2011 Late-Breaking Clinical Trial/Clinical Science: Special Reports Abstracts
2011 Late-Breaking Clinical Trial/Clinical Science: Special Reports Abstracts
Session Title: Late-Breaking Clinical Trials I
Intracoronary Compared with Intravenous Bolus Abciximab Application During Primary Percutaneous Coronary Intervention: AIDA STEMI Trial
Holger Thiele1, Jochen Wöhrle2, Rainer Hambrecht3, Harald Rittger4, Ralf Birkemeyer5, Bernward Lauer6, Petra Neuhaus7, Oana Brosteanu7, Peter Sick8, Marcus Wiemer9, Sebastian Kerber10, Ingo Eitel1, Klaus Kleinertz11, Gerhard Schuler1 1Herzzentrum Leipzig, Leipzig, Germany 2Univ of Ulm, Ulm, Germany 3Klnikum Links der Weser, Bremen, Germany 4Klnikum Coburg, Coburg, Germany 5Klnikum Villingen-Schwenningen, Villingen-Schwenningen, Germany 6Zentralklinik Bad Berka, Bad Berka, Germany 7KKSL, Leipzig, Germany 8Krankenhaus Barmherzige Brüder, Regensburg, Germany 9HERHerz- und Diabeteszentrum NRW, Bad Oeynhausen, Germany 10Herz- und Gefäβ-Klinik, Bad Neustadt, Germany 11Ambulantes Herzzentrum Chemnitz, Chemnitz, Germany
Background: Intracoronary (IC) abciximab bolus application during PCI results in high local drug concentration, improved perfusion, reduction of infarct size, and less microvascular obstruction in comparison to intravenous (IV) bolus application. Metaanalyses of randomized small to medium-sized trials suggest a reduction of death and reinfarction with the IC bolus application. The hypothesis of this trial is that IC abciximab bolus in comparison to standard IV application will improve the outcome of patients undergoing primary PCI in STEMI. Methods and Results: The AIDA STEMI study randomized 2072 STEMI patients at 27 tertiary centers in a 1:1 fashion from July 2008 to April 2011 to either IC or IV bolus abciximab administration during primary PCI with subsequent IV infusion for 12 h. The primary efficacy endpoint is the composite of all-cause mortality, recurrent infarction or new congestive heart failure within 90 days of randomization. Secondary clinical endpoints are each individual component of the endpoint within 90 days after randomization. Furthermore, ST-segment resolution and infarct size assessed indirectly by enzyme release are assessed. The trial is registered under www.clinicaltrials.gov: NCT00712101 and the study design has been published previously.1 Current patient characteristics showed no significant differences in baseline characteristics. The last clinical follow-up will be performed in the end of July 2011 and the final study results will be available during the Late Breaking Clinical Trial session. Conclusions: The AIDA STEMI study is the first adequately powered trial for clinical endpoints addressing important questions regarding efficacy and safety of IC versus IV abciximab bolus administration during primary PCI in patients with STEMI. The trial results will impact the route of glycoprotein IIb/IIIa-inhibitor administration. References: 1. Thiele H, et al. Intracoronary compared with intravenous bolus abciximab application during primary percutaneous coronary intervention: design and rationale of the Abciximab Intracoronary versus intravenously Drug Application in ST-Elevation Myocardial Infarction (AIDA STEMI) trial. Am Heart J. 2010;159:547–554.
Author Disclosures: H. Thiele: Research Grant; Modest; Lilly Germany. Speaker's Bureau; Modest; Lilly Germany. J. Wöhrle: None. R. Hambrecht: None. H. Rittger: None. R. Birkemeyer: None. B. Lauer: None. P. Neuhaus: None. O. Brosteanu: None. P. Sick: None. M. Wiemer: None. S. Kerber: None. I. Eitel: None. K. Kleinertz: None. G. Schuler: None.
Abciximab Plus Unfractionated Heparin versus Bivalirudin in Patients with Non-ST-Segment Elevation Myocardial Infarction Undergoing Percutaneous Coronary Intervention. The ISAR-REACT 4 Randomized Trial
Adnan Kastrati1, Franz-Josef Neumann2, Stefanie Schulz1, Steffen Massberg1, Karl-Ludwig Laugwitz3, Miroslaw Ferenc2, David Antoniuccu4, Peter B Berger5, Julinda Mehilli1, Albert Schomig1 1Deutsches Herzzentrum, Munich, Germany 2Herz-Zentrum, Bad Krozingen, Germany 3Klinikum rechts der Isar, Munich, Germany 4Azienda Ospedaliero-Universitaria Careggi, Florence, Italy 5Geisinger Med Cntr, Danville, PA
Background: Current guidelines recommend an early invasive strategy with percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation myocardial infarction (NSTEMI). The direct thrombin inhibitor bivalirudin and glycoprotein (GP) IIb/IIIa inhibitors have both been studied in patients with acute coronary syndromes (ACS). In the randomized, double-blind, placebo-controlled ISAR-REACT 2 trial that included both biomarker positive and negative ACS patients undergoing PCI, the benefit of adding abciximab to unfractionated heparin (UFH) was confined to NSTEMI patients. The ACUITY trial was an open-label trial that included both biomarker positive and negative ACS patients, only 57% underwent PCI. An appropriately sized, randomized comparison of abciximab plus UFH versus bivalirudin in which only ACS patients with NSTEMI undergoing PCI were enrolled has never been performed. Methods: ISAR-REACT 4 was designed to determine whether abciximab plus UFH is superior to bivalirudin in patients with NSTEMI undergoing PCI. Patients who presented with unstable symptoms and elevated biomarkers (troponin or creatine kinase (CK)-MB) without ST-segment elevation were eligible for enrollment. Eligible patients who required PCI were randomized in a double-blind manner to receive in the cath lab either abciximab, or bivalirudin. Results: The primary endpoint of the study is a composite of death, myocardial infarction (Q-wave or CK-MB elevation >5 times the upper limit of normal), urgent target vessel revascularization (TVR), or major bleeding at 30 days. Secondary endpoints include the efficacy composite endpoint of death, any myocardial infarction or urgent TVR, and the safety endpoint of major bleeding. The incidence of the primary endpoint was predicted to be 10.7% in the abciximab group and 15.3% in the bivalirudin group, which would represent a 30% relative risk reduction with abciximab. For a power of 80% and an α-level of 0.05, 850 patients per group were needed. We enrolled 1721 patients at 8 centers in Europe and the US. Results will be available in August 2011. Conclusion: ISAR-REACT 4 will help to identify the optimal adjunct antithrombotic regimen in patients with NSTEMI undergoing PCI.
Author Disclosures: A. Kastrati: Honoraria; Modest; Lilly, The Medicines. F. Neumann: None. S. Schulz: None. S. Massberg: None. K. Laugwitz: None. M. Ferenc: None. D. Antoniuccu: None. P.B. Berger: None. J. Mehilli: Honoraria; Modest; Lilly. A. Schomig: None.
Extended Anticoagulant Prophylaxis in Initially Hospitalized Medically Ill Patients: Results of the ADOPT (Apixaban Dosing to Optimize Protection from Thrombosis) Trial
Samuel Z Goldhaber1, Sylvia Haas2, Ajay Kakkar3, Robert M Knabb4, Alain Leizorovicz5, Geno Merli6, Jeffrey Weitz7 1Brigham and Women's Hosp, Boston, MA, 2Institute for Experimental Oncology and Therapy Rsch, Technical Univ of Munich, Munich, Germany 3Thrombosis Rsch Institute and Univ College London, London, United Kingdom 4Bristol-Myers Squibb, Princeton, NJ, 5Unité de Pharmacologie Clinique, Université Claude Bernard Lyon I, Lyon, France 6Jefferson Med College, Thomas Jefferson Univ Hosps, Philadelphia, PA, 7Thrombosis and Atherosclerosis Rsch Institute and McMaster Univ, Hamilton, Canada
Introduction: The efficacy and safety of extended venous thromboembolism (VTE) prophylaxis in medically ill patients remains uncertain. We hypothesized that administration of oral apixaban (2.5 mg BID) to acutely ill medical subjects for 1 month reduces the incidence of VTE compared with a minimum of 6 days of subcutaneous enoxaparin (40 mg QD). Objectives: The primary endpoint was total VTE through 30 days–defined as the combination of fatal or nonfatal pulmonary embolism, symptomatic deep vein thrombosis (DVT), asymptomatic proximal DVT detected by compression ultrasound (performed 5 to 14 days after randomization and on day 30), or VTE-related death through 30 days–defined as sudden death for which VTE could not be excluded as a cause. A key secondary objective was to demonstrate non-inferior efficacy for the same endpoint up to the time that parenteral study drugs were discontinued. The main safety outcome was bleeding. Study Design: Randomized, double-blind, double-dummy, 2-arm, multicenter trial in hospitalized medically ill patients with additional risk factors for VTE, including expected hospitalization of ≥ 3 days after randomization and moderately or severely restricted mobility. Those with congestive heart failure or respiratory failure required no other conditions for inclusion. Those with infection, acute rheumatic disorder, or inflammatory bowel disease required at least one additional VTE risk factor (e.g., age > 75, cancer, prior VTE, BMI > 30). With planned enrollment of 6,524 subjects, there would be 90% power to demonstrate superiority of apixaban (p<0.05) for the primary endpoint if true event rates were 2.5% and 4.0% for apixaban and enoxaparin, respectively, and 85% power to demonstrate non-inferiority for the key secondary endpoint if rates were 1.6% and 2.0%, respectively. Results: Between June 2007 and February 2011, 6,760 subjects were enrolled at 302 centers in 35 countries, and 6,528 subjects were randomized in a 1:1 allocation ratio. Based on preliminary data, 49% of enrolled subjects were male, the average age was 67 years, and 30% were age 75 or older. Approximately 38% were admitted to the hospital for congestive heart failure, 37% for acute respiratory failure, and 22% for infection. Full results will be presented.
Author Disclosures: S.Z. Goldhaber: Research Grant; Significant; Sanofi-Aventis, Eisai, Johnson & Johnson, EKOS, Bristol-Myers Squibb, Daiichi Sankyo. Consultant/Advisory Board; Modest; Sanofi-Aventis, Eisai, EKOS, Merck, Pfizer, Portola, Bristol-Myers Squibb, Daiichi Sankyo. S. Haas: Research Grant; Modest; Bristol-Myers Squibb. Other Research Support; Modest; Sanofi-Aventis. Speaker's Bureau; Modest; Bayer-Healthcare, Bristol-Myers Squibb. Consultant/Advisory Board; Modest; Bayer-Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, CSL Behring. A. Kakkar: Research Grant; Modest; Bayer Healthcare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Eisai. Honoraria; Modest; Bayer Healthcare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline. Consultant/Advisory Board; Modest; Bayer Healthcare, Sanofi-Aventis, Boehringer-Ingelheim, Pfizer, Bristol-Myers Squibb, Eisai, Aryx Therapeutics, Canyon Pharmaceuticals. R.M. Knabb: Employment; Significant; Bristol-Myers Squibb. Ownership Interest; Significant; Bristol-Myers Squibb. A. Leizorovicz: Research Grant; Significant; Bristol-Myers Squibb, GlaxoSmithKline. Consultant/Advisory Board; Modest; Bayer Healthcare, Sanofi-Aventis, Leo Pharmaceuticals, GlaxoSmithKline, Boehringer Ingelheim. G. Merli: Research Grant; Modest; Bristol-Myers Squibb, Bayer Healthcare, Sanofi-Aventis. Consultant/Advisory Board; Modest; Bristol-Myers Squibb, Bayer Healthcare, Sanofi-Aventis. J. Weitz: Research Grant; Modest; Bristol-Myers Squibb. Honoraria; Significant; Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi-Aventis, Daiichi-Sankyo, Takeda, Portola, Bayer Healthcare, Pfizer, Merck. Consultant/Advisory Board; Significant; Daiichi-Sankyo, Bristol-Myers Squibb, Sanofi-Aventis, Schering Plough, Portola.
The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA•CER) Trial
Kenneth W Mahaffey1, Pierluigi Tricoci1, Yuliya Lokhnygina1, Paul W Armstrong2, Philip Aylward3, Edmond Chen4, Claes Held5, Sergio Leonardi1, Ann M Kilian4, David J Moliterno6, Tyrus L Rorick1, John Strony4, Frans Van de Werf7, Lars Wallentin5, Harvey D Wite8, Robert A Harrington1 1Duke Clinical Rsch Institute, Durham, NC, 2Univ of Alberta, Edmonton, Canada 3Flinders Med Cntr, Adelaide, Australia 4Merck & Co., Inc., Whitehouse Station, NJ, 5Uppsala Clinical Rsch Cntr, Uppsala, Sweden 6Univ of Kentucky, Lexington, KY, 7Univ of Leuven, Leuven, Belgium 8Green Lane Cardiovascular Service, Auckland, New Zealand
Background: The platelet protease-activated receptor-1 (PAR-1), the main thrombin receptor, is a novel target for treatment and prevention of arterial thrombosis. The TRA•CER trial evaluated the efficacy and safety of vorapaxar, a first-in-class, orally active, potent, and selective PAR-1 antagonist, compared with placebo in high-risk patients with non-ST-segment elevation (NSTE) ACS treated with current standard of care. Methods: TRA•CER is a prospective, randomized, double-blind, placebo-controlled trial in which 12,942 patients were enrolled in 37 countries. Eligible patients had ischemic symptoms within 24 hrs of hospital presentation and either elevated troponin or CK-MB or ST-segment changes on ECG, and at least 1 additional high-risk criterion: age >=55, prior MI or revascularization procedure (PCI or CABG), diabetes mellitus, or peripheral arterial disease. Vorapaxar or placebo was given as a loading dose (40 mg) followed by a maintenance dose (2.5 mg daily). The primary end point was the composite of cardiovascular death, MI, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization. The first 3 components of the primary composite (cardiovascular death, MI, or stroke) defined the key secondary efficacy end point. Safety-related end points included the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. As an end point-driven trial, TRA•CER was to continue until 1900 centrally adjudicated primary end point and 1457 key secondary end point events had occurred and all subjects were followed for at least 1 year. Based on planned end point accrual, the trial has >95% and 90% power to detect a 15% relative risk reduction in the composite primary and key secondary end points, respectively. Recruitment was completed on June 4, 2010. On January 13, 2011, prior to the scheduled completion of the trial follow-up phase, the DSMB informed the trial leadership that the trial should be closed out and that there were a sufficient number of primary and key secondary end point events for the primary analysis. Conclusion: TRA•CER will define the efficacy and safety of vorapaxar in the treatment of high-risk patients with NSTE ACS.
Author Disclosures: K.W. Mahaffey: Research Grant; Significant; Schering-Plough (now Merck), Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Novartis, Portola Pharmaceuticals, Pozen, Regado, Sanofi-Aventis, The Medicines Company, AstraZeneca. Consultant/Advisory Board; Modest; Schering-Plough (now Merck), Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Ortho/McNeill, Sanofi-Aventis, Novartis, Polymedix. Consultant/Advisory Board; Significant; AstraZeneca. P. Tricoci: Research Grant; Significant; Merck. Consultant/Advisory Board; Modest; Merck. Y. Lokhnygina: None. P.W. Armstrong: Research Grant; Significant; Merck, Eli Lilly. P. Aylward: Research Grant; Modest; Merck/Schering-Plough, Servier, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer/J&J, Bristol-Myers Squibb, Sanofi-Aventis, The Medicines Company, CSL, Pfizer. Speaker's Bureau; Modest; Merck/Schering-Plough, Servier, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer/J&J, Bristol-Myers Squibb, Sanofi-Aventis, The Medicines Company, CSL, Pfizer. Consultant/Advisory Board; Modest; Merck/Schering-Plough, Servier, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer/J&J, Bristol-Myers Squibb, Sanofi-Aventis, The Medicines Company, CSL, Pfizer. E. Chen: Employment; Significant; Merck. C. Held: Research Grant; Significant; Schering-Plough (Merck), GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca. S. Leonardi: None. A.M. Kilian: Employment; Significant; Merck. D.J. Moliterno: Research Grant; Significant; Merck/Schering-Plough. Consultant/Advisory Board; Significant; Merck/Schering-Plough. T.L. Rorick: None. J. Strony: Employment; Significant; Merck. F. Van de Werf: Research Grant; Significant; Schering-Plough (now Merck). Speaker's Bureau; Modest; Schering-Plough (now Merck). Consultant/Advisory Board; Modest; Schering-Plough (now Merck). L. Wallentin: Research Grant; Significant; Schering-Plough, GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, BMS. Speaker's Bureau; Modest; AstraZeneca, Eli Lilly, Boehringer Ingelheim. Honoraria; Modest; AstraZeneca, Eli Lilly, Boehringer Ingelheim, BMS, GlaxoSmith Kline, Schering Plough. Consultant/Advisory Board; Modest; Boehringer Ingelheim, Eli Lilly, AstraZeneca, Regado Biotechnologies, Athera Biotechnologies, GlaxoSmithKline. H.D. White: Research Grant; Significant; Daiichi Sankyo Pharma Development, Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, The Medicines Company, NIH, Pfizer, Roche, Johnson & Johnson, Schering-Plough/Merck, Sharpe & Dohme, AstraZeneca, GSK. Consultant/Advisory Board; Modest; Regado Biosciences. R.A. Harrington: Research Grant; Significant; Portola, Merck, The Medicines Company, Novartis, AstraZeneca, Sanofi-aventis, Bristol-Myers Squibb. Honoraria; Modest; AstraZeneca. Consultant/Advisory Board; Modest; Bristol-Myers Squibb, Sanofi-aventis, Novartis. Consultant/Advisory Board; Significant; AstraZeneca, Merck.
Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) Trial: A Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of Rivaroxaban in Subjects with Acute Coronary Syndrome
C Michael Gibson1, Jessica L Mega2, Eugene Braunwald2 1Beth Israel Deaconess Med Cntr, Boston, MA, 2Brigham and Women's Hosp, Boston, MA
Background: Despite treatment with aspirin or aspirin plus a thienopyridine, there is a residual risk of cardiovascular death, recurrent myocardial infarction (MI) or stroke among patients with acute coronary syndromes (ACS). Based upon the safety and efficacy results in a large phase 2 dose-finding trial, two doses of rivaroxaban, an oral factor Xa inhibitor, were selected for further testing in a pivotal phase 3 trial. Design: The ATLAS ACS 2-TIMI 51 trial is a randomized, double-blind, placebo-controlled, event-driven (n = 983), international phase 3 trial enrolling 15,526 patients who had been hospitalized with ACS (ClinicalTrials.gov NCT00809965). All patients are treated with low-dose aspirin, and at physician discretion, patients are further stratified by the concomitant administration of a thienopyridine (clopidogrel or ticlopidine; stratum 2) or not (stratum 1). Patients are randomly assigned in a 1:1:1 ratio within each stratum to treatment with either rivaroxaban 2.5 mg twice daily, rivaroxaban 5.0 mg twice daily, or placebo twice daily. The primary efficacy end point is the composite of cardiovascular death, MI, or stroke. The primary safety end point is Thrombolysis in MI (TIMI) major bleeding not associated with coronary artery bypass graft surgery. Results: Rivaroxaban significantly reduced the primary efficacy endpoint of the composite of cardiovascular death, myocardial infarction or stroke compared to standard therapy plus placebo. There was a significant increase in the primary safety endpoint of TIMI major bleeding among patients administered rivaroxaban versus placebo. Conclusion: Among ACS patients who are treated with guideline-based therapies for ACS, the addition of the oral factor Xa inhibitor rivaroxaban significantly reduces the risk of cardiovascular death, MI or stroke with an accompanying increase in TIMI major bleeding.
Author Disclosures: C. Gibson: Research Grant; Significant; Johnson & Johnson, Bayer Healthcare. Consultant/Advisory Board; Significant; Johnson & Johnson, Bayer Healthcare. J.L. Mega: Research Grant; Significant; Johnson & Johnson, Bayer Heatlhcare, Daiichi Sankyo, BMS/Sanofi-aventis. Consultant/Advisory Board; Modest; Bayer Healthcare, BMS/Sanofi-aventis. E. Braunwald: Research Grant; Significant; Johnson & Johnson, Bayer Healthcare, Daiichi Sankyo.
Session Title: Late-Breaking Clinical Trials II
The Impact of Full Coverage for Preventive Medications After Myocardial Infarction on Recurrent Vascular Events and Health Spending: The Post-Myocardial Infarction Free Rx Event and Economic Evaluation (MI FREEE) Trial
Niteesh K Choudhry1, Jerry Avorn1, Robert Glynn1, Elliott M Antman1, Sebastian Schneeweiss1, Michele Toscano2, Lonny Reisman2, Joaquim Fernandes2, Claire M Spettell2, Joy L Lee1, Raisa Levin1, Troyen Brennan3, William H Shrank1 1Harvard Med Sch, Boston, MA, 2Aetna, Hartford, CT, 3CVS Caremark, Woonsocket, RI
Background: Adherence to evidence-based medication regimens prescribed after myocardial infarction (MI) is suboptimal, with negative implications for cardiovascular morbidity and mortality. Eliminating patient out-of-pocket prescription costs may increase adherence and improve clinical outcomes. Methods: We enrolled patients discharged after MI and randomized their insurance plan sponsors to full (1494 plan sponsors, 2845 patients) or usual prescription coverage (1486 plan sponsors, 3010 patients) for all statins, beta-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers. The primary outcome was first major vascular event or revascularization. Secondary outcomes were medication adherence, rates of total major vascular events or revascularization, first major vascular event, and health expenditures. Results: Adherence to the study drugs ranged from 35.9% to 49.0% among controls and was 4% to 6% higher in the intervention group (all p<0.001). The primary outcome was not significantly reduced (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.82–1.04, p=0.21)). When subsequent events were also considered, rates of total major vascular events or revascularization were reduced by 11% (HR 0.89, 95%CI 0.90–0.99, p=0.03). Fewer intervention patients had a first major vascular event (HR 0.86, 95%CI 0.74–0.99, p=0.03). Eliminating copayments did not increase total spending ($66,001 for intervention patients and $71,778 for controls [relative spending 0.89, 95%CI 0.50–1.56, p=0.68]). Patient out-of-pocket costs were reduced for drugs and other non-drug services (relative spending 0.74, 95%CI 0.68–0.80, p<0.001). Conclusions: While eliminating copayments for post-MI drugs did not significantly reduce rates of the primary outcome of first major vascular events or revascularization, the enhanced coverage improved secondary outcomes including medication adherence and first major vascular events, and decreased patient spending without increasing overall health costs.This simple and scalable adherence improvement intervention could contribute to efforts to improve the quality and outcomes of post-MI care without adversely affecting health spending.
Author Disclosures: N.K. Choudhry: Research Grant; Significant; Post-MI FREEE was supported by a research grant from Aetna to Brigham and Women's Hospital. Consultant/Advisory Board; Significant; Consultant on insurance benefit design and program evaluation to Mercer Health and Benefits, Inc.. J. Avorn: None. R. Glynn: None. E.M. Antman: None. S. Schneeweiss: None. M. Toscano: Employment; Significant; employee of Aetna. L. Reisman: Employment; Significant; employee of Aetna. J. Fernandes: Employment; Significant; employee of Aetna. C.M. Spettell: Employment; Significant; employee of Aetna. J.L. Lee: None. R. Levin: None. T. Brennan: Employment; Significant; employee of CVS Caremark. W.H. Shrank: Consultant/Advisory Board; Significant; Consultant on research methodology to United Healthcare.
Pharmacist Intervention to Prevent Hospitalization and Death in Patients with Heart Failure: A Prospective Cluster Randomised Controlled Trial
Richard Lowrie1, Frances Mair2, Nicola Greenlaw3, Paul Forsyth1, Alex McConnachie4, Brian Rae1, Pardeep S Jhund5, John McMurray6 1National Health Service, Greater Glasgow and Clyde, Glasgow, United Kingdom 2Dept of General Practice and Primary Care, Univ of Glasgow, Glasgow, United Kingdom 3Robertson Cntr for Biostatistics, Glasgow, United Kingdom 4The Robertson Cntr for Biostatistics, Glasgow, United Kingdom 5BHF Cardiovascular Rsch Cntr, Univ of Glasgow, Glasgow, United Kingdom 6BHF Cardiovascular Rsch Cntr, Glasgow, United Kingdom
Introduction: Pharmacologic treatment of left ventricular systolic dysfunction (LVSD) is frequently sub-optimal because disease-modifying therapies are often under-used and under-dosed, contributing to the high risk of hospital admission and premature death. Meta-analysis of small trials with short follow up suggests pharmacist-provided medication review may improve outcomes in Heart Failure (HF). Hypothesis: Pharmacist-led medication review and revision will reduce HF hospitalization and mortality in community-dwelling patients with LVSD, as compared with usual care. Methods: We conducted a large-scale, long-term, prospective cluster randomized controlled-trial. We collected baseline data for 2169 patients from 174 medical centers and randomized 87 primary care medical centers to pharmacist intervention and 87 practices to routine family-physician care. Twenty seven pharmacists with generalist-level training, optimized medicines for HF and co-morbidities, using protocols adapted from evidence-based guidelines. The intervention included initiation and dose up-titration of beneficial therapies and adherence counselling, usually during a single consultation. The primary endpoint was a composite of death from any cause or hospitalization for HF, analyzed as time to first event. Results: At randomization, mean age was 71 years (SD 10.6), 70% were male, 86% received an ACE inhibitor or angiotensin receptor blocker, 62% a beta-blocker and 5% an aldosterone antagonist. The mean number of prescriptions per patient at baseline was 8.7. Median follow up was 4.7 years. More than 750 patients are expected to experience the primary outcome, providing 80% power to detect a 19% reduction in risk from pharmacist intervention. Results will be presented November2011. Conclusion: This is the largest pharmacist intervention trial in LVSD/HF to date (and also larger than any prior nurse-led/multidisciplinary intervention trial) with the longest follow up and will provide a statistically robust assessment of this intervention in a “real world” setting. If effective, the intervention is readily transferrable to other health care systems.
Author Disclosures: F. Mair: None. N. Greenlaw: None. P. Forsyth: None. A. McConnachie: None. B. Rae: None. P.S. Jhund: None. J. McMurray: None.
Testing an Evidence-Based, Individualized Informed Consent Form to Improve Patients' Experiences with PCI
John Spertus1, Eizabeth Gialde1, Adnan Chhatriwalla1, Kensey Gosch1, Philip G Jones1, John McCartan1, Edward J McNulty2, Mayra Guerrero3, Aaron Kugelmass4, Richard Bach5, Jeptha Curtis6, Charles Bethea7, Marc Shelton8, Bradley Leonard9, Henry Ting10, Carole Decker1 1Mid America Heart Institute, Kansas City, MO, 2Kaiser Permanente - San Francisco, San Francisco, CA, 3Henry Ford Health System, Detroit, MI, 4Baystate Med Cntr, Springfield, MA, 5Washington Univ, Saint Louis, MO, 6Yale Univ, New Haven, CT, 7Integris Healthsystem, Oklahoma City, OK, 8Prairie Cardiovascular Institute, Springfield, IL, 9Baylor Health System - Plano, Plano, TX, 10Mayo Clinic, Rochester, MN
Introduction: Informed consent for PCI has repeatedly been shown to be deficient. In light of the Institute of Medicine's mandate for the delivery of more evidence-based, safer, cost-effective, personalized care, we implemented a novel program, PRISM, for generating individualized consent forms with patient-specific risk estimates from ACC NCDR Cath-PCI models and tested its impact on patients' experiences with PCI. Hypothesis: We hypothesized that PRISM-generated consents for PCI would improve patients' experiences, knowledge transfer and participation in shared medical decision-making. Methods: A 9-center, pre-post test design of patients undergoing PCI. Primary outcomes included the percentage of patients who read the consent form, knowledge transfer, and patients' participation in decision-making. Results: We interviewed 590 patients receiving traditional consent documents and 527 receiving PRISM consents. Across the entire sample, marked improvements in reviewing (72% for PRISM vs. 45% for original consents) and understanding the consent forms were observed. Site-adjusted analyses revealed better understanding of the PRISM consents (odds ratios (ORs)=1.8–3.0, depending upon the outcome), but there was marked heterogeneity across sites (median relative difference (MRD) in ORs of PRISM's effect = 2–3.2). Patients receiving the PRISM consents were more likely to understand the purposes and risks of the procedure (ORs=1.9–3.9, MRDs=1.1–6.2), to engage in shared decision-making (proportional OR=2.1 [95%CI=1.02–4.4], MRD=2.2) and to discuss stent options with their physicians (58% vs. 31%; site-adjusted odds ratio=2.7 [95% CI=1.2, 6.3], MRD=2.6). Conclusions: Informed consent documents, embedded with patient-specific risk estimates, can improve the process of informed consent and shared decision-making. Marked heterogeneity of benefits across hospitals highlights that consent documents are but one aspect of engaging patients in understanding and participating in treatment decisions.
Author Disclosures: J. Spertus: Research Grant; Significant; AHA Outcomes Center, NHLBI. Ownership Interest; Significant; Health Outcomes Sciences. Consultant/Advisory Board; Modest; United Healthcare Scientific Advisory Board. E. Gialde: None. A. Chhatriwalla: None. K. Gosch: None. P.G. Jones: None. J. McCartan: Consultant/Advisory Board; Significant; Health Outcomes Sciences. E.J. McNulty: None. M. Guerrero: None. A. Kugelmass: None. R. Bach: None. J. Curtis: None. C. Bethea: None. M. Shelton: None. B. Leonard: None. H. Ting: None. C. Decker: None.
Outcomes of Non-Primary PCI at Hospitals with and Without On-Site Cardiac Surgery: A Randomized Study
Thomas Aversano Johns Hopkins Med Insts, Baltimore, MD
The Cardiovascular Patient Outcomes Research Team (CPORT) compared 6 week and 9 month outcomes of non-primary percutaneous coronary intervention (PCI) performed at hospitals with (SOS) and without (no-SOS) on-site cardiac surgery. We tested the hypothesis that two primary outcomes: (1) mortality 6 weeks post index PCI (safety outcome) and (2) the composite of death, Q-wave MI and target vessel revascularization 9 months post index PCI (quality outcome) would not be inferior at no-SOS hospitals. The 60 no-SOS centers had to be capable of performing 200 PCIs yearly, complete a PCI development program. Interventionalists performed > 75 PCI per year. PCIs requiring atherectomy and patients with ejection fraction <20% were excluded. 18,867 patients who underwent diagnostic catheterization at no-SOS hospitals and required PCI, were randomly assigned to have PCI performed at the no-SOS or were transferred to an SOS hospital for PCI using a 3:1 (no-SOS:SOS) randomization scheme. 18,518 patients received a PCI procedure after randomization. The results of the first (“safety”) primary outcome are available and reported here. Assuming 6 week mortality to be 0.8%, sample size was selected to define a non-inferiority margin of 0.4% with a one-sided test for non-inferiority using α=0.05 and β=0.80 for both primary endpoints. The table below summarizes the data from 18,518patients who had PCI performed by treatment assigned. The (6wk mortality% in no-SOS) - (6wk mortality% in SOS) is −0.014% with 90% CI (-0.26% to 0.28%). The upper bound is < .4% so that the hypothesis of inferior 6 wk mortality for no-SOS is rejected at one-sided P < 0.05. Thus, 6 week mortality and the rate of emergency CABG is no different when PCI is performed at hospitals with or without SOS. Long term outcomes are being monitored and will be reported when results are available.
Author Disclosures: T. Aversano: Other Research Support; Significant; funding from participating hospitals.
Session Title: Late-Breaking Clinical Trials III
Double Blind Placebo Controlled Dose Ranging Study of the Efficacy and Safety of Celivarone 50, 100 Or 300 Mg OD with Amiodarone as Calibrator for the Prevention of ICD Interventions or Death (ALPHEE)
Peter R Kowey1, Etienne M Aliot2, Alessandro Capucci3, Stuart J Connolly4, Harry J Crijns5, Stefan H Hohnloser6, David Radzik7, Piotr Kulakowski8, Denis Roy9 1MLH Heart Cntr Lankenau Med Cntr, Wynnewood, PA, 2Cardiovascular Institute Univ of Nancy, Nancy, France 3Ospedale Torrette, Ancona, Italy 4McMaster Univ, Hamilton, Canada 5Univ Hosp Maastricht, Maastricht, Netherlands 6J.W. Goethe Univ, Frankfurt, Germany 7Sanofi Rsch and Development, Paris, France 8Grochowski Hosp, Warsaw, Poland 9Universite de Montreal, Quebec, Canada
Background: Implantable cardioverter defibrillators (ICDs) improve survival in patients (pts) at risk of ventricular tachycardia/fibrillation (VT/VF). Many ICD pts need adjunctive therapy with amiodarone or sotalol but these drugs often have incomplete efficacy and are poorly tolerated. Celivarone (C) is a new benzofuran derivative with an electrophysiological profile similar to amiodarone. C showed promising results in a pilot ICD study. Aims/Methods: Assess if C prevents VT/VF triggering ICD interventions (ICD shock or anti-tachycardia pacing). The study was conducted at 151 centers in 26 countries in America, Europe, Australia, Africa and Japan. A total of 486 pts with an ICD, left ventricular ejection fraction (LVEF) ≤ 40% and at least one appropriate ICD intervention or implanted for secondary prevention during the previous month were randomized to receive C orally: 50 mg, 100 mg, 300 mg, placebo (P) or amiodarone 200 mg (after loading dose of 600 mg for 10 days) once daily. Primary and secondary endpoints were appropriate ICD intervention or sudden cardiac death, and ICD shock or death, respectively. The primary analysis was based on a stratified log-rank test of cumulative Kaplan-Meier incidence estimates. Hazard ratios with 95% confidence interval for each C dose versus P were estimated using a Cox model. Statistical significance was assessed using the Hochberg multiple comparison procedure. Pts' safety was monitored by a Data Monitoring Committee. Results: These blinded data (figure) are preliminary pending follow-up and subsequent unblinding. Mean (SD) pt age was 64.4 (10.9) yrs, 88.7% were males mainly with coronary disease. Mean (SD) LVEF was 29.1 (7.6)%. Median follow-up and treatment duration were 12.4 and 8.9 months, respectively. Fatal events were centrally adjudicated. Final results will be available in August. Conclusions: ALPHEE will define the efficacy and safety of celivarone for prevention of ICD interventions or death. [NCT00993382]
Author Disclosures: P.R. Kowey: Speaker's Bureau; Modest; sanofi-aventis. Honoraria; Significant; sanofi-aventis. Consultant/Advisory Board; Significant; sanofi-aventis. E.M. Aliot: Honoraria; Modest; sanofi aventis, Bayer, Meda pharma, Pfizer, BMS, Boehringer Ingelheim, St. Jude Medical, Medtronic, Biotronik. Consultant/Advisory Board; Modest; sanofi aventis, Bayer, Meda pharma, Pfizer, BMS, Boehringer Ingelheim, St. Jude Medical, Medtronic, Biotronik. A. Capucci: Honoraria; Significant; sanofi-aventis. Consultant/Advisory Board; Significant; sanofi-aventis. S.J. Connolly: Research Grant; Significant; sanofi-aventis. Consultant/Advisory Board; Significant; sanofi-aventis. H.J. Crijns: Honoraria; Significant; sanofi-aventis. Consultant/Advisory Board; Significant; sanofi-aventis. S.H. Hohnloser: Speaker's Bureau; Modest; St. Jude Medical, Boehringer Ingelheim, BMS, Cardiome, Medtronic. Speaker's Bureau; Significant; sanofi-aventis. Honoraria; Modest; St. Jude Medical, Boehringer Ingelheim, BMS, Cardiome, Medtronic. Honoraria; Significant; sanofi-aventis. Consultant/Advisory Board; Significant; sanofi-aventis. D. Radzik: Employment; Significant; FTE. Ownership Interest; Modest; Sanofi. P. Kulakowski: Honoraria; Modest; sanofi-aventis. Consultant/Advisory Board; Modest; sanofi-aventis. Other; Modest; sanofi-aventis. D. Roy: Research Grant; Modest; Cardiome. Consultant/Advisory Board; Modest; sanofi-aventis, Merck, Boehringer Ingelheim, Daiichi Sankyo.
Atrial Fibrillation Catheter Ablation versus Surgical Ablation Treatment: a Multi-center Randomized Clinical Trial
Lucas Boersma1, Manuel Castella2, WimJan Van Boven1, Antonio Berruezo2, Alaadin Yilmaz1, Mercedes Nadal3, E Sandoval3, Naiara Calvo4, Johannes Kelder1, Josep Brugada2, Maurits Wijffels1, Lluís Mont2 1St.Antonius Hosp, Nieuwegein, Netherlands 2Hosp Clinic, Barcelona, Spain 3Hosp Clínic, Barcelona, 4Hosp Clínic, Barcelona, Netherlands
Purpose: Pulmonary Vein (PV) Catheter Ablation (CA) has become therapy of choice for drug-refractory AF in the last decade. More recently minimal invasive epicardial surgical AF ablation (SA) has shown high efficacy. A multi-center, randomized clinical trial (Clin. Trials. Gov. NCT00662701) was designed to compare CA and SA for efficacy and safety. Methods: pts with drug-refractory AF where CA efficacy was expected to be lower based on LA diameter>44 mm, LA diameter 41–44 mm&hypertension, or prior unsuccessful CA for AF, were randomized for (renewed) CA or SA. Randomization was blinded and balanced per individual site. Pts with significant structural disease were excluded. CA comprised of PV isolation with single tip RF catheter&3-D navigation under conscious sedation, while SA comprised of epicardial bipolar clamp (AtriCure) PV isolation, with ganglion ablation, and LAA amputation, under general anesthesia. Additional lines were at the discretion of the operator. A 12-mo follow-up (FU) was performed with ECG at 3&6&12 mo, 48-hour Holter at 6&12 mo, and MRI at 6 mo. All procedural and chronic major and minor adverse events were noted. Results: Of 124 pts (101 male, mean age 56±8), 63 were randomized to CA and 61 to SA. In the population, AF was paroxysmal in 66% and (longstanding<1yr) persistent in 34%, while 67% had unsuccessful prior CA. Mean LA diameter was 43 mm. Baseline characteristics were not significantly different between SA and CA groups, nor between sites. Mean procedure, fluoroscopy, and RF times were 162, 27, and 33 min for CA, mean SA time was 188 min, with mean of 9 PV RF applications. Additional LA lines were made in 49% of CA pts (roofline), and 31% of SA pts (trigone, roof, or Box). At 12 mo, freedom of left atrial arrhythmia without AAD was seen in 36.5% of the CA group, and 65.6% of the SA group (p=0.0022). The effect was not significantly different for type of AF, additional lines, inclusion criterion, or hospital. Procedural major adverse event rate was 3.2% for CA and 23.0% for SA (p=0.0431), and 13.1% and 11.5% respectively during chronic FU. Conclusion: In pts with enlarged atria and hypertension, or unsuccessful prior CA, minimal invasive SA is superior to CA to achieve freedom of LA arrhythmia during 1 yr follow-up, with higher procedural adverse event rate.
Author Disclosures: L. Boersma: Research Grant; Significant; Medtronic, St.Jude. Speaker's Bureau; Modest; Medtronic, St.Jude. Expert Witness; Modest; Medtronic. Consultant/Advisory Board; Modest; Medtronic. M. Castella: Consultant/Advisory Board; Modest; AtriCure. W. Van Boven: Research Grant; Significant; AtriCure. Consultant/Advisory Board; Modest; AtriCure. A. Berruezo: Speaker's Bureau; Modest; St.Jude, Biosense-Webster. Consultant/Advisory Board; Modest; St.Jude, Biosense Webster. A. Yilmaz: Consultant/Advisory Board; Modest; AtriCure. M. Nadal: None. E. Sandoval: None. N. Calvo: None. J. Kelder: None. J. Brugada: Research Grant; Significant; St.Jude, Biosense-Webster. Speaker's Bureau; Modest; St.Jude. Biosense-Webster. Consultant/Advisory Board; Modest; St.Jude. Biosense-Webster. M. Wijffels: None. L. Mont: Speaker's Bureau; Modest; St.Jude. Biosense-Webster. Consultant/Advisory Board; Modest; St.Jude. Biosense-Webster.
A Randomized Multicenter Comparison of Radiofrequency Ablation and Antiarrhythmic Drug Therapy as First-Line Treatment in 294 Patients with Paroxysmal Atrial Fibrillation
Jens Cosedis Nielsen1, Arne Johannessen2, Pekka Raatikainen3, Gerhard Hindricks4, Håkan Walfridsson5, Ole Kongstad6, Steen Michael Pehrson7, Anders Englund8, Juha Hartikainen9, Leif Spange Mortensen10, Peter Steen Hansen11 1Aarhus Univ Hosp, Skejby, Aarhus N, Denmark 2Gentofte Hosp, Hellerup, Denmark 3Oulu Univ Hosp, Oulu, Finland 4Herzzentrum Leipzig, Leipzig, Germany 5Linköping Univ Hosp, Linköping, Sweden 6Lund Univ Hosp, Lund, Sweden 7Rigshospitalet, Copenhagen, Denmark 8Örebro Univ Hosp, Örebro, Sweden 9Kuopio Univ Hosp, Kuopio, Finland 10UNI-C, Aarhus N, Denmark 11Varde Heart Cntr, Varde, Denmark
The Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation (MANTRA-PAF) trial compared radiofrequency catheter ablation (RFA) with antiarrhythmic drug therapy (AAD) as first-line therapy in patients with paroxysmal atrial fibrillation (PAF). Methods: AAD naïve patients with PAF were randomized to RFA pulmonary vein isolation or AAD (class IC or III AAD). Follow-up included 7-days Holter monitoring (HM) at 3, 6, 12, 18, and 24 months. Primary endpoints were cumulative AF burden (% of time in AF) during 35 days HM and AF burden at each HM. Secondary endpoints included freedom from any and symptomatic AF in HM after 24 months and adverse events. Analysis was intention-to-treat. Results: We included 294 patients (mean age 55±10 years, 206 males), randomized to RFA (n=146) or AAD (n=148). Baseline characteristics were well balanced. Patients in the RFA group underwent 1.5±0.8 RFA procedures. There were no significant differences between the treatment groups in cumulative AF burden (p=0.10) and AF burden at 3, 6, 12, and 18 months. AF burden was significantly lower in the RFA group after 24 months (p=0.007). Number of patients with any AF (22/146 vs. 43/148, p=0.004) and symptomatic AF (10/146 vs. 24/148, p=0.012) episodes were lower in the RFA group at 24 months. Occurrence of atrial flutter did not differ between the groups. Serious adverse events were recorded in 19 patients in the RFA group and in 15 patients in the AAD group. In the AAD group 54 patients underwent RFA. At 24 months 13 patients in the RFA group were treated with AAD. Conclusions: At 24 months AF burden, occurrence of AF and symptomatic AF were significantly lower in the RFA group than in the AAD group, although there was no significant difference in cumulative AF burden. These data support RFA as a first-line treatment in patients with PAF.
Author Disclosures: J. Nielsen: None. A. Johannessen: None. P. Raatikainen: Consultant/Advisory Board; Modest; Consultant for Biosense Webster. G. Hindricks: Honoraria; Modest; Travel grants from Biosense Webster, Lecture grants from Biosense Webster. Consultant/Advisory Board; Modest; Member of the Advisory Board of Biosense Webster. H. Walfridsson: None. O. Kongstad: None. S. Pehrson: None. A. Englund: None. J. Hartikainen: None. L. Mortensen: None. P. Hansen: None.
The Results of the PALLAS Study
Stuart J Connolly1, Stefan H Hohnloser2 1Dept of Medicine, Hamilton General Hosp, Hamilton, Canada 2JW Goethe Univ, Frankfurt, Germany
Patients with permanent atrial fibrillation (AF) often have multiple vascular risk factors and are therefore at high risk for major vascular events and premature death. No previous trials have investigated interventions to reduce morbidity and mortality in this high risk population. Dronedarone is an antiarrhythmic drug which has been shown to reduce unplanned cardiovascular hospitalization or death and cardiovascular death in patients with non-permanent AF. The PALLAS study hypothesized that dronedarone would reduce major vascular events in patients with permanent AF who also had major vascular event risk factors. This international multicenter clinical trial enrolled patients with documented permanent AF for greater than 6 months who also had any of the following major vascular risk factors: prior stroke, myocardial infarction, coronary artery disease, peripheral arterial disease, left ventricular ejection fraction ≤40%, heart failure symptoms with hospitalization for heart failure between 1 and 12 months prior to enrolment. Patients were also eligible if they were >75 years with both diabetes and hypertension. There were 2 co-primary outcomes: The first was a composite of stroke, myocardial infarction, systemic embolism or cardiovascular death. The second co-primary outcome was unplanned cardiovascular hospitalization or death. Patients were randomized to receive either dronedarone 400 mg BID or matching double-blind placebo. After enrolment of 3149 patients, the Data Monitoring Committee recommended that the study be stopped due to highly significant excesses of events in the active group for both co-primary outcomes as well as hospitalizations and heart failure events with no evidence of benefit in other secondary endpoints. The final study results will be presented.
Author Disclosures: S.H. Hohnloser: Research Grant; Significant; sanofi-aventis. Honoraria; Significant; sanofi-aventis.
Session Title: Late-Breaking Clinical Trials IV
Practice-Based Opportunities for Weight Reduction (POWER)
Lawrence J AppelJohns Hopkins Med Insts Univ, Baltimore, MD
Background: Obesity and its CVD complications are extraordinarily common medical problems. Yet, there is a dearth of evidence on how to accomplish weight loss in the outpatient setting. Methods: We conducted an NHLBI-sponsored, randomized controlled, comparative effectiveness trial that tested two behavioral weight loss interventions, both of which could be implemented as part of routine medical care. Participants were 415 obese outpatients with at least one cardiovascular risk factor who were recruited from 6 primary care practices. The two interventions [Call-Center-Directed (CCD) and In-Person-Directed (IPD)] were compared to a Self-Directed (SD) control group and to each other. In CCD, trained coaches from Healthways, Inc counseled participants by phone without face-to-face contacts. In IPD, coaches from Hopkins delivered the intervention in which counseling occurred at in-person group and individual sessions and over the phone. In both IPD and CCD, participants periodically received automated email messages. A study-specific website with portals for participants and coaches facilitated communication. In both interventions, primary care physicians reinforced participation at routinely scheduled clinic visits. Trial duration was 24 months. Results: Of the 415 participants, 64% were women, and 41% were African-American; mean age was 54 years. At baseline, mean BMI was 36.6 kg/m2, and mean weight was 104 kg. At 24 months, 95% of participants had a measured weight. See figure for main results. Mean weight loss from baseline to 24 months was 0.8 kg in SD, 4.6 kg in CCD (P<0.001 vs. SD) and 5.1 kg in IPD (P<0.001 vs SD). The percent of individuals with at least 5% weight loss was 19% in SD, 38% in CCD, and 41% in IPD. CCD and IPD did not differ significantly from each other. Conclusions: Two behavioral interventions, one with no in-person contacts, achieved and sustained clinically significant weight loss over a 24 month period in obese medical outpatients at risk for CVD.
Author Disclosures: L.J. Appel: None.
Comparison of the Progression of Coronary Atherosclerosis for Two High Efficacy Statin Regimens with Different HDL Effects: SATURN Study Results
Stephen J Nicholls1, Christie M Ballantyne2, Philip J Barter3, M J Chapman4, Raimund M Erbel5, Peter Libby6, Joel S Raichlen7, Marilyn Borgman1, Kathy Wolski1, Steven E Nissen1 1Cleveland Clinic, Cleveland, OH, 2Baylor College of Medicine, Houston, TX, 3Heart Rsch Institute, Sydney, Australia 4Hôpital de la Pitié, Paris, France 5West-German Heart Cntr, Essen, Germany 6Brigham and Womens Hosp, Boston, MA, 7AstraZeneca, Wilmington, DE
Purpose: Favorable changes in low-density lipoprotein (LDL) cholesterol associate with slowing of progression of coronary atherosclerosis. Yet, it is unknown whether individual high-potency statins with distinct effects on high-density lipoprotein (HDL) cholesterol levels will affect atherosclerotic plaques differently. This study aimed to compare the rate of disease progression using intravascular ultrasound for the highest dosages of two potent statins with different effects on the ratio of atherogenic to protective lipids, rosuvastatin 40 mg vs. atorvastatin 80mg. Study Design: A double-blind, randomized controlled trial of patients with angiographic coronary artery disease, treated for 24 months with rosuvastatin 40 mg/daily or atorvastatin 80 mg/daily. Sample Size: Of 4251 patients screened, 1385 patients were randomized in 215 centers between February 2008 and June 2009. Endpoints: The primary endpoint was the nominal change in percent atheroma volume in patients treated with rosuvastatin compared to atorvastatin. Additional objectives include changes in total atheroma volume, lipid and biochemical measurements, in addition to safety and tolerability over the 24-month treatment period. Power Calculations: It was estimated that 450 patients would be required in each treatment group to provide 90% power to detect a 0.65 difference in progression of percent atheroma volume between the treatment groups, assuming a standard deviation of 3.0%. It was assumed that 30% of patients would discontinue or have non-evaluable imaging, requiring randomization of at least 1300 patients. Conclusion: The last patient received their final dose of treatment in June 2011 and complete study results will be available before the AHA Scientific Sessions. This study provides the first opportunity to compare directly the effects of the highest-efficacy statin agents on the rate of progression of coronary atherosclerosis.
Author Disclosures: S.J. Nicholls: Research Grant; Significant; Eli Lilly, AstraZeneca, Novartis, Resverlogix, Roche, Anthera, LipoScience. Speaker's Bureau; Modest; Merck. Consultant/Advisory Board; Modest; Merck, Takeda, Roche, CSL Behring, Sanofi-Aventis, Omthera, Eli Lilly, Boehringer Ingelheim, Abbott. C.M. Ballantyne: Research Grant; Significant; Abbott, AstraZeneca, Bristol-Myers Squibb, diaDexus, GlaxoSmithKline, Kowa, Merck, Novartis, Roche, Sanofi-Synthelabo, Takeda. Speaker's Bureau; Modest; Abbott. Speaker's Bureau; Significant; AstraZeneca, GlaxoSmithKline, Merck. Honoraria; Modest; Sanofi-Synthelabo, Takeda. Honoraria; Significant; Abbott, AstraZeneca, GlaxoSmithKline, Merck. Consultant/Advisory Board; Modest; Abbott, Adnexus, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, Takeda. P.J. Barter: Research Grant; Significant; Merck. Honoraria; Modest; Kowa, Pfizer, Roche. Honoraria; Significant; AstraZeneca, Merck. Consultant/Advisory Board; Modest; CSL Behring. M.J. Chapman: Research Grant; Significant; Merck, Pfizer. Honoraria; Modest; Merck, Roche, Kowa. R.M. Erbel: Consultant/Advisory Board; Significant; AstraZeneca. P. Libby: Other; Modest; Dr. Libby is an unpaid consultant or involved in clinical trials for AstraZeneca, GlaxoSmithKline, Merck, Novartis, Pfizer, ProNova, and Sigma-Tau; and is a member of the scientific advisory boards fo. J.S. Raichlen: Employment; Significant; AstraZeneca. M. Borgman: None. K. Wolski: None. S.E. Nissen: Other; Modest; Dr. Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding perform clinical trials from Pfizer, Astra Zeneca, Novartis, Karo Bio, Takeda, Resverlogix, and Eli Lilly.
Lipid-Modulating Effects of Evacetrapib, a Novel CETP Inhibitor, Administered as Monotherapy or in Combination with the Most Commonly-Used Statins
Stephen J Nicholls1, Bryan Brewer2, John J Kastelein3, Kathryn A Krueger4, Ming-Dauh Wang4, Kathy Wolski1, Ellen McErlean1, Steven E Nissen1 1Cleveland Clinic, Cleveland, OH, 2MedStar Rsch Institute, Washington, DC, 3Academic Med Cntr / Univ of Amsterdam, Amsterdam, Netherlands 4Eli Lilly, Indianapolis, IN
Purpose: Cholesteryl ester transfer protein (CETP) inhibitors interfere with lipid transfer between atherogenic and protective lipoprotein particles and have been proposed as a potential strategy to reduce cardiovascular risk. The aim of this study was to evaluate the lipid efficacy, safety and tolerability of a novel CETP inhibitor, evacetrapib, as monotherapy and in combination with statin regimens most commonly employed in contemporary clinical practice. Study Design: A double-blind, randomized placebo and active-controlled trial of patients with either hypercholesterolemia or low levels of high-density lipoprotein cholesterol (HDL-C). The study compared evacetrapib to placebo administered as monotherapy (30, 100 and 500 mg/day) and compared the combination of evacetrapib (100 mg/day) with either atorvastatin 20 mg/day, rosuvastatin 10 mg/day or simvastatin 40 mg/day to each respective statin alone for 12 weeks. Sample Size: Of 1154 patients screened, 430 patients were randomized in 57 centers between May 2010 and March 2011. Endpoints: The primary endpoints were the change in HDL-C and LDL-C in patients treated with evacetrapib combined with atorvastatin compared with atorvastatin alone. Additional objectives include changes in other lipid and biochemical parameters, safety, tolerability and pharmacokinetics of evacetrapib both as monotherapy and in combination with different statin agents. Power Calculations: It was estimated that 35 patients per group would provide 93% power to detect a 40% increase in HDL-C and 15% decrease in LDL-C with evacetrapib monotherapy compared with placebo and 87% power to detect a 40% increase in HDL-C and 10% decrease in LDL-C with evacetrapib combination therapy compared with statin alone. Assuming a 15% dropout rate, approximately 40 patients were randomized in each treatment group. Conclusion: The last patient received their final dose of treatment in May 2011. This study provides the first opportunity to characterize lipid efficacy, safety and tolerability of the novel CETP inhibitor, evacetrapib, as monotherapy and in combination with the major statins currently used in clinical practice.
Author Disclosures: S.J. Nicholls: Research Grant; Significant; Eli Lilly, AstraZeneca, Novartis, Resverlogix, Roche, Anthera, LipoScience. Honoraria; Modest; AstraZeneca. Consultant/Advisory Board; Modest; Merck, Takeda, Roche, CSL Behring, Sanofi-Aventis, Omthera, Eli Lilly, Abbott, Karo Bio, Boehringer Ingelheim. B. Brewer: Speaker's Bureau; Modest; Merck, Sanof-Aventis, Genentech, Roche, Eli Lilly, InfraReDx, AstraZeneca. Ownership Interest; Significant; HDL Therapeutics, Medicines Company, InfraReDx. Consultant/Advisory Board; Modest; Merck, Sanofi-Aventis, Roche, Eli Lilly, InfraReDx, AstraZeneca. J.J. Kastelein: Consultant/Advisory Board; Modest; Eli Lilly, Roche, Merck, Novartis, Boehringer Ingelheim, Genzyme, Isis, Cerenis. K.A. Krueger: Employment; Significant; Eli Lilly. M. Wang: Employment; Significant; Eli Lilly. K. Wolski: None. E. McErlean: None. S.E. Nissen: Other; Modest; Dr. Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding perform clinical trials from Pfizer, Astra Zeneca, Novartis, Karo Bio, Takeda, Resverlogix, and Eli Lilly.
Extended-Release Niacin Does Not Reduce Clinical Events in Patients with Established Cardiovascular Disease Whose LDL-Cholesterol is Optimally Controlled with Statin Therapy: Results from the AIM-HIGH Trial
William E Boden1, Jeffrey L Probstfield2 1Univ of Buffalo, Buffalo, NY, 2Univ of Washington, Seattle, WA
Background: Despite significant reductions in LDL-C and cardiovascular (CV) events with statins, residual risk for subsequent events in CHD patients remains unacceptably high, and may be attributable to low levels of HDL-C. Methods: AIM-HIGH was a randomized, placebo-controlled, event-driven trial in patients with a history of atherosclerotic CV disease and atherogenic dyslipidemia (low HDL-C, elevated triglycerides). We hypothesized that raising HDL-C with extended-release niacin (ERN) would reduce the risk of CV events by 25% among patients who had achieved target levels of LDL-C (40–80 mg/dL) with intensive simvastatin ± ezetimibe therapy. Participants tolerating 1,500–2,000 mg were randomly assigned to ERN or placebo. Follow-up was scheduled until late 2012. Results: A total of 3,414 men and women, mean age 64 years, from 92 U.S. and Canadian centers were followed for an average of 3 years. At entry, 94% were taking a statin, with a mean baseline LDL-C of 71 mg/dL, HDL-C 35 mg/dL, and triglycerides (TG) 161 mg/dL. Compared to placebo, ERN raised HDL-C by 16%, lowered TG by 19% after one year and mean LDL-C was < 70 mg/dL in both groups throughout follow-up. The trial was stopped at a formal interim analysis due to lack of efficacy of ERN. The primary endpoint (time to CHD death, non-fatal MI, ischemic stroke, hospitalization for ACS or symptom-driven coronary /cerebral revascularization) occurred in 16.6% of ERN vs 15.9% of placebo participants, HR=1.02 (95% CI, 0.87, 1.21). The overall ischemic stroke incidence was 1.4%, but higher in the ERN arm (1.7 %) than the placebo arm (1.0%); 8 strokes occurred after ERN had been discontinued. Conclusions: Data from AIM-HIGH show that ERN offers no additional clinical benefit in stable CHD patients with low HDL-C and high TG levels whose already low LDL-C levels at baseline remained optimally controlled with aggressive LDL-lowering agents.
Author Disclosures: W.E. Boden: Speaker's Bureau; Modest; Abbott Laboratories. J.L. Probstfield: None.
Session Title: Late-Breaking Clinical Trials V
Randomized Trial of Early Surgery versus Conventional Treatment for Infective Endocarditis (EASE)
Duk-Hyun Kang1, Yong-Jin Kim2, Sung-Han Kim1, Byung Joo Sun1, Dae-Hee Kim1, Jong-Min Song1, Suk Jung Choo1, Joo-Hee Zo3, Kee-Joon Choi1, Jae-Kwan Song1, Jae-Won Lee1, Dae-Won Sohn2 1Asan Med Cntr, Seoul, Korea, Republic of 2Seoul National Univ Hosp, Seoul, Korea, Republic of 3Boramae Hosp, Seoul, Korea, Republic of
Background: The optimal timing and indications for surgical intervention to prevent systemic embolism in infective endocarditis (IE) remain controversial. We conducted a trial to compare clinical outcomes of early surgery and conventional treatment in IE. Methods: We enrolled patients with left-sided native valve IE accompanied by severe valve disease and length of vegetation > 10 mm. The exclusion criteria included heart failure; annular or aortic abscess; age > 80 years; coexisting major embolic stroke; prosthetic valve IE; right-sided vegetation; and/or poor medical status. We randomly assigned patients to undergo early surgery (37 patients) or conventional treatment (39 patients). The primary end point was a composite of in-hospital death and embolic events that occurred within 6 weeks from randomization. Results: There were no significant differences in baseline clinical characteristics between the groups (Table). All the patients in the early surgery group underwent valve surgery within 48 hours after randomization, whereas 30 (77%) patients in the conventional treatment group underwent surgery during initial hospitalization (n=27) or during follow-up (n=3). The primary end point occurred in 1 (2.7%) patient of the early surgery group and in 9 (23.1%) of the conventional treatment group (hazard ratio [HR], 0.248; 95% confidence interval [CI], 0.069–0.883; P=0.031). There was no significant difference in all-cause mortality at 6 months (2.7% vs 5.1%; HR, 0.51; 95% CI, 0.05–5.66; P=0.59). The rate of the composite of death from any cause, embolic events or recurrence of IE at 6-months was 2.7% in the early surgery group as compared with 28.2% in the conventional treatment group (HR, 0.083; 95% CI, 0.011–0.640; P=0.017). Conclusion: Compared with conventional treatment, early surgery in IE patients with large vegetations significantly reduced the composite end point of death from any cause and embolic events by effectively decreasing systemic embolism.
Author Disclosures: D. Kang: None. Y. Kim: None. S. Kim: None. B. Sun: None. D. Kim: None. J. Song: None. S. Choo: None. J. Zo: None. K. Choi: None. J. Song: None. J. Lee: None. D. Sohn: None.
Claudication Treatment Comparative Effectiveness: 6 Month Outcomes From the CLEVER Study
Timothy P Murphy1, Donald Cutlip2, Judith Regensteiner3, Emile Mohler4, Suzanne Goldberg5, Joseph Massaro6, David Cohen7, Matthew Reynolds2, Beth Lewis8, Joselyn Cerezo1, Niki Oldenburg9, Claudia Thum10, Alan Hirsch91Rhode Island Hosp, Providence, RI, 2Beth Israel Deaconess Hosp, Boston, MA, 3Univ of Colorado Health Sciences Cntr, Denver, CO, 4Univ of Pennsylvania, Philadelphia, PA, 5National Heart Lung and Blood Institute, Bethesda, MD, 6Boston Univ, Boston, MA, 7St. Luke's Hosp, Kansas City, MO, 8Health Partners, Minneapolis, MN, 9Univ of Minnesota, Minneapolis, MN, 10Harvard Clinical Rsch Institute, Boston, MA
Background: At least 9 million Americans have peripheral artery disease (PAD) and > 1 million suffer symptom-limiting claudication. The Institute of Medicine ranked evaluation of claudication care strategies as one of the highest national comparative effectiveness priorities. Yet, the optimal strategy of care for claudication is not known. Methods: CLEVER is a multicenter (29 site) trial that evaluated major claudication strategies of care in 111 patients with symptom-limiting claudication. Subjects were required to have aortoiliac PAD, representing a cohort optimized for beneficial responses to endovascular therapy. Three treatments were randomly assigned: (1) optimal medical care (OMC, cilostazol with home exercise); (2) OMC plus supervised exercise (SE) for 6 months; or (3) OMC plus primary stent revascularization (ST). Each site received training and central oversight to assure uniform deployment of the SE intervention. The primary endpoint was change in maximal treadmill walking distance (MWD) between baseline and 6 months and was assessed with sequential pairwise comparisons. Secondary endpoints to be presented include community-based walking activity, QoL, and biomarkers of cardiovascular disease risk. Results: The mean age is (64±9), 61% were male, 54% were current smokers, and 23% had a diagnosis of diabetes. Compliance with cilostazol (94%), aspirin (80%), and lipid lowering medications was high (77%). Compliance with supervised exercise was 77%. The final primary endpoint results will be available in August 2011. As well, associated major adverse cardiac and limb event rates and the impact on community walking distance and QOL of each treatment strategy will be available. Conclusions: CLEVER represents the first prospective, multicenter randomized clinical trial of patients with anatomically defined aortoiliac PAD designed to measure efficacy, harm, and cost-effectiveness of the three major guideline-based strategies of care. Symptomatic PAD represents one of the most challenging cardiovascular diseases, for which endovascular treatment in increasing used at very high cost. These data will define _ for patients, clinicians, and payers _ the optimal care pathway for this common disease.
Author Disclosures: T.P. Murphy: Research Grant; Significant; Cordis/Johnson&Johnson, Abbott Vascular. D. Cutlip: None. J. Regensteiner: None. E. Mohler: None. S. Goldberg: None. J. Massaro: None. D. Cohen: None. M. Reynolds: None. B. Lewis: None. J. Cerezo: None. N. Oldenburg: None. C. Thum: None. A. Hirsch: None.
Colchicine Reduces Post-Operative Atrial Fibrillation. Results of the COPPS Atrial Fibrillation Study
Massimo Imazio1, Antonio Brucato2, Paolo Ferrazzi2, Maria Elena Rovere3, Anna Gandino4, Roberto Cemin5, Stefania Ferrua6, Riccardo Belli1, Rita Trinchero1, David H Spodick7, Yehuda Adler81Maria Vittoria Hosp, Torino, Italy 2Ospedali Riuniti, Bergamo, Italy 3Ospedale Mauriziano, Torino, Italy 4Ospedale Niguarda, Milano, Italy 5San Maurizio Regional Hosp, Bolzano, Italy 6Cardiology, Ospedale degli Infermi, Rivoli, Italy 7St. Vincent Hosp, Univ of Massachusetts, Worcester, MA, 8Sackler Faculty of Medicine, Tel-Aviv and Misgav ladach Hosp, Jerusalem, Kupat Holim Meuhedet, Jerusalem, Israel
Background. Inflammation and pericarditis may represent contributing factors for post-operative atrial fibrillation (POAF), both potentially affected by anti-inflammatory drugs and colchicine, that has been shown to be safe and efficacious for prevention of pericarditis and the post-pericardiotomy syndrome (PPS). Aim of the COlchicine for the Prevention of the Post-Pericardiotomy Syndrome (COPPS) POAF study is to test the efficacy and safety of colchicine for the prevention of POAF after cardiac surgery. Methods. The COPPS-POAF study included 336 patients (mean age 65.7±12.3 years, 69% males) of the COPPS trial, a multicentre, double-blind, randomised trial. Study patients were on sinus rhythm before starting the intervention (placebo/colchicine 1.0 mg twice daily starting on 3rd post-operative day followed by a maintenance dose of 0.5 mg twice daily for 1 month in patients ≥70 kg, and halved doses for patients <70 kg or intolerant to the highest dose). The study primary endpoint was the incidence of POAF on intervention at 1 month. Results. Baseline characteristics were well balanced between the study groups. Compared with the placebo group, patients on colchicine had a reduced incidence of POAF: respectively 12.0% vs. 22.0%; p=0.021 (RRR 45%; NNT 11) with a shorter duration (respectively 3.0±1.2 days vs.7.7±2.5 days; p<0.001). Moreover patients treated with colchicine had a shorter in-hospital stay (9.4±3.7 vs. 10.3±4.3 days; p=0.040), and rehabilitation stay (12.1±6.1 vs. 13.9±6.5 days; p=0.009). Side effects were similar in the study groups. Conclusions. Colchicine seems safe and efficacious in the reduction of POAF with the potentiality of halving the complication and reducing the hospital stay. ClinicalTrials.gov number. NCT00128427.
Author Disclosures: M. Imazio: None. A. Brucato: None. P. Ferrazzi: None. M. Rovere: None. A. Gandino: None. R. Cemin: None. S. Ferrua: None. R. Belli: None. R. Trinchero: None. D.H. Spodick: None. Y. Adler: None.
ELEVATE-TIMI 56: Escalating Clopidogrel by Involving a Genetic Strategy-TIMI 56
Jessica L Mega1, Willibald Hochholzer2, Andrew L Frelinger III3, Michael J Kluk1, Steven Isserman4, William J Rogers5, Dominick J Angiolillo6, Dean J Kereiakes7, Christian T Ruff1, David D Berg1, John Cyr1, Benjamin M Scirica1, Laura Grip1, Robert A Mesa1, John F Mattimore1, Janina A Longtine1, Alan D Michelson3, Marc S Sabatine11Brigham and Women's Hosp, Boston, MA, 2Herz-Zentrum Bad Krozigen, Bad Krozingen, Germany 3Children's Hosp Boston, Boston, MA, 4Clinical Trials of America, Hickory, NC, 5Univ of Alabama at Birmingham Med Cntr, Birmingham, AL, 6Univ of Florida College of Medicine, Jacksonville, FL, 7The Christ Hosp Heart & Vascular Cntr / The Lindner Rsch Cntr, Cincinnati, OH
Background: Variants in the CYP2C19 gene influence the response to clopidogrel. The FDA label suggests using alternative treatment strategies in patients with particular CYP2C19 genotypes. However, specific data to base such recommendations are lacking. Methods and Results: ELEVATE-TIMI 56 (clinicaltrials.gov NCT01235351) is a multicenter, randomized, double-blind trial designed to test if higher maintenance doses of clopidogrel (up to 300 mg daily, IND107635, Fig) can overcome diminished platelet inhibition due to reduced-function CYP2C19 genotypes. From 32 sites, 335 pts with CAD were enrolled and underwent rapid turn-around genotyping for the major reduced-function CYP2C19 allele (CYP2C19*2). Genotype results were: non-carriers 247/333 (74%); carriers of one *2 allele 80/333 (24%); carriers of two *2 alleles 6/333 (2%). Carriers of CYP2C19*2 received: 75, 150, 225, and 300 mg daily of clopidogrel (in various 2 wk sequences) whereas non-carriers received 75 and 150 mg (in various 2 wk sequences). At visit 1 and every 2 wks, pts had platelet function testing (by VASP & VerifyNow) and review of clinical events. Enrollment is complete and follow-up is underway. Data will be available in Nov 2011 to address these hypotheses: (1) subjects who carry a reduced-function CYP2C19 allele will have improvement in platelet inhibition with higher maintenance doses of clopidogrel and (2) higher maintenance doses of clopidogrel in carriers of a reduced-function CYP2C19 allele will result in similar platelet inhibition as compared to a standard maintenance dose of clopidogrel in non-carriers. Cardiovascular and bleeding events will also be reported. Conclusion: ELEVATE-TIMI 56 tests if higher maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele and thus will provide data to help determine how to best tailor clopidogrel dosing in patients with reduced-function CYP2C19 genotypes.
Author Disclosures: J.L. Mega: Research Grant; Significant; Bristol Myers Squibb / Sanofi Aventis, Eli Lilly, Daiichi Sankyo, Johnson & Johnson / Bayer. Other Research Support; Significant; Nanophere, Accumetrics. Consultant/Advisory Board; Modest; Bristol Myers Squibb, Sanofi Aventis, AstraZeneca. W. Hochholzer: Consultant/Advisory Board; Modest; Sanofi-Aventis. A.L. Frelinger III: Research Grant; Significant; Eli Lilly, Daiichi Sankyo, GL Synthesis, Takeda. Consultant/Advisory Board; Modest; Eli Lilly. M.J. Kluk: None. S. Isserman: None. W.J. Rogers: Research Grant; Significant; Eli Lilly. Speaker's Bureau; Modest; Eli Lilly / Daiichi Sankyo. D.J. Angiolillo: Research Grant; Significant; Eli Lilly, Daiichi Sankyo, The Medicines Company, Portola, Accumetrics, Schering-Plough, AstraZeneca, Eisai, Johnson & Johnson, Bristol Myers Squibb/Sanofi-Aventis. Other Research Support; Significant; James and Esther King Biomedical Research Grant. Speaker's Bureau; Significant; Bristol Myers Squibb/Sanofi-Aventis, Eli Lilly, Daiichi Sankyo. Consultant/Advisory Board; Modest; The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, Evolva. Consultant/Advisory Board; Significant; Bristol Myers Squibb/Sanofi-Aventis, Eli Lilly/Daiichi Sankyo, AstraZeneca. D.J. Kereiakes: Research Grant; Modest; Boston Scientific, Cordis Corporation, Medronic, Abbott Vascular. Speaker's Bureau; Modest; Abbott Vascular. Speaker's Bureau; Significant; Boston Scientific. Consultant/Advisory Board; Modest; Abbott Vascular. Consultant/Advisory Board; Significant; Boston Scientific. C.T. Ruff: Research Grant; Significant; Bristol Myers Squibb / Sanofi Aventis. D.D. Berg: None. J. Cyr: Ownership Interest; Significant; Johnson & Johnson, Boston Scientific. B.M. Scirica: Research Grant; Significant; AstraZeneca, Bristol Myers Squibb, Merck, Johnson & Johnson, Bayer Healthcare, Gilead, Daiichi Sankyo. Consultant/Advisory Board; Modest; Gilead, Arena Pharmaceuticals. L. Grip: None. R.A. Mesa: None. J.F. Mattimore: None. J.A. Longtine: None. A.D. Michelson: Research Grant; Significant; Eli Lilly, Daiichi Sankyo, GL Synthesis, Takeda. Consultant/Advisory Board; Modest; Eli Lilly. M.S. Sabatine: Research Grant; Significant; AstraZeneca, Bristol Myers Squibb / Sanofi Aventis, Daiichi Sankyo, Sanofi Aventis. Other Research Support; Significant; Nanosphere. Consultant/Advisory Board; Modest; Bristol Myers Squibb / Sanofi Aventis, Daiichi Sankyo / Eli Lilly. Consultant/Advisory Board; Significant; Sanofi Aventis.
Session Title: Clinical Science: Special Reports I
Results From LateTIME: A Randomized, Placebo Controlled Trial of Intracoronary Stem Cell Delivery Two to Three Weeks Following Acute Myocardial Infarction
Jay H Traverse1, Timothy D Henry1, Stephen G Ellis2, Carl J Pepine3, James T Willerson4, David X Zhao5, Lara M Simpson6, Emerson C Perin4, Marc S Penn2, Kenneth W Baran7, Jeffrey Chambers8, Charles Lambert9, Ganesh Raveendran10, Daniel I Simon11, Adrian P Gee12, John R Forder13, Doris A Taylor14, Christopher R Cogle3, Rachel E Olson1, Beth C Jorgenson1, Deirdre X Smith4, Carrie Geither2, Sonia I Skarlatos15, Lemuel A Moyé6, Robert D Simari161Minneapolis Heart Institute at Abbott Northwestern Hosp, Minneapolis, MN, 2The Cleveland Clinic Foundation, Cleveland, OH, 3Univ of Florida Sch of Medicine, Gainesville, FL, 4Texas Heart Institute, Houston, TX, 5Vanderbilt Univ Sch of Medicine, Nashville, TN, 6Univ of Texas Sch of Public Health, Houston, TX, 7St. Paul Heart Clinic United Hosp, St. Paul, MN, 8Metro Cardiology Mercy Hosp, Coon Rapids, MN, 9Pepin Heart Hosp and Patel Res Institute, Tampa, FL, 10Univ of Minnesota, Minneapolis, MN, 11Univ Hosp Case Med Cntr, Cleveland, OH, 12Baylor Univ Sch of Medicine, Houston, TX, 13Univ of Florida Sch of Medicine, Gainsville, FL, 14Univ of Minnesota Sch of Medicine, Minneapolis, MN, 15National Heart, Lung and Blood Institute, Bethesda, MD, 16Mayo Clinic, Rochester, MN,
Background: Results from clinical trials suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, it is not known if cell delivery is effective when delayed 2–3 weeks post-MI to allow for broader inclusion of subjects who lack clinical stability or present outside a clinical trial center. Additionally, it is not known if changes in the myocardium or bone marrow will alter the homing and engraftment of BMCs when delivered several weeks post-MI. Methods and Results: LateTIME is a randomized, double-blind, placebo-controlled trial of the Cardiovascular Cell Therapy Research Network (CCTRN) developed to investigate safety and therapeutic efficacy of intracoronary autologous BMCs delivered 2–3 weeks following successful primary PCI with stenting in patients with significant post-MI LV dysfunction (LVEF < 45%). All patients underwent bone marrow aspiration and isolation of BMCs using a local distributed, standardized automated system (Sepax device, Biosafe SA, Geneva, Switzerland) under rigid quality control followed by intracoronary infusion of 150 million BMCs or cell-free solution (2:1 BMC:Placebo) within 12 hours of bone marrow harvest in a blinded fashion. In addition to safety, the co-primary endpoints were changes in global and regional LV function at 6 months as assessed by cardiac MRI. A total of 87 patients (72 M, 15 F) 57 ± 11 years old, were randomized at 5 CCTRN sites and their satellites between July 2008 and February 2011. After 6 months of follow-up, the change in LVEF between the BMC group (48.7 ± 12% to 49.2 ± 13%) and the placebo group (45.3 ± 9.9 % to 48.8 ± 7.8 %) was not different. No treatment effect on regional LV function was observed in the infarct or border zone and there was no significant change in LV volumes. Infarct volume decreased by a similar amount in both groups at 6 months. Conclusion: Harvesting and intracoronary infusion of autologous BMCs can be safely performed 2–3 weeks following primary PCI. However, this strategy did not result in improvement in global or regional LV function at 6 months. ClinicalTrials.gov Number, NCT00684060.
Author Disclosures: J.H. Traverse: None. T.D. Henry: None. S.G. Ellis: None. C.J. Pepine: None. J.T. Willerson: None. D.X. Zhao: None. L.M. Simpson: None. E.C. Perin: None. M.S. Penn: None. K.W. Baran: None. J. Chambers: None. C. Lambert: None. G. Raveendran: None. D.I. Simon: None. A.P. Gee: None. J.R. Forder: None. D.A. Taylor: None. C.R. Cogle: None. R.E. Olson: None. B.C. Jorgenson: None. D.X. Smith: None. C. Geither: None. S.I. Skarlatos: None. L.A. Moyé: None. R.D. Simari: None.
A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients with Ischemic and Nonischemic Heart Failure
Emerson C Perin1, Nabil Dib2, Anthony DeMaria3, Oscar C Marroquin4, Paul P Huang5, Jay H Traverse6, Guilherme V Silva1, Henry Krum7, Donna Skerrett8, Susan C Jagger6, Nicole Taylor1, Kendra Bartels2, Ann Campbell9, James T Willerson10, Silviu Itescu8, Timothy D Henry6 1Texas Heart Institute, Houston, TX, 2Catholic Healthcare West, Gilbert, AZ, 3Univ of California, San Diego, San Diego, CA, 4Univ of Pittsburgh, Pittsburgh, PA, 5New York Univ Langone Med Cntr, New York, NY, 6Minneapolis Heart Institute Foundation, Minneapolis, MN, 7Monash Univ, Melbourne, Australia 8Mesoblast Limited, Melbourne, Australia 9Mercy Gilbert Med Cntr, Gilbert, AZ, 10Texas Heart Institute at St. Luke's Episcopal Hosp, Houston, TX,
Background: Immunoselected, cultured mesenchymal precursor cells (MPCs) have been shown to induce cardiac arteriogenesis, reduce cardiac fibrosis, and prevent remodeling in preclinical models of heart failure (HF). This study describes preliminary results of the first use of allogeneic MPCs (Mesoblast, Melbourne, AU) in patients with HF. Methods: In a phase II, controlled, randomized (3:1), single-blind, multicenter trial, 3 escalating doses (25, 75, and 150 million) of MPCs were evaluated in a study of 60 patients with ischemic (n=46) or nonischemic HF. Patients had NYHA class II-IV and an ejection fraction (EF) <40%. MPCs from a single healthy donor were delivered into viable myocardium in 45 patients via NOGA-guided transendocardial injections; 15 control patients underwent mock injections. Primary endpoints were procedure tolerance, feasibility, and safety. Secondary efficacy endpoints were major adverse cardiac events (MACE), hospitalizations, NYHA class, perfusion (SPECT), and EF (echo). Results: Procedures were well tolerated; no cell-related adverse events occurred. Donor specific antibody response occurred in 6/45 (13.3%) of the MPC-treated patients. Compared with control, MPC treatment reduced the overall risk of MACE by 78% (P=0.011), cardiac mortality by 89% (P=0.05), and HF hospitalization by 43%. At 12 months, 40% of MPC-treated patients reverted to NYHA class I status compared with only 14% of controls. From baseline to 6 months, overall perfusion by SPECT (Stress Total Severity Score) showed no improvement in MPC-treated patients (mean 1033 to 1017). However, in the 75 million dose group the improvement was significant within the group (1236 to 1127, P=0.019) and when compared to controls (mean change (-)81 vs 58, P=0.038). EF from baseline to 12 months did not change in MPC-treated patients (mean, 30 to 31%) nor in controls (mean, 32 to 31%), but in the 75 million dose group there was significant improvement in EF (mean, 30 to 32%, P=0.038). Conclusions: Allogeneic MPC treatment of patients with HF was safe and well tolerated. MPC treatment may provide significant reduction in MACE events. Interestingly, the 75 million MPC dose group showed improved EF and reduced myocardial ischemia.
Author Disclosures: E.C. Perin: None. N. Dib: None. A. DeMaria: None. O.C. Marroquin: None. P.P. Huang: None. J.H. Traverse: None. G.V. Silva: None. H. Krum: None. D. Skerrett: Employment; Significant; Employee. S.C. Jagger: None. N. Taylor: None. K. Bartels: None. A. Campbell: None. J.T. Willerson: None. S. Itescu: Employment; Significant; Employee. T.D. Henry: None.
Cardiac Extracorporal Shock Wave Application to Enhance the Efficiency of Intracoronary Cell Therapy in Chronic Heart Failure - Results of the Randomized, Double-Blind, Placebo-Controlled CELLWAVE Trial
Birgit Assmus1, Dirk H Walter1, Florian H Seeger1, David M Leistner1, Andreas Lutz2, Walaa Khaled2, Stefanie Dimmeler1, Andreas M Zeiher1 1J. W. Goethe Univ, Frankfurt, Germany 2Dornier Med Tech Systems GmbH, 82234 Wessling, Germany
Initial clinical studies have demonstrated that intracoronary administration of autologous bone marrow-derived mononuclear cells (BMC) may improve left ventricular contractile function (LVEF) in patients with chronic post-infarction heart failure (CHF), although to a rather limited extent. The lack of a more pronounced effect has been attributed to impaired recruitment and homing of the applied cells to the remodelled heart in these patients. Extracorporal shockwave (SW) treatment was experimentally shown to increase the expression of homing factors like SDF-1 in the target tissue, resulting in enhanced homing and neovascularization following application of BMC. Therefore, we performed the randomized, double-blind, Placebo-controlled CELLWAVE trial, designed to demonstrate improved recovery of LVEF by combining targeted SW application with subsequent BMC application in patients with CHF. Methods: A total of 100 patients with stable CHF (NYHA class 2.3±0.6), at least 3 months old previous anterior myocardial infarction (time from last AMI 5.7±6.1 years) and an open infarct-related artery were randomized to receive echo-guided low-dose (0.014mJ/mm²; n=40), high-dose (0.051mJ/mm², n=40) or Placebo (n=20) SW (Biotripter, Dornier) targeted to the LV anterior wall 24 hours prior to cell administration. Then, patients with SW pretreatment were further randomized (1:1; double-blind) to either intracoronary administration of autologous BMC or cell-free medium (Placebo), whereas patients with Placebo-SW pretreatment received intracoronary BMC application. Main exclusion criteria were the presence of LV thrombus and poor ultrasound access to the heart. The primary efficacy endpoint is absolute change in global LVEF at 4 months. Secondary endpoints include changes in NYHA class, LV volumes and regional LV function, as well as NT-proBNP serum levels. Safety endpoints comprise tolerance of SW application, absence of ventricular arrhythmias and troponin T increase after SW treatment and MACE during follow-up. Conclusion: 4-month follow-up will be completed for all patients in September 2011.The results of this first recruitment-enhancing phase II cell therapy trial in patients with CHF will be reported (clinicaltrials.gov: NCT00326989).
Author Disclosures: B. Assmus: None. D.H. Walter: None. F.H. Seeger: None. D.M. Leistner: None. A. Lutz: Employment; Modest; Dornier Med Tech. W. Khaled: Employment; Modest; Dornier Med Tech. S. Dimmeler: Consultant/Advisory Board; Modest; t2cure. A.M. Zeiher: Consultant/Advisory Board; Modest; t2cure.
The CADUCEUS (CArdiosphere-Derived aUtologous Stem CElls to Reverse ventricUlar dySfunction) Trial
Rajendra Makkar1, Rachel R Smith1, Ke Cheng1, Konstantinos Malliaras1, Linda Marban1, Louise Thomson1, Daniel Berman1, Lawrence Czer1, Adam Mendizabal2, Peter V Johnston3, Stuart Russell3, Karl Schuleri3, Al Lardo3, Gary Gerstenblith3, Eduardo Marban1 1Cedars Sinai Heart Institute, Los Angeles, CA, 2The EMMES Corp, Rockville, MD, 3Johns Hopkins, Baltimore, MD,
CADUCEUS is a randomized controlled prospective two-center first-in-human trial of autologous cardiosphere-derived cells (CDCs) in subjects with LV dysfunction (EF 25–45%) 2–3 months post-MI. The goals were (1) to demonstrate safety of tissue harvesting by endomyocardial biopsy followed by infusion of CDCs into the infarct-related artery, and (2) to assess regenerative efficacy by MRI at 6 and 12 months. Qualifying subjects, randomized to control (conventional therapy, n=10), 12.5M CDCs (low dose, n=4) or 25M CDCs (high dose, n=12), had baseline mean EF = 38% and mean scar size = 24% of LV mass. There were no complications from the biopsy or from the infusion of CDCs. Independent data analysis of safety endpoints, including arrhythmia, showed equivalence among groups at an average follow-up from randomization of >13 months. Blinded analysis of MRI efficacy data revealed major reductions of scar mass in CDC-treated subjects, but not controls, at 6 and 12 months post-infusion (Fig., panel A). When expressed as % of LV mass, scar size shrinks markedly (by 30%–47%) in CDC-treated subjects, but not controls; the reductions in scar size are much greater than reported with bone marrow mononuclear or mesenchymal cells. An expectation of true regeneration is that viable myocardium should increase as scar shrinks. Indeed, viable LV mass goes up in CDC-treated subjects but not controls (Fig., panel B), and the correlation between scar shrinkage and increased viability is striking (r=-0.59, p<0.001). This stringent test of genuine regeneration has not been satisfied by any other therapeutic modality. Significant increases in regional function were seen in CDC-treated subjects relative to controls, along with trends for increased EF and reductions in end-diastolic and end-systolic volumes. These proof-of-concept data demonstrate the safety and efficacy of intracoronary CDCs in regenerating infarcted myocardium. Funded by NHLBI.
Author Disclosures: R. Makkar: None. R.R. Smith: Other; Significant; Capricor. K. Cheng: None. K. Malliaras: None. L. Marban: Employment; Significant; Capricor, Inc. Ownership Interest; Significant; Capricor, Inc.. L. Thomson: None. D. Berman: None. L. Czer: None. A. Mendizabal: None. P.V. Johnston: None. S. Russell: None. K. Schuleri: None. A. Lardo: None. G. Gerstenblith: None. E. Marban: Ownership Interest; Significant; Capricor. Consultant/Advisory Board; Modest; Capricor.
Session Title: Clinical Science: Special Reports II
ABSORB Cohort B Trial: Two Year OCT Results of the ABSORB Bioresorbable Everolimus Eluting Vascular Scaffold
Robert-Jan van Geuns1, Patrick W Serruys1, John Ormiston2 1Thoraxcenter, Rotterdam, Netherlands 2Auckland City Hosp, Auckland, New Zealand
Background: Optical Coherence Tomography (OCT) is a high resolution imaging technique capable of accurate assessment of the polymeric struts, changes in luminal and scaffold dimensions, and quantification of neointimal hyperplasia. Our aim is to assess neointimal response and qualitative changes in strut appearance of the ABSORB bioresorbable everolimus eluting vascular scaffold (Abbott Vascular, Santa Clara, CA, USA) designed to biodegrade in approximately 2 years. Methods: The ABSORB Cohort B trial enrolled 101 patients at 12 sites in the European and Asia Pacific regions in 2009. The patients were divided into Group B1 (45 patients) with imaging follow-up at 6 months and 2 years and Group B2 (56 patients) with imaging follow-up at 1 and 3 years. Results: OCT imaging data at 6 months for Group 1 and at 1 year for Group 2 are currently available. The ABSORB scaffold presents important differences from metallic stents when imaged by OCT. The optically translucent polymeric struts appear as a black central core framed by light-scattering borders that do not shadow the vessel wall and allow complete imaging of the strut thickness and neointimal coverage and the vessel behind the struts. For the Group B1 patients, there was no significant change in mean scaffold area between post procedure and 6 months. The mean luminal area decreased slightly between post procedure and 6 months. For the Group B2 patients, there was no significant change in the mean scaffold area between post procedure and 1 year despite early optical signs of bioresorbtion. At one year, 97% of the struts appeared covered but are still visible. Conclusion: 1-year OCT results from ABSORB Cohort B2 showed that there was no scaffold area reduction, well controlled inhibition of neointima, and almost complete coverage of the struts. The 2-year OCT follow-up of the 45 patients in ABSORB Cohort B1 are currently on going and the results will be presented to confirm bioresorbtion and continued neointimal inhibition.
Author Disclosures: R. van Geuns: None. P.W. Serruys: None. J. Ormiston: None.
2011 Late-Breaking ReSS Abstracts
Session Title: Late-Breaking Abstracts in Resuscitation Science and Challenges in Resuscitation Clinical Practice
Comparison of Survival to Hospital Discharge between Integrated AutoPulse-CPR and Manual-CPR during out-of-hospital cardiac arrest of presumed cardiac origin: The Circulation Improving Resuscitation Care (CIRC) Trial
Lars Wik1, Jan-Aage Olsen1, David Persse2, Fritz Sterz3, Michael Lozano, Jr4, Marc A Brouwer5, Mark Westfall6, Chris M Souders2, Reinhard Malzer7, Pierre M van Grunsven8, David Travis9, Anne Whitehead10, Ulrich R Herken11, E Brooke Lerner12 1National Competence Cntr of Emergency Medicine, Oslo Univ Hosp, Oslo, Norway 2Houston Fire Dept and the Baylor College of Medicine, Houston, TX, 3Dept of Emergency Medicine, Med Univ of Vienna, Vienna, Austria 4Dept of Emergency Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 5Heart Lung Cntr, Dept of Cardiology, Radboud Univ Med Cntr, Nijmegen, Netherlands 6Theda Clark Regional Med Cntr, Neenah, WI, 7Vienna City Administration, Municipal Dept 70, Emergency Med Services, Vienna, Austria 8Regional Ambulance Service Gelderland-Zuid, Nijmegen, Netherlands 9Hillsborough County Fire Rescue, Tampa, FL, 10Med & Pharmaceutical Statistics Rsch Unit, Dept of Mathematics and Statistics, Fylde College, Lancaster Univ, Lancaster, United Kingdom 11ZOLL Med Corp, Chelmsford, MA, 12Med College of Wisconsin, Milwaukee, WI
Background: Quality of chest compressions affects survival from cardiac arrest and mechanical devices may facilitate maintaining high-quality compressions. We compared integrated AutoPulse CPR (iA-CPR) with high-quality manual CPR (M-CPR) to determine equivalence or superiority of either treatment. Methods: A randomized controlled trial of EMS treated adult out-of-hospital cardiac arrests of presumed cardiac origin was conducted at 3 US and 2 European sites between March 2009 and January 2011. Systematic study-wide training and monitoring of CPR quality was implemented. When CPR was indicated, EMS responders initiated manual compressions and then patients were randomized to receive immediate iA-CPR or continued M-CPR. The primary outcome was survival to hospital discharge. Secondary outcomes were return of spontaneous circulation (ROSC), 24-hour survival, and modified Rankin Score (mRS) ≤3 at discharge. The Group Sequential Double Triangular Test was used to analyze covariate adjusted survival data at predefined intervals to identify superiority - a log odds ratio (log OR) of 0.37 (OR 1.44) with a two-sided significance level of 5% and a power of 97.5% - or equivalence, defined as the 95% confidence interval (CI) for the log OR fully lying between −0.37 and 0.37. Results: Of 4,559 eligible patients, 328 (7%) were not enrolled. 2,099 subjects received iA-CPR (49.6%) and 2,132 M-CPR (50.4%). Discharge status was unknown for 12 cases. After adjustment for enrollment site, age, witnessed arrest, and initial cardiac rhythm, survival was statistically equivalent for iA-CPR compared to M-CPR (adjusted OR 1.061, 95% CI 0.829 - 1.365). The 95% CI for the log OR (-0.188 to 0.311) was fully within the equivalence boundaries. There was no significant difference in discharge mRS ≤3 (adjusted OR 0.843, 95% CI 0.618 - 1.149). Unadjusted values for iA- and M-CPR were: survival to hospital discharge 9.4% vs. 11.0%, ROSC 28.6% vs. 32.3%, 24-hour survival 21.8% vs. 25.1%, median mRS 2 vs. 2, and hands-off fraction 19.6% vs. 20.2%, respectively. Conclusion: Compared to high-quality M-CPR, iA-CPR resulted in statistically equivalent survival to hospital discharge and no difference in neurologic status at discharge in adults with out-of-hospital cardiac arrest.
Author Disclosures: L. Wik: Research Grant; Modest; ZOLL. J. Olsen: Research Grant; Significant; ZOLL. D. Persse: Research Grant; Modest; ZOLL. F. Sterz: Research Grant; Modest; ZOLL. M. Lozano: Research Grant; Modest; ZOLL. M.A. Brouwer: Research Grant; Modest; ZOLL. M. Westfall: Research Grant; Modest; ZOLL. C.M. Souders: Research Grant; Modest; ZOLL. R. Malzer: Research Grant; Modest; ZOLL. P.M. van Grunsven: Research Grant; Modest; ZOLL. D. Travis: Research Grant; Modest; ZOLL. A. Whitehead: Research Grant; Modest; ZOLL. U.R. Herken: Employment; Significant; ZOLL. E. Lerner: Research Grant; Significant; ZOLL.
Emergency Physician Initiated ECMO: Our Experience
Zachary Shinar1, Joseph Bellezzo21Emergency Medicine, Sharp Memorial Hosp, San Diego, CA, 2Sharp Memorial Hosp, San Diego, CA
Background: Many studies worldwide document the use of Extracorporeal Membrane Oxygenation (ECMO) in the resuscitation of arresting adult patients. Most of these studies focus on in-hospital arrests where cardiothoracic (CT) surgeons insert femoral venoarterial bypass catheters. Arresting patients often present to the emergency department (ED) when CT surgeons are not readily available. At our institution, emergency physicians (EP) initiate ECMO in the ED for patients who have failed traditional Advanced Cardiac Life Support (ACLS). EP-initiated ECMO may improve outcomes due to faster time to successful bypass. Design: This is an observational study over a 14 month period documenting our experience with EP- initiated ECMO. We implemented inclusion and exclusion criteria for which patients should be considered ECMO candidates. A three-stage protocol was developed where percutaneous arterial and venous femoral central catheters were placed in the presenting arresting patient (stage I). If the patient failed initial resuscitative efforts, these catheters were exchanged for the larger ECMO catheters (stage II). If ACLS measures continued to be unsuccessful, bypass was initiated (stage III). At our facility, EPs were electively trained in the ECMO protocol as well as the technique of catheter placement. Ongoing monthly training was held to continue physician education in this newly developed skill. Only trained physicians were allowed to initiate ECMO. Results: We recorded the outcomes of EP-initiated ECMO since our first attempt in March 2010. Over our study period, stage I was attempted on 19 patients. Of these, 2 had return of spontaneous circulation prior to bypass initiation. Four were pronounced in the ED after post-bypass asystole was recognized. Despite successful initiation of ECMO, six were pronounced dead secondary to anoxic brain injury in the hospital. Four patients were discharged from the hospital neurologically intact. Of these four, the cause of arrest was myocardial infarction (MI) (2), aortic dissection with cardiac tamponade, and profound hypothermia. One of the MI patients arrested out-of-hospital. Conclusions: Our small 14 month experience shows promise for emergency physician-initiated ECMO.
Author Disclosures: Z. Shinar: None. J. Bellezzo: None.
Real-time Calculation of System-level Complexity During Trauma/Hemorrhage: Can We Do It?
Andriy Batchinsky1, William Baker1, Claire Isbell1, Corina Necsoiu1, Kerfoot Walker1, Jacek Marczyk2, José Salinas1, Leopoldo Cancio1 1US Army Institute of Surgical Rsch, Fort Sam Houston, TX, 2Ontonix S.r.l., Como, Italy
Objectives: We previously showed that sample entropy (SampEn), and other nonlinear measures of the complexity of the ECG time series, decrease in response to hypovolemia and/or injury. These measures characterize only one signal, and thus refer to signal-level complexity. In contrast, system-level complexity quantifies the amount of interaction among the signals arising from all available sensors attached to a patient (ECG, blood pressure, oxygen saturation, etc.). We found that system-level complexity (OSC) calculated with OntoSpace software (Ontonix S.r.l., Como, Italy) fluctuates during critical events such as asphyxia. Relatedly, system robustness (OSR) represents the margin between current OSC and maximal or minimal possible OSC. OSR thus is greatest when OSC is in the middle range; it decreases when OSC approaches either extreme, where the system becomes unstable and is prone to crash. Here, we present data calculated in real time from both signal-level and system-level complexity in a model of acute respiratory distress syndrome (ARDS) due to trauma, hemorrhagic shock and resuscitation. Methods: Nine swine were anesthetized with ketamine and midazolam and underwent baseline measurements (BL), right-chest pulmonary contusion (PC), hemorrhage of 12 mL/kg (Bleed), resuscitation with lactated Ringer's (LR), transfusion of shed blood (Tx), and post-resuscitation observation (Post-Resus). Data were collected continuously and analyzed in 15-min datasets. We calculated heart rate (HR, bpm); mean arterial pressure (MAP, mmHg); PaO2-to-FiO2 ratio (PFR); ECG SampEn (unitless); ECG multiscale entropy (MSE, unitless), and percentage of normal-to-normal RRIs differing by more than 50 ms (pNN50). We calculated OSC and OSR (both unitless) from 56 different channels of single-sensor data. Results: see table. Means±SEMs are reported. Statistics: one way ANOVA with Tukey's adjustment. Conclusions: Measures of signal-level complexity like SampEn, and measures of system-level complexity like OSC, address fundamentally different characteristics of a patient's physiology. This is the first report containing data acquired in real-time and combining both approaches in a model of ARDS caused by trauma/hemorrhage. Future work will address whether this combined approach to monitoring can be used to improve outcomes in critical care by enabling earlier or more effective intervention in potentially unstable patients.
Author Disclosures: A. Batchinsky: None. W. Baker: None. C. Isbell: None. C. Necsoiu: None. K. Walker: None. J. Marczyk: Employment; Significant; Founder and owner of OntoSpace software. J. Salinas: None. L. Cancio: None.
- © 2011 American Heart Association, Inc.