.5 years and until ≥ 5250 patients experienced a primary endpoint. Average follow up is approximately 5.68 years. Final visits are planned to be completed by July 2014, with database lock by October 2014. Conclusion: IMPROVE-IT will determine if the addition of ezetimibe to statin therapy improves cardiovascular outcomes, and as such, whether further LDL-C lowering with a non-statin drug can lead to clinical benefit. In addition, with median achieved LDL-C levels anticipated to be <70 mg/dl for S vs <55 mg/dl for ES, the trial will provide data on whether more intensive LDL-C reduction in this low range yields incremental clinical benefit, and if lowering LDL-C to such levels should be considered.
Author Disclosures: C.P. Cannon on behalf of the IMPROVE IT Invesgtigators: Research Grant; Modest; Accumetrics. Research Grant; Significant; Merck, Arisaph, Astra-Zeneca, GSK, Janssen, Takeda, Boehringer-Ingelheim. Honoraria; Modest; BMS, Pfizer, Takeda, Merck, GSK, Essentialis, CSL. Honoraria; Significant; Lipimedix, Regeneron, Sanofi. O. IMPROVE IT Investigators: Research Grant; Significant; Merck.
Key Words: Cholesterol, Cholesterol-lowering drugs, Clinical trials, Prevention, Acute coronary syndromes
Late-Breaking Clinical Trials: Treatment of Structural Heart Disease
Randomized Trial of Atenolol Versus Losartan in Children and Young Adults With Marfan Syndrome
Ronald V Lacro1, Harry C Dietz2, Lynn A Sleeper3, Anji T Yetman4, Timothy J Bradley5, Steven D Colan1, Gail D Pearson6, Elif S Selamet Tierney1, Jami C Levine1, Andrew M Atz7, D. W Benson8, Alan C Braverman9, Shan Chen3, Julie De Backer10, Bruce D Gelb11, Paul D Grossfeld12, Gloria L Klein3, Wyman W Lai13, Aimee Liou14, Bart L Loeys15, Larry W Markham16, Aaron K Olson17, Stephen M Paridon18, Victoria L Pemberton6, Mary E Pierpont19, Reed E Pyeritz20, Elizabeth Radojewski5, Mary J Roman21, Angela M Sharkey22, Mario P Stylianou6, Stephanie B Wechsler23, Luciana T Young24, Lynn Mahony25; 1Cardiology, Boston Children’s Hosp, Boston, MA; 2Pediatrics, Johns Hopkins Univ Sch of Medicine, Baltimore, MD; 3Pediatric Heart Network, New England Rsch Institutes, Watertown, MA; 4Cardiology, Primary Children’s Hosp and the Univ of Utah, Salt Lake City, UT; 5Cardiology, Hosp for Sick Children, Toronto, Canada; 6National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; 7Pediatrics, Med Univ of South Carolina, Charleston, SC; 8Cardiology, Cincinnati Children’s Med Cntr, Cincinnati, OH; 9Internal Medicine/Cardiovascular Diseases, Washington Univ Sch of Medicine, St. Louis, MO; 10Cardiology, Univ Hosp Ghent, Ghent, Belgium; 11Pediatrics/Cardiology, Icahn Sch of Medicine at Mt. Sinai, New York, NY; 12Pediatrics/Cardiology, Rady Children’s Hosp, Univ of California San Diego, San Diego, CAll; 13Pediatrics/Cardiology, New York-Presbyterian, Weill Med College, New York, NY; 14Cardiology, Texas Children’s Hosp, Houston, TX; 15Genetics, Univ Hosp Ghent, Ghent, Belgium; 16Pediatrics, Vanderbilt Univ Sch of Medicine, Nashville, TN; 17Cardiology, Seattle Children’s Hosp, Seattle, WA; 18Cardiology, The Children’s Hosp of Philadelphia, Philadelphia, PA; 19Pediatrics/Cardiology, Children’s Hosp and Clinics of Minnesota, Minneapolis, MN; 20Internal Medicine/Med Genetics, Univ of Pennsylvania Health System, Philadelphia, PA; 21Internal Medicine/Cardiovascular Disease, New York-Presbyterian/Weill Cornell Med College, New York, NY; 22Pediatrics/Cardiology, Washington Univ Sch of Medicine, St. Louis, MO; 23Pediatrics/Cardiology, Duke Univ Med Cntr, Durham, NC; 24Cardiology, Ann & Robert H. Lurie Children’s Hosp of Chicago, Chicago, IL; 25Pediatrics/Cardiology, UT Southwestern Med Cntr, Dallas, TX
Background: Aortic-root dissection is the leading cause of mortality in Marfan syndrome. Recent studies suggest that losartan may be more effective in slowing aortic-root enlargement than β-blockers, the current standard therapy in most centers. Methods: The NHLBI-funded Pediatric Heart Network conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in body-surface area-adjusted maximum aortic-root dimension z-score (hereafter “aortic-root z-score”) over 3 years. Secondary outcomes included rate of change in absolute aortic-root dimension; progression of aortic regurgitation; time to aortic dissection, aortic-root surgery, or death; somatic growth; and incidence of adverse events. Results: Between 2007 and 2011, 21 clinical centers enrolled 608 subjects, aged 6 months to 25 years (mean 11.2±6.3 years), who met original Ghent diagnostic criteria and who had an aortic-root z-score greater than 3.0 and an absolute aortic diameter of 5 cm or less. Of these, 60% were male, 25% were older teenagers and young adults, and the mean aortic-root z-score was 4.3±1.3. There were no important differences in baseline clinical or echocardiographic characteristics. The withdrawal rate was 11% (median follow-up 2.0 years). The baseline-adjusted rate of change for the aortic-root z-score (mean±standard error) did not differ significantly by treatment group (-0.139±0.013 standard deviation [SD] units/year with atenolol versus -0.107±0.013 SD units/year with losartan; P=0.08). Both slopes were significantly less than zero, indicating a decrease in aortic-root dimension relative to body-surface area with either treatment. The three-year rates of aortic-root surgery, aortic dissection, death, and their composite did not differ by treatment group. Conclusion: In children and young adults with Marfan syndrome randomly assigned to either losartan or atenolol, we found no significant difference in the rate of aortic-root dilation between the two treatment groups over three years. (ClinicalTrials.gov number, NCT00429364)
Author Disclosures: R.V. Lacro: None. H.C. Dietz: None. L.A. Sleeper: None. A.T. Yetman: None. T.J. Bradley: None. S.D. Colan: None. G.D. Pearson: None. E.S. Selamet Tierney: None. J.C. Levine: None. A.M. Atz: None. D.W. Benson: None. A.C. Braverman: None. S. Chen: None. J. De Backer: None. B.D. Gelb: None. P.D. Grossfeld: None. G.L. Klein: None. W.W. Lai: None. A. Liou: None. B.L. Loeys: None. L.W. Markham: None. A.K. Olson: None. S.M. Paridon: None. V.L. Pemberton: None. M.E. Pierpont: None. R.E. Pyeritz: None. E. Radojewski: None. M.J. Roman: None. A.M. Sharkey: None. M.P. Stylianou: None. S.B. Wechsler: None. L.T. Young: None. L. Mahony: None.
Key Words: Aortic aneurysm, Pediatric cardiology, Clinical trials, Beta-blocker, Drugs
A Randomized Trial of Losartan In Hypertrophic Cardiomyopathy - The INHERIT Trial
Anna Axelsson1, Kasper Iversen2, Niels Vejlstrup1, Carolyn Ho3, Jakob B Norsk1, Lasse Langhoff1, Kiril Ahtarovski1, Pernille Corell4, Ole Havndrup4, Morten K Jensen1, Henning Bundgaard1; 1Dept of Cardiology, Rigshospitalet, Univ of Copenhagen, Copenhagen, Denmark; 2Dept of Cardiology, Hillerod hospital, Hillerod, Denmark; 3Cardiovascular Div, Brigham and Women’s Hosp, Boston, MA; 4Dept of Cardiology, Roskilde Hosp, Roskilde, Denmark
Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is associated with heart failure, angina, arrhythmia and sudden cardiac death. No medical treatment has yet been reliably shown to halt or reverse disease progression, but pilot studies have indicated beneficial effects of angiotensin II receptor blockers. Left ventricular (LV) hypertrophy and fibrosis are predictors of adverse outcome in HCM and seem as clinically relevant surrogate end-points in a randomized trial. Objective: The INHERIT trial is a randomized, double-blind, placebo-controlled study of the effects of losartan in patients with HCM. The primary endpoint is change in LV mass. Secondary endpoints include LV fibrosis. Methods: The study was designed to include 132 patients to detect difference in LV mass of 12g/m2 with a power of 90%, a 2-sided alpha of 5% and allowing for a drop-out rate of 10%. The inclusion criterion was overt HCM according to international criteria. Exclusion criteria included blood pressure >140/90 mmHg, LVEF <50% and significant valvular disease. Patients were randomized to losartan (100 mg/d) or placebo for 12 months. LV mass was assessed by cardiac magnetic resonance imaging (CMR) in patients who had no ICD or pacemaker and by CT in patients with a device. Dense replacement fibrosis was defined as areas with delayed gadolinium enhancement on CMR. Results: A total of 133 patients were randomized. Demographic characteristics were: age 52±13 years (1 SD); 35% women; 44% had known, disease-causing sarcomere gene mutations; 12% had obstructive physiology (left ventricular outflow tract [LVOT] gradient ≥30 mmHg) and 83% had fibrosis at baseline CMR. Key baseline measures were: LV mass 211±74 g; MWT 23±6 mm; fibrosis 2% of LV mass (interquartile range 1–6%); LVOT gradient at rest 8 mmHg (5–14 mmHg) and LVOT gradient during Valsalva maneuver 14 mmHg (8–42 mmHg). Conclusions: INHERIT is the largest randomized trial to date in patients with HCM. The study is adequately powered to determine if losartan has an effect on the primary endpoint LV hypertrophy. The study also addresses the potential differences in response between sarcomere gene mutation carries and non-carriers as well as safety in patients with obstructive physiology (NCT01447654).
Author Disclosures: A. Axelsson: Ownership Interest; Modest; Previously owned stock in Astra Zeneca. K. Iversen: None. N. Vejlstrup: None. C. Ho: None. J.B. Norsk: None. L. Langhoff: None. K. Ahtarovski: None. P. Corell: None. O. Havndrup: None. M.K. Jensen: None. H. Bundgaard: Honoraria; Modest; Lecture-fees for MSD, AstraZeneca and Amgen.
Key Words: Hypertrophic cardiomyopathy, Hypertrophy, Fibrosis, Angiotensin II
The Incidence of Infective Endocarditis in England is Increasing-An Assessment of the Impact of Cessation of Antibiotic Prophylaxis Using Population Statistics
Mark J Dayer1, Simon Jones2, Bernard Prendergast3, Larry M Baddour4, Peter B Lockhart5; Martin H Thornhill6; 1Cardiology, Taunton and Somerset NHS Trust, Taunton, United Kingdom; 2Dept of Health Care Management and Policy, Univ of Surrey, Guildford, United Kingdom; 3Cardiology, John Radcliffe Hosp, Oxford, United Kingdom; 4Div of Infectious Diseases, Mayo Clinic College of Medicine, Rochester, MN; 5Oral Medicine, Carolinas Med Cntr, Charlotte, NC; 6Unit of Oral & Maxillofacial Surgery & Medicine, Univ of Sheffield Sch of Clinical Dentistry, Sheffield, United Kingdom
Introduction: Antibiotic prophylaxis (AP) at the time of invasive procedures in patients at risk of developing infective endocarditis (IE) has historically been the focus of IE prevention. Recent changes in IE prevention guidelines in the US and Europe have reduced by more than 80% the numbers for whom AP is recommended. The National Institute for Health and Care Excellence (NICE) guidelines recommended complete cessation of AP in the UK in March 2008. We report the impact of this on AP prescribing and describe the incidence of IE in England before and after implementation. Hypothesis: We assessed the null hypothesis that reduction in AP prescribing would not be associated with an increase in IE incidence. Methods: We used English AP prescribing data from January 2004 to March 2013 and hospital discharge episode statistics for patients with a primary diagnosis of IE from January 2000 to March 2013. Results: AP prescription rates fell dramatically after introduction of the NICE guidance (10935 prescriptions/month vs. 2236 prescriptions/month, p<0.001). In the 6 months up to March 2013 the rate was even lower (1307 prescriptions/month). 19804 IE cases were recorded during the study period, with a significant increase in the number of cases/month above the baseline trend in IE incidence commencing in March 2008 (0.556 cases/month, CI 0.281–0.832, p<0.001, Figure). By March 2013 there were an additional 33 cases/month than would have been expected if the previous incidence trend continued. There was a significant rise in the rates of IE in both high risk and non high risk groups. Conclusions: Since introduction of the NICE guidelines, there has been a substantial reduction in AP prescribing and a significant increase in IE incidence in England. A reappraisal of current strategies to prevent IE may be warranted.
Author Disclosures: M.J. Dayer: None. S. Jones: None. B. Prendergast: None. L.M. Baddour: None. P.B. Lockhart: None. M.H. Thornhill: None.
Key Words: Endocarditis, Epidemiology, Valvular disease
The Surgical Treatment of Moderate Ischemic Mitral Regurgitation: A Randomized Clinical Trial From The Cardiothoracic Surgical Trials Network
Peter K Smith1, John Puskas2, Deborah Ascheim3, Pierre Voisine4, Gorav Ailawadi5, Judy Hung6, Annetine Gelijns3, Alan J Moskowitz3, Louis Perrault7, Michael Parides3, Michael Acker8, Michael Argenziano9, Vinod Thourani10, James Gammie11, Frederick Chen12, Marissa Miller13, Pierre Pagé14, Jessica R Overbey3, Emilia Bagiella3, François Dagenais15, Eugene Blackstone16, Irving Kron5, Daniel Goldstein17, Ellen Moquete3, Neal Jeffries13, Timothy Gardner18, Patrick O'Gara19, John Alexander20, Robert E Michler17; 1Surgery, Duke Univ, Durham, NC; 2Surgery, Mount Sinai Beth Israel, New york, NY; 3Health Evidence & Policy, Icahn Sch of Medicine at Mount Sinai, New York, NY; 4Cardiac Surgery, INSTITUT UNIVERSITAIRE DE CARDIOLOGIE DE QUEBEC, Quebec, Canada; 5Surgery, Univ of Virginia Health System, Charlottesville, VA; 6Echocardiography, Massachusetts General Hosp, Boston, MA; 7Surgery, Montreal Heart Institute, Montreal, Canada; 8Surgery, UNIVERSITY OF PENNSYLVANIA, Philadelphia, PA; 9Surgery, COLUMBIA UNIVERSITY MEDICAL CENTER, New York, NY; 10Surgery, Emory Univ Hosp Midtown, Atlanta, GA; 11Cardiac Surgery, Univ of Maryland, Baltimore, MD; 12Cardiac Surgery, Brigham and Women’s Hosp, Boston, MA; 13National Heart, Lung and Blood Institute, NIH, Bethesda, MD; 14Surgery, Hôpital du Sacré-Cœur de Montréal, Montréal, Canada; 15Cardiothoracic Surgery, INSTITUT UNIVERSITAIRE DE CARDIOLOGIE DE QUEBEC, Quebec, Canada; 16Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH; 17Surgery, Montefiore-Einstein Heart Cntr, New York, NY; 18Surgery, Christiana Care Health System, Newark, DE; 19Cardiology, Brigham and Women’s Hosp, Boston, MA; 20Duke Clinical Rsch Institute, Duke Univ, Durham, NC
Background: Ischemic mitral regurgitation (IMR) is associated with increased mortality and morbidity. For surgical patients with moderate IMR, the benefits of adding MV repair (MVr) to CABG are uncertain.METHODS We randomly assigned 301 patients with moderate IMR to CABG alone or CABG with MVr. The primary endpoint was left ventricular end systolic volume index (LVESVI) at one-year, assessed using a Wilcoxon rank sum test categorizing deaths as the lowest LVESVI rank. Results: Mean one-year LVESVI among surviving patients was 46.1±22.4 mL/m2 in the CABG and 49.6±31.5 mL/m2 in the CABG/MVr groups (mean change from baseline -9.4 and -9.3 mL/m2, respectively). One-year mortality was 6.7% in CABG/MVr patients versus 7.3% in CABG patients (HR 0.90; 95% CI 0.38–2.12; p=0.81). The rank-based assessment of LVESVI at one-year (incorporating deaths) showed no difference between groups (Z=0.50, p=0.61). MVr was associated with longer bypass time (p<0.001), longer postoperative LOS (p=0.002), and more neurological events (p=0.03). Moderate or severe MR was less common in the MVr group (11% vs. 31%, p<0.001). There were no observed differences in MACCE, death, readmissions, functional status or quality-of-life at one-year. Conclusions: In patients with moderate IMR, the addition of MVr to CABG did not result in a higher degree of reverse LV remodeling. MVr was associated with a lower prevalence of moderate or severe MR, but increased neurological events. Whether the lower prevalence of MR will portend a net benefit requires longer-term follow-up. The routine addition of MVr to CABG in this patient population may not be warranted.
Author Disclosures: P.K. Smith: Consultant/Advisory Board; Modest; CSL Behring clinical trial Steering Committee. J. Puskas: None. D. Ascheim: None. P. Voisine: None. G. Ailawadi: Consultant/Advisory Board; Modest; Edwards Lifesciences. Other; Modest; St. Jude consultant/teacher for fellows course. J. Hung: None. A. Gelijns: Ownership Interest; Significant; MERS, LLC. A.J. Moskowitz: Ownership Interest; Significant; MERS, LLC.. L. Perrault: None. M. Parides: None. M. Acker: Consultant/Advisory Board; Modest; Thoratec, HeartWare. M. Argenziano: None. V. Thourani: Other Research Support; Modest; Edwards Lifesciences. J. Gammie: None. F. Chen: None. M. Miller: None. P. Pagé: None. J.R. Overbey: None. E. Bagiella: None. F. Dagenais: None. E. Blackstone: None. I. Kron: None. D. Goldstein: None. E. Moquete: None. N. Jeffries: None. T. Gardner: None. P. O’Gara: None. J. Alexander: None. R.E. Michler: None.
Key Words: Mitral regurgitation, Coronary artery disease, Coronary artery bypass grafting (CABG), Valvuloplasty, Clinical trials
Late-Breaking Clinical Trials: Ischemic Heart Disease: Drugs, Devices and Systems of Care
Long-term Outcome of Biodegradable Compared to Durable Polymer Drug-eluting Stents and Bare Metal Stents - Main Results of a Prospective Randomized Trial
Christoph A Kaiser1, Soeren Galatius2, Matthias Pfisterer1; 1Cardiology, Univ Hosp Basel, Basel, Switzerland; 2Cardiology, Gentofte Univ Hosp, Hellerup, Denmark
Background: Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe >1 year as bare-metal stents (BMS). Thus, late stent thrombosis attributed to the durable polymer should no longer appear. A comprehensive evaluation of these aspects of BP-DES within one long-term trial is lacking, however. Methods: Between April 2010 and May 2014, 2291 patients presenting with acute or stable coronary disease needing stents >3.0mm in diameter were randomly assigned to biolimus-A9-eluting BP-DES, second-generation everolimus-eluting DP-DES or thin-strut silicon-carbide-coated BMS in eight European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary endpoint was combined cardiac death, myocardial infarction and clinically indicated target-vessel revascularization within two years. The combined secondary safety endpoint was stent thrombosis with related myocardial infarction or death.Findings: The cumulative incidence of the primary endpoint was 7.6% with BP-DES, 6.8% with DP-DES and 12.7% with BMS. By intention-to-treat BP-DES were non-inferior compared to DP-DES (absolute risk difference 0.78%, [-1.93%,3.50%], p for non-inferiority 0.042) and superior to BMS (absolute risk difference -5.16,[-8.32,-2.01], p=0.0011)). The three stent groups did not differ in the combined safety endpoint, with no decrease in these events, particularly stent thrombosis, >1 year with BP-DES.Interpretation: BP-DES proofed non-inferior to DP-DES and more effective than thin-strut BMS, but there was no evidence for a reduced rate of late stent thrombosis and related clinical events with BP-DES. Findings challenge the concept that durable polymers are key in late stent thrombosis formation.
Author Disclosures: C.A. Kaiser: Research Grant; Modest; Stentys, Biotronik Switzerland. Research Grant; Significant; Basel Cardiovascular Research Fundation. Speakers Bureau; Modest; Eli Lilly Switzerland, Daiichy Sankyo Switzerland, Abbott Vacular Switzerland, Astra Zeneca Switzerland. Consultant/Advisory Board; Modest; Abbott Vascular Switzerland, Eli Lilly Switzerland, Daiichy Sankyo Switzerland, Astra Zeneca Switzerland, GE Healthcare Switzerland, Bayer Switzerland. S. Galatius: Other Research Support; Modest; Pfizer (SPIRE-1-trial), Servier (MODIFY-trial), GSK (SOLID-trial), Novartis (Atmorsphere-trial), Stentys (SIZING -trial), Terumo (E-NOBORI-trial), Eli Lilly (EF JE-trial). Consultant/Advisory Board; Modest; Eli Lilly, Servier. M. Pfisterer: None.
Key Words: Drug eluting stents, Efficacy, Stent
Primary Outcomes of the EVOLVE II Trial: A Prospective Randomized Investigation of a Novel Bioabsorbable Polymer-Coated, Everolimus-Eluting Coronary Stent
Dean J Kereiakes1, Ian T Meredith2, Stephan Windecker3, R. Lee Jobe4, Shamir R Mehta5, Ian J Sarembock1, Robert L Feldman6, Christophe Dubois7, Timothy Grady8, Shigeru Saito9, Takeshi Kimura10, Thomas Christen11, Dominic J Allocco11, Keith D Dawkins11; 1Cardiology, The Christ Hosp Heart and Vascular Cntr/The Lindner Rsch Cntr, Cincinnati, OH; 2Monash Cardiovascular Rsch Cntr, MonashHEART, Southern Health/Monash Med Cntr, Clayton, Australia; 3Dept of Cardiology and Radiology, Bern Univ Hosp, Bern, Switzerland; 4Wake Heart and Vascular, Wake Med Cntr, Raleigh, NC; 5Interventional Cardiology, McMaster Univ and Hamilton Health Sciences, Hamilton, Canada; 6Mediquest Rsch, Mediquest Rsch at Munroe Regional Med Cntr, Ocala, FL; 7Dept of Cardiology, Univ Hosp Leuven, Leuven, Belgium; 8Rsch and Education, Aspirus Heart and Vascular Institute, Wausau, WI; 9Dept of Cardiovascular Medicine, Shonan Kamakura General Hosp, Kanagawa, Japan; 10Dept of Cardiovascular Medicine, Kyoto Univ Hosp, Kyoto, Japan; 11Clinical Sciences, Boston Scientific, Marlborough, MA
Introduction: Durable polymers have been associated with hypersensitivity, delayed healing and incomplete endothelialization which may contribute to increased risk of late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. The SYNERGY stent (Boston Scientific Corporation, Natick, MA) consists of a thin-strut, platinum chromium metal alloy platform and an ultrathin bioabsorbable poly(DL-lactide-co-glycolide) abluminal polymer which elutes everolimus. Drug release and polymer absorption are complete within 4 months. The SYNERGY metal platform was designed specifically to improve flexibility, radiopacity, radial strength, and fracture resistance compared to previous stents. We compared the SYNERGY everolimus-eluting stent (EES) to the durable polymer PROMUS Element EES in a large-scale, multicenter, multinational, prospective, single-blind randomized controlled pivotal trial for regulatory approvals. Methods: Patients with up to 3 native coronary artery lesions in up to 2 major epicardial vessels undergoing PCI were considered for enrollment. Lesion inclusion criteria included reference vessel diameter (RVD) ≥2.25 mm to ≤4.00 mm, and length ≤34 mm. Exclusion criteria included STEMI and complex lesion morphology, including left main or ostial location, major bifurcation disease, chronic total occlusion, vein grafts, thrombus or 3 vessel disease. Eligible patients were randomized 1:1 to SYNERGY or PROMUS Element. The primary endpoint is target lesion failure (composite occurrence of ischemia-driven target lesion revascularization, target vessel related MI, or cardiac death) to 12 months. Results: Between November 2012 and August 2013, 1684 patients were enrolled and randomized at 125 sites in North America, Europe, Australia, New Zealand, Japan, and Singapore. Mean patient age was 63.7 years, 28.4% were women, 30.9% had medically-treated diabetes and 34.3% presented with unstable angina. Mean RVD was 2.63 mm; mean lesion length was 13.9 mm.Conclusions: Enrollment in the EVOLVE II pivotal trial for evaluation of the novel bioabsorbable polymer SYNERGY EES, has been completed. The primary endpoint and major secondary endpoint results through 12 months will be available for presentation at AHA 2014.
Author Disclosures: D.J. Kereiakes: Consultant/Advisory Board; Modest; Harvard Clinical Research Institute, Ablative Solution, Inc. Consultant/Advisory Board; Significant; Boston Scientific, Abbott Vascular, REVA Medical Inc. I.T. Meredith: Consultant/Advisory Board; Significant; Boston Scientific, Medtronic. S. Windecker: Research Grant; Modest; Research grants to the institution from Biotronik and St. Jude. R. Jobe: Consultant/Advisory Board; Modest; Boston Scientific. S.R. Mehta: Research Grant; Modest; Boston Scientific. I.J. Sarembock: None. R.L. Feldman: Research Grant; Modest; Boston Scientific, Abbott, Medtronic. C. Dubois: Consultant/Advisory Board; Modest; Boston Scientific, Edwards LifeSciences. T. Grady: None. S. Saito: Consultant/Advisory Board; Modest; Terumo, Abbott Vascular, Boston Scientific, Medtronic. T. Kimura: None. T. Christen: Employment; Significant; Boston Scientific. D.J. Allocco: Employment; Significant; Boston Scientific. K.D. Dawkins: Employment; Significant; Boston Scientific.
Key Words: Drug eluting stents, Percutaneous coronary intervention (PCI), Bioabsorbable stents
A Randomised Controlled Trial of Oxygen Therapy in Acute St-segment Elevation Myocardial Infarction: The Air Versus Oxygen in Myocardial Infarction (AVOID) Study
Dion Stub1, Karen Smith2, Stephen Bernard3, Ziad Nehme2, Michael Stephenson4, Janet Bray5, Peter Cameron5, Bill Barger6, Andris Ellims7, Andrew J Taylor7, Ian T Meredith8, David M Kaye; 1Cardiology, Baker IDI Heart and Diabetes Institute, St Pauls Hosp Vancover Canada, Melbourne, Australia; 2DEPM, Ambulance Victoria, Monash Univ, Melbourne, Australia; 3Intensive Care, Alfred Hosp, Monash Univ, Melbourne, Australia; 4MICA, Ambulance Victoria, Monash Univ, Melbourne, Australia; 5DEPM, Monash Univ, Melbourne, Australia; 6Quality and Improvement, Ambulance Victoria,, Melbourne, Australia; 7Cardiology, Baker IDI Heart and Diabetes Institute, Alfred Hosp, Melbourne, Australia; 8Monash Heart, Monash Health, Melbourne, Australia
Background: Oxygen is commonly administered to patients with ST-elevation myocardial infarction (STEMI) despite previous studies suggesting a possible increase in myocardial injury due to coronary vasoconstriction and heightened oxidative stress. Methods: We conducted a multicenter, prospective, randomized, controlled trial comparing oxygen (8 L/min) with no supplemental oxygen in patients with STEMI diagnosed on paramedic 12-lead electrocardiogram. Of 638 patients randomized, 441 were confirmed STEMI patients who underwent primary endpoint analysis. The primary endpoint was myocardial infarct size as assessed by cardiac enzymes, troponin (cTnI) and creatine kinase (CK). Secondary endpoints included recurrent myocardial infarction, cardiac arrhythmia and myocardial infarct size assessed by cardiac magnetic resonance (CMR) imaging at 6 months. Results: There was a significant increase in mean peak CK in the oxygen group compared to the no oxygen group (1948 U/Lvs.1543 U/L; means ratio, 1.27; 95% CI, 1.04 to 1.52; P= 0.01). Mean peak troponin was similar in the oxygen and no oxygen groups (57.4 mcg/L vs. 48.0 mcg/L; ratio, 1.20; 95% confidence interval [CI], 0.92 to 1.56;P=0.18).There was an increase in the rate of recurrent myocardial infarction in the oxygen group compared to the no oxygen group (5.5%vs.0.9%, P=0.006) and an increase in frequency of cardiac arrhythmia (40.4%vs.31.4%; P=0.05). At 6-months the oxygen group had an increase in myocardial infarct size on CMR n=139;20.3grams vs. 13.1grams; P=0.04). Conclusion: Supplemental oxygen therapy in patients with STEMI but without hypoxia increased early myocardial injury and was associated with larger myocardial infarct size assessed at six months.
Author Disclosures: D. Stub: None. K. Smith: None. S. Bernard: None. Z. Nehme: None. M. Stephenson: None. J. Bray: None. P. Cameron: None. B. Barger: None. A. Ellims: None. A.J. Taylor: None. I.T. Meredith: None. D.M. Kaye: None.
Key Words: Oxygen, Myocardial infarction, STEMI, Emergency medical services (EMS)
Developing Regional STEMI Systems of Care: Final Results of the Mission: Lifeline STEMI ACCELERATOR Study
Matthew W Sherwood1, Hussein R Al-Khalidi2, James G Jollis3, Mayme L Roettig4, Peter B Berger5, Claire C Corbett6, Harold L Dauerman7, Kathleen Fox4, J L Garvey8, Timothy D Henry9, Ivan C Rokos10, B H Wilson11, Christopher B Granger1; 1Cardiology, Duke Univ, Durham, NC; 2Biostatistics & Bioinformatics, Duke Clinical Rsch Institute, Durham, NC; 3Cardiology, Univ of North Carolina Chapel Hill, Raleigh, NC; 4Cardiology, Duke Clinical Rsch Institute, Durham, NC; 5Cardiology, Geisinger Health System, Danville, PA; 6Cardiology, New Hanover Med Cntr, Wilmington, NC; 7Medicine, Univ of Vermont College of Medicine, Burlington, VT; 8Emergency Medicine, Carolinas Med Cntr, Charlotte, NC; 9Cardiology, Cedar Sinai, LA, CA; 10Emergency Medicine, UCLA - Olive View Med Cntr, LA, CA; 11Cardiology, The Sanger Heart and Vascular Institute, Charlotte, NC
Background: Current guidelines recommend implementation of regional systems of care to improve the timely reperfusion for STEMI patients. While door-to-device times are generally excellent in primary PCI centers, the new standards of EMS first medical contact (FMC) to device and transfer times remain suboptimal. Methods: We intervened in 16 large US metropolitan regions involving 171 PCI hospitals and over 200 non-PCI hospitals and 1253 EMS agencies. We required PCI hospitals to participate in a common database, organized local regional leadership and coordination, and established STEMI protocols for EMS activation and inter-hospital transfer, with ongoing measurement and feedback through Mission: Lifeline regional quarterly reports containing blinded hospital comparison reports. Primary outcomes were first medical contact (FMC) to device times, and first door to device (as well as door-in to door-out times in emergency departments) for transfer patients for hospitals implementing protocols. Results are compared from baseline to one year later and stratified according to the adoption of specific process interventions from final survey data. Results: In 16 regions across the US for the baseline quarter of involvement (Q3 2012), 3538 STEMI patients were admitted to participating sites, 2727 of which directly presented to a PCI center, 811 transferred from a non-PCI (age 61years, 30% female, 7.7% cardiogenic shock). For those presenting directly to PCI centers, median FMC to device time was 85 min (interquartile range 68, 107). For patients transferred for primary PCI, median FMC to device time was 132 min with a median door in to door out time of 63 min. Coordination with EMS was highly correlated with better survival (ED wait time / mortality: less than or =30 min / 2.3%; 30–45 min / 7.7%; >45 min / 11.2%, P=0.0001). Conclusions: In a diverse group of cities and states across the US, baseline data show important opportunities to improve timely reperfusion therapy beginning at the new standard, first medical contact. Final results will be presented including what process interventions may have led to improved times and outcomes.
This research has received full or partial funding support from the American Heart Association.
Author Disclosures: M.W. Sherwood: None. H.R. Al-Khalidi: None. J.G. Jollis: Research Grant; Modest; Medtronic Foundation, Astra Zeneca, The Medicines Co, Philips Health Care. M.L. Roettig: None. P.B. Berger: Research Grant; Modest; The Medicines Co, Janssen, Astra Zeneca, Lilli, Sanofi. Consultant/Advisory Board; Modest; Janssen, Medicure. C.C. Corbett: None. H.L. Dauerman: Research Grant; Significant; Medtronic, Abbott Vascular. Consultant/Advisory Board; Significant; The Medicines Company,Daichi Sankyo, Boston Scientific, Medtronic. K. Fox: None. J.L. Garvey: None. T.D. Henry: Research Grant; Modest; Aastrom(MODEST), Baxter(MODEST), Mesoblast(MODEST). Consultant/Advisory Board; Modest; Abbott Vascular(MODEST), capricor(MODEST), Daiichi Sankyo (MODEST), Eli Lilly and Company(MODEST), Baxter(MODEST), cytori(MODEST), Medicines Company(MODEST). I.C. Rokos: None. B.H. Wilson: Consultant/Advisory Board; Modest; Boston Scientific. C.B. Granger: Research Grant; Modest; BMS, DSI, Bayer, The Medicines Company, Astra Zeneca, Janssen.
Key Words: Systems of care, STEMI
2014 Clinical Science Special Reports Abstracts
Clinical Science Special Reports: Update on Randomized Trials
On-Treatment Analysis of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)
Michael A Blazing1, Robert P Giugliano2, James DeLemos3, Christopher P Cannon2, Thomas Musliner4, Andrew M Tershakovec5, Jennifer A White6, Craig Reist7, Amy McCagg8, Eugene Braunwald2, Robert M Califf1; 1 Cardiovascular Div, Duke Clinical Rsch Institute, Durham, NC; 2 Cardiovascular Div, TIMI Study Group, Boston, MA; 3 Cardiovascular Div, UT Southwestern Med Cntr, Dallas, TX; 4 Clinical Rsch, Merck & Co. Inc, Whitehouse Station, NJ; 5 Clinical Rsch, Merck & Co Inc., Whitehouse Station, NJ; 6 Statistics, Duke Clinical Rsch Institute, Durham, NC; 7 Clinical Trials, Duke Clinical Rsch Institute, Durham, NC; 8 Cardiovascular Div, TIMI Study Group, Boston, MN
Introduction: IMPROVE-IT enrolled 18,144 patients post ACS with an LDL-C ≤ 125 mg/dL. The trial assessed effects on major cardiovascular (CV) outcomes of adding the non-statin LDL-C lowering drug ezetimibe (EZ) vs placebo to 40 mg/day of simvastatin (S). The S was uptitrated to 80 mg/day if the LDL-C was confirmed < 79 mg/dL during follow-up. Treatment duration averaged 5.2 + 2.2 years. The long trial duration, ongoing controversy around EZ and label changes related to S 80mg led to higher than anticipated premature treatment discontinuation. The targeted LDL-C for S-alone was <70 mg/dL and addition of EZ was anticipated to lower LDL-C by~15 mg/dL. In addition to the intention to treat (ITT) analysis (presented earlier at this meeting) we prespecified an on-treatment (OT) analysis to provide additional understanding of the effect of further LDL-C lowering with EZ on CV outcomes. Methods: The OT analyses will include patients who took at least one dose of study drug and will evaluate time while on drug through 30 days after permanent discontinuation or end-of-study whichever came first. Events will be assessed on the prespecified primary endpoint (CV death, MI, stroke, hospitalization for unstable angina and coronary revascularization) and its components using the Cox proportional hazards model with multivariate adjustments. Results: As of May 30 th 2104, the median LDL-C at entry was 95 mg/dL, for both populations and 59 mg/dL for the ITT population but 57 mg/dL for the OT population at 1 year. Follow-up time for the ITT and OT populations were 94,363 and 71,526 patient-years respectively. Table 1 compares key baseline characteristics of patients who did and did not prematurely stop drug before end-of-trial or within 30 days of dying. Unblinded data will be available in late Sept/Oct2014 to evaluate effects on treatment benefit. Conclusions: The results of the OT analysis will enhance the understanding of the effects of LDL-C lowering with EZ
Author Disclosures: M.A. Blazing: Honoraria; Modest; Novartis, Astra Zenica. Consultant/Advisory Board; Modest; Merck. Other Research Support; Significant; Merck. R.P. Giugliano: Honoraria; Modest; Daiichi Sankyo, Merck. Consultant/Advisory Board; Modest; Amgen Inc., Daiichi Sankyo, Merck, Janssen. Research Grant; Significant; Amgen, Daiichi Sankyo, Merck. J. DeLemos: Consultant/Advisory Board; Modest; Amgen, Sanofi/Regeneron. C.P. Cannon: Research Grant; Modest; Accumetrics. Consultant/Advisory Board; Modest; BMS, CSL, Essentialis, Pfizer, GSK, Merck, Takeda. Research Grant; Significant; Arisaph, AstraZeneca, Boehringer-Ingelheim, Janssen, GSK, Merck, Takeda. Consultant/Advisory Board; Significant; Lipimedix, Regeneron, Sanofi. T. Musliner: Employment; Significant; Merck. Ownership Interest; Significant; Merck stock/stock options. A.M. Tershakovec: Employment; Significant; Merck. Ownership Interest; Significant; Merck stock/stock options. J.A. White: None. C. Reist: None. A. McCagg: None. E. Braunwald: Research Grant; Significant; AstraZeneca (TIMI), Johnson & Johnson (TIMI), Beckman Coulter (TIMI), Daiichi-Sankyo (TIMI), Merck (TIMI), Roche Diagnostics (TIMI), Sanofi-Aventis (TIMI), GalaxoSmithKline (TIMI), Bristol Meyers Squibb (TIMI). Honoraria; Modest; Amorcyte, The Medicines Company, Medscape, Bayer, Daiichi-Sankyo, Menarini International, Sanofi-Aventis. R.M. Califf: Research Grant; Significant; Amylin, Bristol-Meyers Squibb, Eli Lilly, Janssen Research and Development, Merck, Novartis. Ownership Interest; Significant; N30 Pharma, Portola. Consultant/Advisory Board; Modest; Medscape. Consultant/Advisory Board; Significant; Amgen, Novartis.
Key Words: Clinical trials Cholesterol-lowering drugs Outcomes LDL Prevention
Lifetime Clinical and Economic Benefits of Statin-Based LDL Lowering in the 20-Year Followup of the West of Scotland Coronary Prevention Study
Chris J Packard1, Ian Ford2, Heather Murray2, Colin McCowan2; 1Institute of Cardiovascular Sciences, Univ of Glasgow, Glasgow, United Kingdom; 2Robertson Cntr for Biostatistics, Univ of Glasgow, Glasgow, United Kingdom
Background: Current focus in prevention of cardiovascular disease has changed recently to consider the use of lifetime risk estimation rather than shorter 10-year-based risk calculation. Also, there is still considerable debate over the wider use of LDL lowering drugs, principally statins, in primary prevention. Availability of the unprecedented 20-year patient-level followup of a landmark primary prevention study permits insight into the long-term clinical and economic benefits of LDL lowering in subjects initially free of CVD. Cohort and methods: The West of Scotland Coronary Prevention Study was a randomized, placebo controlled trial of LDL lowering with pravastatin (40mg/d) in 6595 men aged 45 to 64 years old with raised LDLc but no history of myocardial infarction at randomization. Extended follow up through record linkage provided comprehensive information on a range of end points including site-specific cancer, coronary outcomes, heart failure, stroke, coronary revascularizations and hospital admissions (causes, duration). Cox proportional hazards models for major safety and efficacy outcomes demonstrated that the impact of 5 years of pravastatin therapy continued over 20 years with 13% and 27% reductions respectively in total and CHD mortality (both P<0.001) over the entire period. Stroke was not reduced at the 20 year time point but heart failure hospitalisations were 31% lower in the statin treated group (P<0.0001). Likewise total length of stay (days) across all CVD admissions was reduced by 25% in the statin treated subjects (P<0.0001). Cancer rates did not differ between the two treatment arms. The relative benefit appeared to be equal in all age groups. Conclusions: Debate continues over the use of statin based LDL lowering in primary prevention due in part to a failure to take into account the full impact of treatment on disease trajectory. The 20-year follow up data from WOSCOPS provide clear clinical and economic evidence of the 'lifetime benefit' (since the subjects mean age is now 75 years compared to 55years at study start) of LDL lowering therapy
Author Disclosures: C.J. Packard: Research Grant; Significant; Merck, Roche. Honoraria; Modest; MSD, Roche, AstraZeneca. Consultant/Advisory Board; Modest; MSD, Roche. I. Ford: Research Grant; Significant; MSD. H. Murray: None. C. McCowan: Research Grant; Significant; MSD.
Key Words: Statins, Cardiovascular disease prevention, LDL, Interventional studies, Evidence-based medicine
Regional Analysis of Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)
Marc Pfeffer1, Jean-Lucien Rouleau2, Brian Claggett1, Rafael Diaz3, Nadine Clausell4, Ivan Gordeev5, Tamaz Shaburishvili6, Eldrin F Lewis1, Akshay Desai1, Inderjit Anand7, Scott D Solomon1, James C Fang8, Nancy K Sweitzer9, Jerome L Fleg10, Robin Boineau10, Sonja McKinlay11, Bertram Pitt12; 1Cardiovascular Medicine, Brigham & Women's Hosp, Harvard Med Sch, Boston, MA; 2Cardiovascular Medicine, Montreal Heart Rsch Institute, Montreal, Canada; 3Scientific Director and Executive President, Estudios Cardiologicos Latinoamerica, Rosario, Argentina; 4Cardiovascular Medicine, Hosp de Clínicas de Porto Alegre, Porto Alegre, Brazil; 5Cardiovascular Medicine, State Healthcare Inst of Moscow, Moscow, Russian Federation; 6Cardiovascular Medicine, Tbilisi Heart and Vascular Cntr, Tbilisi, Georgia; 7Cardiovascular Medicine, VA Med Cntr, Minneapolis, MN; 8Cardiovascular Medicine, Univ of Utah, Salt Lake City, UT; 9Cardiovascular Medicine, Univ of Wisconsin, Madison, WI; 10Med Officer, National Heart, Lung and Blood Institute, Bethesda, MD; 11Principal Investigator, New England Rsch Institute, Watertown, MA; 12Internal Medicine, Univ of Michigan Med Cntr, Ann Arbor, MI
Background: TOPCAT patients with heart failure and preserved LVEF assigned to spironolactone (spiro) did not achieve a significant reduction in the primary composite outcome (time to cardiovascular death, aborted cardiac arrest, or hospitalization for management of heart failure) compared to placebo. In a post-hoc analysis, an approximately four-fold difference was identified in this composite event rate between the 1678 patients randomized from Russia (n=1066) and Georgia (n=612) (R/G) compared to the 1767 enrolled from the United States (n=1151), Canada (n=326), Brazil (n=167), and Argentina (n=123) (Americas). Methods: To better understand this difference, demographic characteristics of these populations and their responses to spiro were explored. Results: The cohort from R/G were younger, had less atrial fibrillation and diabetes but were more likely to have been hospitalized for heart failure and have prior MI. R/G patients also had lower NYHA class, LVEF, and creatinine but higher diastolic blood pressure (all p<0.001). Hyperkalemia and doubling of creatinine were more likely and hypokalemia less likely in spiro patients in Americas only, as significant changes in potassium and creatinine with spiro relative to placebo were not observed in R/G. In R/G all event rates were lower and there was no detectable impact of spiro on any outcomes. In contrast, in the Americas, the hazard ratios and confidence intervals for the effect of spiro on the primary outcome, as well as cardiovascular death and hospitalization for heart failure, separately, were each below 1. A significant interaction between treatment and region was found for CV death (P=0.01). Conclusion: This post-hoc analysis demonstrated larger potassium and creatinine changes as well as greater clinical benefits with spiro in the Americas population, which had event rates as anticipated in patients with symptomatic heart failure and preserved EF.
Author Disclosures: M. Pfeffer: Research Grant; Significant; Amgen, Celladon, Novartis, Sanofi Aventis. Consultant/Advisory Board; Modest; Aastrom, Abbott Vascular, Amgen, Bristol-Myers Squibb, Cerenis, Concert, Fibrogen, Genzyme, GlaxoSmithKline, Hamilton Health Sciences, Medtronic, Merck, Novo Nordisk, Roche, Salix, Sanderling, Serono, Servier. Consultant/Advisory Board; Significant; Teva. Other; Modest; Novartis: Patent awarded to BWH regarding use of inhibitors of the renin-angiotensin system in selected survivors of MI. Dr. Pfeffer's Creator's Share is irrevocably & unconditionally assigned, to Rockford College. J. Rouleau: None. B. Claggett: None. R. Diaz: None. N. Clausell: None. I. Gordeev: None. T. Shaburishvili: None. E.F. Lewis: None. A. Desai: Research Grant; Significant; AtCor Medical. Consultant/Advisory Board; Modest; St.Jude Medical, Novartis, 5AM Ventures, and CardioMEMS. I. Anand: Employment; Significant; VA Medical Center, Minneapolis, MN. Honoraria; Significant; Amgen, Cyberonics, Novartis, Servier, Zensun. Consultant/Advisory Board; Significant; Novartis, Cyberonics, Zensun. S.D. Solomon: None. J.C. Fang: None. N.K. Sweitzer: Other Research Support; Modest; Novartis. J.L. Fleg: None. R. Boineau: None. S. McKinlay: None. B. Pitt: Consultant/Advisory Board; Modest; Eli-Lilly. Consultant/Advisory Board; Significant; Pfizer, Bayer, Relypsa. Other; Significant; Relypsa.
Key Words: Heart failure, Cardiovascular therapeutics, Patient care
Comparison of Ischemic and Bleeding Events After Drug-Eluting Stents or Bare Metal Stents in Subjects Receiving Dual Antiplatelet Therapy: Results from the Randomized Dual Antiplatelet Therapy Study
Dean J Kereiakes1, Robert J Yeh2, Joseph M Massaro3, Priscilla Driscoll-Shempp4, Donald E Cutlip5, Sharon-Lise T Normand6, Philippe G Steg7, Anthony H Gershlick8, Jean-François Tanguay9, Stephan Windecker10, Kirk N Garratt11, David E Kandzari12, David P Lee13, Daniel I Simon14, Adrian Iancu15, Jaroslaw Trebacz16, Laura Mauri17; 1The Lindner Rsch Cntr, The Christ Hosp Heart and Vascular Cntr/The Lindner Rsch Cntr, Cincinnati, OH; 2Medicine, Cardiology Div, Massachusetts General Hosp, Boston, MA; 3Biostatistics, Harvard Clinical Rsch Institute, Boston, MA; 4Program Development, Harvard Clinical Rsch Institute, Boston, MA; 5Cardiology, Beth Israel Deaconess Med Cntr, Boston, MA; 6Health Care Policy, Harvard Med Sch, Boston, MA; 7Département de Cardiologie, Hôpital Bichat, Assistance Publique - Hôpitaux de Paris, Paris, France; 8Cardiology, National Institute for Health Rsch, Leicester Cardiovascular Biomedical Rsch Unit, Univ Hosps of Leicester Trust, Univ Hosps of Leicester, Glenfield Hosp, Leicester, United Kingdom; 9Medicine, Institut de Cardiologie de Montreal, Montreal, Canada; 10Cardiology, Bern Univ Hosp, Bern, Switzerland; 11Cardiology, Lenox Hill Hosp, New York, NY; 12Cardiology, Piedmont Heart Institute, Atlanta, GA; 13Interventional Cardiology, Stanford Univ, Stanford, CA; 14Cardiovascular Medicine, Harrington Heart & Vascular Institute, Univ Hosps Case Med Cntr, Cleveland, OH; 15Cardiology, Heart Institute “N. Stancioiu”, Clujnapoca, Romania; 16Interventional Cardiology, Jan Pawel II Hosp Krakow, Krakow, Poland; 17Div of Cardiovascular Medicine, The Brigham and Women's Hosp, Boston, MA
Introduction: Treatment of coronary stenosis with drug-eluting stents (DES) might lead to higher rates of stent thrombosis (ST) compared with bare metal stents (BMS), yet few trials have had adequate power or follow-up beyond one year. Additionally, trials of BMS have not systematically ascertained the appropriate duration of dual antiplatelet therapy (DAPT). We evaluated the impact of DES vs BMS on rates of late ischemic events, and the effect of 12 vs 30 months of DAPT in BMS-treated subjects. Methods: The DAPT Study enrolled BMS- (2,816) and DES-treated (22,866) subjects with identical criteria for enrollment (at index procedure) and randomization (at 12 months). At 12 months, subjects without major bleeding or recurrent cardiovascular events continued on aspirin and were randomized 1:1 to either continued thienopyridine (clopidogrel or prasugrel) or placebo for 18 months. Subjects providing consent for full follow-up with an endpoint event or >29 months of follow-up were propensity score-matched (ratio of up to 8 DES:1 BMS) according to 55 clinical and procedural variables. Among matched subjects, non-inferiority of DES vs. BMS will be assessed for the primary effectiveness endpoints of ST and MACCE (composite of death, MI, stroke) occurring after the index procedure through 33 months. Among randomized BMS-treated subjects, the incidence of ST, MACCE, and major bleeding (GUSTO moderate or severe) will be compared between treatment arms (30 vs 12 months of DAPT) according to ITT. Results: Among 15,206 total eligible subjects for propensity-score matching (2,056 BMS; 13,150 DES), 1,720 BMS and 8,185 DES-treated subjects were matched with a standard deviation of <10% for all variables, indicating minimal residual difference in baseline characteristics. Among matched subjects, 28% had diabetes mellitus, 59% had >1 risk factor for ST at the index procedure (43% acute coronary syndromes, 15% acute STEMI, 15% with a thrombus-containing lesion), 80% were treated with clopidogrel, and 20%, prasugrel. Conclusion: The analysis of ST and MACCE at 33 months between DES- and BMS-treated subjects, and the comparison of 12 vs. 30 months of DAPT with regard to ischemic and bleeding outcomes in BMS-treated subjects will be available at the time of presentation.
Author Disclosures: D.J. Kereiakes: Consultant/Advisory Board; Modest; Harvard Clinical Research Institute, Ablative Solution, Inc. Consultant/Advisory Board; Significant; Boston Scientific, Abbott Vascular, REVA Medical Inc. R.J. Yeh: Other Research Support; Modest; Harvard Clinical Research Institute. Consultant/Advisory Board; Modest; Abbott Vascular, Gilead Sciences. J.M. Massaro: None. P. Driscoll-Shempp: Employment; Significant; Harvard Clinical Research Institute. D.E. Cutlip: Research Grant; Modest; Medtronic, Boston Scientific, Celonova, STENTYS. Research Grant; Significant; Modest, Modest, Modest, Modest. S.T. Normand: None. P.G. Steg: Research Grant; Significant; Sanofi, Servier. Honoraria; Modest; Amarin, Bayer, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck, Pfizer, The Medicines Company, Vivus. Honoraria; Significant; Astra Zeneca, Sanofi, Servier. Ownership Interest; Significant; Aterovax. Consultant/Advisory Board; Modest; Novartis, Otsuka. A.H. Gershlick: Other Research Support; Modest; Boehringer Ingleheim. Speakers Bureau; Modest; Abbott Vascular, Metronic Corp, The Medicines Company. Consultant/Advisory Board; Modest; Abbott Vascular, Medtronic, Eli Lilly, The Medicines Company. Other; Modest; Boehringer Ingleheim. J. Tanguay: Research Grant; Modest; Abbott Vascular, Astra Zeneca, Eli Lilly, GlaxoSmithKline, Merck, Roche, Accumetrics, Ikaria. Speakers Bureau; Modest; Abbott Vascular, Astra Zeneca, Eli Lilly. Honoraria; Modest; Abbott Vascular, Accumetrics, Astra Zeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Ikaria, Roche, Sanofi-Aventis, Servier. Consultant/Advisory Board; Modest; Abbott Vascular, Accumetrics, Astra Zeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Ikaria, Roche, Sanofi-Aventis, Servier. S. Windecker: Research Grant; Significant; St Jude Medical, Biotronik. K.N. Garratt: Research Grant; Modest; The Medicines Company. Research Grant; Significant; Boston Scientific, Abbott Vascular, CeloNova, Mayo Foundation. Honoraria; Modest; DSI/Lilly. Ownership Interest; Significant; Guided Delivery Systems, Infarct Reduction Technologies. Consultant/Advisory Board; Modest; The Medicines Company. Consultant/Advisory Board; Significant; Boston Scientific. D.E. Kandzari: Research Grant; Modest; Boston Scientific, Biotronik. Research Grant; Significant; Medtronic. Consultant/Advisory Board; Modest; Boston Scientific, Zoll. Consultant/Advisory Board; Significant; Medtronic. D.P. Lee: Research Grant; Modest; Boston Scientific. Consultant/Advisory Board; Modest; Boston Scientific. D.I. Simon: Honoraria; Modest; Medtronic, Janssen/Johnson & Johnson, Cordis/Johnson & Johnson, Merck. Consultant/Advisory Board; Modest; Medtronic, Janssen/Johnson & Johnson, Cordis/Johnson & Johnson, Merck. A. Iancu: None. J. Trebacz: None. L. Mauri: Research Grant; Significant; Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daichii Sankyo, Bristol Myers Sqibb, Sanofi-Aventis. Consultant/Advisory Board; Modest; Biotronik, St. Jude, Medtronic.
Key Words: Antiplatelet drugs, Platelet receptor blockers, Percutaneous coronary intervention (PCI)
Clinical Science Special Reports: Off the Beaten Pathologies
The Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor (ARNI) With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial
John J McMurray1, Milton Packer2, Akshay Desai3, Jim Gong4, Marty Lefowitz4, Adel Rizkala4, Jean Rouleau5, Victor Shi4, Scott Solomon6, Karl Swedberg7, Michael Zile8; 1BHF Cardiovascular Rsch Cntr, Univ of Glasgow, Glasgow, United Kingdom; 2Dept of Cardiology, Univ of Texas Southwestern Med Cntr, Dallas, TX; 3Cardiovascular Medicine, Brigham & Women's Hosp, Boston, MA; 4Cardiology, Novartis Pharmaceuticals Corp, East Hanover, NJ; 5Cardiology, Univ of Montreal, Montreal, Canada; 6Cardiology, Brigham and Women's Hosp, Boston, MA; 7Cardiology, Univ of Gothenburg, Gothenburg, Sweden; 8Cardiology, Med Univ of South Carolina, Charleston, SC
Background: LCZ696 blocks the action of angiotensin II and inhibits neprilysin, the enzyme degrading natriuretic and other vasoactive peptides. PARADIGM-HF tested the hypothesis that LCZ696 200 mg bid would be superior to enalapril 10 mg bid in improving clinical outcomes in patients with HF-REF. Methods: A randomized, double-blind, parallel-group, active-controlled, event driven, superiority trial. Single-blind active run-in period to ensure that patients tolerated both study drugs, followed by a double-blind phase in which patients randomized 1:1 to LCZ696 or enalapril. The main run-in inclusion criteria were: NYHA class II-IV, LVEF ≤40% (changed December 2010 to ≤35%); BNP ≥150 pg/mL (or NT-proBNP ≥600 pg/mL) or a BNP ≥100 pg/mL (or NT-proBNP ≥400 pg/mL) if HF hospitalization within the last 12 months. At randomization: eGFR ≥30 mL/min/1.73 m2 (and no decrease >35% during the run-in), SBP ≥95 mmHg, and K+ ≤5.4 mmol/L. Primary endpoint: composite of CV mortality or hospitalization for HF, but trial also specifically designed to evaluate CV mortality which determined both sample size and interim monitoring boundaries. Results: 8442 patients randomized at 985 sites in 47 countries. Mean age 64 (SD 11) yrs; 78% male; 70% NYHA class II/24% class III; LVEF 29 (SD 6)%; beta-blocker 93%; mineralocorticoid receptor antagonist (MRA) 56%.The primary endpoint was reduced by 20 (95% CI 13-27)% in the LCZ696 group compared with the enalapril group (p=0.0000004); CV death was reduced by 20 (11-29)% (p=0.00008) and HF hospitalization by 21 (11-29)% (p=0.00008). All-cause death was reduced by 16 (7-24)% (p=0.0009). Both sudden death (relative risk reduction 20%, p=0.008) and death from worsening HF (21%, p=0.04) were reduced by LCZ696. Repeat as well as first admissions for HF were reduced by 23% (p=0.0004). CV admissions as well as admissions for any cause were also reduced significantly by LCZ696. Patient reported outcomes and NYHA Class improved significantly in the LCZ696 compared with the enalapril group. Conclusion: Combined inhibition of both the angiotensin receptor and neprilysin is more effective than RAS blockade alone in improving outcomes in HF-REF.
Author Disclosures: J.J. McMurray: None. M. Packer: Research Grant; Modest; Consultant to Novartis. A. Desai: None. J. Gong: Employment; Significant; Employment. M. Lefowitz: Employment; Significant; Employment. A. Rizkala: Employment; Significant; Employment. J. Rouleau: Research Grant; Modest; Consultant to Novartis. V. Shi: Employment; Significant; Employment. S. Solomon: Research Grant; Modest; Consultant to Novartis. K. Swedberg: Research Grant; Modest; Amgen, Servier. Honoraria; Modest; Astrazeneca, Novartis, Servier. Consultant/Advisory Board; Modest; Novartis, Servier, ZS Pharma. M. Zile: Research Grant; Modest; Consultant to Novartis.
Key Words: Heart failure, Angiotensin II, Natriuretic peptide
PreSERVE-AMI: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Intracoronary Infusion of Autologous CD34+ Cells in Patients With Left Ventricular Dysfunction Post STEMI
Arshed A Quyyumi1, Alejandro Vasquez2, Marc Klapholz3, Dean Kereiakes4, Gary L Schaer5, Ken Fujise6, Ahmed Abdel-Latif7, Robert S Iwaoka8, Ali E Denktas9, Roger S Gammon10, Steve C Frohwein11, Vijaykumar S Kasi12, Michael R Tamberella13, Catalin Toma14, Nabil Dib15, Tanvir K Bajwa16, Richard Schatz17, Timothy D Henry18, Martin Cohen19, David M Shavelle20, Gregory W Barsness21, Charles Davidson22, Thomas Moss23, Pamela Hyde23, AnnaMarie Kanakaraj23, Vitaly Druker23, Le Dich23, Jonathan Sackner-Bernstein23, Robert Preti23, Douglas Losordo23, Andrew Pecora23; 1Medicine, Emory Univ, Atlanta, GA; 2Cardiology, Huntsville Hosp, Huntsville, AL; 3Medicine, Rutgers New Jersey Med Sch, Newark, NJ; 4The Lindner Rsch Cntr, The Christ Hosp Heart and Vascular Cntr, Cincinnati, OH; 5Div of Cardiology, Rush Univ Med Cntr, Chicago, IL; 6Cardiology, UTMB, Galveston, TX; 7Internal Medicine-Cardiology, Univ of Kentucky, Lexington, KY; 8Novant Health Heart and Vascular Institute, Novant Health Heart and Vascular Institute, Charolotte, NC; 9Internal Medicine/Cardiology, Baylor College of Medicine/Michael E. Debakey VA Med Cntr, Houston, TX; 10Cardiology, Austin Heart, Austin, TX; 11Cardiology, Emory St Josephs Hosp, Atlanta, GA; 12Cardiology, Orlando Health, Orlando, FL; 13Cardiology, Caromont health, Gastonia, NC; 14Heart and Vascular Institute, Univ of Pittsburgh Med Cntr, Pittsburgh, PA; 15Heart Sciences Cntr, Heart Sciences Cntr, Gilbert, AZ; 16Cardiology, Aurora St. Luke's Med Cntr, Milwaukee, WI; 17Scripps Health, Scripps Health, La Jolla, CA; 18Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA; 19Cardiology, Westchester Med Cntr, Valhalla, NY; 20Cardiovascular Medicine, Univ of Southern California, Los Angeles, CA; 21Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN; 22Medicine, Bluhm Cardiovascular Institute Northwestern Memorial Hosp, Chicago, GA; 23Neostem, Inc., Neostem, Inc., New York, NY
Background: ST segment Elevation Myocardial Infarction (STEMI) affects 160,000 annually in the US. Guidelines direct immediate revascularization and adjunctive medical therapies. Yet STEMI victims remain at risk for infarct expansion, heart failure, reinfarction, repeat revascularization and death. In pre-clinical studies, human CD34+ stem cells are angiogenic within ischemic myocardium, improving perfusion and function. A precedent Phase 1 study demonstrated feasibility, safety and bioactivity of intracoronary infusion of autologous CD34+ cells in patients with LV dysfunction (LVD) post-MI and identified a threshold dose of 10M cells associated with improved infarct region perfusion. Methods: PreSERVE-AMI is a Phase 2, randomized, double-blind, placebo-controlled trial performed at 60 sites in the US. Those with LVD (EF≤48% by CMR) ≥4 days post-STEMI underwent mini bone marrow harvest and were randomized 1:1 to (A) autologous CD34+ cells (minimum dose of 10M±20% cells in autologous serum) or (B) autologous serum. (A) or (B) was delivered via stop-flow method for intracoronary infusion. The primary efficacy endpoint was change in resting myocardial perfusion measured by gated SPECT over 6 months. Ventricular function was also assessed (CMR). The primary safety endpoint was occurrence of AEs, SAEs and MACE (CV mortality, heart failure, reinfarction, revascularization). Results: 161 patients were randomized and received intracoronary infusion (from Jan 2012 to Dec 2013). Mean age was 57.3±10.6, 81% were men and minority had history of HF, prior MI or DM (12%, 17%, 27%, respectively). LVEF by CMR was 36.5±9.1. The 6-month data will be presented. Conclusions: PreSERVE-AMI represents the largest study of cell-based therapy for STEMI completed in US and will determine endpoints, sample size and suitability of autologous CD34+ cell therapy for upcoming Phase 3 study in patients with LVD post STEMI who are at risk for death and major morbidity.
Author Disclosures: A.A. Quyyumi: Consultant/Advisory Board; Modest; NeoStem, Inc. A. Vasquez: Speakers Bureau; Modest; Jannsen Pharmaceutical, Edwards Lifesciences. M. Klapholz: Research Grant; Modest; Investigator - Clinical Trial. D. Kereiakes: Consultant/Advisory Board; Modest; Harvard Clinical Research Institute, Ablative Solution, Inc. Consultant/Advisory Board; Significant; Boston Scientific, Abbott Vascular, REVA Medical Inc. G.L. Schaer: Other; Modest; Steering Committee Member, RENEW Trial, Baxter, Steering Committee Member, ixCELL Trial, Aastrom. K. Fujise: Speakers Bureau; Modest; Eli Lilly. Consultant/Advisory Board; Modest; St. Jude Medical. A. Abdel-Latif: None. R.S. Iwaoka: None. A.E. Denktas: None. R.S. Gammon: None. S.C. Frohwein: None. V.S. Kasi: Speakers Bureau; Significant; Astrazeneca. M.R. Tamberella: None. C. Toma: None. N. Dib: None. T.K. Bajwa: None. R. Schatz: None. T.D. Henry: None. M. Cohen: None. D.M. Shavelle: None. G.W. Barsness: None. C. Davidson: None. T. Moss: Employment; Significant; Neostem, Inc. P. Hyde: Employment; Significant; Neostem, Inc. A. Kanakaraj: Employment; Modest; Neostem, Inc. V. Druker: Employment; Significant; Neostem, Inc. L. Dich: Employment; Significant; Neostem, Inc. J. Sackner-Bernstein: Employment; Significant; NeoStem, Inc. R. Preti: Employment; Significant; Neostem, Inc. D. Losordo: Employment; Significant; NeoStem, Inc. A. Pecora: Employment; Significant; Neostem, Inc..
Key Words: Myocardial infarction, STEMI, Cells, Clinical trials
Ventricular Functional Response to Spinal Cord Stimulation for Advanced Heart Failure: Primary Results of the Randomized Defeat-HF Trial
Douglas P Zipes1, Petr Neuzil2, Heinz Theres3, David Caraway4, Douglas L Mann5, Clas Mannheimer6, Peter Van Buren7, Cecilia Linde8, Bengt Linderoth8, Fred Kueffer9, Scott A Sarazin9, Michael J DeJongste10; 1Krannert Institute of Cardiology, Indiana Univ Sch of Medicine, Indianapolis, IN; 2Chairman, Dept of Cardiology, Na Homolce Hosp, Prague, Czech Republic; 3Electrophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany; 4Anesthesiology, St. Mary's Med Cntr, Huntington, WV; 5Sch of Medicine, Cardiovascular Div, Washington Univ in St. Louis, St. Louis, MO; 6Multidisciplinary Pain Cntr, Sahlgrenska Universitetssjukhuset, Goteborg, Sweden; 7Cardiology, Fletcher Allen Healthcare, Burlington, VT; 8Dept of Cardiology, Karolinska Universitetssjukhuset, Stockholm, Sweden; 9CRDM Clinical Rsch, Medtronic, Inc., Mounds View, MN; 10Faculty of Med Sciences, Cardiology and Thorax Surgery, Universitair Medisch Centrum Groningen, Groningen, Netherlands
Background: Heart failure is a syndrome associated with symptoms caused by impaired ventricular function and abnormal neuro-hormonal activation that is responsible for further progression of disease. For the last decade, the primary treatment for heart failure has been through pharmacologic blockade of the abnormal neuro-hormonal activation through the use of beta-blockers and ACE inhibitors. Additionally, less than 25% of heart failure patients are indicated for cardiac resynchronization therapy (CRT), leaving many patients in need of new HF therapies that improve morbidity and mortality. The purpose of the Defeat-HF clinical study is to evaluate whether spinal cord stimulation (SCS) improves heart failure (HF) metrics, including cardiac structure (e.g., heart size and muscle wall thickness), functional capacity (e.g., peak VO2 assessment), and symptoms. SCS may provide another method to slow down or reverse the progression of heart failure by modulating abnormal neuro-hormonal activation. Design: The Defeat-HF study is a prospective, multicenter (25 sites in Canada, Europe, South Africa, and the United States), randomized (3:2), parallel single-blind controlled study to investigate whether SCS is a feasible therapy for the treatment of systolic heart failure. The inclusion criteria are (1) NYHA Class III heart failure, (2) LVEF <35%, (3) QRS duration <120ms and LVEDD >55mm. The primary objective of the Defeat-HF study is to evaluate the reduction in left-ventricular end systolic volume index (LVESVi) after 6 months of SCS therapy in the Treatment arm compared to the Control arm. Demographics In total, 82 patients were enrolled with 66 successfully randomized and implanted with the SCS device system. Seventy-six (76) % (50 of 66) had an ICD at the baseline visit, and among randomized subjects, the mean age was 61 years; 79% were male; mean LVEF was 27% and mean QRS duration was 105ms. Results Currently, 66 randomized subjects have completed 6 months of follow-up and are expected to complete 12 month study follow-up visits in July 2014. Analyses of endpoints at 6 and 12 months will be performed and reviewed by the Data Monitoring Committee in September 2014 and available for the AHA presentation.
Author Disclosures: D.P. Zipes: Consultant/Advisory Board; Modest; Medtronic. P. Neuzil: Consultant/Advisory Board; Modest; EV3, EndoSense, CryoCath Technologies, Boston Scientific, CardioFocus. H. Theres: Consultant/Advisory Board; Significant; Medtronic. D. Caraway: Research Grant; Modest; Vertos Medical. Speakers Bureau; Modest; Medtronic, Vertos Medical. Consultant/Advisory Board; Modest; Medtronic, Vertos Medical. D.L. Mann: Consultant/Advisory Board; Modest; Medtronic, BioControl. C. Mannheimer: Research Grant; Modest; Medtronic. P. Van Buren: Consultant/Advisory Board; Modest; Medtronic. C. Linde: Research Grant; Modest; Medtronic. Other Research Support; Modest; Medtronic. Honoraria; Modest; Biotronik, St. Jude Medical. Consultant/Advisory Board; Modest; Cardio3 BioSciences, St. Jude Medical. B. Linderoth: Consultant/Advisory Board; Modest; Medtronic, St. Jude Medical, Boston Scientific. F. Kueffer: Employment; Significant; Medtronic. S.A. Sarazin: Employment; Significant; Medtronic. M.J. DeJongste: Speakers Bureau; Modest; Medtronic, St. Jude Medical.
Key Words: Heart failure, Autonomic nervous system, Arrhythmias, treatment of, Sudden cardiac death, Ventricular fibrillation
Efficacy of Left Ventricular Augmentation With Algisyl-LVR in the Treatment of Advanced Heart Failure Patients With Ischemic and Non-Ischemic Cardiomyopathy: Results of the AUGMENT-HF Multicenter Randomized Controlled Trial
Stefan D Anker1, Andrew Coats2, Gabriel Cristian3, Dinu Dragomir4, Enrico Pusineri5, Luca Bettari6, Maurizio Volterrani7, Randall J Lee8, Hani N Sabbah9, Andy Hinson10, Douglas L Mann11; 1Dept of Innovative Clinical Trials, Univ Med Cntr Göttingen, Göttingen, Germany; 2Cardiovascular Div, Monash Univ, Australia and Univ of Warwick, UK, Melbourne, Australia; 3Cardiovascular Div, Military Hosp Bucharest, Bucharest, Romania; 4Cardiovascular Div, Spitalul Clinic De Urgenta MAI, Bucharest, Romania; 5Cardiovascular Div, IRCCS San Donato, San Donato Milanese, Italy; 6Cardiovascular Div, Istituti Ospitalieri di Cremona, Cremona, Italy; 7Dept. of Cardiology, IRCCS San Raffaele Pisana, Rome, Italy; 8Div of Cardiology – Electrophysiology, Univ of California, San Francisco, San Francisco, CA; 9Director of Cardiovascular Rsch, Henry Ford Health System, Detroit, MI; 10Clinical & Regulatory Affairs, LoneStar Heart, Inc, Laguna Hills, CA; 11Cardiovascular Div, Washington Univ Sch of Med, Barnes Jewish Hosp, St. Louis, MO
Introduction: Therapeutic options for patients with severe heart failure (HF), refractory to pharmacological therapies, are limited. Given the significant morbidity and mortality associated with this stage of the disease, a novel and effective therapeutic approach is greatly needed. Clinically relevant large animal models and computer simulations have suggested that the addition of non-contractile material to the failing myocardium can reduce elevated myofiber stress. Algisyl-LVR is a proprietary biopolymer gel that is injected into strategic areas of the LV free wall, where it remains as a permanent implant. A prior clinical trial suggested Algisyl-LVR to be safe and potentially efficacious in patients with advanced HF. Hypothesis: Algisyl LVR is superior to standard medical therapy in the management of chronic HF with a reduced ejection fraction (EF) secondary to ischemic or non-ischemic etiologies. Methods: Multi-center, prospective, randomized, controlled evaluation of Algisyl-LVR in patients with HF secondary to either ischemic or non-ischemic etiology. Seventy-eight patients were randomized (1:1) to Algisyl-LVR (n=40) and standard medical therapy (n=38). Patients were mean age 62.3 (±9.6) with ischemic (57.7%) or non-ischemic (42.3%) HF, a mean EF of 25.8 (±5.5), and symptomatic HF (mean NYHA class of 2.9±0.5) with a mean Peak VO2 of 12.2 (±1.8) ml/min/kg, and a mean 6 MWT distance of 293.6 (±81.3) m. Patients must have been on stable, evidence-based therapy for HF. Results: The results of the primary endpoint analysis will be presented including 6 month change in Peak VO2, 6 MWT, NYHA class, KCCQ score, biochemical analysis, and electrocardiographic evaluations. Conclusions: The results of the AUGMENT-HF clinical trial will provide the first insights into the potential for this novel concept of LV augmentation with Algisyl-LVR in the failing heart as an effective strategy for improving functional capacity and clinical outcomes in patients with advanced HF.
Author Disclosures: S.D. Anker: Consultant/Advisory Board; Significant; Scientific Advisory Board. A. Coats: Consultant/Advisory Board; Significant; Scientific Advisory Board. G. Cristian: None. D. Dragomir: None. E. Pusineri: None. L. Bettari: Research Grant; Modest; Research Support. M. Volterrani: None. R.J. Lee: Consultant/Advisory Board; Modest; Scientific Advisory Board. H.N. Sabbah: Consultant/Advisory Board; Modest; Scientific Advisory Board. A. Hinson: Employment; Significant; Employee of LoneStar Heart. D.L. Mann: Consultant/Advisory Board; Modest; Scientific Advisory Board.
Key Words: Heart failure, Remodeling
Clinical Science Special Reports: Management of Cardiovascular Disease
Impact of a Multidisciplinary Management Program on Recurrent Hospitalization and Mortality in Older Individuals With Chronic Atrial Fibrillation: A Multicentre Randomized Trial
Simon Stewart1, Jocasta Ball2, Yhi K Chan1, Melinda Carrington1; 1Head, Preventative Cardiology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; 2Preventative Cardiology, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
Background: We tested the hypothesis that an Atrial Fibrillation (AF)-specific, nurse-led, multidisciplinary management program would significantly improve the primary endpoint of death or recurrent unplanned hospitalization in older individuals with chronic AF. Methods: SAFETY (Standard versus Atrial Fibrillation spEcific managemenT studY) was a multicentre, randomized trial with blinded endpoint acquisition and adjudication. 335 eligible subjects were randomized on a 1:1 basis with stratification for intended rate versus rhythm control to the Standard Management (n=167) or SAFETY Intervention (n=168) group. The latter were exposed to a structured, nurse-led, multidisciplinary care program specifically designed to improve AF-specific management and outcomes (including prevention of thrombo-embolic events and progressive cardiac dysfunction). The primary endpoint was measured as both a time-dependent, discrete event (event-free survival) and a continuous variable (days out-of-hospital alive). Key secondary endpoints were rate of hospitalization and days of stay with a specific focus on unplanned, cardiovascular-related and AF-related hospital activity. A full health economic analysis of outcomes is also planned. Results: Mean age of the study cohort was 72±11 years, 48% were female and two thirds were being managed according to rate control. The two groups were well matched according to demographic and clinical profile. Mean follow-up of Standard Management and SAFETY Intervention subjects was 865+286 days and 888+295 days, respectively, with 49 deaths (14.6%) and 1411 hospitalizations comprising 7203 days of hospital stay (cost $AU12.6 million) documented. Overall, there were 987 (70.0%) emergency hospitalizations (including 1 day admissions) and 5530 (76.8%) days of hospital stay. There were also a total of 574 (40.7%) hospitalizations attributable to a primary cardiovascular diagnosis, comprising 2424 (33.7%) days of hospital stay. Endpoint analyses will be presented at the meeting. Conclusions: This is the first trial of an out-reach program designed to reduce re-hospitalization and prolong survival in a representative cohort of older individuals with chronic AF and typically complex clinical presentations.
Author Disclosures: S. Stewart: None. J. Ball: None. Y.K. Chan: None. M. Carrington: None.
Key Words: Atrial fibrillation, Disease management, Cardiovascular nursing, Outcomes, Health services research
Efficacy and Safety of ZS-9 in Patients with Hyperkalemia: Results from the HyperkAlemia RandoMized interventiON multI-dose ZS-9 maintEnance (HARMONIZE) Clinical Trial
Mikhail Kosiborod1, Henrik S Rasmussen2, Philip Lavin3, Wajeh Y Qunibi4, Bruce Spinowitz5, David Packham6, Simon Roger7, Alex Yang8, Edgar Lerma9, Bhupinder Singh2; 1Cardiology, Saint Luke's Mid America Heart Institute, Kansas City, MO; 2N/A, ZS Pharma, Coppell, TX; 3Biostatistics, Boston Biostatistics Rsch Foundation, Framingham, MA; 4Nephrology, Univ of Texas Health Science Cntr at San Antonio, San Antonio, TX; 5Nephrology, Weill Med College of Cornell Univ, New York, NY; 6Nephrology, Melbourne Renal Rsch Group, Reservoir, Australia; 7Renal Medicine, Gosford Hosp, Gosford, Australia; 8N/A, Xelay Acumen, Belmont, CA; 9Cardiology, Univ of Illinois at Chicago College of Medicine, Peoria, IL
Background: Hyperkalemia is a common electrolyte abnormality, associated with potentially lethal cardiac arrhythmias, poor prognosis, and is difficult to manage due to lack of effective therapies. Sodium zirconium cyclosilicate (ZS-9) is a non-absorbed zirconium-based cation exchanger that selectively binds potassium (K+) in the intestine. The long-term efficacy of ZS-9 in maintaining normokalemia has not been evaluated in clinical trials. Methods: HARMONIZE was a multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate long-term efficacy and safety of ZS-9 in patients with hyperkalemia (serum K+ ≥5.1 mEq/L). All patients received 10 g of ZS-9 TID for 48 hours in the acute open label phase. Patients achieving normal K+ (3.5-5.0 mEq/L) were randomized to one of 3 ZS-9 doses (5, 10, 15 g daily) or placebo for 28 days in the maintenance phase. Primary endpoint was mean K+ in each ZS-9 dose vs placebo during days 8-29 of the maintenance. Secondary endpoints included the proportion of patients achieving and maintaining normal K+ in the acute and maintenance phases respectively, and safety. Results: Overall, 258 patients enrolled in the acute phase across 44 sites with 237 patients randomized into the maintenance phase (36% with heart failure, 64% with CKD, 64% with diabetes, 68% on RAAS inhibitors). Mean baseline K+ was 5.6 mEq/L, and was reduced to 4.5 mEq/L at 48 hrs in the acute phase. Significant reduction in K+ was observed within 1 hour of ZS-9 administration, with 84% of patients achieving normokalemia at 24 hours and 98% at 48 hours. K+ was significantly lower with all 3 ZS-9 doses vs placebo in the maintenance phase (4.8, 4.5, 4.4 mEq/L for 5, 10 and 15g of ZS-9, respectively; 5.1 mEq/L for placebo; P ≤ 0.0001 for all comparisons). Greater proportions of patients in all 3 ZS-9 groups maintained normokalemia vs placebo (71%, 76%, 85% for 5, 10 and 15 g of ZS-9, respectively; 48% with placebo). The rate of adverse events was comparable between ZS-9 and placebo. Conclusion: ZS-9 was highly effective in acutely reducing K+ levels in patients with hyperkalemia, and maintaining normokalemia for up to four weeks, with excellent tolerability.
Author Disclosures: M. Kosiborod: Consultant/Advisory Board; Significant; ZS Pharma. H.S. Rasmussen: Employment; Significant; ZS Pharma. Ownership Interest; Significant; ZS Pharma. P. Lavin: Employment; Significant; Boston Biostatistics Research Foundation. Consultant/Advisory Board; Significant; ZS Pharma. W.Y. Qunibi: Research Grant; Modest; ZS Pharma, American Regent. Honoraria; Modest; American Regent. Consultant/Advisory Board; Modest; American Regent. B. Spinowitz: Research Grant; Modest; ZS Pharma, Relypsa, Vifor. Consultant/Advisory Board; Modest; ZS Pharma. D. Packham: Research Grant; Modest; ZS Pharma. Honoraria; Modest; Abbott, REATA, Mesoblast. Consultant/Advisory Board; Modest; ZS Pharma. S. Roger: Honoraria; Modest; ZS Pharma. A. Yang: Employment; Significant; Xelay Acumen. Ownership Interest; Significant; ZS Pharma. Consultant/Advisory Board; Significant; ZS Pharma. E. Lerma: Research Grant; Modest; ZS Pharma. B. Singh: Employment; Significant; ZS Pharma.
Key Words: Potassium, Clinical trials, Heart failure, ACE inhibitor, Renal function
Impact of Additive Use of Olmesartan in Patients With Chronic Heart Failure: The Supplemental Benefit of an Angiotensin Receptor Blocker in Hypertensive Patients With Stable Heart Failure Using Olmesartan (SUPPORT) Trial
Yasuhiko Sakata1, Nobuyuki Shiba2, Jun Takahashi1, Satoshi Miyata1, Kotaro Nochioka1, Masanobu Miura1, Tsuyoshi Takada2, Hiroaki Shimokawa1; 1Dept of Cardiovascular Medicine, Tohoku Univ, Sendai, Japan; 2Dept of Cardiovascular Medicine, International Univ of Health and Welfare Hosp, Nasushiobara, Japan
Background: We examined whether an additive treatment with an angiotensin receptor blocker (ARB), olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin converting enzyme (ACE) inhibitors, beta-blockers or both. Methods: In a prospective randomized open-label blinded endpoint study, a total of 1,147 CHF patients with a history of hypertension (mean age 66 years, 75% male, median left ventricular ejection fraction 54%) were randomized to either the olmesartan group (N=574) or the control group (N=569) in the Supplemental Benefit of Angiotensin Receptor Blocker in Hypertensive Patients with Stable Heart Failure Using Olmesartan (SUPPORT) Trial. The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke and worsening heart failure requiring hospitalization. Results: During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33%) in the olmesartan group and in 166 patients (29%) in the control group (hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P=0.112), while renal dysfunction developed more frequently in the olmesartan group than in the control group (Figure). Subgroup analysis revealed that additive use of olmesartan, when combined with both ACE inhibitors and beta-blockers, was associated with increased incidence of the primary endpoint, all-cause death and renal dysfunction, whereas it was associated with improved mortality when combined with beta-blockers alone, but not with ACE inhibitors alone (Figure). Conclusions: Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and beta-blockers was associated with increased adverse cardiac events.
Author Disclosures: Y. Sakata: None. N. Shiba: None. J. Takahashi: None. S. Miyata: None. K. Nochioka: None. M. Miura: None. T. Takada: None. H. Shimokawa: None.
Key Words: Heart failure, Clinical trials, Hypertension, Pharmacology
Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor PCC
Hamim Zahir1, Alexander Vandell2, Madhuri Desai1, Jen-Fu Maa3, Victor Dishy4, Barbara Lomelli5, Annette Feussner6, Wenquin Feng7, Ling He8, Michael A Grosso9, Hans J Lanz9, Karen S Brown1; 1Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, NJ; 2Clinical Pharmacogenomics, Daiichi Sankyo Pharma Development, Edison, NJ; 3Biostatistics, Daiichi Sankyo, Inc., Parsippany, NJ; 4Experimental Medicine, Daiichi Sankyo Pharma Development, Edison, NJ; 5Early Clinical Development, Quintiles, Inc., Overland, KS; 6Preclinical Rsch & Development, CSL Behring GmbH, Marburg, Germany; 7Clinical Biomarker Analysis, Daiichi Sankyo Pharma Development, Edison, NJ; 8Clinical Bioanalysis, Daiichi Sankyo Pharma Development, Edison, NJ; 9Clinical Development, Daiichi Sankyo Pharma Development, Edison, NJ
Background and Objective: Edoxaban, a novel oral anticoagulant (NOAC), is an investigational, oral, once-daily anticoagulant that specifically and reversibly inhibits factor Xa. There are currently no specific reversal agents for the NOACs, although a 3-factor prothombin complex concentrate (PCC) has shown utility in reversing some biomarker effects. This two part study developed a punch biopsy model in healthy subjects to assess the anticoagulant effects of edoxaban and evaluated reversal by Beriplex®, a 4-factor prothombin complex concentrate (PCC). Bleeding duration (BD) was the primary endpoint, and key secondary endpoints were blood loss volume (BV), endogenous thrombin potential (ETP), and prothrombin time (PT). Methods: This was a phase 1, single-dose, sponsor-unblinded, study. Part 1 was a two-way crossover with a 7 day washout between treatments (single dose of 60 or 180 mg edoxaban). Part 2 was a placebo-controlled, sequential descending PCC dose, two-way crossover with a ≥14-day washout between treatments. Healthy subjects, aged 18-45 y, were enrolled into part 1 (n=18) or into one of three PCC dose cohorts in part 2 (N=28-33 per cohort): 50 IU/kg, 25 IU/kg, or 10 IU/kg. Within each cohort in part 2, subjects received two treatments in random order: a single dose of edoxaban 60 mg followed by an infusion of PCC (treatment A) and a single dose of edoxaban 60 mg followed by an infusion of placebo (Treatment B). Infusions were started at approximately 1.75 h after edoxaban dosing and ended uniformly at 2.25 h after the edoxaban dose. For both parts, time matched punch biopsies were performed on Day -1 (baseline) and on Day 1, 2.75 h after edoxaban dosing. BD and BV were assessed after each biopsy. Serial sampling was performed for biomarkers (PT and ETP) and edoxaban pharmacokinetics. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. The sample size for part 2 was determined based on the effect size and variability observed for BD following 60 mg edoxaban in Part 1. Results: Results will be available in July 2014 and will be presented at the meeting. Conclusions: This is the first trial to show an edoxaban effect on bleeding time following punch biopsy and assess the ability of a 4-factor PCC to reverse the effect of edoxaban on bleeding.
Author Disclosures: H. Zahir: Employment; Significant; Daiichi Sankyo. A. Vandell: Employment; Significant; Daiichi Sankyo. M. Desai: Employment; Significant; Daiichi Sankyo. J. Maa: Employment; Significant; Daiichi Sankyo. V. Dishy: Employment; Significant; Daiichi Sankyo. B. Lomelli: Research Grant; Significant; Daiichi Sankyo. A. Feussner: Employment; Significant; CSL Behring. W. Feng: Employment; Significant; Daiichi Sankyo. L. He: Employment; Significant; Daiichi Sankyo. M.A. Grosso: Employment; Significant; Daiichi Sankyo. H.J. Lanz: Employment; Significant; Daiichi Sankyo. K.S. Brown: Employment; Significant; Daiichi Sankyo.
Key Words: Anticoagulants, Factor xa, Dose-response relation, drug, Anticoagulation
ANNEXA™ A: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial, Demonstrating Reversal of Apixaban-Induced Anticoagulation in Older Subjects by Andexanet alfa (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors
Mark Crowther, Gallia G Levy, Genmin Lu, Janet Leeds, Lee Barron, Pamela B Conley, Janice Castillo, John T Curnutte, Stuart Connolly; Dept of Medicine, McMaster Univ, Hamilton, Canada
Background: Direct FXa inhibitors appear to have superior anticoagulant efficacy and safety relative to warfarin and low molecular weight heparin. However, they are limited by the lack of a specific antidote to reverse anticoagulation in cases of serious bleeding episodes or prior to urgent/emergency surgery. Andexanet alfa (AnXa, PRT064445) is a modified, recombinant human FXa molecule that is catalytically inactive but retains high-affinity binding to direct and indirect fXa inhibitors. Thus, it acts as a FXa decoy and reverses FXa inhibitor-mediated anticoagulation. We have previously reported randomized Phase 2 data in healthy subjects anticoagulated with apixaban, rivaroxaban, or enoxaparin, where AnXa rapidly and significantly reversed anti-FXa activity and the inhibition of thrombin generation. Here we report data from the first Phase 3 registration study of AnXa administered to older subjects anticoagulated with apixaban. Methods: ANNEXATM-A is a Phase 3, double-blind, placebo-controlled study of AnXa in older subjects treated with apixaban. Part 1 of the study investigated a bolus regimen and Part 2 will investigate a bolus followed by a 2 hour continuous infusion. In Part 1, 34 subjects age 50 to 75 were randomized to receive either AnXa or placebo in a 3:1 ratio. All subjects received apixaban 5 mg PO BID for 4 days. AnXa at a dose of 400 mg IV bolus or placebo was administered on Day 4, 3 hours after the last apixaban dose (approximate apixaban Cmax). Safety data were collected through Day 43. The primary efficacy endpoint is the reversal of apixaban-induced anti-FXa activity (mean change from baseline at 2 or 5 min after the end of the bolus). Additional efficacy endpoints included reduction in plasma free fraction of apixaban and restoration of thrombin generation. Results and Conclusions: Part 1 of the pivotal Phase 3 study has been completed. Final efficacy and safety results for Part 1 will be presented and discussed.
Author Disclosures: M. Crowther: Speakers Bureau; Modest; Bayer, Celgene, Leo Pharma, Shire. Consultant/Advisory Board; Modest; Leo Pharma. Consultant/Advisory Board; Significant; Portola. G.G. Levy: Employment; Significant; Portola. Ownership Interest; Significant; Portola. G. Lu: Employment; Significant; Portola. Ownership Interest; Significant; Portola. J. Leeds: Employment; Significant; Portola. Ownership Interest; Significant; Portola. L. Barron: Employment; Significant; Portola. Ownership Interest; Significant; Portola. P.B. Conley: Employment; Significant; Portola. Ownership Interest; Significant; Portola. J. Castillo: Employment; Significant; Portola. Ownership Interest; Significant; Portola. J.T. Curnutte: Employment; Significant; Portola. Ownership Interest; Significant; Portola. S. Connolly: Research Grant; Significant; Sanofi-Aventis, Bristol-Myers Squibb, Boehringer-Ingelheim, Boston Scientific, St. Jude Medical., Portola Pharmaceutical, Johnson and Johnson. Speakers Bureau; Significant; Sanofi-Aventis, Bristol-Myers Squibb, Boehringer-Ingelheim. Consultant/Advisory Board; Significant; Sanofi-Aventis, Bristol-Myers Squibb, Boehringer-Ingelheim, Bayer Pharmaceuticals Inc.
Key Words: Anticoagulants, Blood coagulation, Clinical trials, Direct factor Xa inhibitor, Factor xa
Clinical Science Special Reports: Trials and Cardiovascular Registries
High Density Lipoprotein Efflux Capacity and Incident Cardiovascular Events
Anand Rohatgi1, Amit Khera1, Jarett D Berry1, Edward G Givens1, Colby R Ayers1, Kyle E Wedin2, Ivan S Yuhanna3, Daniel J Rader4, James A de Lemos1, Philip W Shaul3; 1Internal Medicine, Univ of Texas Southwestern Med Cntr, Dallas, TX; 2Internal Medicine, Emory Univ, Atlanta, GA; 3Pediatrics, Univ of Texas Southwestern Med Cntr, Dallas, TX; 4Internal Medicine, Univ of Pennsylvania, Philadelphia, PA
Introduction: Low HDL cholesterol (HDL-C) is a risk factor of atherosclerotic cardiovascular disease (ASCVD) events but recent clinical trials suggest that some interventions that increase HDL-C do not reduce CV events. Measurement of HDL function may lead to a better cardiovascular biomarker. A classic HDL function, namely cholesterol efflux capacity (CEC), has been shown to be inversely associated with prevalent ASCVD, but its relationship to incident events remains uncertain. We sought to determine if CEC is associated with first incident ASCVD outcomes in the Dallas Heart Study, an unselected population-based sample free of CVD at baseline. Methods: HDL-C, HDL particle number (HDL-P) and CEC were measured from stored plasma samples in 2924 participants ages 30-65 from the Dallas Heart Study who were free from CVD, niacin use, or death within one year of enrollment. CEC was measured as the fraction of total BODIPY-labeled cholesterol in macrophages effluxed to apolipoprotein B-depleted plasma. HDL-P was measured by NMR. The primary ASCVD endpoint was a composite of first nonfatal MI and stroke, coronary revascularization, and CV death through a median 9.4 years of follow up. Results: The median age was 43 years, with 57% women and 49% Black participants. A total of 132 first ASCVD events occurred during follow up. CEC was minimally correlated with HDL-C (r=0.07, p=0.0001) and modestly with HDL-P (r=0.15, p<0.0001). Increasing sex- and race-adjusted quartiles of CEC were inversely associated with incident ASCVD (Figure), including in models fully-adjusted for risk factors, HDL-C and HDL-P (HR for Q4: 0.33, 95%CI 0.19-0.55). Similar findings were seen when CEC was analyzed continuously (HR 0.68 per 1 SD, 95%CI 0.55-0.84). Conclusion: HDL CEC robustly and inversely associates with incident ASCVD in the general population, including when adjusted for HDL-C and HDL-P. This novel finding supports the investigation of HDL CEC as a novel cardiovascular biomarker.
This research has received full or partial funding support from the American Heart Association.
Author Disclosures: A. Rohatgi: Research Grant; Significant; Merck. Speakers Bureau; Modest; Astra Zeneca. A. Khera: None. J.D. Berry: Speakers Bureau; Significant; Merck. Consultant/Advisory Board; Significant; Nihon Corp.. E.G. Givens: None. C.R. Ayers: None. K.E. Wedin: None. I.S. Yuhanna: None. D.J. Rader: Other; Significant; VascularStrategies. J.A. de Lemos: Consultant/Advisory Board; Modest; Amgen, Regeneron. P.W. Shaul: Consultant/Advisory Board; Modest; Pfizer.
Key Words: HDL, Lipoproteins, Biomarkers, Coronary heart disease, Population science
A Cluster Randomized Controlled Trial to Evaluate The Effect of a Simplified Multifaceted Management Program in High Cardiovascular Disease Risk Patients in Rural China and India: Simcard Study
Maoyi Tian1, Vamadevan S Ajay2, Danzeng Dunzhu3, Safraj S Hameed2, Xian Li4, Zhong Liu3, Cong Li1, Hao Chen5, KaWing Cho6, Ruilai Li1, Xingshan Zhao7, Devraj Jindal8, Ishita Rawal8, Mohammed K Ali9, Eric D Peterson10, Elizabeth R Delong11, Jiachao Ji4, Ritvik Amarchand12, Anand Krishnan12, Nikhil Tandon13, Li-Qun Xu14, Yangfeng Wu15, Dorairaj Prabhakaran2, Lijing L Yan1; 1Primary Care and Population Health, The George Institute for Global Health, China, Beijing, China; 2Cntr of Excellence - CARRS, Public Health Foundation of India, New Delhi, India; 3Med Sch, Tibet Univ, Lhasa, China; 4Biostatistics and Health Economics, The George Institute for Global Health, China, Beijing, China; 5Cardiology, Beijing Hosp, Beijing, China; 6Pediatrics, Children's Hosp Los Angeles, Los Angeles, CA; 7Cardiology, Jishuitan Hosp, Beijing, China; 8CVD Epidemiology, Cntr for Chronic Disease Control, New Delhi, India; 9Rollins Sch of Public Health, Emory Univ, Atlanta, GA; 10Medicine, Duke Univ, Durham, NC; 11Biostatistics and bioinformatics, Duke Univ, Durham, NC; 12Community Medicine, All India Institute of Med Sciences, New Delhi, India; 13Endocrinology and Metabolism, All India Institute of Med Sciences, New Delhi, India; 141000 Plan, China Mobile Rsch Institute, Beijing, China; 15Hosp Care, The George Institute for Global Health, China, Beijing, China
Background: Cardiovascular disease (CVD) is the leading cause of death in China and India. Access to appropriate healthcare remains limited in resource poor settings in these areas, where CVD burdens are high. Objective: This study aims to develop and evaluate a simplified multifaceted guideline-based CVD management program delivered by the community health workers (CHWs) and targeting high CVD risk subjects. Methods: This study is a cluster randomized trial conducted in 47 rural villages (23 intervention vs 24 control villages) in Tibet, China and Haryana, India. High CVD risk subjects (aged 40 years or older, history of heart disease, stroke, diabetes, or measured systolic blood pressure of 160mmHg or higher) were screened and recruited. CHWs in the intervention villages were trained and assisted by a customized smartphone or tablet based electronic decision support system (EDSS) to follow-up and manage their patients on a periodic basis following a '2+2' multifaceted intervention model: two lifestyle modifications (smoking cessation and sodium reduction) and appropriate prescription of anti-hypertensive medication and aspirin. Villages in the control group continued their usual practice. The primary outcome is the net between-group difference in the proportion of patients taking anti-hypertensive medication pre-and-post intervention after one year. The proportion of patients taking aspirin and changes in blood pressure will also be examined. These outcomes will be analysed according to intent-to-treat principle by logistic-binomial or generalized linear models with random effects to account for clustering effect and repeated measurements. Results: 12596 subjects were screened at baseline, and 2086 subjects (16.6%) were identified as high CVD risk (age: 60.0±11.7 years; 65.3% women). 80 people died during the course of the intervention and 1828 were followed-up at the end of the intervention. Data cleaning and analysis are in progress. Results will be reported at the meeting. Conclusions: To our knowledge, this is the first study to evaluate the effect of a simplified management scheme delivered by CHWs with the help of EDSS on improving the health of high CVD risk patients.
Author Disclosures: M. Tian: None. V.S. Ajay: None. D. Dunzhu: None. S.S. Hameed: None. X. Li: None. Z. Liu: None. C. Li: None. H. Chen: None. K. Cho: None. R. Li: None. X. Zhao: None. D. Jindal: None. I. Rawal: None. M.K. Ali: None. E.D. Peterson: None. E.R. Delong: None. J. Ji: None. R. Amarchand: None. A. Krishnan: None. N. Tandon: None. L. Xu: None. Y. Wu: None. D. Prabhakaran: None. L.L. Yan: None.
Key Words: Cardiovascular disease prevention, Community-based care, Cardiovascular disease, Healthcare innovation
Intention-to-Tweet: A Randomized Trial of Social Media from Circulation
Caroline Fox, Marc Bonaca, John J Ryan, Joseph M Massaro, Karen Barry, Joseph Loscalzo; Circulation, Circulation Journal, Boston, MA
Background: Many medical professionals use social media to share medical information. Medical journals use social media to distribute the findings of published articles. However, whether social media exposure to original articles improves article impact metrics is uncertain. We conducted a randomized controlled trial at the journal Circulation to determine whether social media exposure improves article metrics. Methods: At the time of publication, articles were randomized to receive targeted social media exposure from Circulation, including postings on the Facebook and Twitter accounts of Circulation. Randomization occurred using envelope randomization on a per paper basis. We excluded all papers that received a national AHA press release. The primary end-point is mean 30-day article page views (inclusive of downloads, abstract views); data will be abstracted using Google analytics. We will conduct an intention-to-treat analysis comparing mean 30-day article page views by Fisher's exact test between the papers randomized to social media as compared to those in the control group, which receives no social media from Circulation. Pre-specified subgroups include article type (population/clinical/basic), US vs. non-US corresponding author, and whether the manuscript received an editorial. Assuming a sample size of 119 papers in each group, we will have 90% power to detect an improvement of 20% in the primary endpoint for social media over the control group at a two-sided alpha of 0.05. The study is currently ongoing and will be completed by September, 2014. Results: At the time of presentation, randomization and data acquisition will be complete, the database locked, and analyses completed. At the LBCT session, we will present the primary results of our trial, as well as the pre-specified subgroup analyses. Conclusion: These results will indicate whether a social media strategy for a cardiovascular journal increases the number of times an article is viewed. Randomized controlled trials reported in medical journals are used as the evidence basis for medical decision making. This trial extends this methodology to understand the role of social media-based communication on the impact of information delivery by cardiovascular journals.
This research has received full or partial funding support from the American Heart Association.
Author Disclosures: C. Fox: Employment; Significant; Associate Editor at Circulation. M. Bonaca: Employment; Modest; Section Editor, Circulation. J.J. Ryan: None. J.M. Massaro: Employment; Significant; Statistical Editor, Circulation. K. Barry: Employment; Significant; Managing editor, Circulation. J. Loscalzo: Employment; Significant; Editor, Circulation.
Key Words: Cardiovascular disease, Social media, Clinical trials
Determining the Risks of Magnetic Resonance Imaging at 1.5 Tesla for Patients with Non-MRI Conditional Pacemakers and Implantable Cardioverter Defibrillators: Final Results of The MagnaSafe Registry
Robert J Russo, The MagnaSafe Investigators; Div of Cardiovascular Diseases, Scripps Clinic, La Jolla, CA
Objective: The MagnaSafe Registry is a multicenter study to determine the risk of clinically-indicated non-thoracic MRI at 1.5T in patients with pacemakers (PM) and implantable cardioverter-defibrillators (ICD). Methods: Device interrogation was performed pre-/post-MRI using a standardized protocol. Pacemaker non-dependent patients had pacing functions deactivated; dependent patients had the device programmed to an asynchronous mode. For ICD patients all therapies were disabled if non-pacemaker dependent; dependent ICD patients were excluded. Primary endpoints included death, generator/lead failure, or induced arrhythmia. Secondary endpoints were clinically-relevant device parameter changes. Results: Between April 2009 and April 2014, 1500 clinically-indicated non-thoracic MRI studies (spine 41%; brain 35%) were performed at 21 sites (1000 PMs, 500 ICDs, 2923 leads). No deaths, generator/lead failures, losses of capture, or ventricular arrhythmias occurred during the scan. One ICD generator later required replacement when tachytherapy was inappropriately active during the exam. Six episodes of self-terminating atrial fibrillation (<49 hr) and 6 cases of partial electrical reset were noted. A decrease in battery voltage ≥0.04V occurred in 0.5% of PMs and 7% of ICDs; pacing lead impedance change ≥50Ω in 3% of PMs and 4% of ICDs; and high-voltage impedance change ≥3Ω in 17% of ICDs. A decrease of ≥50% in P-wave amplitude occurred in 5 PMs and 1 ICD. A decrease of ≥25% in R-wave amplitude occurred in 4% of PMs and 2% of ICDs, and a decrease of ≥50% in 1 ICD. A pacing threshold increase ≥0.5V at 0.4 ms occurred in 1% of PM and ICD leads. Overall, one or more clinically-relevant device parameter changes occurred in 12% of PM and 29% of ICD cases. A previous MRI had been performed in 312 cases (21%), and the frequency of a device parameter change event was 20% in those with, and 17% in those without a previous MRI (p=0.3). At 6-month follow up no clinically-significant durable device parameter changes were noted. Conclusions: Final results of the MagnaSafe Registry demonstrate that clinically-indicated non-thoracic MRI at 1.5T may be performed for patients with non-conditional devices at no detectable clinical risk when the device is appropriately programmed.
Author Disclosures: R.J. Russo: Research Grant; Significant; Biotronik, Boston Scientific, St. Jude Medical. T. Investigators: None.
Key Words: Pacemakers, Implantable cardioconvertor defibrillator, Magnetic resonance imaging
Clinical Science Special Reports: Results of ODYSSEY
Efficacy and Safety of Combining Alirocumab With Atorvastatin or Rosuvastatin versus Statin Intensification or Adding Ezetimibe in High Cardiovascular Risk Patients: ODYSSEY OPTIONS I and II
Harold Bays1, Michel Farnier2, Daniel Gaudet3, Robert Weiss4, Juan Lima Ruiz5, Gerald F Watts6, Ioanna Gouni-Berthold7, Jennifer G Robinson8, Peter H Jones9, Randall Severance10, Maurizio Averna11, Elisabeth Steinhagen-Thiessen12, Helen M Colhoun13, Jian Zhao14, Yunling Du15, Corinne Hanotin16, Stephen Donahue17; 1Depts of Epidemiology & Medicine, Louisville Metabolic and Atherosclerosis Rsch Cntr (L-MARC), Louisville, KY; 2Département d'Endocrinologie et de Lipidologie, Point Médical, Dijon, France; 3Dept of Medicine, Université de Montréal, Chicoutimi, Canada; 4none, Maine Rsch Associates, Auburn, ME; 5Lipid and Vascular Rsch Unit, Universitary Hosp Vall d' Hebron, Barcelona, Spain; 6Cardiovascular Medicine, Lipid Disorders Clinic, Royal Perth Hosp, Sch of Medicine and Pharmacology, Univ of Western Australia, Crawley, Australia; 7Cntr for Endocrinology, Diabetes and Preventive Medicine (ZEDP), Univ of Cologne, Cologne, Germany; 8Depts of Epidemiology & Medicine, Univ of Iowa, Iowa City, IA; 9Atherosclerosis and Vascular Medicine, Baylor College of Medicine, Houston, TX; 10none, Radiant Rsch - Phoenix SE, Chandler, AZ; 11Dept of Internal Medicine and Med Specialties, Università di Palermo – Policlinico "Paolo Giaccone", Palermo, Italy; 12Lipidambulanz, Interdisziplinaeres Stoffwechsel-Centrum, Charité - Universitaetsmedizin Berlin Campus Virchow Klinikum, Berlin, Germany; 13none, Univ of Dundee, Dundee, United Kingdom; 14Biostatistics & Data Management, Regeneron Pharmaceuticals, Inc, Tarrytown, NY; 15Biostatistics, Regeneron Pharmaceuticals, Inc, Basking Ridge, NJ; 16Clinical Rsch, Sanofi, Paris, France; 17none, Regeneron Pharmaceuticals, Inc, Tarrytown, NY
Background: ODYSSEY OPTIONS I and II (NCT01730040; NCT01730053) compared the efficacy and safety of alirocumab (ALI), a fully-human monoclonal PCSK9 antibody, as add-on to statin vs. doubling statin dose, switching to a more potent statin or adding ezetimibe (EZE) in patients (pts) not at goal on commonly used statin doses. Methods: Patients (pts) had either prior CV disease (CVD) and LDL-C ≥70 mg/dL or CVD risk factors and LDL-C ≥100 mg/dL. Pts on stable atorvastatin (ATV) 20 or 40 mg/day (OPTIONS I) or rosuvastatin (RSV) 10 or 20 mg/day (OPTIONS II) were randomized to: (1) add-on ALI 75 mg every 2 weeks (Q2W); (2) add-on EZE 10 mg/day; (3) doubling of statin dose; or (4) switch from ATV 40 mg to RSV 40 mg (OPTIONS I only). ALI dose was increased at Week (W) 12 in a blinded manner to 150 mg Q2W if pts W8 LDL-C level was ≥70 or ≥100 mg/dL depending on CV risk (all doses self-administered subcutaneously via 1-mL pre-filled pen). Primary endpoints were the % change in LDL-C from baseline to W24 (intent-to-treat analysis). Safety data were pooled across statin entry regimens for each study. Results: At W24, ALI significantly reduced LDL-C vs. all comparators in OPTIONS I and for pts entering on RSV 10 mg in OPTIONS II (p≤0.0004; Table). ~79-92% ALI pts did not need dose increase (Table). In OPTIONS I, treatment-emergent adverse events (TEAEs) were reported by 65.4% ALI+ATV pts, 64.4% EZE+ATV pts, and 63.8% pts with doubling of ATV dose or switch to RSV. TEAEs in OPTIONS II were reported by 56.3% ALI+RSV pts, 53.5% EZE+RSV pts and 67.3% pts with doubling of RSV dose. In both trials, the % of pts reporting SAEs ranged 3.8%-7.9% and TEAEs leading to discontinuation ranged 4.0%-7.9%; rates were comparable among groups. Most common TEAEs (both studies) were nasopharyngitis and URTI. Conclusions: Adding ALI to ATV significantly reduced LDL-C more than adding EZE, doubling ATV dose or switching ATV 40 to RSV 40 mg, with similar results observed when adding ALI to RSV 10 mg. TEAEs were comparable between groups.
Author Disclosures: H. Bays: Research Grant; Significant; Alere, Amarin, Amgen, Ardea, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, California Raisin Board, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Forest, Gilead, Given, GlaxoSmi. Speakers Bureau; Modest; Amarin, Eisai, Merck. Honoraria; Modest; Amgen, Bristol Meyers Squibb, Catabasis, Daiichi Sankyo, Eisai, Isis, Merck, Novartis, Omthera, VIVUS, WPU. Honoraria; Significant; Amarin, AstraZeneca. Consultant/Advisory Board; Modest; Amgen, Bristol Meyers Squibb, Catabasis, Daiichi Sankyo, Eisai, Isis, Merck, Novartis, Omthera, VIVUS, WPU. Consultant/Advisory Board; Significant; Amarin, AstraZeneca. M. Farnier: Other Research Support; Significant; Amgen, Merck, Sanofi. Speakers Bureau; Modest; Amgen, Sanofi. Speakers Bureau; Significant; Merck. Honoraria; Modest; Abbott, Eli Lilly, Pfizer. Consultant/Advisory Board; Modest; AstraZeneca, Roche, Kowa, Recordati, SMB. Consultant/Advisory Board; Significant; Amgen, Sanofi, Merck. D. Gaudet: Consultant/Advisory Board; Modest; Sanofi, Regeneron, Novartis, Isis, Catabasis, Aegerion, Amgen. R. Weiss: Research Grant; Modest; Sanofi, Amgen, Pfizer. J. Lima Ruiz: None. G.F. Watts: Research Grant; Significant; Amgen, Sanofi. Speakers Bureau; Modest; Merck. Consultant/Advisory Board; Modest; Amgen, Sanofi. I. Gouni-Berthold: Speakers Bureau; Modest; Amgen, Sanofi. Honoraria; Modest; Amgen, Sanofi. Consultant/Advisory Board; Modest; Amgen. J.G. Robinson: Research Grant; Significant; Amarin, Amgen, Astra-Zeneca, Daiichi-Sankyo, Genentech/Hoffman La Roche, Glaxo-Smith Kline, Merck, Regeneron/Sanofi, Zinfandel/Takeda.. Consultant/Advisory Board; Significant; Amgen, Hoffman LaRoche, Merck, Pfizer, Sanofi. P.H. Jones: Employment; Significant; Chief Science Officer for National Lipid Association. Speakers Bureau; Modest; Merck. Consultant/Advisory Board; Modest; Merck, Amgen, Sanofi/Regeneron. Consultant/Advisory Board; Significant; Atherotech. R. Severance: None. M. Averna: Speakers Bureau; Modest; Aegerion, Sanofi, Amgen, MSD, Chiesi, Mediolanum, AstraZeneca. Consultant/Advisory Board; Modest; Aegerion, Sanofi, Amgen, MSD, Chiesi, Mediolanum, AstraZeneca, Kowa, Roche. E. Steinhagen-Thiessen: Honoraria; Significant; MSD, Pfizer, Sanofi, Fresenius, Amgen. Consultant/Advisory Board; Significant; MSD, Pfizer, Sanofi, Fresenius, Amgen. H.M. Colhoun: Research Grant; Modest; Roche, Pfizer, Eli Lilly, Boehringer Ingelheim, AstraZeneca. Speakers Bureau; Modest; Pfizer. Honoraria; Modest; Pfizer. Ownership Interest; Modest; Roche. Consultant/Advisory Board; Modest; Pfizer, Sanofi Aventis, Regeneron, Novartis, and Eli Lilly. J. Zhao: Employment; Significant; Regeneron (contractor). Y. Du: Employment; Significant; Regeneron Pharmaceuticals, Inc. C. Hanotin: Employment; Significant; Sanofi. S. Donahue: Employment; Significant; Regeneron Pharmaceuticals, Inc.
Key Words: PCSK9, Cholesterol-lowering drugs, Statins, Clinical trials, Lipoproteins
ODYSSEY HIGH FH: Efficacy and Safety of Alirocumab in Patients With Severe Heterozygous Familial Hypercholesterolemia
Henry N Ginsberg1, Daniel J Rader2, Frederick J Raal3, John R Guyton4, Christelle Lorenzato5, Robert Pordy6, Marie T Baccara-Dinet7, Eric S Stroes8; 1Medicine, Columbia Univ College of Physicians and Surgeons, New York, NY; 2none, Perelman Sch of Medicine, Univ of Pennsylvania, Smilow Cntr for Translational Rsch, Philadelphia, PA; 3Faculty of Health Sciences, Univ of the Witwatersrand, Johannesburg, South Africa; 4Dept of Medicine, Duke Univ Med Cntr, Durham, NC; 5none, Sanofi, Chilly Mazarin, France; 6Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc, Tarrytown, NY; 7PCSK-9 development and Launch Unit, Sanofi, Paris, France; 8Dept of Vascular Medicine, Academic Med Cntr, Amsterdam, Netherlands
Background: Patients with heterozygous familial hypercholesterolemia (heFH) typically have very high untreated levels of low-density lipoprotein cholesterol (LDL-C). Even with existing lipid-lowering therapies (LLTs), many patients continue to have elevated LDL-C levels and remain at increased risk for premature cardiovascular disease. The ODYSSEY HIGH FH study (NCT01617655) compared the LDL-C-lowering efficacy and safety of alirocumab (ALI), a fully human PCSK9 monoclonal antibody, to placebo (PBO) in heFH patients with LDL-C ≥160 mg/dL despite maximally tolerated statin ± other LLT. Methods: In this Phase 3, randomized, double-blind, PBO-controlled study, patients were randomized in a 2:1 ratio to ALI 150 mg every 2 weeks (Q2W) or PBO, both self-administered subcutaneously via 1-mL pre-filled pen, for 78 weeks (W). The primary endpoint was the percent change in LDL-C from baseline to W24 in the intention-to-treat population. The pre-specified safety analysis includes all data from baseline to W78 (up to W52 for all patients). During the trial, 2 sites were found to have significant Good Clinical Practice (GCP) issues and a sensitivity analysis was performed excluding the patients from these sites. Results: Significant reductions in LDL-C from baseline to W24 were observed with ALI vs. PBO (Table), which were maintained to W52. Absolute LS mean (SE) LDL-C levels were reduced by 90.8 (6.7) mg/dL with ALI at W24. Excluding the 2 sites with significant GCP issues, the LS mean (SE) difference vs PBO in % change from baseline to W24 was -48.0 (5.8)% (Table). Treatment-emergent adverse events (TEAEs) were generally comparable between groups (Table). Conclusions: ALI demonstrated significant reductions in LDL-C vs. PBO after 24W of treatment in this population of patients with severe heFH and very high baseline levels of LDL-C despite maximally tolerated statin ± other LLT. ALI was generally well-tolerated and TEAEs were generally comparable between groups.
Author Disclosures: H.N. Ginsberg: Research Grant; Significant; Sanofi. Consultant/Advisory Board; Modest; Regeneron, Sanofi. D.J. Rader: Consultant/Advisory Board; Modest; Sanofi. F.J. Raal: Research Grant; Modest; Amgen, Sanofi/Regeneron for clinical trials with PCSK9 inhibitors. Speakers Bureau; Modest; Amgen, Sanofi/Regeneron, Pfizer, AstraZeneca. Honoraria; Modest; Amgen, Sanofi/Regeneron, Pfizer, AstraZeneca, Pfizer. Consultant/Advisory Board; Modest; Amgen, Sanofi/Regeneron, Pfizer, AstraZeneca. J.R. Guyton: Research Grant; Significant; Regeneron/Sanofi, Abbott, Genzyme/Sanofi, GlaxoSmithKline, Amarin Pharma, Amgen. Honoraria; Modest; Merck. Ownership Interest; Modest; Eli Lilly. Consultant/Advisory Board; Modest; Regeneron/Sanofi, Novella, Merck. C. Lorenzato: Employment; Significant; Sanofi. R. Pordy: Employment; Significant; Regeneron Pharmaceuticals, Inc. M.T. Baccara-Dinet: Employment; Significant; Sanofi. E.S. Stroes: Consultant/Advisory Board; Modest; MSD, Amgen, Sanofi, Regeneron, Torrent.
Key Words: Cholesterol-lowering drugs, PCSK9, Hyperlipidemia, Cardiovascular disease prevention, LDL
Efficacy and Safety of Alirocumab in High Cardiovascular Risk Patients With Suboptimally Controlled Hypercholesterolemia on Maximally Tolerated Doses of Statins: The ODYSSEY COMBO I Study
Dean J Kereiakes1, Jennifer G Robinson2, Christopher P Cannon3, Christelle Lorenzato4, Robert Pordy5, Umesh Chaudhari6, Helen M Colhoun7; 1none, The Christ Hosp Heart and Vascular Cntr/The Lindner Rsch Cntr, Cincinnati, OH; 2Depts of Epidemiology & Medicine, Univ of Iowa, Iowa City, IA; 3none, Harvard Clinical Rsch Institute, Boston, MA; 4none, Sanofi, Chilly Mazarin, France; 5Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc, Tarrytown, NY; 6none, Sanofi, Bridgewater, NJ; 7none, Univ of Dundee, Dundee, United Kingdom
Background: ODYSSEY COMBO I (NCT01644175) evaluated efficacy and safety of alirocumab (ALI), a fully human monoclonal antibody to PCSK9, as add-on therapy to stable, maximally tolerated daily statin ± other lipid-lowering therapy (LLT) in high-risk patients with sub-optimally controlled hypercholesterolemia. Methods: This Phase 3, randomized, double-blind, placebo (PBO)-controlled, parallel-group, multicenter study enrolled 316 patients with hypercholesterolemia and established CHD or CHD risk equivalents. Patients received a maximally tolerated daily statin dose ± other LLT throughout the study. Eligible patients were randomized 2:1 ALI:PBO and entered a double-blind treatment period of 52 weeks (W). Patients randomized to ALI self-administered a 75 mg dose every 2W (Q2W) subcutaneously via 1-mL pre-filled pen, from randomization to W12; at W12, the ALI dose was increased to 150 mg Q2W (also 1 mL) if W8 LDL-C was ≥70 mg/dL. PBO was also self-administered Q2W via an identical 1 mL pre-filled pen for 52W. The primary efficacy endpoint was the % change in LDL-C from baseline to W24 (intent-to-treat analysis). Results: Significant LDL-C reductions were observed with ALI vs. PBO at W24 (Table), with reductions maintained to W52. At W24, LS mean (SE) percentage changes from baseline were -48.2 (1.9)% and -2.3 (2.7)% for ALI and PBO, respectively, a LS mean (SE) difference of -45.9 (3.3)%, ALI vs. PBO (P<0.0001). At W12, 159/191 evaluable ALI-treated patients (83.2%) did not require a dose increase to 150 mg Q2W based on their LDL-C levels at W8. Treatment-emergent adverse events (TEAEs) were comparable between groups (Table). Conclusions: ALI treatment achieved a significantly greater reduction in LDL-C vs. PBO after 24W in high-risk patients with sub-optimally controlled hypercholesterolemia at baseline despite being on optimal therapy. More patients achieved treatment goals on ALI therapy. The frequency of TEAEs and discontinuations were generally comparable.
Author Disclosures: D.J. Kereiakes: Consultant/Advisory Board; Modest; Harvard Clinical Research Institute, Ablative Solution, Inc. Consultant/Advisory Board; Significant; Boston Scientific, Abbott Vascular, REVA Medical Inc. J.G. Robinson: Research Grant; Significant; Amarin, Amgen, Astra-Zeneca, Daiichi-Sankyo, Genentech/Hoffman La Roche, Glaxo-Smith Kline, Merck, Regeneron/Sanofi, Zinfandel/Takeda.. Consultant/Advisory Board; Significant; Amgen, Hoffman LaRoche, Merck, Pfizer, Sanofi. C.P. Cannon: Research Grant; Modest; Accumetrics, CSL Behring, Essentialis, Regeneron, Sanofi, Takeda. Research Grant; Significant; Arisaph, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janssen, Merck. Consultant/Advisory Board; Modest; Bristol-Myers Squibb, Pfizer. Consultant/Advisory Board; Significant; Lipimedix. C. Lorenzato: Employment; Significant; Sanofi. R. Pordy: Employment; Significant; Regeneron Pharmaceuticals, Inc. U. Chaudhari: Employment; Significant; Sanofi. H.M. Colhoun: Research Grant; Modest; Roche, Pfizer, Eli Lilly, Boehringer Ingelheim, AstraZeneca. Speakers Bureau; Modest; Pfizer. Honoraria; Modest; Pfizer. Ownership Interest; Modest; Roche. Consultant/Advisory Board; Modest; Pfizer, Sanofi Aventis, Regeneron, Novartis, and Eli Lilly.
Key Words: PCSK9, Lipids, Cardiovascular therapeutics
Long-term Safety, Tolerability and Efficacy of Alirocumab versus Placebo in 2,341 High Cardiovascular Risk Patients: ODYSSEY LONG TERM
Jennifer G Robinson1, Michel Farnier2, Michel Krempf3, Jean Bergeron4, Gérald Luc5, Maurizio Averna6, Eric S Stroes7, Gisle Langslet8, Frederick J Raal9, Mahfouz El Shahawy10, Michael J Koren11, Norman E Lepor12, Christelle Lorenzato13, Robert Pordy14, Umesh Chaudhari15, John J Kastelein7; 1Depts of Epidemiology & Medicine, Univ of Iowa, Iowa City, IA; 2Département d'Endocrinologie et de Lipidologie, Point Médical, Dijon, France; 3Endocrinology / Nutrition, Hôpital G & R Laënnec, 44800 Saint-Herblain, France; 4Dept of Medicine (Service of Lipidology), Laval Univ Hosp, Quebec, Canada; 5Dept of Internal Medicine A, Univ Hosp of Lille, Lille, France; 6Dept of Internal Medicine and Med Specialties, Università di Palermo – Policlinico "Paolo Giaccone", Palermo, Italy; 7Dept of Vascular Medicine, Academic Med Cntr, Amsterdam, Netherlands; 8Lipid Clinic, Oslo Univ Hosp, Oslo, Norway; 9Faculty of Health Sciences, Univ of the Witwatersrand, Johannesburg 2193, South Africa; 10none, Cardiovascular Rsch Cntr of Sarasota, Sarasota, FL; 11none, Jacksonville Cntr for Clinical Rsch, Jacksonville, FL; 12Clinical Rsch, Westside Med Associates of Los Angeles, Beverley Hills, CA; 13none, Sanofi, Chilly Mazarin, France; 14Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals, Inc, Tarrytown, NY; 15none, Sanofi, Bridgewater, NJ
Background: ODYSSEY LONG TERM (NCT01507831) is an ongoing study assessing safety, tolerability and efficacy of alirocumab (ALI) vs. placebo (PBO) in 2,341 high CV risk patients (pts). In a pre-specified analysis (52 weeks [W] for all pts continuing treatment, and 817 pts exposed for ≥76 W [543 ALI, 274 PBO]), ALI demonstrated safety generally comparable with PBO when both were added to maximally tolerated statin ± other lipid-lowering therapy (LLT). LS mean difference for ALI vs PBO in change from baseline to W24 in LDL-C (primary efficacy endpoint) was -61.9% (P<0.0001). This pre-specified analysis explores consistency of effect and safety within subgroups of pts including those who achieved very low LDL-C levels with ALI. Methods: Pts had either (1) heterozygous familial hypercholesterolemia (n=415, 17.7%) or (2) coronary heart disease (CHD) or risk equivalent, and LDL-C ≥70 mg/dL on maximally tolerated statin ± other LLT. Pts were randomized 2:1 to self-administer either ALI 150 mg or PBO subcutaneously every two weeks (Q2W) as single 1-mL injection via prefilled syringe for 78 W. Results: Rates of TEAEs in 562 (36%) ALI pts with 2 consecutive calculated LDL-C <25 mg/dL were comparable with the ALI group as a whole, and with the PBO group (Table). TEAEs led to treatment discontinuation in 6.2% and 5.5% of overall ALI and PBO pts, respectively. ALI showed homogeneity of treatment effect (LDL-C % reductions from baseline to W24 vs. PBO) in patients with heFH (-63.2%) vs. non-FH (-61.5%; p=0.6038) and across various other demographic and baseline characteristic factors (including race, age, diabetes, and baseline LDL-C). Conclusions: In the largest reported double-blind study of a PCSK9 inhibitor to date, a large number of ALI pts (36%) achieved low LDL-C (defined as <25 mg/dL). The safety/tolerability profile was similar in this subset compared with both the ALI group as whole and PBO. Percent reductions in LDL-C from baseline to W24 were similar across various subgroups.
Author Disclosures: J.G. Robinson: Research Grant; Significant; Amarin, Amgen, Astra-Zeneca, Daiichi-Sankyo, Genentech/Hoffman La Roche, Glaxo-Smith Kline, Merck, Regeneron/Sanofi, Zinfandel/Takeda.. Consultant/Advisory Board; Significant; Amgen, Hoffman LaRoche, Merck, Pfizer, Sanofi. M. Farnier: Other Research Support; Significant; Amgen, Merck Sanofi. Speakers Bureau; Modest; Amgen, Sanofi. Speakers Bureau; Significant; Merck. Honoraria; Modest; Abbott, Eli Lilly, Pfizer. Consultant/Advisory Board; Modest; AstraZeneca, Roche, Kowa, Recordati, SMB. Consultant/Advisory Board; Significant; Amgen, Sanofi, Merck. M. Krempf: None. J. Bergeron: Consultant/Advisory Board; Modest; Amgen (Canada), Sanofi (Canada). Other; Modest; Educational lecture to GPs for Merck (Canada), Valeant. G. Luc: Honoraria; Modest; Regeneron, Sanofi. M. Averna: Research Grant; Significant; MSD. Speakers Bureau; Modest; Aegerion, Sanofi, Amgen, MSD, Chiesi, Mediolanum, AstraZeneca. Consultant/Advisory Board; Modest; Aegerion, Sanofi, Amgen, MSD, Chiesi, Mediolanum, AstraZeneca, Kowa, Roche. E.S. Stroes: Consultant/Advisory Board; Modest; MSD, Amgen, Sanofi, Regeneron, Torrent. G. Langslet: Consultant/Advisory Board; Modest; Amgen, Sanofi-Aventis, Janssen Pharmaceuticals. F.J. Raal: Research Grant; Modest; Amgen, Sanofi/Regeneron for clinical trials with PCSK9 inhibitors. Speakers Bureau; Modest; Amgen, Sanofi/Regeneron, Pfizer, AstraZeneca. Honoraria; Modest; Amgen, Sanofi/Regeneron, Pfizer, AstraZeneca, Pfizer. Consultant/Advisory Board; Modest; Amgen, Sanofi/Regeneron, Pfizer, AstraZeneca. M. El Shahawy: None. M.J. Koren: Research Grant; Significant; Regeneron/Sanofi. Consultant/Advisory Board; Significant; Regeneron/Sanofi. N.E. Lepor: Consultant/Advisory Board; Modest; Sanofi. C. Lorenzato: Employment; Significant; Sanofi. R. Pordy: Employment; Significant; Regeneron Pharmaceuticals, Inc. U. Chaudhari: Employment; Significant; Sanofi. J.J. Kastelein: Honoraria; Modest; Dezima Pharmaceuticals, Regeneron, Sanofi, Eli Lilly, Pfizer, Amgen, Genzyme, Aegerion, Esperion. Honoraria; Significant; Isis. Consultant/Advisory Board; Modest; Dezima Pharmaceuticals, Regeneron, Sanofi, Eli Lilly, Pfizer, Amgen, Genzyme, Aegerion, Esperion. Consultant/Advisory Board; Significant; Isis.
Key Words: Cholesterol-lowering drugs, Lipids, Prevention
2014 Late-Breaking Resuscitation Science Abstracts
Session IX: Late-Breaking Abstracts in Resuscitation Science
Mechanical Versus Manual Chest Compression For Out-of-hospital Cardiac Arrest: A Cluster Randomized Trial
Gavin D Perkins1, Ranjit Lall2, Tom Quinn3, Charles D Deakin4, Matthew W Cooke2, Jessica Horton2, Sarah E Lamb5, Anne-Marie Slowther2, Andy Carson6, Mike Smyth6, Richard Whitfield7, Amanda Williams7, Helen Pocock8, John J Black8, John Wright9, Kyee H Han9, Simon Gates2, PARAMEDIC trial collaborators; 1Warwick Med Sch, Univ of Warwick, Coventry, United Kingdom; 2Univ of Warwick, Coventry, United Kingdom; 3Univ of Surrey, Guildford, United Kingdom; 4Univ of Southampton, Southampton, United Kingdom; 5Univ of Oxford, Oxford, United Kingdom; 6West Midlands Ambulance Service NHS Trust, West Midlands, United Kingdom; 7Welsh Ambulance Services NHS Trust, Wales, United Kingdom; 8South Central Ambulance Service NHS Foundation Trust, South Central, United Kingdom; 9North East Ambulance Service NHS Foundation Trust, North East, United Kingdom
Background Mechanical chest compression devices may overcome the problems of maintaining high quality cardiopulmonary resuscitation(CPR), but there is little evidence of their effectiveness. This trial compared the LUCAS-2 mechanical compression device with manual compressions during non-traumatic adult out-of-hospital cardiac arrest. Methods The PARAMEDIC trial was a cluster-randomized open-label trial involving adults with non-traumatic, out-of-hospital cardiac arrest from four UK Ambulance Services. Patients were assigned to LUCAS-2 mechanical chest compression or manual chest compressions. The primary outcome was survival at 30 days following cardiac arrest. Secondary outcomes were return of spontaneous circulation (ROSC), survival of event (sustained ROSC to arrival at hospital) and survival and neurological function at 3 months. We present the complier average causal effect (CACE) analyses, to evaluate the effects of LUCAS-2 in participants who complied with the allocated treatment. Results: 4471 eligible patients were enrolled (LUCAS-2: 1652; control: 2819). 985 (59.6%) patients in the LUCAS-2 group received mechanical chest compression, and 11 (0.4%) patients in the control group received LUCAS-2. 30 day survival was similar in the LUCAS-2 and manual CPR groups (5.1% vs 5.8%), OR 0.87 (95% CI 0.61-1.23). Fewer patients had favourable neurological outcome in the LUCAS-2 group than in the manual CPR group (3.9 vs 5.9%) OR 0.65 (95% CI 0.45 - 0.96). There was no difference ROSC rates (32.8% vs 32.3%, OR 1.01 (95% CI 0.86-1.19) or survived event (sustained ROSC) (36.7% vs 38.4%, OR 0.96 (95% CI 0.79-1.16). Conclusions: There was no evidence of improvement in 30-day survival with LUCAS-2 over manual compressions. Therefore we cannot recommend the routine use of LUCAS-2 as a substitute for manual chest compression. (Funded by the National Institute for Health Research, ISRCTN08233942).
Author Disclosures: G.D. Perkins: None. R. Lall: None. T. Quinn: None. C.D. Deakin: None. M.W. Cooke: None. J. Horton: None. S.E. Lamb: None. A. Slowther: None. A. Carson: None. M. Smyth: None. R. Whitfield: None. A. Williams: None. H. Pocock: None. J.J. Black: None. J. Wright: None. K.H. Han: None. S. Gates: None.
Key Words: Cardiac arrest, Cardiopulmonary resuscitation, Device, Effectiveness
Association between Hospital Performance and Patient Outcomes after In-Hospital Cardiac Arrest Care
Monique L Anderson1, Graham Nichol2, Paul S Chan3, Sana M Al-Khatib4, David D Dai4, Robert A Berg5, Steven M Bradley6, Eric D Peterson4, and the GWTG-R Investigators; 1Duke Clinical Rsch Institute, Duke Univ, Durham, NC; 2Univ of Washington, Seattle, WA; 3Mid-America Heart Institute, Kansas City, MO; 4Duke Univ, Durham, NC; 5Univ of Pennsylvania, Philadelphia, PA; 6Eastern Colorado VA Health System, Denver, CO
Introduction: There is significant variation in hospital survival rates for in-hospital cardiac arrest (IHCA). Evidence-based performance measures (PM) have been proposed to estimate the quality of care for patients with IHCA. It is unclear if better quality of care for IHCA is associated with better outcomes. We evaluated: a) the degree of variability in quality of care after IHCA among US hospitals and b) whether PM were associated with patient outcomes. Methods: Hospital composite performance was calculated using six guideline recommended PM (Table) among US hospitals participating in the Get With The Guidelines-Resuscitation (GWTG-R). Opportunity based composite performance scores were calculated for all patients, aggregated at the hospital level, divided into quartiles, and then associated with patient survival. Generalized linear mixed models assessed the independent association between these quartiles and risk-standardized rates of survival. Results: Our analysis included 149,551 IHCA patients treated at 447 GWTG-R hospitals between 2000 and 2012. Hospitals in the highest quartile had a composite performance score of 87.9% (IQR, 86.5 to 89.8%) compared with 70.5% (IQR, 66.7 to 73.2%) in the lowest performance quartile. There was significant variation in individual PM by hospital quartiles (Table). Risk standardized rates of survival were 16.7%, 18.4%, 19.1%, and 19.8% from the lowest to highest performance quartiles (p<0.001). Each 10% increase in a hospital's composite performance remained associated with an 18% higher odds of survival (adjusted OR, 1.18 [95% CI, 1.12-1.23]); this relationship was consistent among subgroups with an initial cardiac arrest rhythm of VT/VF and asystole/pulseless electrical activity. Conclusions: The quality of evidenced-based care for IHCA varies widely among US hospitals and is associated with patient survival for both shockable and non-shockable rhythms.
Author Disclosures: M.L. Anderson: None. G. Nichol: Employment; Significant; University of Washington. Research Grant; Significant; NHLBI, Bethesda, MD. Resuscitation Outcomes Consortium Coordinating Center. Co-PI. -, Food and Drug Administration, Silver Spring, MD; Cardiac Science Corp, Waukesha, WI; Heartsine Technologies Inc., Newtown, PA; Philips Healthcare Inc., Bothell, WA; Physio-Control Inc., Redmond, WA; Z, NHLBI, Bethesda, MD. Randomized Field Trial of Cold Saline IV After Resuscitation from Cardiac Arrest. Co-I., Velomedix Inc., Menlo Park, CA. Velocity Pilot Study of Ultrafast Hypothermia in Patients with ST-Elevation Myocardial Infarction. National Co-PI. *Waived personal compensation., Philips Healthcare Inc., Bothell, WA. Washington Study of Ultrasound in Resuscitation.. Other; Significant; Non-provisional patent for novel method tracking medical device using smartphone, and dynamic electronic database (assisgned to UW). P.S. Chan: None. S.M. Al-Khatib: None. D.D. Dai: None. R.A. Berg: None. S.M. Bradley: None. E.D. Peterson: Research Grant; Significant; PI of Data Analysis Center for AHA GWTG.
Key Words: Quality of medical care, Resuscitation, Outcomes, Cardiopulmonary resuscitation
Safety and Possible Damage from Mechanical Chest Compression during Resuscitation
Rudolph W Koster1, Ludo F Beenen2, Esther B van der Boom2, Rob Adams2, Anje M Spijkerboer2, Robert Tepaske2, Stefanie G Beesems2, Jan G Tijssen2; 1Cardiology, Academic Med Cntr, Amsterdam, Netherlands; 2Academic Med Cntr, Amsterdam, Netherlands
Aim: Mechanical chest compression (CC) by load distributed band or sternal compression devices has not shown to improve survival from cardiac arrest (CA) in several large RCTs. Nevertheless, these devices are widely used worldwide. We conducted two RCTs to investigate possible serious or life-threatening damage caused by mechanical CC devices. Methods: In two parallel RCTs AutoPulse (AP) compressions vs. control (AP study) and LUCAS (L) compressions vs. control (L study) was studied with randomization by envelopes. Control was manual CC with corrective depth and rate feedback from a sternal transducer. Patients with in-hospital CA or out of hospital CA arriving with manual CPR at the ER were included. Excluded was trauma, age <18y and mechanical CC before ER arrival. Damage was assessed blind either by postmortem CT scan, autopsy or clinical course of arrest survivors. Hypothesis: mechanical CC compared to control does not increase serious or life-threatening visceral (chest and abdominal organs) resuscitation-related damage (primary outcome) by >10%. The non-inferiority power of 0.8 required 2x112 analyzable patients in each study. Results: Included were 116 AP cases with 132 AP controls and 122 L cases with 131 L controls. Postmortem CT and/or autopsy was done in 116 AP study patients and in 121 L study patients. Clinical outcome was assessed in 109 AP study and 107 L study patients. Thus, outcome analysis was possible in 453 of 501 (90.4%) of included patients. Mean CC depth in manual CPR was 47 mm (S.D. 8 mm). Serious or life-threatening visceral resuscitation-related damage was seen in 12 of 104 AP patients (11.5%) and 8 of 121 AP controls (6.6%) (Risk difference +4.9% (95% CI -2.6% - +13.3%) and in 8 of 108 L patients (7.4%) and 9 of 120 L controls (7.5%) (Risk difference -0.9% (95% CI -7.3% - +7.3%). Serious rib- and sternal damage was observed in 47 AP patients (45%) and 51 AP controls (42%) (RR 1.04, 95% CI 0.77,1.40) and in 43 L patients (40%) and 50 L controls (42%) (RR 0.96, 95% CI 0.70,1.31). Conclusion: LUCAS does not cause significantly more serious or life-threatening visceral damage than manual CC. For AutoPulse the non-inferiority hypothesis was not accepted and significantly more serious or life-threatening visceral damage than manual CC cannot be excluded.
Author Disclosures: R.W. Koster: Research Grant; Modest; Zoll Medical, Jolife. Other Research Support; Modest; Zoll Medical, Jolife, Philips Medical. L.F. Beenen: None. E.B. van der Boom: None. R. Adams: None. A.M. Spijkerboer: None. R. Tepaske: None. S.G. Beesems: None. J.G. Tijssen: None.
Key Words: Cardiopulmonary resuscitation, Advanced life support, Basic life support, Emergency care
A Pilot Clinical Trial of Single-dose Estrogen for Resuscitation of Severe Traumatic Brain Injury (TBI) (RESCUE - TBI)
Jane G Wigginton1, Kareem Abdelfattah2, Paul Pepe2, Scott Emerson3, Joshua Gatson2, Jim Simpkins4, Eileen Bulger3, Michael Foreman5, David Hoyt6, Jeff Kerby7, David Maass2, Christopher Madden2, Susanne May3, Joseph Minei2, Judy Powell3, Michael A Ramsey5, Jack Roberts8, Karla Saner2, Kevin Schug9, Debra Egan10, George Sopko10, Victoria Warren2, Ahamed H Idris2; 1Surgery, UT Southwestern Med Cntr, Dallas, TX; 2UT Southwestern Med Cntr, Dallas, TX; 3Univ of Washington, Seattle, WA; 4West Virginia Univ, Morgantown, WV; 5Baylor Health and Hosp System, Dallas, TX; 6American College of Surgeons, Chicago, IL; 7Univ of Alabama at Birmingham, Birmingham, AL; 8Vanderbilt Univ, Nashville, TN; 9Univ of Texas at Arlington, Arlington, TX; 10National Heart, Lung and Blood Institute, Bethesda, MD
Background: Despite pro-thrombotic safety issues associated with long-term oral estrogen, single-dose parenteral estrogen has anti-inflammatory, anti-oxidant, and anti-apoptotic properties in injury models including trauma, stroke and sepsis. Despite these compelling scientific findings, clinical trials examining the use and safety of estrogens as resuscitative drugs are lacking. Hypothesis: Early single-dose intravenous (IV) estrogen is feasible and safe in adults with severe TBI. Methods: A double-blinded, 1:1 randomized pilot clinical trial was conducted using estrogen (0.5 mg/kg Premarin® IV) in the ED in adults with severe TBI (GCS 3-8). We tracked feasibility of rapid drug delivery, adverse events including pulmonary embolism (PE), acute myocardial infarction (AMI), infections. and deaths not explained by the Injury severity – as well as % passing the Galveston Orientation-Amnesia Test (GOAT). Results: Subjects receiving estrogen were predicted to have lower probability of survival based on mean TRISS. A similar percentage of estrogen patients passed the GOAT (55 vs 54%). Mean days alive having passed the GOAT during the first 28 days was nonsignificantly lower in the estrogen group than placebo group (6.7 vs 10.4 days, p=0.21). There was a trend to decreased 28 day survival in the estrogen group (p=0.03). In exploratory analyses adjusting for observed imbalances in injury severity, the trend toward increased risk of death in the estrogen group was no longer statistically significant (HR = 1.67, 95% CI 0.74–3.77; p=0.22 after adjustment for age, RTS, and ISS). Conclusions: This pilot study provides the first step in documenting the feasibility of early single-dose estrogen for TBI patients. Some measures of efficacy were in the wrong direction, but the study was not designed to address the primary clinical endpoint of time to passing GOAT with high precision and observed imbalances in injury severity complicate the interpretation of those results.
Author Disclosures: J.G. Wigginton: Research Grant; Modest; NIH. K. Abdelfattah: None. P. Pepe: Research Grant; Modest; NIH. S. Emerson: Research Grant; Modest; NIH. J. Gatson: None. J. Simpkins: Research Grant; Modest; NIH. E. Bulger: Research Grant; Modest; NIH. M. Foreman: None. D. Hoyt: Research Grant; Modest; NIH. J. Kerby: Research Grant; Modest; NIH. D. Maass: None. C. Madden: None. S. May: Research Grant; Modest; NIH. J. Minei: Research Grant; Modest; NIH. J. Powell: Research Grant; Modest; NIH. M.A. Ramsey: None. J. Roberts: Research Grant; Modest; NIH. K. Saner: None. K. Schug: Research Grant; Modest; NIH. D. Egan: Employment; Significant; NIH. G. Sopko: Employment; Significant; NIH. V. Warren: None. A.H. Idris: Research Grant; Modest; NIH.
Key Words: Resuscitation, Clinical trials, Estrogen, Brain
Session VII: Late-Breaking Abstracts in Resuscitation Science
Automated Remote Ischemic Conditioning Device Easier to Use than Manual Cuff to Reduce Reperfusion Injury
Emily Junck1, Deborah Fly2, Francis Kim2, Michael Sayre2, David Carlbom2, Jo Ann Elrod2, Graham Nichol3; 1Emergency Medicine, Univ of Washington, Seattle, WA; 2Univ of Washington, Seattle, WA; 3Univ of Washington - Harborview Cntr for Prehospital Emergency Care and Clinical Trial Cente, Univ of Washington, Seattle, WA
Rationale-Prompt restoration of blood flow is essential to reduce mortality after cardiac arrest (CA) or myocardial infarction (STEMI). This reperfusion causes release of circulating inflammatory molecules, changes in coagulation, and cellular injury. Controlled studies in animal and humans suggest that remote ischemic conditioning (RIC) applied to an arm or leg before or after restoration of blood flow around the heart, in which brief episodes of ischemia then reperfusion are applied, attenuates reperfusion injury as well as reduces infarct size and mortality in STEMI. Controlled studies in animal models suggest that RIC before or after restoration of myocardial blood flow is also beneficial in CA. RIC can be applied with a manual pneumatic cuff, clamp and timer cycles of 5-mins. inflation to 200 mmHg followed by 5-mins. deflation of the cuff on an upper arm or thigh (MAN). This method is prone to leakage of air out of the cuff, requiring periodic reinflation. A novel automated medical device (autoRIC, CellAegis Devices Inc., Toronto, ON) can be used to apply RIC with automated inflation, deflation and reinflation (AUTO). Methods- Emergency medicine physicians and residents (n=12) rated ease of use of MAN vs. AUTO on a five-point Likert scale from 1 (MAN easier) to 5 (AUTO easier) after use of both methods on an upper arm. Order of use was determined via random allocation. An institutional review board determined this study to be exempt from human subjects research. Results- AUTO was consistently rated easier to use than MAN (Table). Conclusions- The ease of AUTO makes uniform application of RIC more feasible in a clinical trial. Controlled studies are needed to assess the efficacy and effectiveness of RIC in patients with CA or STEMI.
Author Disclosures: E. Junck: None. D. Fly: None. F. Kim: Research Grant; Significant; NHLBI, Bethesda, MD. Randomized trial of chilled intravenous fluid in field after resusciation from cardiac arrest. Co-I.. M. Sayre: None. D. Carlbom: None. J. Elrod: None. G. Nichol: Employment; Significant; University of Washington. Research Grant; Modest; American Heart Association, Dallas, TX. Simple EMS Registry. PI.. Research Grant; Significant; NHLBI, Bethesda, MD. Resuscitation Outcomes Consortium Coordinating Center. Co-PI., Food and Drug Administration, Silver Spring, MD; Cardiac Science Corp, Waukesha, WI; Heartsine Technologies Inc., Newtown, PA; Philips Healthcare Inc., Bothell, WA; Physio-Control Inc., Redmond, WA;. Other Research Support; Modest; Velomedix Inc., Menlo Park, CA. Velocity Pilot Study of Ultrafast Hypothermia in Patients with ST-Elevation Myocardial Infarction, National Co-PI. *Waived personal compensation.
Key Words: Cardiac arrest, Basic life support, Advanced life support, Emergency medical services (EMS), Device
The Prevalence and Magnitude of Leaning During Chest Compressions in the Bystander Community and Whether Leaning Can be Reduced by Coaching.
Robert H Trenkamp, Jr.1, Fernando J Perez2; 1Rsch and Education, Saving Lives In Chatham County, Savannah, GA; 2Saving Lives In Chatham County, Savannah, GA
Context; Failure to achieve full recoil ("leaning") during CPR chest compressions reduces the victim's probability of survival. The detrimental effect of leaning on cardiac index and myocardial blood flow have been documented in studies on piglets and children. What is not known are the prevalence and magnitude of leaning in the Bystander population and the extent to which coaching can correct leaning. Objective; To investigate the prevalence and magnitude of leaning by Bystanders and to test the hypothesis that coaching can reduce leaning. Design, Setting, Subjects; Because about 70% of cardiac arrests occur in the home, many resuscitation attempts begin as a lone-rescuer of approximately the same age as the victim. A cohort of test subjects was selected by pre-calculating how many "age slots" had to be filled in each age group to make the test subject cohort age distribution approximately match the age distribution of cardiac arrest victims. Potential subjects were approached randomly in Maple Springs, NY. A remaining opening for a person of their age and gender resulted in an invitation to participate. The total cohort is forty adults. The subjects were blinded to the purpose of the study until they had completed the first trial. At the time of the testing each was asked if they knew the purpose of the trial. If they did, they were excused. If they exhibited excessive leaning during the first trial, they were coached regarding the importance of not leaning and the initial trial was repeated. The trial required the subjects to perform compressions on a force-measuring device. Excessive leaning was defined as more than 1.9 pounds, a threshold calculated from studies on piglets and children and adult human chest stiffness data. Main Outcome Measure; Group average reduction in leaning of at least 50% after coaching.. Results; Coaching reduced leaning by more than 50%. Conclusion; Excessive leaning is exhibited by more than half of the Bystander community. Coaching can reduce leaning in a group by more than fifty percent. Limitations; This study does not address how long the benefit of coaching will last.
Author Disclosures: R.H. Trenkamp: None. F.J. Perez: None.
Key Words: Resuscitation, Cardiac arrest
Hydrocortisone for the Treatment of Post-cardiac Arrest Shock: A Prospective, Randomized Trial
Michael Donnino1, Katherine Berg2, Maureen Chase2, Lars Andersen3, Peter Zimetbaum2, Long Ngo2, Donald Cutlip2, Howard Smithline4, Robert Sherwin5, Parth Patel2, Michael Cocchi2; 1Emergency, Beth Israel Deaconess Med Cntr, Boston, MA; 2Beth Israel Deaconess Med Cntr, Boston, MA; 3Beth Israel Deaconess Med Cntr / Aarhus Univ Hosp, Boston, MA; 4Baystate Med Cntr, Springfield, MA; 5Wayne State Univ, Detroit, MI
Background: Previous studies have shown that relative adrenal insufficiency is prevalent in post-arrest patients and associated with worse outcome. Whether the provision of steroids improves time to shock reversal and outcomes in post-cardiac arrest shock remains unknown. Methods: We conducted a prospective, randomized, double-blinded trial of post-cardiac arrest patients in shock, defined as need for vasopressor support for a minimum of 1 hour. Patients were randomized to receive hydrocortisone 100 mg IV or placebo every 8 hours for 7 days or until shock reversal. The primary endpoint was time to shock reversal. We classified death as a competing risk event and used the estimated cumulative incidence functions (CIF) which were derived from the estimation of the Fine-Gray competing risk model. A pre-planned analysis of patients with adrenal insufficiency based on low baseline cortisol (<15 ug/dl) and failure to respond to the ACTH stimulation test was performed. Results: Fifty patients were included with 25 in each group (steroid or placebo). Baseline characteristics were similar between groups. There was no difference in the primary outcome of time to shock reversal between groups (hazard ratio: 0.83 [95%CI: 0.40 - 1.75], p = 0.63). We found no difference in secondary outcomes including shock reversal (52% vs. 60%, p = 0.57), good neurological outcome (24% vs. 32%, p = 0.53) or survival to discharge (28% vs. 36%, p = 0.54) between hydrocortisone and placebo groups. Of the patients with a baseline cortisol <15 ug/dl, 100% (6/6) in the steroid group achieved shock reversal compared to 33% (1/3) in the placebo group (p = 0.08). All in the placebo group died 100% (3/3) whereas 50% (3/6) died in the steroid group (p=0.43). There were no differences among those who did not respond to an ACTH stimulation test. Conclusion: In the overall population of cardiac arrest patients with vasopressor-dependent shock, treatment with hydrocortisone did not improve time to shock reversal (primary outcome), rate of shock reversal, or clinical outcomes when compared to placebo. In the subgroup with relative adrenal insufficiency defined by baseline cortisol <15 ug/dl, there was a trend toward increased rate of shock reversal in the hydrocortisone group.
This research has received full or partial funding support from the American Heart Association.
Author Disclosures: M. Donnino: None. K. Berg: None. M. Chase: None. L. Andersen: None. P. Zimetbaum: None. L. Ngo: None. D. Cutlip: Research Grant; Modest; Medtronic, Boston Scientific, Celonova, STENTYS. Research Grant; Significant; Modest, Modest, Modest, Modest. H. Smithline: None. R. Sherwin: None. P. Patel: None. M. Cocchi: None.
Key Words: Cardiac arrest
Molecular Mechanisms Underlying the Physiological Response of Cyanotic Congenital Heart Patients to Hypoxia: Activation of the Hypoxia Inducible Factor (HIF) Through the Modulation of the Glycosphingolipid Cell Content Mediated By Sialidase Neu3
Erika Conforti1, Alessandro Varrica2, Marco Piccoli2, Andrea Ghiroldi2, Francesca Pluchinotta2, Matteo Reali2, Guido Tettamanti2, Alessandro Giamberti2, Alessandro Frigiola2, Luigi Anastasia2; 1Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, San Donato Milanese, Italy; 2IRCCS Policlinico San Donato, San Donato Milanese, Italy
Hypoxia contributes significantly to the pathophysiology of many common congenital heart diseases, including the tetralogy of Fallot (TOF). When the oxygen level goes down, mammalian cells have developed an adaptive system to overcome conditions of moderate-severe hypoxia, mainly regulated by the hypoxia inducible factor (HIF) which ultimately activates pro-survival signaling pathways, including the vascular endothelial growth factor (VEGF), erythropoietin (EPO), glycolysis, cell cycle, heme oxygenase-1 and inducible nitric oxide synthase. We recently reported a novel mechanism of activation of HIF, mediated by sialidase NEU3, the enzyme that releases sialic acid residues from sialoglycoconjugates, and that we found to be triggered under hypoxia. On this premise, the objective of the current study was to assess whether NEU3 sialidase is up-regulated in the myocardium of chronic cyanotic congenital patients as compared to acyanotic congenital hearts, that were used as controls. We report that endogenous NEU3 expression and activity of NEU3 is up-regulated in the heart of cyanotic congenital heart pediatric patients (under 13 yrs), and that this caused an up-regulation of the EGFR signaling pathway, which is mediated by NEU3-iduced gangliosides GM3 reduction. This causes the activation of a signaling cascade, down-stream of EGFR, ultimately leading to an activation of HIF-1a and down-stream prosurvival signaling pathways. These results support the notion that NEU3 sialidase may play a critical role in the response of the myocardium to hypoxia and the preservation of cell viability. The possibility of mimicking NEU3 sialidase activation, by the inhibition of gangliosides GM3 synthesis through synthetic inhibitors, is currently underway, and it may result in the development of new drug candidates for the treatment of hypoxic diseases of the cardiovascular system.
Author Disclosures: E. Conforti: None. A. Varrica: None. M. Piccoli: None. A. Ghiroldi: None. F. Pluchinotta: None. M. Reali: None. G. Tettamanti: None. A. Giamberti: None. A. Frigiola: None. L. Anastasia: None.
Key Words: Pediatric cardiology, Congenital heart disease, Hypoxia, Signal transduction, Tetralogy of Fallot
A Feasibility and Safety Pilot Clinical Trial of Single-dose, Intravenous Estrogen for Resuscitation of Traumatic Hemorrhagic Shock: The RESCUE - Shock Study
Jane Wigginton1, Kareem Abdelfattah2, Joshua Gatson2, Paul Pepe2, Scott Emerson3, Jim Simpkins4, Debra Egan5, Michael Foreman6, David Hoyt7, Jeff Kerby8, David Maass2, Christopher Madden2, Susanne May3, Joseph Minei2, Judy Powell3, Michael Ramsey6, Jack Roberts9, Karla Saner2, Kevin Schug10, Eileen Bulger3, George Sopko5, Victoria S Warren2, Ahamed Idris2; 1Surgery, UT Southwestern Med Cntr, Dallas, TX; 2UT Southwestern Med Cntr, Dallas, TX; 3Univ of Washington, Seattle, WA; 4West Virginia Univ, Morgantown, WV; 5National Heart, Lung and Blood Institute, Bethesda, MD; 6Baylor Health and Hosp System, Dallas, TX; 7American College of Surgeons, Chicago, IL; 8Univ of Alabama at Birmingham, Birmingham, AL; 9Vanderbilt Univ, Nashville, TN; 10Univ of Texas at Arlington, Arlington, TX
Background: Parenteral estrogen administration has strong anti-inflammatory, anti-oxidant, and anti-apoptotic properties across all organ systems in experimental injury models, including trauma, sepsis, and burns. Pro-thrombotic effects have been associated with long-term oral estrogen use, but a single-dose of intravenous (IV) estrogen is unlikely to have such complications and may be a key pre-emptive intervention for multi-organ failure, a common complication of trauma. Hypothesis: We hypothesized that early single-dose IV estrogen is both feasible and safe in adults with post-traumatic hypotension Methods: A double-blinded, 1:1 randomized pilot clinical trial was conducted using estrogen (0.5 mg/kg Premarin® IV) administered in the ED to adults with post-traumatic hypotension (SBP <90 mmHg). In addition to evaluating the feasibility of rapid randomization and drug delivery, 28 day survival and adverse outcomes were tracked prospectively including deep venous thrombosis (DVT), pulmonary embolism (PE), acute myocardial infarction (AMI), infections and deaths unexplained by injury severity. Results: No significant problems were identified with rapidly providing the drug (n=48). There was a nonsignificant trend to decreased 28 day survival in the estrogen group (70% vs 84%, p=0.25). Exploratory analyses adjusting for age, revised trauma score, and injury severity score suggested higher risk of death in the estrogen group (HR = 2.47; 95% CI 1.16–5.25; p=0.02). Conclusions: This pilot study provided the first step in documenting the feasibility of administering early single-dose estrogen for patients with presumed traumatic hemorrhage. The study was not designed to address the primary clinical endpoint of 28 day survival with high precision, and thus both the observed nonsignificant unadjusted and the exploratory injury severity-adjusted trends toward increased mortality in the estrogen arm must be interpreted cautiously.
Author Disclosures: J. Wigginton: Research Grant; Modest; NIH. K. Abdelfattah: None. J. Gatson: None. P. Pepe: Research Grant; Modest; NIH. S. Emerson: Research Grant; Modest; NIH. J. Simpkins: Research Grant; Modest; NIH. D. Egan: Employment; Significant; NIH. M. Foreman: None. D. Hoyt: Research Grant; Modest; NIH. J. Kerby: Research Grant; Modest; NIH. D. Maass: None. C. Madden: None. S. May: Research Grant; Modest; NIH. J. Minei: Research Grant; Modest; NIH. J. Powell: None. M. Ramsey: None. J. Roberts: Research Grant; Modest; NIH. K. Saner: None. K. Schug: Research Grant; Modest; NIH. E. Bulger: Research Grant; Modest; NIH. G. Sopko: Employment; Significant; NIH. V.S. Warren: None. A. Idris: Research Grant; Modest; NIH.
Key Words: Resuscitation, Clinical trials, Estrogen
Non-invasive Carbon Dioxide Gradient - A Novel Approach To Monitoring Resuscitation During Severe Hemorrhagic Shock
Slava Belenkiy1, Timothy Park2, Andriy Batchinsky3, William Baker3, Corina Necsoiu3, Bryan Jordan3, James Aden3, Jose Salinas3, Leopoldo Cancio3; 1CICR, United States Army Institute of Surgical Rsch, JBSA Ft Sam Houston, TX; 2San Antonio Military Med Cntr, JBSA Ft Sam Houston, TX; 3United States Army Institute of Surgical Rsch, JBSA Ft Sam Houston, TX
Introduction: During hemorrhagic shock (HS), we previously observed that decreased cardiac output causes an increase in the transcutaneous CO2 (tPCO2), but a decrease in the end-tidal CO2 (etCO2). We hypothesized that the non-invasive carbon dioxide gradient (NICO2G), i.e. tPCO2 - etCO2,could be used to monitor the progress of resuscitation. Methods: Consciously sedated swine with tracheostomies were allowed to breathe spontaneously. They were shed 65% of blood volume over 1 hour, and were randomized to 2 groups (n=7 each): no resuscitation (group 1), and transfusion of all shed blood (group 2). NICO2G, lactate (Lac), mean arterial pressure (MAP), and heart rate (HR) were recorded.Values during HS (H60) and 30 min after resuscitation (R30) were compared to baseline (BL); data are means±SD. Results: See Table 1. At R30, NICO2G values returned to BL levels in group 2. Lac remained elevated.
Conclusions: NICO2G combines the divergent trajectories of etCO2 and tPCO2 during HS into a single metric. It is non-invasive and continuously available, and responds appropriately to hemodynamic changes during HS and resuscitation. However, it does not substitute for metabolic variables such as lactate.
Author Disclosures: S. Belenkiy: None. T. Park: None. A. Batchinsky: None. W. Baker: None. C. Necsoiu: None. B. Jordan: None. J. Aden: None. J. Salinas: None. L. Cancio: None.
Key Words: Resuscitation, Monitoring, physiologic, New technology
Cerebral Oximetry is a Predictor of Return of Spontaneous Circulation in Cardiac Arrest
Sam Parnia1, Jie Yang2, Loren Inigo-Santiago2, Anna Ahn2, Jiawen Zhu2, Asad Nasir2, Kim Golder3, Robert Nguyen1, Shreyas Ravishankar2, Pauline Bartlett3, David Pogson4, Sarah Cooke4, Christopher Walker4, Ken Spearpoint5, Stephen Brett5, David Kitson5, Teresa Melody6, Mehboob Chilwan6, Celia Warlow7, Siobhan Bullock7, Elinor Schoenfeld2, Jerry Nolan8, Gavin Perkins6, Charles D Deakin3; 1Pulmonary Critical Care, Stony Brook Univ, Stony Brook, NY; 2Stony Brook Univ, Stony Brook, NY; 3Univ Hosp Southampton, Southampton, United Kingdom; 4Queen Alexandra Hosp, Portsmouth, United Kingdom; 5Hammersmith Hosp Imperial College, London, United Kingdom; 6Heartlands Hosp, Birmingham, United Kingdom; 7Northampton General Hosp, Northampton, United Kingdom; 8Royal United Hosp, Bath, United Kingdom
Background: End-tidal CO2 is a marker of return spontaneous circulation (ROSC). Its utility is limited by V:Q mismatch and it cannot monitor cerebral oxygen delivery. Methods: A multicenter observational study of in-hospital cardiac arrest (CA) to determine the utility of regional cerebral oxygen saturation (rSO2) derived from cerebral oximetry to predict ROSC during non-shockable (Asystole/PEA) and shockable (VF/VT) CA. 7 summary measures derived from rSO2 during CPR were analyzed to determine the optimal read-out (Figure 1 a-f) (a) Mean rSO2 during CPR (b) Median rSO2 during CPR (c) Mean rSO2 during last 5 minutes CPR (d), Median rSO2 during last 5 minutes CPR (e), %time rSO2 >50% during CPR (f), %time rSO2 >50% during last 5 minutes CPR (g) Absolute change rSO2 during last 5 minutes CPR). Results: 153 patients were enrolled; 140 (90.55%) had a non-shockable rhythm. No demographic differences or differences in Hb or PaO2 were noted. Patients with ROSC had higher mean rSO2 during CPR than those without (mean±SD: 50.22±11.93% vs. 40.02±12.84%, p<0.0001)[Fig.2]. The 7 summary measures had similar classification accuracy, but mean rSO2 during last 5 minutes CPR provided the best prediction for ROSC (AUC=0.76 with 95% CI: 0.68-0.84). Mean rSO2 <30% provided a 95% (CI:75%-100%) NPV for ROSC, while >65% provided 100% PPV (CI:69-100%) for ROSC in non-shockable CA. Patients with shockable CA didn't exhibit differences in the tested parameters. Conclusions: A rSO2 >65% during a 5 minute period of CPR is a strong predictor of ROSC, while values <30% are strong predictors of the inability to achieve ROSC. Efforts should be targeted to a minimum rSO2 >30% with the ideal goal being >65%.
Author Disclosures: S. Parnia: None. J. Yang: None. L. Inigo-Santiago: None. A. Ahn: None. J. Zhu: None. A. Nasir: None. K. Golder: None. R. Nguyen: None. S. Ravishankar: None. P. Bartlett: None. D. Pogson: None. S. Cooke: None. C. Walker: None. K. Spearpoint: None. S. Brett: None. D. Kitson: None. T. Melody: None. M. Chilwan: None. C. Warlow: None. S. Bullock: None. E. Schoenfeld: None. J. Nolan: None. G. Perkins: None. C.D. Deakin: None.
Key Words: Cardiac arrest, Resuscitation, Return of spontaneous circulation (ROSC), Cardiopulmonary resuscitation, Oxygen
Sodium Nitroprusside, Adenosine and Levosimendan Improve Cell Survival Over Epinephrine and Amiodarone in a Rat Model of Cardiac Arrest
Jason Bowman1, Matthew McClure2, David E Dostal3; 1College of Medicine, Texas A&M Health Science Cntr College of Medicine, Temple, TX; 2Univ of North Texas Health Science Cntr - Texas College of Osteopathic Medicine, Fort Worth, TX; 3Central Texas Veterans Health Care System, Texas A&M Health Science Cntr College of Medicine, Temple, TX
Introduction: After prolonged cardiac arrest the standard of care (ACLS) resuscitation drugs epinephrine and amiodarone may induce cell death. Controlled pauses at the start of resuscitation called "ischemic post-conditioning" (IPC) have shown to be advantageous but are difficult to implement in practice. We propose that a novel drug combination consisting of sodium nitroprusside, adenosine and levosimendan (SNPAL) will improve cell survival over ACLS and will induce the effects of IPC without the use of tricky CPR timings. Methods: 9 adult Sprague-Dawley rats were assigned to one of three groups: Epinephrine and amiodarone (ACLS, n=3); ACLS drugs with 4 cycles of 30 seconds pauses during resuscitation (ACLS+IPC, n=3); and (SNPAL, n=3) sodium nitroprusside, adenosine and levosimendan. Using a Langendorff perfusion apparatus we induced 15 minutes of no flow arrest then reperfusion. Cells were then isolated with collagenase and stained with annexinV, propidium iodide and for protein phosphorylation. Results were collected by flow cytometry and analyzed using two-way ANOVA and chi-square statistics. Results: Compared to ACLS, the SNPAL treatment group reduced necrosis by 29%±0.3% (p<.001) and apoptosis by 71%±0.1% (p<.001). ACLS+IPC reduced necrosis by 4%±0.2% (p=.05) and apoptosis by 3%±0.1% (p=.01). Phosphorylation is displayed in Figure 1. Heart rates were similar in all groups, however both ACLS groups showed severe ventricular dysfunction upon resuscitation, whereas the group receiving SNPAL did not. Conclusion: SNPAL significantly reduced necrosis and apoptosis over both ACLS and ACLS+IPC. SNPAL appears to trigger the same survival pathways as IPC plus additional survival pathways. SNPAL not only improved cell survival from cardiac arrest, but mechanical dysfunction as well. These results warrant further investigation into the cellular effects of ACLS drugs and suggest this drug combination as a new treatment for cardiac arrest.
Author Disclosures: J. Bowman: None. M. McClure: None. D.E. Dostal: None.
Key Words: Cardiac arrest, Cardioprotective drugs, Ischemia reperfusion, Vasodilator agents, Resuscitation
Recurrent Ventricular Fibrillation: Experience with First Responders Prior to Advanced Life Support Interventions
Brian Telesz1, Erik Hess2, Elizabeth Atkinson2, Roger White2; 1Dept of Anesthesiology, Mayo Clinic Rochester, Rochester, MN; 2Mayo Clinic Rochester, Rochester, MN
Aim: Following defibrillation, ventricular fibrillation (VF) frequently recurs during out-of-hospital cardiac arrest (OHCA). Prior studies have reported conflicting results regarding its association with survival. The aim of this study was to examine the impact of recurrent VF in the presence of first responders before advanced life support (ALS) interventions. Methods: Electrocardiographic data from first responder automated external defibrillators (AEDs) were analyzed. A successful shock was defined as termination of VF for 5 seconds or longer. Recurrent VF was defined as any VF that occurred after a successful shock. The primary outcome was neurologically-intact survival to hospital discharge (CPC 1-2). Results: 108 patients within our Emergency Services System experienced a witnessed VF arrest. Of these, 73 (68%) had at least one recurrence of VF. Median time to recurrence of VF was 25 seconds [interquartile range (IQR) 11 to 66 seconds]. Median time in recurrent VF was 180 seconds (IQR 105 to 266 seconds). Survival was observed in 25 (71%) of patients with no recurrent VF and in 36 (49%) who had recurrence. Recurrent VF was associated with a lower odds of survival on univariate analysis (odds ratio 0.39, 95% CI 0.16-0.92, p=0.0325). Conclusions: In the presence of first responders, VF recurred in 68% of patients and was significantly associated with lower odds of survival. First responder AED algorithms that recognize recurrent VF and enable prompt shock delivery rather than delaying a shock should be a design priority.
Author Disclosures: B. Telesz: None. E. Hess: None. E. Atkinson: None. R. White: None.
Key Words: Ventricular fibrillation, Cardiopulmonary resuscitation, Emergency medical services (EMS), Return of spontaneous circulation (ROSC), Defibrillator
Bradycardia During Hypothermia: A New Early Marker of Lower Mortality and Favorable Neurological Outcome in Comatose Survivors of Out-of-Hospital Cardiac Arrest
Jakob H Thomsen1, Christian Hassager2, Niklas Nielsen3, Michael Wanscher4, Steen Pehrson2, Lars Køber2, John Bro-Jeppesen2, Helle Søholm2, Hans Friberg5, Jesper Kjærgaard2; 1Dept of Cardiology B, The Heart Cntr, Rigshospitalet, The Heart Cntr, Copenhagen O, Denmark; 2Rigshospitalet, The Heart Cntr, Copenhagen O, Denmark; 3Dept of Anesthesia and Intensive Care, Helsingborg Hosp, Helsingborg, Sweden; 4Dept of Thoracic Anaesthesiology, The Heart Cntr, Rigshospitalet, Copenhagen O, Denmark; 5Dept of Anesthesia and Intensive Care, Skåne Univ Hosp, Lund Univ, Lund, Sweden
Background: Bradycardia is common during targeted temperature management (TTM), likely being a physiological response to lower body temperature. We recently hypothesized that bradycardia during TTM at 33°C indicates less neurological damage and could represent a new predictor of lower mortality and found a strong association between bradycardia and lower risk of death in a tertiary single centre observational study of 234 comatose out-of-hospital cardiac arrest (OHCA) patients with shockable rhythm treated 2004-10 (Presented October 2014, ACCA). The present study sought to validate this finding in a comparable but larger cohort of comatose OHCA survivors. Method: We studied 447 comatose survivors of OHCA treated with TTM at 33°C enrolled in the TTM-trial from 2010-13 (NEJM 2013). Endpoints were 180-day mortality and unfavourable neurological function (Cerebral Performance Category 3-5). Patients were stratified by minimum heart rate (≤50bpm, 51-60bpm, >60bpm (reference)) during hypothermia. Results: Heart rates ≤50bpm and 51-60bpm were recorded in 160 (36%) and 124 (28%) patients, respectively. Time to ROSC and lactate level were higher in >60bpm patients, but other baseline characteristics did not differ. Crude 180-day mortality increased with increasing minimum heart rate (Fig. 1, Plog rank <0.0001). Bradycardia ≤50bpm was independently associated with lower 180-day mortality (HRadjusted=0.50 (0.35-0.72, p<0.001)) and lower odds of unfavourable neurological outcome (ORadjusted=0.35 (0.20-0.63, p<0.001) in models adjusting for potential confounders including age, initial rhythm, time to ROSC and admission lactate. Conclusion: This study confirms and validates a strong and robust association of bradycardia and lower mortality and favorable neurological outcome in a large cohort of comatose OHCA patients treated by TTM at 33°C. Bradycardia during TTM may thus be a novel, very early marker of favorable outcome in comatose survivors of OHCA.
This research has received full or partial funding support from the American Heart Association.
Author Disclosures: J.H. Thomsen: None. C. Hassager: None. N. Nielsen: None. M. Wanscher: None. S. Pehrson: None. L. Køber: None. J. Bro-Jeppesen: None. H. Søholm: None. H. Friberg: None. J. Kjærgaard: None.
Key Words: Cardiac arrest, Therapeutic hypothermia, Prognosis, Electrophysiology, Heart rate/Heart rate variability
The Necessity of Skeletal Muscle Paralysis in Patients During Mild Therapeutic Hypothermia After Cardiac Arrest. Results of a Prospective Randomized, Double Blinded, Double Dummy Study
Mathias Stoeckl1, Fritz Sterz2, Michael Holzer2, Christoph Weiser2, Andreas Schober2, Christoph Testori2, Jasmin Kechvar-Parast3, Graham Nichol4, Martin Frossard2, Harald Herkner2, Heidrun Losert2; 1Dept. of Emergency Medicine, Med Univ Vienna, Dept of Emergency Medicine, Vienna, Austria; 2Med Univ Vienna, Dept of Emergency Medicine, Vienna, Austria; 3Med Univ Vienna, Dept of Neurology, Vienna, Austria; 4Univ of Washington, Harborview Med Cntr, Washington, WA
Introduction Evidence-based guidelines recommend therapeutic hypothermia (TH) to improve neurological outcome after cardiac arrest (CA). Besides analgesia and sedation, neuromuscular blockers (NMBs) are used during induction and maintaining TH to prevent shivering, which leads to temperature counter-regulation and delayed achievement of target temperature. However, NMBs are reported to be associated with side effects and prolonged intensive care stay. Importantly, their use may mask epileptic activity so post hypoxic seizures might remain undetected. Therefore, we assessed whether continuous administration of NMBs reduces shivering episodes during TH. Methods This prospective randomized double blind, double dummy trial allocated patients resuscitated from CA of presumed cardiac origin to receive a) continuous rocuronium infusion 0.25 mg/kg/h or b) identically-appearing continuous saline infusion during the first 29 hours after induction of TH. When shivering was observed, standardized and weight-adjusted bolus injections of a) saline or b) rocuronium were given. The primary outcome was number of shivering episodes; secondary outcomes were survival and neurological status one year after CA, time to target temperature of 33°C, dissipated energy of cooling device, and changes in basal metabolism during TH. Train of four measured depth of relaxation, bispectral index measured depth of sedation and continuous EEG was used to detect seizures. Sixty-three patients (30 and 33 per group) were required to detect shivering rates of 91% compared to 30%. The study was approved by a research ethics committee. Results Sixty-six patients (33 intervention group; 33 control group) were enrolled from November 2010 to September 2013. Mean age was 60.1±11.9 years. 80% had male gender. After at least 10 months of follow up, cumulative survival is 55% and cumulative dropout or withdrawal is 8%. Final follow-up will be completed in October 2014 then results unblinded to show whether NMB decrease shivering, or increase survival or neurologic status. Conclusions Randomization of patients resuscitated from CA to NMB or placebo was feasible. Primary and secondary outcomes will be presented at ReSS 2014. ClinicalTrials.gov Identifier: NCT01719770
Author Disclosures: M. Stoeckl: None. F. Sterz: None. M. Holzer: None. C. Weiser: None. A. Schober: None. C. Testori: None. J. Kechvar-Parast: None. G. Nichol: None. M. Frossard: None. H. Herkner: None. H. Losert: None.
Key Words: Cardiac arrest, Hypothermia, Resuscitation, Post cardiac arrest care
Coronary Thrombectomy in a Cardiogenic Shock Complicating ST-Segment Elevation Myocardial Infarction
Makoto Suzuki1, Tetsuya Sumiyoshi2, Hideki Miyaji3, Masatomo Yoshikawa3, Hiroyuki Tanaka3, Masao Yamasaki3, Katsumi Miyauchi4, Atsushi Takagi5, Takeshi Yamamoto3, Ken Nagao3, Hitonobu Tomoike2, Morimasa Takayama2; 1Cardiovascular medicine, Sakakibara Heart Institute, Tokyo, Japan; 2Sakakibara Heart Institute, Tokyo, Japan; 3Tokyo CCU network scientific committee, Tokyo, Japan; 4Tokyo CCU scientifc committee, Tokyo, Japan; 5Tokyo CCU netwrok scientifc committee, Tokyo, Japan
Background: We investigated our hypothesis that pre-percutaneous coronary intervention (PCI) procedural coronary thrombectomy may provide some clinical advantages to attempt optimal coronary reflow which is the critical key issue to ameliorate clinical outcomes in patients with a cardiogenic shock complicating ST-segment elevation myocardial infarction (STEMI). Methods Of 7,650 patients with acute myocardial infarction registered in the Tokyo CCU Network Council between January 2009 and December 2011, a total of 180 consecutive patients (144 male, 68±13 years) with a cardiogenic shock complicating STEMI who showed pre-PCI procedural Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 (absent initial coronary flow) were recruited. Achievements of post-PCI procedural TIMI flow grade 3 (normal coronary reflow) and also in-hospital mortality were evaluated in those in accordance with the presence or absence of pre-PCI procedural coronary thrombectomy. Results Coronary thrombectomy was performed in 128 patients with a cardiogenic shock complicating STEMI (71% of all). Overall in-hospital mortality was 41% and that in an anterior STEMI increased by 52%. Pre-PCI procedural coronary thrombectomy did not affect any improvements in the achievement of TIMI grade 3 reflow (65% vs. 58%, p=0.368) and in-hospital mortality (42% vs. 37%, p=0.484). Even when focused on 93 patients with an anterior cardiogenic shock complicating STEMI, achievements of TIMI grade 3 reflow (59% vs. 56%, p=0.754) and also in-hospital mortality (53% vs. 48%, p=0.669) were not different in accordance with a presence or absence of coronary thrombectomy. Multivariate logistic analysis did not demonstrate any association of coronary thrombectomy (p=0.798), left main STEMI (p=0.258), and use of mechanical circulatory support (p=0.119) except lack of anemia (odds ratio, 1.247, 95% CI 1.035 to 1.531, p=0.019) with TIMI flow grade 3 reflow. Conclusion Pre-PCI procedural coronary thrombectomy may have serious limitations on attempting optimal coronary reflow which indicate a necessity of promising strategies for this critical illness.
Author Disclosures: M. Suzuki: None. T. Sumiyoshi: None. H. Miyaji: None. M. Yoshikawa: None. H. Tanaka: None. M. Yamasaki: None. K. Miyauchi: None. A. Takagi: None. T. Yamamoto: None. K. Nagao: None. H. Tomoike: None. M. Takayama: None.
Key Words: Acute coronary syndromes, Shock, cardiogenic, Interventional cardiology, Myocardial infarction, STEMI, Percutaneous coronary intervention (PCI)
- © 2014 American Heart Association, Inc.