slides - ClinicalWebcasts.com
Upcoming SlideShare
Loading in...5
×
 

slides - ClinicalWebcasts.com

on

  • 1,294 views

 

Statistics

Views

Total Views
1,294
Views on SlideShare
1,294
Embed Views
0

Actions

Likes
0
Downloads
88
Comments
0

0 Embeds 0

No embeds

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • The treatment of UA/NSTEMI has evolved considerably over the last decade. In the early 1990s, the “standard” of care was aspirin, unfractionated heparin, a conservative management strategy, and, if done, PCI involved primarily balloon angioplasty. Subsequently a number of management options (upper portion of the slide) as well as major trials (middle portion of the slide) have come forward. The clinical availability of GP IIb/IIIa blockers (green) in 1995, with trials such as PRISM-PLUS and PURSUIT (also in green) showing their efficacy in UA/NSTEMI patients, particularly those undergoing coronary intervention. The LMWH enoxaparin was studied in the mid-1990s in ESSENCE (in dark blue), and was released for use in unstable angina in 1997. Clopidogrel (in orange) released in 1998, was a mainstay of therapy for coronary intervention (particularly the rapidly-growing world of stents). It’s utility in UA/NSTEMI was confirmed in the large scale CURE trial. Bivalirudin also was approved (based on the REPLACE 2 trial) for use as procedural anticoagulation for PCI in about 2001. Finally, on the basis of trials such as TACTICS, the rapid invasive management strategy began to predominate, particularly in the US, in the late 1990s. Newer data (gray boxes) have come forward (the trial names are color-coded to correspond to the agent and prior trials) that need to be assimilated into modern-day practice. Trials such as SYNERGY ( enoxaparin vs UFH in high-risk ACS patients managed with a rapid invasive management strategy), OASIS 5 (fondaparinux vs enoxaparin in higher-risk ACS), ICTUS (testing a rapid invasive strategy versus a selective invasive strategy in troponin (+) patients). ISAR-REACT 2 (assessing the utility of abciximab in ACS patients already pre-loaded with high doses of clopidogrel), and ACUITY(evaluating bivalirudin in rapidly invasively managed UA/NSTEMI) are going to help define the practice standards for the future. In the bottom of the slide are schematic graphs of the general trends in bleeding and thrombotic (ischemic) events over this same period. The arrival of GP IIb/IIIa antagonists brought with it substantial increases in bleeding. Thienopyridines both reduced this rate (by substituting for IIb/IIIa antagonists in lower-risk patients) and worsened it (by further adding to the antithrombotic milieu. Enoxaparin had some issues in that it did not fit well with anticoagulation management (traditionally done with ACTs and UFH in the cath lab). The emerging early invasive strategy served to further highlight the importance of the transition to the cath lab. The arrival of bivalirudin brought with it an option for reducing the risk of bleeding complications. With time, better technologies, and better adjunctive therapies the clinical events rates have continued to fall, but this is to a large extent somewhat balanced by the emerging use of more sensitive markers for myocardial damage (such as troponin).
  • We begin with an introduction to the need for IV antihypertensive agents in the management of acute hypertension.
  • We begin with an introduction to the need for IV antihypertensive agents in the management of acute hypertension.
  • We begin with an introduction to the need for IV antihypertensive agents in the management of acute hypertension.
  • We begin with an introduction to the need for IV antihypertensive agents in the management of acute hypertension.
  • In a post hoc analysis, clinical events were significantly reduced in the fondaparinux group at long-term follow-up at 6 months. At 6 months the incidence of death was 5.8% in the fondaparinux group and 6.5% in the enoxaparin group (P=0.05); the incidence of death/MI was 10.5% in the fondaparinux group and 11.4% in the enoxaparin group (P<0.007).
  • As one focuses on the subset of patients undergoing PCI in OASIS 5 (n=6,239), there are significant reductions in major bleeding at net clinical outcome with fondaparinux, but no difference in ischemic events (and trends that slightly favor enoxaparin). It is interesting to note that the close association between bleeding and mortality that was present in the overall patient cohort is NOT present in the PCI subset.
  • This slide shows graphically the cumulative composite ischemic events out to 35 days for the three groups of patients. There were no significant differences between groups.
  • This slide shows graphically the cumulative major bleeding events out to 35 days for the three groups of patients. Major bleeding was significantly lower in the bivalirudin alone group.
  • When both ischemic endpoints and bleeding were factored together into “net clinical outcome”, the bivalirudin alone group did significantly better. This slide depicts cumulative net clinical benefit for the three groups out to 35 days.
  • Since its inception in 2001, CRUSADE has recruited from one or more hospitals in 44 states. Data from January 2006 showed that the highest regional rate of participation is on the east coast. Participation in other regions of the country varied. Midwestern states such as Ohio, Michigan, and Texas had more participating sites than northwestern and southwestern states, most likely because there are fewer facilities in these lower-population areas. California and Washington state collectively had 39 sites participating in CRUSADE, giving solid representation for the west coast.
  • The recommendation of conservative vs. invasive strategies may change based on the new data. The guidelines state either strategy is acceptable, but patients with high risk characteristics may lead to invasive therapy.
  • The recommendation of conservative vs. invasive strategies may change based on the new data. The guidelines state either strategy is acceptable, but patients with high risk characteristics may lead to invasive therapy.
  • The recommendation of conservative vs. invasive strategies may change based on the new data. The guidelines state either strategy is acceptable, but patients with high risk characteristics may lead to invasive therapy.

slides - ClinicalWebcasts.com slides - ClinicalWebcasts.com Presentation Transcript

  •  
            • E. Magnus Ohman, MD, FRCPI, FACC
            • Program Chairman
    • Professor of Medicine
    • Director, Program for Advanced Coronary Disease
    • Division of Cardiology
    • Duke University Medical Center
    • Durham, North Carolina
    Critical Challenges in Cardiovascular Medicine Translating Landmark Trials and AHA/ACC Guidelines into the Front Lines of Cardiovascular Care for Acute, Ischemic Heart Disease Getting in the ACS (Up)Stream of Things
  • CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from The Medicines Company Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview
  • Program Educational Objectives
    • As a result of this educational activity, physicians will:
            • Learn to identify signs, symptoms, and prognostic features of acute coronary syndrome (ACS) and related ischemic conditions, and their implications for invasive vascular management.
            • Learn how recently issued 2007 AHA/ACC Guidelines for UA/Non ST-Elevation Myocardial Infarction are best applied to appropriately risk-stratified patients with UA and NSTEMI.
            • Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy, in the upstream setting, for patients presenting with manifestations of UA, NSTEMI and related conditions.
            • Learn to understand the implications of recent clinical data, trials, and recommendations on switching antithrombotic therapy in patients who present with acute ischemic coronary syndromes, with an emphasis on determining when switching from one agent to another is appropriate, safe, and feasible; and, when switching among antithrombotic agents may be problematic.
  • Program Educational Objectives
    • As a result of this educational activity, physicians will:
            • Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including: Aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors.
            • Learn to understand the specific advantages and potential disadvantages of pharmacologic agents currently used to reduce ischemic and bleeding end points in the setting of cardiovascular emergencies.
            • Learn to identify the ideal properties of antithrombotic agents used in conjunction with stent insertion.
            • Learn to discuss and assess the impact that new trials and Year 2007 AHA/ACC Guidelines are likely to have on future invasive management of patients with UA and NSTEMI.
            • Learn to apply national guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with acute, ischemic heart disease.
  • Program Faculty
            • Program Chairman
            • E. Magnus Ohman, MD, FRCPI, FACC
            • Professor of Medicine
            • Director, Program for Advanced Coronary
            • Disease
            • Division of Cardiology
            • Duke University Medical Center
            • Durham, North Carolina
            • Distinguished Faculty
            • C. Michael Gibson, MS, MD
            • Director, TIMI Core Laboratories and Data Coordinating Center
            • Associate Professor
            • Harvard Medical School
            • Boston, Massachusetts
            • A. Michael Lincoff, MD
            • Vice Chairman for Research
            • Department of Cardiovascular Medicine
            • Director, Cleveland Clinic Cardiovascular
            • Coordinating Center
            • Professor of Medicine
            • Cleveland Clinic Lerner College of Medicine of
            • Case Western Reserve University
            • The Cleveland Clinic Foundation
            • Cleveland, Ohio
            • Charles V. Pollack Jr, MA, MD, FACEP, FAAEM
            • Chairman, Department of Emergency Medicine
            • Pennsylvania Hospital
            • Professor of Emergency Medicine
            • University of Pennsylvania School of Medicine
            • Philadelphia, Pennsylvania 
  • Faculty COI Disclosures   E. Magnus Ohman, MD, FRCPI, FACC Research Grants: Berlex, sanofi-aventis, Schering-Plough Corporation, Bristol Meyer Squibb, and Millennium. Stockholder: Medtronic. Consultant: Response Biomedical, Liposcience, and Inovise Medical C. Michael Gibson, MS, MD Present Research/Grant Funding: CardioKinetix, Eli Lilly, KAI Pharmaceuticals, Nuvelo, Schering Plough Corporation, Sanofi-Aventis, St. Jude Medical, Baxter, Novartis, FoldRx, INO Therapeutics, LLC Speakers Bureau: Genentech, Inc., GlaxoSmithKline, Schering Plough Corporation, The Medicines Company Consultant: Angel Medical Systems, The Medicines Company. HeartScape Technologies, Inc., Ascenta Therapeutics, Inc., Archemix Corp., PDL Pharmaceuticals, Atrium Medical Corporation, TIMI3 Systems, Biogen IDEC Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, Genentech Speaker’s Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech
    • Abraxis
    • Alexion Pharma
    • AstraZeneca
    • Atherogenics
    • Aventis
    • Biosense Webster
    • Biosite
    • Boehringer Ingelheim
    • Boston Scientific
    • Bristol-Myers Squibb (BMS)
    • Cardionet
    • Centocor
    • Converge Medical Inc.
    • Cordis
    • Dr. Reddy’s Laboratory
    • Novartis
    • Novo Nordisk
    • Orphan Therapeutics
    • P&G Pharma
    • Pfizer
    • Roche
    • Sankyo
    • Sanofi-Aventis
    • Schering-Plough
    • Scios
    • St. Jude Medical
    • Takeda
    • VasoGenix
    • Viacor
    • Edwards Lifesciences
    • Esperion
    • GE Medical
    • Genentech
    • Gilford
    • GSK
    • Guidant
    • J&J
    • Kensey-Nash
    • Lilly
    • Medicines Company
    • Medtronic
    • Merck
    • Mytogen
    • Novartis
    • Novo Nordisk
    • Orphan Therapeutics
    • P&G Pharma
    • Pfizer
    • Roche
    • Sankyo
    • Sanofi-Aventis
    • Schering-Plough
    • Scios
    • St. Jude Medical
    • Takeda
    • VasoGenix
    • Viacor
    • Novartis
    • Novo Nordisk
    • Orphan Therapeutics
    • P&G Pharma
    • Pfizer
    • Roche
    • Sankyo
    • Sanofi-Aventis
    • Schering-Plough
    • Scios
    • St. Jude Medical
    • Takeda
    • VasoGenix
    • Viacor
    A. Michael Lincoff, MD Relationships with Industry Research Sponsors C5Research Faculty COI Disclosures
            • Critical Challenges in Acute
            • Ischemic Heart Disease — Overview
            • Where Metal Meets Thrombus, Drugs, and Vascular Endothelium: A State of the “Union” Synthesis
    • E. Magnus Ohman MD, FRCPI, FACC
    • Program Chairman
    • Professor of Medicine | Director, Program for Advanced Coronary Disease | Division of Cardiology | Duke University Medical Center |
    • Durham, North Carolina
    Getting in the ACS (Up)Stream of Things
  • SYNERGY 1994 1995 1996 1997 1998 1999 2000 2002 2003 2004 2005 2006 2001 Bleeding risk Ischemic risk ACUITY ISAR-REACT 2 Milestones in ACS Management ICTUS Adapted from and with the courtesy of Steven Manoukian, MD LMWH ESSENCE CURE Clopidogrel GP IIb/IIIa blockers PRISM-PLUS PURSUIT TACTICS TIMI-18 Early invasive PCI ~ 5% stents ~85% stents Drug-eluting stents OASIS-5 [ Fondaparinux ] Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative Bivalirudin REPLACE 2
  • Major Bleeding Bhatt DL et al. In Braunwald: Harrison’s Online 2005. Possible Relationship Between Bleeding and Mortality in ACS Mortality Transfusion Hypotension Cessation of ASA/Clopidogrel Ischemia Stent Thrombosis Inflammation
            • Issues We Will Address Tonight
            • • GUIDELINES — Do we need them? If so, why? In what situations? And how do we adapt to new evidence presented after guidelines are released?
            • • UPSTREAM THERAPY— How do we identify optimal strategies?
            • • COLLABORATION —How do we facilitate collaboration among ED physicians and CV specialists?
            • • CASE STUDIES— Translating science and evidence to practice
    Getting in the ACS (Up)Stream of Things
  • THE BIG PICTURE: EARLY INVASIVE VS. INITIAL CONSERVATIVE THERAPY “ An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events .” “ In initially stabilized patients, an initially conservative (i.e., a selectively invasive) strategy may be considered as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, including those who are troponin positive .” “ The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference .” UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
  • BIG PICTURE: ANTIPLATELET AGENTS “ Support for thienopyridine use (primarily with clopidogrel) continues to grow, including higher loading-dose options, earlier (upstream) administration , and longer administration (especially after drug-eluting stent placement).” “ The question of how best to integrate thienopyridine use with parenteral glycoprotein (GP) IIb/IIIa antagonists to provide optimal antiplatelet therapy early in the course of UA/NSTEMI therapy, including cardiac catheterization, is an evolving area .” UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
  • BIG PICTURE: ANTICOAGULANTS “ Two new anticoagulants, fondaparinux and bivalirudin , have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) for specific or more general applications.” ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. UA/NSTEMI Strategy Overview
  • PIVOTAL TRIALS Snapshot of Trial Results that Supported Addition of Bivalirudin and Fondaparinux to Year 2007 AHA/ACC UA/NSTEMI Guidelines ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. UA/NSTEMI Pivotal Trials
  • OASIS-5: Efficacy at Day 9 0.8 1 1.2 Non-inferiority Margin = 1.185 Hazard Ratio Fonda Better Enox Better Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 —— %—— 5.9 5.8 Death/MI/RI 2.05 1.9 Refractory Ischemia 2.7 2.7 MI 1.8 1.9 Death 4.1 4.1 Death/MI Fonda Enox
  • OASIS-5: Bleeding Rates at Day 9 Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 < 0.0001 < 0.0001 < 0.0001 < 0.0001 P 0.35 (0.28 – 0.43) 0.54 (0.41 – 0.73) 0.53 (0.45 – 0.62) 0.44 (0.39 – 0.51) HR (95% CI) 3.2 7.0 Total Bleed (%) 1.1 3.1 Minor Bleed (%) 10,057 10,021 No. Randomized 0.7 1.3 TIMI Major Bleed (%) 2.1 4.0 Major Bleed (%) Fonda Enox Outcome
  • OASIS-5 Efficacy End Points at 6 Months Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 0.04 1.3% 1.7% Stroke 0.007 11.3% 12.5% Death/MI/stroke* NS 6.3% 6.6% MI 0.05 5.8% 6.5% Death 0.05 10.5% 11.4% Death/MI 0.06 12.3% 13.2% Death/MI/ refractory ischemia P value Fondaparinux Enoxaparin End point
  • PCI — Procedural Complications Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 <0.0001 1.6% 4.4% Large hematoma 0.39 1.0% 1.6% Pseudo-aneurysm <0.0001 3.3% 8.1% Vascular access 0.001 1.3% 0.5% Catheter thrombus 0.20 1.5% 1.1% Abrupt closure 0.18 9.6% 8.6% Any procedural complication 18.8% 53.8% Any UFH during PCI P value Fondaparinux n=3118 Enoxaparin n=3089 Events (30 Days)
  • ACUITY—Ischemic Composite Endpoint 0 5 10 15 0 5 10 15 20 25 30 35 Cumulative Events (%) Days from Randomization Estimate P (log rank) 7.3% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.37 7.7% Bivalirudin alone (N=4612) 0.30 7.8% Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16.
  • ACUITY—Major Bleeding Endpoint Cumulative Events (%) Days from Randomization Estimate P (log rank) Bivalirudin + IIb/IIIa (N=4604) 0.41 5.3% Bivalirudin alone (N=4612 ) <0.0001 3.0% Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16. 0 5 10 15 0 5 10 15 20 25 30 35 5.7% UFH/Enoxaparin + IIb/IIIa (N=4603)
  • ACUITY — Net Clinical Outcome 0 5 10 15 0 5 10 15 20 25 30 35 Cumulative Events (%) Days from Randomization Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16. Estimate P (log rank) 11.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.89 11.8% Bivalirudin alone (N=4612) 0.014 10.1%
  • ACUITY Mortality at One Year 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 4 5 Mortality (%) Days from Randomization 2 1 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) 30 day 3 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) Stone GW, ACC 2007 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 1.4% 0.53 1.6% 0.39 1.6% — Estimate P (log rank) 4.4% 0.93 4.2% 0.66 3.8% 1 year — p=0.90
  • Addressing the Challenge of Selecting an Anticoagulation Strategy Bleeding Risk Ischemic Risk Renal function Age Time to cath Cost Ease of use PCI vs CABG vs Med Rx
  • Sea and Stream Changes in ACS
    • The 2007 Guidelines have created a “Sea Change” in the care of patients with UA/NSTEMI
      • New “Streams” of care, with new anticoagulants, are in play
      • Clopidogrel use has been liberalized
      • Bleeding end points play a more important role in drug selection
      • Dogmatism is out, customization is in
      • Collaboration is emphasized
    • C. Michael Gibson, M.S., M.D., FACC
            • Director, TIMI Core Laboratories and Data Coordinating Center
            • Associate Professor, Harvard Medical School
            • Boston, Massachusetts
    Getting in the Stream(s) of Antithrombotic Therapy for ACS: What Do The Trials Tell Us? To Switch or Not to Switch — If, When, How, To What? Getting in the ACS Stream of Things
  • Overview of Presentation
    • Mechanistic rational for switching
    • Why is there a concern about switching antithrombins in patients with ACS (lessons from SYNERGY)
    • Why should switching to bivalirudin for PCI be reasonable?
    • Clinical evidence in support of switching
      • SWITCH
      • REPLACE 2
      • ACUITY
  • Background — Issues and Concerns
    • ACS patients
      • 87% of patients receive either UFH, enoxaparin, or fondaparinux within 24 hours after admission 1
      • 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3
    • Published studies and perceptions
      • Patients in SYNERGY who crossed over between UFH and enoxaparin had an increase in bleeding complications 2
        • This activity occurred at various times through the study period: At times in response to clinical or clinician perception
      • Consistent therapy is better 4
    1 CRUSADE( 1Q-2006 results); 2 SYNERGY results; JAMA 2004; 3 OASIS -5; Yusuf et al,NEJM 2006; 4 Cohen et al, JACC 2006.
  • Bivalirudin: A Guidelines-Supported Alternative to UFH/LMWH in ACS
    • Advantages of the direct thrombin inhibitor bivalirudin
      • No requirement for antithrombin III
      • Effective on clot-bound thrombin
      • Inhibits thrombin-mediated platelet activation
      • No interactions with PF- 4
      • Plasma half-life 25 minutes
      • No requirement for anticoagulant monitoring
    • Clinical results with bivalirudin in PCI
      • Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1
    • Not previously tested in contemporary ACS patients
    REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.
  • Switching Antithrombins: SYNERGY
    • The SYNERGY trial suggested a switch in anthithrombins (from heparin to LMWH) can lead to increase in bleeding.
    • What outcomes are observed when switching from heparin, LMWH, or fondaparinux to bivalirudin in PCI?
    • Is it better to switch or to stay on consistent therapy?
  • Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes Without ST-segment Elevation Undergoing Percutaneous Coronary Intervention (PCI) Ron Waksman, MD, FACC, FSCAI Associate Director Division of Cardiology Washington Hospital Center Washington, DC The study was sponsored in part by The Medicines Company The SWITCH Study
  • SWITCH: Study Design 31 30 30 Primary Endpoint — BLEEDING 91 ACS patients undergoing PCI (3 US sites) Open-label, prospective, 3-arm study LMWH 1mg/kg SC 0-4 h before PCI LMWH 1mg/kg SC 4-8 h before PCI LMWH 1mg/kg SC 8-12 h before PCI Bivalirudin during PCI 0.75 mg/kg bolus 1.75 mg/kg/h IV infusion Arms Switched Waksman J Invasive Cardiol 2006;18:370-375.
  • Results: Study Drug-Related Bleeding Events All, % N=91 Group 1,% n=30 Group 2,% N=30 Group 3,% N=31 p value All Major Bleed 7.7 (7) 13.3 (4) 3.2 (1) 6.5 (2) 0.39 Transfusion ≥2 units 4.4 (4) 3.2 (1) 3.2 (1) 6.5 (2) 1.0 Intracranial Bleed 0 (0) 0 (0) 0 (0) 0 (0) -- Retroperitoneal Bleed 0 (0) 0 (0) 0 (0) 0 (0) -- Spontaneous Hematuria or Hematemesis 1.1 (1) 3.2 (1) 0 (0) 0 (0) 0.66 Drop in Hg > 4g/dL, no site 2.2 (2) 6.7 (2) 0 (0) 0 (0) 0.21 Drop in Hg ≥ 3 g/dL 0 (0) 0 (0) 0 (0) 0 (0) -- All Transfusions 4.4 (4) 6.7 (2) 0 (0) 6.5 (2) 1.0 Minor Bleed 4.4 (4) 6.7 (2) 6.7 (2) 0 (0) 0.39
  • SWITCH: Conclusions
    • Switching from LMWH to bivalirudin during PCI for patients with ACS was safe
    • Switching was not associated with major bleeding complications regardless of when LMWH was administered
    • The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours post the last dose of LMWH
  • Association of Pre-Randomization Anticoagulant Switching with Bleeding in the Setting of Percutaneous Coronary Intervention: A REPLACE-2 Analysis
    • The goal of this analysis was to evaluate whether a hazard existed when either UFH or LMWH were administered prior to study medication in the REPLACE-2 trial
    C. Michael Gibson, Yuli Ten, Sabina A. Murphy, Lauren N. Ciaglo, Matthew C. Southard, A. Michael Lincoff, and Ron Waksman Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90. REPLACE-2 Trial: Impact of Antithrombin Switching
  • Pre-Randomization Anticoagulant Switching and Bleeding
    • The present study compared bleeding among patients treated either with preceding antithrombin therapy or no preceding antithrombin therapy in the prior 48 hours.
    Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90.
    • The method of switching or transition involved administration of bivalirudin as follows:
    • >8 hours after last low molecular weight heparin
    • (LMWH) dose
    • OR
    • > 6 hours after unfractionated heparin, unless in the case of UFH therapy the activated partial thromboplastin time was ≤ 50 seconds or the activated clotting time was ≤ 175 seconds
    Pre-Randomization Anticoagulant Switching and Bleeding Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90.
  • Bleeding and Switching in REPLACE-2 * p=NS for all 3-way comparisons vs BIV alone ** p<0.05 for 3-way comparison vs glycoprotein IIbIIIa (GP IIbIIIa), unfractionated heparin (UFH) naïve as well as 2-way comparisons of unfractionated heparin (UFH) naïve vs either preceding unfractionated heparin (UFH) or preceding low molecular weight heparin (LMWH) Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90. Variable Naive-> BIV* (n=2,345) UFH-> BIV (n=287) LMWH-> BIV (n=258) Naive-> GP IIbIIIa /UFH (n=2,325) UFH-> GP IIbIIIa/UFH (n=349) LMWH-> GP IIbIIIa/UFH (n=313) Protocol Major Bleed 2.3%* 1.7% 2.7% 3.6% 4.9% 5.8% Protocol Minor Bleed 13.4%* 13.6% 14.0% 25.0% 28.9% 29.1% Protocol Major/Minor Bleed 15.6%* 15.3% 16.7% 28.6%** 33.8% 34.8% TIMI Major/Minor Bleed 1.9%* 1.4% 1.9% 3.5% 4.3% 5.4% ≥ 2 Non-CABG Transfusions 0.8%* 1.1% 1.2% 1.0%** 2.3% 2.9%
  • Time from Last Dose of LMWH to PCI in Bivalirudin Patients by Presence of Protocol Major/Minor Bleed Time to PCI (hours) NO BLEED Median = 18 hrs IQ 14.5 – 24 hrs N=228 BLEED Median = 18.5 hrs IQ 12.6 – 24.5 N=51 p = 0.91 Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90.
  • Switching and One Year Mortality Cumulative events (mortality), % REPLACE-2 Subanalysis: 1-Year Mortality Results Consistent with Overall Trial Results Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90.
  • Pre-Randomization Anticoagulant Switching and Bleeding
    • When switching to bivalirudin was undertaken in this fashion, preceding therapy with either LMWH or UFH was not associated with an excess of bleeding or transfusions compared with bivalirudin therapy alone in the cardiac catheterization laboratory.
    Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90.
  • How to Switch — Science to Practice From UFH to Bivalirudin — • Discontinue UFH for 30 minutes before starting bivalirudin for PCI From LMWH to Bivalirudin — • Discontinue LMWH for 8 hours before starting bivalirudin for PCI Gibson CM, Am J Cardiol . 2007 Jun 15;99(12):1687-90.
  • ACUITY: Study Medications
    • Antithrombin Agents Started Pre-angiography
    1 Target aPTT 50-75 seconds. 2 If last enoxaparin dose ≥ 8h - <16h before PCI. 3 If maintenance dose discontinued or ≥16h from last dose. 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used. 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before. 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion. UF Heparin Enoxaparin Bivalirudin U/Kg mg/Kg mg/kg Bolus 60 1.0 sc bid 0.1 iv Infusion/h 12 1 0.25 iv PCI ACT 200-250s 0.30 iv bolus 2 0.75 iv bolus 3 0.50 bolus iv 1.75/h infusion iv 4 CABG Per institution Per institution Per institution 5 Medical mgt None 6 None 6 None 6
  • Switching Hypothesis and Question
    • Hypothesis:
    • Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation.
    • Question:
    • Is it better to switch to bivalirudin or remain on consistent therapy with the antithrombin originally started?
  • ACUITY: “Switching” Analysis
    • Study Methods
      • Patients on prior antithrombin therapy
        • Consistent: No switching from pre-randomization antithrombin agent to randomized therapy:
          • Enoxaparin -> Enoxaparin or UFH -> UFH
        • Switch: Single switch to bivalirudin determined by randomization code
          • from Enoxaparin -> Bivalirudin or UFH -> Bivalirudin
      • Event rates at 30-days
        • Net clinical outcome
        • Ischemic composite
        • Major bleeding
  • ACUITY Primary Endpoints at 30 Days
    • Net Clinical Endpoint
      • Composite ischemic and non-CABG major bleeding endpoints
    • Ischemic Endpoint
      • Death, MI, or unplanned revascularization
    • Non-CABG Major Bleeding Endpoint
      • Intracranial, intraocular, or retroperitoneal bleeding
      • Access site bleed requiring intervention/surgery
      • Hematoma ≥5 cm
      • Hgb  ≥3g/dL with an overt source or  ≥4g/dL w/o overt source
      • Blood transfusion
  • “ Switching” Consort Diagram ACUITY 13819 CONSISTENT UFH/Enox N = 2223 SWITCH Bivalirudin* N = 2237 Patients on Prior AT N = 6606 ╪
    • * Includes 67 pts. who had UFH and Enox
    • ╪ excludes Arm B and pts. with multiple crossovers, missing data
  • Baseline Characteristics Consistent UFH/Enox vs. Switch to Bivalirudin * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes Consistent UFH/Enox N = 2223 Switch Bivalirudin N = 2237 P-value Age (median [range], yrs) 63 [23, 91] 62 [20, 92] 0.02 Male (%) 71.6 70.0 NS Weight (median [IQR], kg) 83 [73, 96] 84 [73, 96] NS Diabetes(%) 27.6 25.0 0.05 Hypertension (%) 64.5 63.8 NS Hyperlipidemia (%) 54.6 54.0 NS Current smoker (%) 29.5 30.7 NS Prior MI (%) 31.0 30.4 NS Prior PCI (%) 36.8 36.8 NS Prior CABG (%) 18.4 18.1 NS Thienopyridine exposure 63.8 66.1 NS Renal insufficiency* (%) 19.6 17.4 NS High Risk* (%) 77.6 74.6 0.02 Troponin + (%) 65.4 63.6 NS
  • Results: Consistent vs. Switch Comparison of Consistent therapy on UFH/Enox vs. Switch to Bivalirudin Alone Harvey White, ESC 2007 P=0.002 0.77 [0.63 – 0.91] P=0.601 0.95 [0.76 – 1.17] P<0.001 0.47 [0.35 – 0.64]
  • Consistent vs. Switch MV Adjusted Results in all Patients 0.83 (0.67-1.02) OR (95% CI) Odds ratio ±95% CI Switch to Bivalirudin alone better Consistent UFH/Enox better Major Bleeding Ischemia Net Clinical Outcome 1.10 (0.86-1.41) 0.47 (0.34-0.65) P-value 0.073 0.464 <0.001 * Comparing consistent UFH/Enox vs Switch Bivalirudin
  • Consistent vs. Switch High Risk Patients — Adjusted Analysis 0.86 (0.68-1.07) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent UFH/Enox better Major Bleeding Ischemia Net Clinical Outcome 1.11 (0.85-1.46) 0.51 (0.36-0.72) P-value 0.177 0.445 <0.001 Comparing Consistent UFH/Enox vs Switch Bivalirudin
  • Consistent vs. Switch Comparing Consistent therapy on Enoxaparin vs. Switch from Enoxaparin to Bivalirudin Alone P=0.145 0.81 [0.61 – 1.07] P=0.626 0.92 [0.65 – 1.30] P=0.013 0.54 [0.34 – 0.88]
  • Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone Consistent vs. Switch P=0.012 0.75[0.60 – 0.94] P=0.857 0.98[0.74 – 1.28] P<0.001 0.44[0.30 – 0.65]
  • Conclusions
    • Switching to bivalirudin is safe
      • Switching from any heparin (either enoxaparin or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events.
    • Furthermore
      • Switching to bivalirudin provides patients the 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin.
  • NSTE Acute Coronary Syndromes The Year 2007 ACC/AHA Guidelines and Upstream Therapy — How Do We Collaborate Across Best Evidence?
    • Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA
    • Professor and Chairman
    • Emergency Medicine, Pennsylvania Hospital University of Pennsylvania Health System
    • Philadelphia
    Getting in the ACS (Up)Stream of Things
    • Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157, and Circulation 2007;116:e148-e304, and at www.acc.org and at www.americanheart.org.
    • Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2007, in press.
    NSTE ACS: Optimal Therapy, 8/6/07
  • The Role of the Emergency Physician in the Management of Chest Pain
    • Stabilization
      • When required
    • Recognition
      • “ Atypical is the new typical”
    • Prompt STEMI management
      • ~ 15% of our ACS population—new data to follow
    • Risk Stratification of the rest
      • > 50% don’t have ACS
      • Of those who do, fewer than 30% are high (ischemic) risk in the ED
  • The Role of the Emergency Physician in the Management of Chest Pain
    • Communication with Cardiology
      • Often hospital medicine, PCP, and noninterventionalists as part of process-of-care in ACS
    • Confluent Therapeutic Choices — Considerations Include:
      • Ischemic risk
      • Bleeding risk
      • Choice of upstream therapy
      • Reversibility of upstream therapy—re CABG and bleeding
      • Likely duration of upstream therapy
    • Transition of care
      • If patient going to cath, time frame increasingly compressed
      • If to tele/CCU, emergency physician has more impact
  • Patients with Chest Pain Syndrome Must Be Risk-Stratified in ED
    • Three levels of risk stratification are pertinent to the ED:
      • Low , intermediate, or high risk that ischemic symptoms are a result of CAD
      • Low , intermediate , or high risk of short-term death or nonfatal MI from ACS
      • Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for “conversion” to high-risk status that is linked to intensity of treatment
    Risk Stratification
  • “ Dynamic Risk Stratification” Tools
    • History and Physical
    • Standard EKG and Non-standard EKG leads
      • 15-lead ECGs should perhaps be “standard” in all but very-low-risk patients
    • Markers
      • CPK-MB, Troponins I and T, Myoglobin
      • Markers of inflammation and ischemia
      • BNP
    • Non-Invasive Imaging
      • Echocardiogram
      • Stress testing
      • Technetium-99m-sestamibi
      • CT coronary angiography
    • Predictive Indices/Schemes
      • TIMI, GRACE, PURSUIT
  • CRUSADE: A National Quality Improvement Initiative C an R apid Risk Stratification of U nstable Angina Patients S uppress AD verse Outcomes with E arly Implementation of the ACC/AHA Guidelines 2002-2007 The CRUSADE Experience
  • January 2007 443 Participating Sites 205,528 Patients AK (0) WA (5) OR (5) CA (34) ID (0) NV (2) MT (0) WY (0) CO (9) NM (1) ND (1) SD (3) NE (3) KS (3) OK (7) TX (13) MN (3) IA (6) MO (8) AR (2) LA (6) WI (5) MI (20) MI UT (1) AZ (8) HI (0) IL (17) IN (7) KY (8) TN (9) MS (6) AL (9) GA (14) FL (31) SC (7) NC (14) VA (17) OH (35) WV (2) PA (36) NY (34) MD (13) ME (0) VT (1) NH (1) NJ (12) MA (10) CT (7) DE (3) RI (1) DC (1) The CRUSADE Experience Data on file, Duke Clinical Research Institute.
  • Quality and Outcomes
  • Invasive Procedures 2006 (Among Patients Without Contraindications to Cath
    • Median Times
    • Cath - 22 hrs
    • PCI - 21 hrs
    • CABG - 69 hrs
  • Management Strategies: 2007 Early Invasive versus Selectively Invasive
    • Early Invasive: Diagnostic angiography with intent to perform revascularization
      • Cath anticipated within 4-24 hours
      • Follows a foundation of risk-directed medical therapy
    • Selectively Invasive (or Early Conservative ): Invasive evaluation only if optimal medical management fails
    • Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy
  • What Is “Risk-Directed” Medical Management?
    • ASA
    • Antithrombin therapy
      • I-A: Enoxaparin or UFH
      • I-B: Bivalirudin or fondaparinux
    • Antiplatelet therapy
      • Oral anti-activation therapy
      • Parenteral anti-aggregation therapy
    As number of therapies increases, bleeding risk generally increases
  • The Upstream Antithrombin Challenge: Collaboration Across Many Choices Bleeding Risk Ischemic Risk Renal function Age Time to Cath Cost Ease of use PCI vs CABG vs Med Rx Low: Enox, Bival, UFH Mod: Enox, Bival, UFH High: Enox, Fonda, Bival? Low: Enox, UFH, Bival Mod: Bival, Fonda, UFH High: Bival, Fonda, UFH Elderly: ??? Normal: Enox, Bival, Fonda, UFH CKD: Bival, UFH Enox, UFH Fonda? Bival? Enox, Bival, Fonda Rapid: Bival, UFH Early: Enox, UFH, Bival? Delayed: Enox PCI: Enox, Bival, UFH CABG: UFH Med Rx: Enox, Fonda, Bival? Courtesy Dr. Sunil Rao, DCRI
  • Recent ACS Trials — Forging A New Paradigm for Upstream Management ISCHEMIA : The traditional, primary concern of the emergency physician BLEEDING: Newer, important concern for the cardiologist — A novel issue for the emergency physician ISCHEMIA BLEEDING
  • Major Bleeding Bhatt DL et al. In Braunwald: Harrison’s Online 2005. Possible Relationship Between Bleeding and Mortality Mortality Transfusion Hypotension Cessation of ASA/Clopidogrel Ischemia Stent Thrombosis Inflammation
  • Recent ACS Trials — Forging A New Paradigm for Upstream Management ISCHEMIA BLEEDING TIME TO CATH
  • Invasive Procedures 2006 (Among Patients Without Contraindications to Cath
    • Median Times
    • Cath - 22 hrs
    • PCI - 21 hrs
    • CABG - 69 hrs
  • Management Strategies: 2007 Early Invasive versus Selectively Invasive
    • Early Invasive: Diagnostic angiography with intent to perform revascularization
      • Cath anticipated within 4-24 hours
      • Follows a foundation of risk-directed medical therapy
    • Selectively Invasive (or Early Conservative ): Invasive evaluation only if optimal medical management fails
    • Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy
  • Case Studies in Upstream Management How Many Ways Can We Cut the Cake?
    • Consider Case Scenario 1:
      • 55 year-old man with chest pain syndrome for 4 hours
      • Smoker, diabetic, normal renal function
      • Troponin not elevated ; nonspecific ST-T wave changes
      • Unless he deteriorates, not likely to go to cath before tomorrow
    • Optimal Upstream Therapy in Emergency Department :
      • Enoxaparin or UFH
      • Strongly consider clopidogrel
      • GPI if troponin ↑ overnight
  • Case Studies in Upstream Management How Many Ways Can We Cut the Cake?
    • Consider Case Scenario 2 :
      • 55 year-old man with chest pain syndrome for 4 hours
      • Smoker, diabetic, normal renal function
      • Troponin not elevated; Non-specific ST-T wave changes
      • Going to cath later today
    • Optimal Upstream Therapy in Emergency Department :
      • Bivalirudin or UFH
      • Stronger support for clopidogrel
  • Case Studies in Upstream Management How Many Ways Can We Cut the Cake?
    • Consider Case Scenario 3:
    • 80 year-old woman with chest pain syndrome for 4 hours
      • Smoker, diabetic, Cr Cl 40 ml/min
      • Troponin elevated; ST-T Wave changes
      • Going to cath later today
    • Optimal Upstream Therapy in Emergency Department:
      • Bivalirudin
      • Consider clopidogrel, but CABG risk may be higher here
  • Case Studies in Upstream Management How Many Ways Can We Cut the Cake?
    • Consider Case Scenario 4:
      • 80 year-old woman with chest pain syndrome for 4 hours
      • Smoker, diabetic, Cr Cl 40 ml/min
      • Troponin elevated, NSSTT Δ s
      • No catheterization lab in hospital; transfer time uncertain
    • Optimal Upstream Therapy:
      • Enoxaparin or fondaparinux
      • Strongly consider clopidogrel
      • Consider renal-adjusted small-molecule GPI
  • Recent ACS Trials — Forging A New Paradigm for Upstream Management ISCHEMIA BLEEDING
  • Optimal Upstream Management Ischemic Risk Assessment
    • Basis for Assessment:
      • “ Pain story”
      • Background ASCVD risk
      • ECG
      • Troponin in pertinent time frame
      • Predictive score
    • Options:
      • UFH and enoxaparin established
      • Bivalirudin and fondaparinux: New options that are non-inferior
      • Antiplatelet therapy increasingly more important as ischemic risk increases
  • Recent ACS Trials — Forging A New Paradigm for Upstream Management ISCHEMIA BLEEDING
  • Optimal Upstream Management Bleeding Risk Assessment
    • Basis for Assessment :
      • Female > male
      • Old > young
      • CKD > normal renal function
      • Anemic > normal H/H
      • Diabetic > nondiabetic
    • Options:
      • Bivalirudin and fondaparinux associated with less bleeding than UFH and enoxaparin
      • Clopidogrel not reversible
      • GPIs increase bleeding risk but with renal-adjusted doses seem to have reasonable safety margin
  • A New Paradigm in Upstream Management ISCHEMIA BLEEDING TIME TO CATH
  • Optimal Upstream Management Time to Catheterization
    • Basis for Assessment:
      • Time to catheterization is frequently an unknown variable in the ED for UA/NSTEMI patients: May have impact on initial antithrombin selection
      • Improved collaboration among CV specialists and ED physicians—and perhaps, development of EDICT for ACS therapeutic teams—would lead to more consistent management of ACS and predictability of time to catheterization
    • Options:
      • With shorter times to catheterization, increasing support for bivalirudin
      • With longer times to catheterization or medical management, increasing support for enoxaparin and UFH
      • Role of fondaparinux in patients going to cath may be problematic and not adequately tested
      • Note Dr. Gibson’s “switch” data re: bivalirudin
    • Chest Pain or ACS Committee
    • Meets quarterly or PRN
      • PRN means after . . .
        • Pertinent, “practice-changing” new study published
        • ACC / AHA / TCT meetings
        • M & M or sentinel event
        • New guidelines published
    Optimal Management of NSTE ACS: ED to Cardiology — A Functional Model
    • Chest Pain or ACS Committee comprised of:
      • Emergency physicians
      • Interventional cardiologists
      • Medical cardiologists
      • Hospitalists
      • CT surgeons
      • ED nursing
      • Cath lab nursing
      • CCU nursing
      • Lab
      • Imaging
    Optimal Management of NSTE ACS ED to Cardiology — A Functional Model
    • Chest Pain or ACS Committee discusses:
      • Protocols and standing orders
      • Practice variations versus evidence
      • Time to catheterization predictability
      • Reduction of medical errors in ACS care
      • DTB times
      • QI issues (CRUSADE / NRMI / ACTION)
      • Transfers in, transfers out
      • New data: How should it impact our protocols?
    Optimal Management of NSTE ACS ED to Cardiology — A Functional Model
    • ED physicians should be using optimal, evidence-based, guideline-consistent medical therapy for NSTE ACS
    • ED physicians must work with their colleagues in cardiology to develop pathways and approaches (EDICT for ACS) for proper use of antithrombotic and antiplatelet therapy at all levels
    • ED physicians should facilitate early invasive management of ACS whenever feasible and appropriate
    • ED physicians should address issues related to bleeding risk as well as ischemic risk.
    • A seamless transition of care is most likely to result in good outcomes.
    Optimal Management of NSTE ACS ED to Cardiology — Summary and Game Plan
  • The Mandate to Cooperate and Collaborate UPSTREAM ACS CARE Collaborations, Models, and Protocols ED Emergency Department IC Interventional Cardiology + T Therapeutic Teams + ACS for
  • The Mandate to Cooperate and Collaborate Same model applies to STEMI care: It’s not just a discussion of D2B time UPSTREAM ACS CARE Collaborations, Models, and Protocols ED Emergency Department IC Interventional Cardiology + T Therapeutic Teams + ACS for
  • A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction – 30 Day Results – Gregg W. Stone MD For the HORIZONS AMI Investigators TCT 2007 HORIZONS AMI
  • H armonizing O utcomes with R evascular iz ati on and S tents in AMI * All stent randomization results are still blinded HORIZONS AMI ≥ 3400* pts with STEMI with symptom onset ≤12 hours UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Aspirin, thienopyridine R 1:1 Pharmacology Arm Primary Endpoints* 30 Day Intention to Treat Population Emergent angiography, followed by triage to… Primary PCI CABG – Medical Rx –
  • Inclusion Criteria
    • STEMI >20 mins and <12 hours in duration
      • ST-segment elevation of  1 mm in  2 contiguous leads; or
      • Presumably new left bundle branch block; or
      • True posterior MI with ST depression of  1 mm in  2 contiguous anterior leads
      • Patients with cardiogenic shock, left main disease, etc., were not excluded
    • Age ≥18 years
    • Written, informed consent
  • Principal Exclusion Criteria
    • Contraindication to any of the study medications
    • Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed)
    • Current use of coumadin
    • History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions
    • History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm 3 or hgb <10 g/dL
    • Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment
  • Study Medications (i)
    • Unfractionated heparin
      • 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed
    • Bivalirudin
      • Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)
    • Glycoprotein IIb/IIIa inhibitors
      • Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm
      • Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12  (abcx) or 12-18  (eptif)
    * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus
  • Study Medications (ii)
    • Aspirin
      • 324 mg chewed non enteric coated or 500 mg IV in the ER, followed by 300-325 mg/day in-hospital and 75-81 mg/day as out patient indefinitely
    • Thienopyridines
      • Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended )
        • Ticlopidine load + daily dose permissible if clopiodgrel is unavailable or patient is allergic
    • Other
      • Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF <40%; Statin if LDL >100 mg/dl
  • 2 Primary Endpoints (at 30 Days) and 1) Net Adverse Clinical Events 2) Major Bleeding (non CABG)
      • Intracranial bleeding
      • intraocular bleeding
      • Retroperitoneal bleeding
      • Access site bleed requiring
      • intervention/surgery
      • Hematoma ≥5 cm
      • Hgb  ≥3g/dL with an overt source
      • Hgb  ≥4g/dL w/o overt source
      • Reoperation for bleeding
      • Blood product transfusion
  • 2 Primary Endpoints (at 30 Days) = or 1) Net Adverse Clinical Events 2) Major Bleeding (non CABG)
      • All cause death
      • Reinfarction
      • Ischemic TVR
      • Stroke
    Major adverse cardiovascular events (major secondary endpoint)
  • Baseline Characteristics *P=0.04 * UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) Age (years) 60.7 [52.9, 70.1] 59.8 [51.9, 69.5] Male 76.1% 77.1% Diabetes 17.3% 15.6% Hypertension 55.2% 51.8% Hyperlipidemia 42.7% 43.4% Current smoking 45.0% 47.2% Prior MI 11.4% 10.4% Prior PCI 11.0% 10.5% Prior CABG 2.6% 3.3%
  • Primary Outcome Measures (ITT) Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] P sup = 1.00 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] P NI ≤ 0.0001 P sup ≤ 0.0001 Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] P NI ≤ 0.0001 P sup = 0.006 1  endpoint 1  endpoint
      • *Not related to CABG
      • **MACE = All cause death, reinfarction, ischemic TVR or stroke
  • 30 Day Net Adverse Clinical Events
      • *MACE or major bleeding (non CABG)
    Number at risk Bivalirudin 1800 1660 1633 1626 1620 1607 1544 Heparin + GPIIb/IIIa 1802 1635 1591 1578 1569 1552 1482 Primary Endpoint Net adverse clinical events (%)* Time in Days 12.2% 9.3% HR [95%CI] = 0.75 [0.62, 0.92] P=0.006 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)
  • 30 Day Major Bleeding (non-CABG) Number at risk Bivalirudin 1800 1697 1675 1668 1664 1653 1590 Heparin + GPIIb/IIIa 1802 1651 1617 1606 1598 1581 1511 Primary Endpoint Major Bleeding (%) Time in Days 8.4% 5.0% HR [95%CI] = 0.59 [0.45, 0.76] P<0.0001 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)
  • 30 Day Bleeding Endpoints *Primary endpoint; **Life threatening UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) P Value Protocol Major, non CABG* 8.3% 4.9% <0.0001 Protocol Major, All 10.8% 6.8% <0.0001 Protocol Minor 15.4% 8.6% <0.0001 Blood transfusion 3.5% 2.1% 0.01 TIMI Major 5.0% 3.1% 0.003 TIMI Minor 4.6% 2.8% 0.008 TIMI Major or Minor 9.6% 5.9% <0.0001 GUSTO LT** or Severe 0.6% 0.4% 0.65 GUSTO Moderate 5.0% 3.1% 0.003 GUSTO LT or Sev or Mod 5.6% 3.5% 0.003
  • 30 Day Major Adverse CV Events Number at risk Bivalirudin 1800 1716 1701 1695 1689 1673 1608 Heparin + GPIIb/IIIa 1802 1744 1712 1699 1688 1668 1590 Major adverse CV events (%)* Time in Days 5.5% 5.5% HR [95%CI] = 1.00 [0.75, 1.32] P=0.98
      • *MACE = All cause death, reinfarction, ischemic TVR or stroke
    Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)
  • 30 Day MACE Components* *CEC adjudicated UFH + GP IIb/IIIa (N=1802) Bivalirudin (N=1800) P Value Death 3.1% 2.1% 0.058 - Cardiac 2.9% 1.8% 0.035 - Non cardiac 0.2% 0.3% 0.75 Reinfarction 1.8% 1.8% 0.90 - Q-wave 1.2% 1.4% 0.66 - Non Q-wave 0.7% 0.4% 0.50 Ischemic TVR 1.9% 2.6% 0.18 - Ischemic TLR 1.8% 2.5% 0.14 - Ischemic remote TVR 0.3% 0.3% 1.0 Stroke 0.6% 0.7% 0.69
  • 30 Day Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630 Death (%) Time in Days 2.9% 1.8% 0.3% 0.2% Cardiac Non cardiac HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)
  • Primary Management Strategy* *Primary ITT analysis includes all pts regardless of treatment UFH + GP IIb/IIIa Inhibitor N=1802 Bivalirudin Monotherapy N=1800 Primary PCI Deferred PCI CABG Medical Rx
  • Primary PCI Cohort (N=3,340; 92.7%) Diff = - 0.1% [-1.6, 1.5] RR = 0.99 [0.75, 1.32] P sup = 1.00 Diff = -3.5% [-5.2, -1.7] RR = 0.59 [0.46, 0.77] P NI ≤ 0.0001 P sup ≤ 0.0001 Diff = -3.0% [-5.2, -2.9] RR = 0.75 [0.62, 0.92] P NI ≤ 0.0001 P sup = 0.005
      • *Not related to CABG
      • **MACE = All cause death, reinfarction, ischemic TVR or stroke
  • 30 Day Net Clinical Events: PCI Cohort
      • *MACE or major bleeding (non CABG)
    Number at risk Bivalirudin 1678 1554 1528 1521 1516 1505 1448 Heparin + GPIIb/IIIa 1662 1510 1467 1456 1448 1436 1372 Net Adverse Clinical Events (%)* Time in Days 12.3% 9.2% HR [95%CI] = 0.74 [0.60, 0.92] P=0.005 Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678)
  • 30 Day Major Bleeding: PCI Cohort Number at risk Bivalirudin 1678 1590 1568 1561 1558 1548 1490 Heparin + GPIIb/IIIa 1662 1525 1492 1482 1475 1463 1399 Major Bleeding (Non-CABG) (%) Time in Days 8.6% 5.1% HR [95%CI] = 0.58 [0.44, 0.76] P<0.0001 Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678)
  • 30 Day Major Adverse CV Events: PCI Cohort
      • *MACE = All cause death, reinfarction, ischemic TVR or stroke
    Number at risk Bivalirudin 1678 1606 1592 1585 1581 1567 1509 Heparin + GPIIb/IIIa 1662 1613 1581 1570 1561 1546 1474 Major Adverse CV Events (%)* Time in Days 5.5% 5.4% HR [95%CI] = 1.00 [0.74, 1.33] P=0.98 Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678)
  • Number at risk Bivalirudin 1678 1647 1640 1635 1632 1620 1563 Heparin + GPIIb/IIIa 1662 1631 1615 1604 1598 1583 1512 Death (%) Time in days 1.8% 0.2% 0.1% Cardiac Non cardiac 30 Day Mortality: PCI Cohort 2.8% HR [95%CI] = 0.63 [0.40, 0.99] P=0.049 Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678)
  • 30 Day Stent Thrombosis (N=3,124) *Protocol definition of stent thrombosis, CEC adjudicated UFH + GP IIb/IIIa (N=1553) Bivalirudin (N=1571) P Value ARC definite or probable* 1.9% 2.5% 0.33 - definite 1.4% 2.2% 0.11 - probable 0.5% 0.3% 0.26 - acute (≤24 hrs) 0.3% 1.3% 0.0009 - subacute (>24 hrs – 30d) 1.7% 1.2% 0.30
  • Conclusions
    • In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy with GP IIb/IIIa inhibitors reserved for suboptimal PCI outcomes resulted in:
      • A significant 24% reduction in the 30 day primary endpoint of net adverse clinical events
      • A significant 40% reduction in the 30 day primary endpoint of major bleeding
    • Risk Stratification is an essential function of the ED evaluation.
    • “ Treatment stratification” must be coupled to risk stratification.
    • Risk stratification must be considered for bleeding as well as ischemia.
    • Time issues also direct therapeutic choices, but management of these issues must be multidisciplinary.
    • We now have evidence across the ACS spectrum that bivalirudin is associated with superior bleeding outcomes.
    • A seamless transition of care is most likely to result in good outcomes.
    Optimal Management of ACS ED to Cardiology — Summary and Game Plan
            • Chairman and Distinguished Faculty
    Where Metal Meets Thrombus and Vascular Endothelium A Case Study Analysis of Upstream Interventions Getting in the ACS Stream of Things
  • ACS Case Presentation #1
    • 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes
      • History of Type 2 DM, HTN, cigarette smoking
      • Weight 65 kg
    • ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl
    • Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG
    • Continued chest pain
      • Anticoagulation options in the ED?
      • Risk stratification strategy?
      • Which upstream strategy makes most sense?
      • Collaboration with cardiology colleagues?
    • Decision made to pursue rapid invasive risk stratification
      • High-risk features
        • Elevated troponin
        • Ongoing chest pain despite medical therapy
    • Antithrombin therapy choices
      • Risk for bleeding
        • Age, Female sex, renal insufficiency, anemia
      • Bivalirudin bolus and drip initiated
    • Angiography
    ACS Case Presentation #1
    • A 76 year-old white male with h/o stent to LAD 1 year ago
    • Presents with multiple episodes of recurrent chest pain including rest pain over 2 days
    • Pain similar to time of PCI in past
    • Symptoms relieved in ED with sl NTG
    • PMH: IDDM, HTN, CHOL elevation
    • PE: benign (weight 84 kg).
    • Labs: Hgb 10.7 , Cr 1.9, CK 173/2, Tr <0.03.
    • ECG (next slide)
    ACS Case Presentation #2
  • Case #2: ECG New anterior and lateral ST / T changes.
  • Based on your clinical assessment, this patient’s risk of short-term (30-Day) ischemic events is:
    • Low
    • Moderate
    • High
    • Very high
    ACS Case Presentation #2
  • Which of this patient’s baseline factors do you consider most important for determining this patient’s ischemic risk?
    • A. Advanced age
    • B. Anginal pattern
    • C. ECG findings
    • D. Biomarkers
    * ACS Case Presentation #2
  • Based on your clinical assessment, this patient’s risk of incurring a short-term (30-Day) hemorrhagic event related to PCI is:
    • Low
    • Moderate
    • High
    • Very high
    ACS Case Presentation #2
  • Which of this patient’s baseline factors do you consider most important for determining hemorrhagic risk?
    • A. Advanced age
    • B. Hypertension
    • C. Impaired creatinine clearance
    • D. Anemia
    * ACS Case Presentation #2
  • In ACS patients, do you alter your choice of anticoagulant/ antithrombotic therapy based upon an assessment of the individual patient’s risk of hemorrhagic complications?
    • A. Yes
    • B. No
    * ACS Case Presentation #2
  • Among those of you who would alter or customize antithrombotic therapy based on an ACS patient’s risk for hemorrhage in the setting of PCI, which of the following baseline characteristics would you consider most important in supporting the use of a “hemorrhage-minimizing” anithrombotic regimen:
    • Elderly and female
    • Renal insufficiency and positive biomarkers
    • Anemia and high risk ischemic features
    * ACS Case Presentation #2
  • What would you likely use for anticoagulation in this patient, prior to catheterization, if you anticipated catheterization would occur in 4 hours or less?
    • A. Unfractionated heparin alone
    • B. Enoxaparin alone
    • C. Bivalirudin alone
    • D. A heparin with a GP IIb/IIIa inhibitor
    • E. Fondaparinux
    * ACS Case Presentation #2
  • What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the same day (within 12 hours)?
    • A. Unfractionated heparin alone
    • B. Enoxaparin alone
    • C. Bivalirudin alone
    • D. A heparin with a GP IIb/IIIa inhibitor
    • E. Fondaparinux
    * ACS Case Presentation #2
  • What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the next day (within 24 hours)?
    • A. Unfractionated heparin alone
    • B. Enoxaparin alone
    • C. Bivalirudin alone
    • D. A heparin with a GP IIb/IIIa inhibitor
    • E. Fondaparinux
    * ACS Case Presentation #2
  • At this point, your anticoagulation regimen for PCI in this patient would be?
    • A. Additional heparin
    • B. Switch to enoxaparin
    • C. Switch to bivalirudin
    • D. Additional heparin plus GP IIb/IIIa inhibitor
    * ACS Case Presentation #2