Interventor.ru

2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients
With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and
2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous
Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update).
A Report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines
Frederick G. Kushner, Mary Hand, Sidney C. Smith, Jr, Spencer B. King, III, Jeffrey L. Anderson, Elliott M. Antman, Steven R. Bailey, Eric R. Bates, James C. Blankenship, Donald E. Casey, Jr, Lee A. Green, Judith S. Hochman, Alice K. Jacobs, Harlan M. Krumholz, Douglass A. Morrison, Joseph P. Ornato, David L. Pearle, Eric D. Peterson, Michael A. Sloan, Patrick L. Whitlow and David O. Williams published online Nov 18, 2009; DOI: 10.1161/CIRCULATIONAHA.109.192663 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX Copyright 2009 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online The online version of this article, along with updated information and services, is located on the World Wide Web at: Subscriptions: Information about subscribing to Circulation is online at Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of WoltersKluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Fax:410-528-8550. E-mail: Reprints: Information about reprints can be found online at


AHA Scientific Statement
2009 Focused Updates: ACC/AHA Guidelines for the
Management of Patients With ST-Elevation Myocardial
Infarction (Updating the 2004 Guideline and 2007 Focused
Update) and ACC/AHA/SCAI Guidelines on Percutaneous
Coronary Intervention (Updating the 2005 Guideline and 2007
A Report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines
Frederick G. Kushner, MD, FACC, FAHA, FSCAI, Co-Chair; Mary Hand, MSPH, RN, FAHA, Co-Chair*; Sidney C. Smith, Jr, MD, FACC, FAHA, Chair; Spencer B. King III, MD, MACC, FSCAI, Co-Chair; Jeffrey L. Anderson, MD, FACC, FAHA; Elliott M. Antman, MD, FACC, FAHA; Steven R. Bailey, MD, FACC, FSCAI; Eric R. Bates, MD, FACC, FAHA; James C. Blankenship, MD, FACC, FSCAI; Donald E. Casey, Jr, MD, MPH, MBA; Lee A. Green, MD, MPH; Judith S. Hochman, MD, FACC, FAHA; Alice K. Jacobs, MD, FACC, FAHA, FSCAI; Harlan M. Krumholz, MD, SM, FACC, FAHA; Douglass A. Morrison, MD, PhD, FACC, FSCAI; Joseph P. Ornato, MD, FACC, FAHA; David L. Pearle, MD, FACC, FAHA; Eric D. Peterson, MD, MPH, FACC, FAHA; Michael A. Sloan, MD, MS, FACC, FAHA; Patrick L. Whitlow, MD, FACC, FAHA; David O. Williams, MD, FACC, FAHA, FSCAI *The opinions expressed in this article should not be construed as necessarily representing an official position of the US Department of Health and Human Services, the Agency for Healthcare Research and Quality, or the US Government, by whom M. Hand is employed.
†Recused from Section 3, Thienopyridines; Section 4, Parenteral Anticoagulants; Section 5, Triage and Transfer for PCI.
‡Recused from Section 3, Thienopyridines; Section 4, Parenteral Anticoagulants.
§Recused from Section 6, Intensive Glucose Control.
储Recused from Section 2, Glycoprotein IIb/IIIa Receptor Antagonists; Section 3, Thienopyridines.
¶Recused from Section 3, Thienopyridines.
#Recused from Section 3, Thienopyridines; Section 7, Thrombus Aspiration; Section 8, Use of Stents; Section 11, PCI for Left Main Coronary Artery Disease.
**Recused from Section 3, Thienopyridines.
††Society for Cardiovascular Angiography and Interventions Representative.
‡‡Recused from Section 10, Fractional Flow Reserve.
§§Recused from Section 3, Thienopyridines; Section 5, Triage and Transfer for PCI; Section 8, Use of Stents.
储储Former Task Force member during this writing effort.
This document was approved by the American College of Cardiology Foundation Board of Trustees in September 2009, by the American Heart Association Science Advisory and Coordinating Committee in September 2009, and by the Society for Cardiovascular Angiography and Interventions Board of Trustees in October2009.
The American Heart Association requests that this document be cited as follows: Kushner FG, Hand M, Smith SC Jr, King SB 3rd, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DJ Jr, Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA, Ornato JP, PearleDL, Peterson ED, Sloan MA, Whitlow PL, Williams DO. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevationmyocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention(updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association TaskForce on Practice Guidelines. Circulation. 2009;120:2271–2306.
This article has been copublished in the Journal of the American College of Cardiology and Catheterization and Cardiovascular Interventions.
Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.acc.org), the American Heart Association (my.americanheart.org), and the Society for Cardiovascular Angiography and Interventions (scai.org). A copy of the document is alsoavailable at http://www.americanheart.org/presenter.jhtml?identifier⫽3003999 by selecting either the "topic list" link or the "chronological list" link (No.
KJ-0734). To purchase additional reprints, call 843-216-2533 or e-mail [email protected].
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.americanheart.org/presenter.jhtml?identifier⫽4431. A link to the "Permission Request Form" appears on the right side of the page.
(Circulation. 2009;120:2271-2306.)
2009 American College of Cardiology Foundation and American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org


December 1, 2009
STEMI WRITING GROUP MEMBERS Frederick G. Kushner, MD, FACC, FAHA, FSCAI, Co-Chair; Mary Hand, MSPH, RN, FAHA, Co-Chair*; Elliott M. Antman, MD, FACC, FAHA†; Eric R. Bates, MD, FACC, FAHA‡; Donald E. Casey, Jr, MD, MPH, MBA; Lee A. Green, MD, MPH§; Judith S. Hochman, MD, FACC, FAHA储; Harlan M. Krumholz, MD, SM, FACC, FAHA; Joseph P. Ornato, MD, FACC, FAHA¶; David L. Pearle, MD, FACC, FAHA; Michael A. Sloan, MD, MS, FACC, FAHA; Sidney C. Smith, Jr, MD, FACC, FAHA PCI WRITING GROUP MEMBERS Sidney C. Smith, Jr, MD, FACC, FAHA, Chair; Spencer B. King III, MD, MACC, FSCAI, Co-Chair#; Jeffrey L. Anderson, MD, FACC, FAHA**; Steven R. Bailey, MD, FACC, FSCAI††‡‡; James C. Blankenship, MD, FACC, FSCAI††; Alice K. Jacobs, MD, FACC, FAHA, FSCAI§§; Douglass A. Morrison, MD, PhD, FACC, FSCAI††; Eric D. Peterson, MD, MPH, FACC, FAHA**; Patrick L. Whitlow, MD, FACC, FAHA; David O. Williams, MD, FACC, FAHA, FSCAI** ACCF/AHA TASK FORCE MEMBERS Alice K. Jacobs, MD, FACC, FAHA, Chair 2009 –2011; Sidney C. Smith, Jr, MD, FACC, FAHA, Immediate Past Chair 2006 –2008储储; Jeffrey L. Anderson, MD, FACC, FAHA, Vice Chair; Christopher E. Buller, MD, FACC; Mark A. Creager, MD, FACC, FAHA; Steven M. Ettinger, MD, FACC; Robert A. Guyton, MD, FACC, FAHA; Jonathan L. Halperin, MD, FACC, FAHA; Harlan M. Krumholz, MD, SM, FACC, FAHA储储; Frederick G. Kushner, MD, FACC, FAHA; Rick Nishimura, MD, FACC, FAHA储储; Richard L. Page, MD, FACC, FAHA储储; Lynn G. Tarkington, RN; William G. Stevenson, MD, FACC, FAHA; Clyde W. Yancy, MD, FACC, FAHA Table of Contents
8. Recommendations for the Use of Stents in STEMI . 2288 8.1. Stent Selection for STEMI . . . . . .2288 2009 STEMI and PCI Focused Updates . . . . .2273 PCI Focused Update Section . . . . . . . .2289 9. Recommendation for Angiography in Patients 1. Introduction . . . . . . . . . . .2274 With Chronic Kidney Disease . . . . . . 2289 1.1. Methodology and Evidence Review . . . 2274 9.1. Angiography in Patients With Chronic 1.2. Organization of Committee and Relationships Kidney Disease. . . . . . . . . 2289 With Industry and Other Entities. . . . 2275 10. Recommendations for Use of Fractional 1.3. Document Review and Approval. . . . 2275 Flow Reserve. . . . . . . . . . .2289 STEMI and PCI Focused Update Section . . . . 2276 10.1. Fractional Flow Reserve. . . . . . 2289 2. Recommendations for the Use of 11. Recommendations for PCI for Unprotected Glycoprotein IIb/IIIa Receptor Antagonists. . .2276 Left Main Coronary Artery Disease. . . . .2290 2.1. Glycoprotein IIb/IIIa Receptor Antagonists . 2276 11.1. Unprotected Left Main Coronary 3. Recommendations for the Use of Thienopyridines . 2277 Artery Disease . . . . . . . . .2290 3.1. Thienopyridines . . . . . . . . .2277 12. Recommendations for the Timing of Angiography 3.1.1. Additional Thienopyridine Information . 2280 and Antiplatelet Therapy in UA/NSTEMI . . .2292 3.1.2. Choice of Thienopyridine for PCI 12.1. Timing of Angiography . . . . . . 2292 12.2. Timing of GP IIb/IIIa Receptor Antagonist 3.2. Proton Pump Inhibitors and Therapy in UA/NSTEMI Patients Dual-Antiplatelet Therapy for ACS . . . 2281 Undergoing Angiography . . . . . .2292 4. Recommendations for the Use of Appendix 1. Author Relationships With Industry and Parenteral Anticoagulants . . . . . . . 2282 Other Entities—ST-Elevation Myocardial 4.1. Parenteral Anticoagulants. . . . . . 2282 Infarction . . . . . . . . .2294 5. Recommendations for Triage and Transfer for PCI . .2283 Appendix 2. Author Relationships With Industry and 5.1. Triage and Transfer for PCI . . . . . 2283 Other Entities—Percutaneous Coronary 5.1.1. STEMI Patients Who Are Candidates Intervention . . . . . . . . . 2295 for Reperfusion . . . . . . .2283 Appendix 3. Reviewer Relationships With Industry 6. Recommendations for Intensive Glucose and Other Entities—2009 STEMI and PCI Focused Updates . . . . . .2296 6.1. Intensive Glucose Control . . . . . .2286 Appendix 4. Dosing Table for Antiplatelet and Anticoagulant 7. Recommendation for Thrombus Aspiration Therapy Discussed in This Focused During PCI for STEMI . . . . . . . .2287 Update to Support PCI in STEMI . . . 2299 7.1. Thrombus Aspiration . . . . . . . 2287 Appendix 5. Triage and Transfer for PCI . . . .2301


Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Appendix 6. Outcomes of PCI Versus CABG for size of the treatment effect and an estimate of the certainty of Unprotected Left Main Coronary the treatment effect. Note that a recommendation with level Artery Disease . . . . . . . . 2301 of evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed inguidelines do not lend themselves to clinical trials. Although 2009 STEMI and PCI Focused Updates
randomized trials may not be available, there may be a very clear clinical consensus that a particular test or therapy is A primary challenge in the development of clinical practice useful and effective. Both the classification of recommenda- guidelines is keeping pace with the stream of new data on tions and level of evidence listed in the focused updates are which recommendations are based. In an effort to respond based on consideration of the evidence reviewed in previous promptly to new evidence, the American College of Cardi- iterations of the guideline and the focused update. Of note, ology Foundation/American Heart Association (ACCF/AHA) the implications of older studies that have informed recom- Task Force on Practice Guidelines has created a "focused mendations but have not been repeated in contemporary update" process to revise the existing guideline recommen- settings are considered carefully.
dations that are affected by evolving data or opinion. Before The ACCF/AHA practice guidelines address patient popula- the initiation of this focused approach, periodic updates and tions (and healthcare providers) residing in North America. As revisions of existing guidelines required up to 3 years to such, drugs that are not currently available in North America are complete. Now, however, new evidence will be reviewed in discussed in the text without a specific class of recommendation.
an ongoing fashion to more efficiently respond to important For studies performed in large numbers of subjects outside of science and treatment trends that could have a major impact North America, each writing group reviews the potential impact on patient outcomes and quality of care. Evidence will be of different practice patterns and patient populations on the reviewed at least twice a year, and updates will be initiated on treatment effect and on the relevance to the ACCF/AHA target an as-needed basis as quickly as possible, while maintaining population to determine whether the findings should inform a the rigorous methodology that the ACCF and AHA have developed during their 25 years of partnership.
The ACCF/AHA practice guidelines are intended to assist These updated guideline recommendations reflect a con- healthcare providers in clinical decision making by describ- sensus of expert opinion after a thorough review primarily of ing a range of generally acceptable approaches for the late-breaking clinical trials identified through a broad-based diagnosis, management, and prevention of specific diseases vetting process as being important to the relevant patient or conditions. The guidelines attempt to define practices that population, as well as a review of other new data deemed to meet the needs of most patients in most circumstances. The have an impact on patient care (see Section 1.1, Methodology ultimate judgment regarding care of a particular patient must and Evidence Review, for details). This focused update is not be made by the healthcare provider and patient in light of all intended to represent an update based on a full literature the circumstances presented by that patient. Thus, there are review from the date of the previous guideline publication.
circumstances in which deviations from these guidelines may Specific criteria/considerations for inclusion of new data be appropriate. Clinical decision making should consider the include the following: quality and availability of expertise in the area where care isprovided. These guidelines may be used as the basis for publication in a peer-reviewed journal; regulatory or payer decisions, but the ultimate goals are large randomized, placebo-controlled trial(s); quality of care and serving the patient's best interests.
nonrandomized data deemed important on the basis of Prescribed courses of treatment in accordance with these results that affect current safety and efficacy assumptions; recommendations are effective only if they are followed by strength/weakness of research methodology and findings; the patient. Because a lack of patient adherence may ad- likelihood of additional studies influencing current findings; versely affect treatment outcomes, healthcare providers impact on current performance measure(s) and/or likeli- should engage the patient in active participation with the hood of need to develop new performance measure(s); requests and requirements for review and update from the The ACCF/AHA Task Force on Practice Guidelines makes practice community, key stakeholders, and other sources every effort to avoid actual, potential, or perceived conflicts free of relationships with industry or other potential bias; of interest that may arise as a result of industry relationships number of previous trials showing consistent results; and or personal interests among the writing committee. Specifi- need for consistency with a new guideline or guideline revision.
cally, all members of the writing committee, as well asreviewers of the document, are asked to disclose all such In analyzing the data and developing updated recommen- relevant relationships pertaining to the trials and other evi- dations and supporting text, the focused update writing group dence under consideration (see Appendixes 1, 2, and 3). All used evidence-based methodologies developed by the ACCF/ guideline recommendations require a confidential vote by the AHA Task Force on Practice Guidelines, which are described writing group and must be approved by a consensus of the members voting. Members who recused themselves from The schema for classification of recommendations and voting are noted on the title page of this document. Members level of evidence is summarized in Table 1, which also must recuse themselves from voting on any recommendations illustrates how the grading system provides an estimate of the to which their relationships with industry and other entities


December 1, 2009
Applying Classification of Recommendations and Level of Evidence
*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak.
Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there maybe a very clear clinical consensus that a particular test or therapy is useful or effective.
†In 2003, the ACCF/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart fromthe rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this willincrease readers' comprehension of the guidelines and will allow queries at the individual recommendation level.
apply. Writing group members who did not participate are not focused update or the full-text guidelines are revised. This listed as authors of this focused update. The work of the focused update is published in the December 1, 2009, issues writing group was supported exclusively by the ACCF and of the Journal of the American College of Cardiology and AHA without commercial support. Writing group members Circulation as an update to the full-text guideline, and it is volunteered their time for this effort.
also posted on the American College of Cardiology (ACC; With the exception of the recommendations presented here, www.acc.org), AHA (my.americanheart.org), and Society for the full-text guidelines remain current.2,3 Only the recommen- Cardiovascular Angiography and Interventions (SCAI; dations from the affected section(s) of the full-text guidelines are scai.org) World Wide Web sites.
included in this focused update. Recommendations from any Alice K. Jacobs, MD, FACC, FAHA section of a guideline affected by a change are presented with Chair, ACCF/AHA Task Force on Practice Guidelines notation as to whether they are new or have been modified;however, recommendations that remain unchanged in each section are not included in this focused update. When evidenceaffects recommendations in more than 1 set of guidelines, those 1.1. Methodology and Evidence Review
guidelines are updated concurrently whenever possible.
Late-breaking clinical trials presented at the 2007 and 2008 The recommendations in this focused update will be annual scientific meetings of the ACC, AHA, Transcatheter considered current until they are superseded by another Cardiovascular Therapeutics, the European Society of Cardi-


Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
ology, and the 2009 annual scientific sessions of the ACC America. The writing group also notes that the AHA/ACCF were reviewed by the standing guideline writing committee and the Heart Rhythm Society have published updated along with the parent Task Force and other experts to identify recommendations for the standardization and interpretation of those trials and other key data that may impact guideline the electrocardiogram with a separate section on acute recommendations. On the basis of the criteria/considerations noted above, recent trial data and other clinical information were To provide clinicians with a comprehensive set of data, considered important enough to prompt a focused update of the whenever possible, the exact event rates in various treatment ACC/AHA 2004 Guidelines for the Management of Patients arms of clinical trials are presented to permit calculation of With ST-Elevation Myocardial Infarction and the ACC/AHA the absolute risk difference and number needed to treat 2005 Guidelines for Percutaneous Coronary Intervention, inclu- (NNT) or harm; the relative treatment effects are described sive of their respective 2007 focused updates.2–5 either as odds ratio, relative risk (RR), or hazard ratio (HR) The ST-elevation myocardial infarction (STEMI) and per- depending on the format used in the original publication.
cutaneous coronary intervention (PCI) writing groups to- Along with all other statistical point estimates, the confidence gether considered the following studies: Two meta-analyses, interval (CI) for those statistics are added when available.
"A Comparison of Abciximab and Small Molecule Glyco- Consult the full-text or executive summary versions of the protein IIb/IIIa Inhibitors in Patients Undergoing Primary ACC/AHA 2004 Guidelines for the Management of Patients Percutaneous Coronary Intervention,"6 and "Benefits From With ST-Elevation Myocardial Infarction or the ACC/AHA/ Small Molecule Administration as Compared With Abcix- SCAI 2005 Guidelines for Percutaneous Coronary Interven- imab Among Patients With ST-Segment Elevation Myo- tion, as well as their respective 2007 focused updates, for cardial Infarction Treated With Primary Angioplasty,"7 policy on clinical areas not covered by the present focused FINESSE (Facilitated PCI in Patients With ST-Elevation update.2–5 Unchanged recommendations from previous itera- Myocardial Infarction),8 the HORIZONS-AMI (Harmonizing tions of the guidelines are not listed in this document and Outcomes With Revascularization and Stents in Acute Myo- remain current policy. Individual recommendations updated cardial Infarction),9 BRAVE-3 (Bavarian Reperfusion Alter- in this focused update will be incorporated into future natives Evaluation-3),10 MULTISTRATEGY (Multicentre revisions of the full-text guidelines.
Evaluation of Single High-Dose Bolus Tirofiban VersusAbciximab With Sirolimus-Eluting Stent or Bare Metal Stent 1.2. Organization of Committee and Relationships With
Industry and Other Entities

in Acute Myocardial Infarction Study),11 ON-TIME 2 (On- For this focused update, all members of the 2004 STEMI going Tirofiban in Myocardial Infarction Evaluation),12 guideline, 2007 STEMI focused update, 2005 PCI guideline, TRITON-TIMI 38 (Trial to Assess Improvement in Thera- and 2007 PCI focused update writing committees were peutic Outcomes by Optimizing Platelet Inhibition With invited to participate; those who agreed (referred to as the Prasugrel–Thrombolysis in Myocardial Infarction),13 2009 Focused Update Writing Group) were required to TRANSFER-AMI (Trial of Routine ANgioplasty and Stent- disclose all relationships with industry and other entities ing after Fibrinolysis to Enhance Reperfusion in Acute relevant to the data under consideration. The policies used for Myocardial Infarction),14 CARESS-in-AMI (Combined Ab- relationships with industry were those in effect at the initial ciximab Reteplase Stent Study in Acute Myocardial Infarc- meeting of this committee, which included disclosure of tion),15 NICE-SUGAR (Normoglycemia in Intensive Care relationships 12 months prior to initiation and a chair with no Evaluation—Survival Using Glucose Algorithm Regula- relevant relationships except in a situation where more than tion),16 TAPAS (Thrombus Aspiration during Percutaneous one chair is named. In this circumstance, one chair will have no relevant relationships and the other may have relation- Study),17 and EXPIRA (Thrombectomy With Export Catheter ships. Each recommendation required a confidential vote by in Infarct-Related Artery During Primary Percutaneous Cor- the writing group members before and after external review onary Intervention).18 Additionally, the PCI writing group of the document. Any writing group member with a relation- considered the CARE (Cardiac Angiography in Renally ship with industry relevant to the recommendation was Impaired Patients),19 FAME (Fractional Flow Reserve versus recused from voting on that recommendation. The PCI Angiography for Multivessel Evaluation) study,20 SYNTAX writing group included 2 representatives from SCAI.
(Synergy Between Percutaneous Intervention With Taxus andCardiac Surgery),21 Early ACS (Early versus Delayed, Pro- 1.3. Document Review and Approval
visional Eptifibatide in Acute Coronary Syndromes),22 and This document was reviewed by 3 official reviewers nomi- TIMACS (Timing of Intervention in Patients With Acute nated by the ACCF and 4 official reviewers nominated by the Coronary Syndromes) studies.23 When considering the new AHA, 1 official reviewer nominated by the SCAI, 6 review- data for this focused update, the writing group faced the task ers from the ACCF Interventional Council, 2 reviewers from of weighing evidence from studies that had enrolled large the ACCF Imaging Council, and 22 content reviewers. All numbers of subjects outside North America. Although noting reviewer information on relationships with industry and other that practice patterns and the rigor applied to data collection, entities was collected and distributed to the writing commit- as well as the genetic makeup of subjects, may influence the tee and is published in Appendix 3. This document was observed magnitude of a treatment's effect, the writing group approved for publication by the governing bodies of the believed the data were relevant to the formulation of recom- ACCF, the AHA, and the SCAI (specifically, the PCI portion mendations for management of STEMI and PCI in North of the guideline).


December 1, 2009
Recommendations for the Use of Glycoprotein IIb/IIIa Receptor Antagonists
2004/2005/2007 Recommendations: 2004 STEMIGuideline Section 6.3.1.6.8.2.3; Also 2005 PCIGuideline Section 6.2.2 2009 Joint STEMI/PCI Focused Update Recommendations Class IIa
1. It is reasonable to start treatment with abciximab 1. It is reasonable to start treatment with glycoprotein IIb/IIIa Modified recommendation as early as possible before primary PCI (with or receptor antagonists (abciximab9,11 关Level of Evidence: A, without stenting) in patients with STEMI. (Level of tirofiban11,12 关Level of Evidence: B兴 or eptifibatide6,7,9 关Level of Evidence: B) Evidence: B兴) at the time of primary PCI (with or without stenting) changed from IIb to IIa in selected patients with STEMI.
for tirofiban andeptifibatide).
Class IIb
1. Treatment with tirofiban or eptifibatide may be 1. The usefulness of glycoprotein IIb/IIIa receptor antagonists (as part Modified recommendation considered before primary PCI (with or without of a preparatory pharmacological strategy for patients with STEMI (text modified; level of stenting) in patients with STEMI. (Level of before their arrival in the cardiac catheterization laboratory for evidence changed from Evidence: C) angiography and PCI) is uncertain.8,10 (Level of Evidence: B) STEMI and PCI Focused Update Section
receiving high-dose tirofiban (25 mcg/kg bolus followed by0.15 mcg/kg per min for 18 hours) at first medical contact 2. Recommendations for the Use of Glycoprotein
before transport for primary PCI were also treated with IIb/IIIa Receptor Antagonists
unfractionated heparin (UFH; 5000 U), clopidogrel (600 mg), (See Table 2 and Appendix 4.) and ASA. Patients in the high-dose tirofiban group had 2.1. Glycoprotein IIb/IIIa Receptor Antagonists
improved ST-segment resolution (primary end point) before In considering the use of intravenous glycoprotein (GP) and 1 hour after PCI (P⫽0.003) compared with those receiv- IIb/IIIa receptor antagonists for STEMI, the writing group ing placebo (NNT⫽100). However, there was no significant noted that much of the evidence favoring the use of these difference in Thrombolysis In Myocardial Infarction (TIMI) agents was established in the era before dual oral antiplatelet grade 3 flow or blush grade and no significant difference in therapy and largely by placebo-controlled comparisons. Con- major bleeding or minor bleeding. There was no significant temporary management of STEMI patients involves a com- difference in death, recurrent MI, or urgent target-vessel plex array of antithrombotics, including dual oral antiplatelet revascularization (TVR) between the tirofiban and placebo therapy (aspirin [acetylsalicylic acid; ASA] plus a thienopy- groups at 30 days.25 ridine) and an anticoagulant. There is a paucity of trials In the HORIZONS-AMI trial,9 patients undergoing pri- adequately powered for assessment of clinical end points that mary PCI for STEMI were randomized to treatment with have reevaluated the current relative role of intravenous GP UFH plus a GP IIb/IIIa receptor antagonist (abciximab or IIb/IIIa receptor antagonists with respect to other pharmacolog- double-bolus eptifibatide) or to bivalirudin alone with provi- ical therapy in STEMI patients. Accordingly, a reevaluation of sional IIb/IIIa. Aspirin and a thienopyridine were adminis- the value of GP IIb/IIIa antagonists in STEMI is appropriate, but tered before catheterization. (See the full discussion of the the ability to draw definitive conclusions is limited.
trial under Section 4, Recommendations for the Use of At least 3 trials evaluated GP IIb/IIIa antagonists as Parenteral Anticoagulants.) Seven hundred fifty-seven of the adjuncts to oral antiplatelet therapy in the setting of primary 1661 patients who received UFH received a double bolus of PCI. The findings of these trials question whether GP IIb/IIIa eptifibatide and infusion, whereas 53 of 1661 in the bivaliru- antagonists provide significant additional benefit to STEMI din arm received eptifibatide. At 30 days, rates of major patients who have received dual-antiplatelet therapy before bleeding and total adverse events were higher among patients catheterization. In the BRAVE-3 study, 800 patients pres- treated with GP IIb/IIIa antagonists and heparin than among enting within 24 hours of a STEMI were pretreated with 600 those given bivalirudin alone.
mg of clopidogrel and then randomly assigned in a double- Two meta-analyses of randomized trials were published blind manner to receive either abciximab or placebo in the that compared small-molecule GP IIb/IIIa antagonists with intensive care unit before being sent for PCI.10 The primary abciximab in STEMI patients undergoing primary PCI.6,7 In end point was infarct size measured by single photon emis- each case, there was no statistically significant difference in sion computed tomography before hospital discharge. At 30 30-day mortality, reinfarction, or major TIMI bleeding, and days, the composite of death, recurrent myocardial infarction there was no significant difference in death or reinfarction at (MI), stroke, or urgent revascularization of the infarct-related 8 months between groups. There was also no statistically artery was not significantly different in the 2 groups (abcix- significant difference in postprocedural TIMI flow grade 3 or imab 5%, placebo 3.8%; 95% CI 0.7 to 2.6; P⫽0.4). There ST-segment resolution. On the basis of these studies, the was no significant difference in infarct size or major bleeding.
present writing group judged that the totality of evidence ON-TIME 2 was a randomized, placebo-controlled, multi- indicates that the various GP IIb/IIIa antagonists demonstrate center European trial that included 491 patients receiving similar effectiveness in the setting of primary PCI.
high-dose tirofiban and 493 receiving placebo within a MULTISTRATEGY was an open-label, multicenter, ran- median of 76 minutes from onset of symptoms.12 Patients domized European trial with a 2-by-2 factorial design that


Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
randomized 745 STEMI patients undergoing primary PCI to high-dose bolus tirofiban versus abciximab infusion and Since the publication of the last guidelines,4,5 evidence has sirolimus-eluting stent versus bare-metal stent (BMS).11 The emerged about prasugrel, a thienopyridine that achieves prespecified primary end points were the achievement of 50% greater inhibition of platelet aggregation than clopidogrel.27 resolution of ST-segment elevation at 90 minutes after PCI, The pivotal trial for prasugrel, TRITON-TIMI 38, focused on powered for noninferiority, and the rate of major adverse patients with ACS who were referred for PCI.
cardiac events (MACE) at 8 months, powered for superiority.
TRITON-TIMI 38 randomly assigned 13 608 patients with All patients received ASA at the usual doses, clopidogrel 300 moderate- to high-risk ACS, 3534 of whom had STEMI, to mg orally then 75 mg per day, and UFH. There was a similar receive prasugrel (6813 patients received a 60-mg loading rate of at least 50% ST-segment resolution at 90 minutes after dose and a 10-mg daily maintenance dose) or clopidogrel primary PCI with abciximab and tirofiban (RR 1.020; 97.5% (6795 patients received a 300-mg loading dose and a 75-mg CI 0.958 to 1.086; P⫽0.001 for noninferiority). Rates of daily maintenance dose) for an average follow-up of 14.5 MACE, including all-cause death, clinical reinfarction, or months. Aspirin was prescribed within 24 hours of PCI.
TVR, and hemorrhagic (major and minor bleeding) compli- Clinical end points were assessed at 30 and 90 days and then cations were similar. The incidence of severe or moderate every 3 to 15 months.27 thrombocytopenia was more common with abciximab than Prasugrel was associated with a significant 2.2% absolute with tirofiban (4.0% versus 0.8%, P⫽0.004).
reduction and a 19% relative reduction in the primary In an analysis of the predictors of stent thrombosis after efficacy end point, a composite of the rate of death due to primary PCI in acute MI presented at the 2009 ACC Scien- cardiovascular causes (including arrhythmia, congestive heart tific Sessions, titled "Predictors of Stent Thrombosis After failure, shock, and sudden or unwitnessed death), nonfatal Primary Angioplasty in Acute Myocardial Infarction: The MI, or nonfatal stroke during the follow-up period. The HORIZONS-AMI Trial,"69 there was no significant differ- primary efficacy end point occurred in 9.9% of patients ence in the 1-year rate of stent thrombosis with the heparin receiving prasugrel and 12.1% of patients receiving clopi- plus GP IIb/IIIa receptor antagonists compared with eptifi- dogrel (HR for prasugrel versus clopidogrel 0.81; 95% CI batide and abciximab (3.6% versus 2.8%, P⫽0.93), which 0.73 to 0.90; P⬍0.001). A significant reduction in the suggests that eptifibatide has the same impact as abciximab primary end point was seen in the prasugrel group by the first on stent thrombosis incidence.
prespecified time point, which was 3 days (4.7% in the One investigation, FINESSE, addressed the issue of timing prasugrel group versus 5.6% in the clopidogrel group; HR of GP IIb/IIIa antagonist administration. This double-blind, 0.82; 95% CI 0.71 to 0.96; P⫽0.01), and persisted throughout randomized, placebo-controlled study of 2453 patients with the follow-up period. From Day 3 to the end of the study, the STEMI explored the use of pre-PCI treatment with a half- primary end point had occurred in 5.6% of patients receiving dose fibrinolytic agent plus abciximab, pre-PCI abciximab prasugrel and in 6.9% of patients receiving clopidogrel (HR alone, and abciximab at the time of PCI.8 The primary end 0.80; 95% CI 0.70 to 0.93; P⫽0.003). Prasugrel decreased point was the composite of death due to all causes, ventricular cardiovascular death, MI, and stroke by 138 events fibrillation that occurred more than 48 hours after random- (NNT⫽46).27 The rate of MI with subsequent death due to ization, cardiogenic shock, and congestive heart failure dur- cardiovascular causes was also reduced in the prasugrel group ing the first 90 days after randomization. The results of the (P⫽0.02). The difference in the primary end point was trial are discussed in Section 5.1, Triage and Transfer for PCI.
largely related to the difference in rates of nonfatal MI (7.3% This trial showed no benefit (and a tendency toward excess for prasugrel versus 9.5% for clopidogrel; HR 0.76; 95% CI bleeding) with prehospital abciximab compared with abcix- 0.67 to 0.85; P⬍0.001). There were no significant differences imab at the time of PCI. The writing group concluded there in the 2 treatment groups in the rates of stroke or of death due was no benefit of administration of abciximab before primary to cardiovascular causes not preceded by recurrent MI (at 15 PCI, alone or in combination with reteplase. On the basis of months, the nonfatal stroke rate was 1.0% for both prasugrel this trial and ON-TIME 2, the writing group concluded thatthe use of GP IIb/IIIa antagonists before primary PCI is of and clopidogrel; HR for prasugrel⫽1.02; CI 0.71 to 1.45; uncertain benefit.
P⫽0.93; the rate of deaths due to cardiovascular causes not Given the results of the studies cited above, the writing preceded by recurrent MI was 2.1% for prasugrel versus 2.4% group concluded that in the setting of dual-antiplatelet ther- for clopidogrel; HR 0.89; CI 0.70 to 1.12; P⫽0.31). There apy with UFH or bivalirudin as the anticoagulant, current were significant reductions in the rates of ischemic events in evidence indicates that adjunctive use of a GP IIb/IIIa the prasugrel group compared with the clopidogrel group: antagonist can be useful at the time of primary PCI but cannot Rates of MI were 7.4% for prasugrel versus 9.7% for be recommended as routine therapy. These agents might clopidogrel (P⬍0.001); urgent TVR rates were 2.5% for provide more benefit in selective use, for example, for the prasugrel versus 3.7% for clopidogrel (P⬍0.001); and rates patient with a large thrombus burden or for patients who have of stent thrombosis were 1.1% for prasugrel versus 2.4% for not received adequate thienopyridine loading.
clopidogrel (HR 0.48; 95% CI 0.36 to 0.64; P⬍0.001).
Prasugrel was associated with a significant increase in the 3. Recommendations for the Use of
rate of bleeding, notably, TIMI major hemorrhage, which was observed in 2.4% of patients taking prasugrel and in 1.8% of (See Table 3 and Appendix 4.) patients taking clopidogrel (HR for prasugrel versus clopidogrel


December 1, 2009
Recommendations for the Use of Thienopyridines
Comments (All Modified Recommendations Are for STEMI Recommendations PCI Recommendations 2009 Joint STEMI/PCI Focused Update Recommendations Patients With ACS) 2004 STEMI Guidelines, 2007 PCI Update, Table 14 4. For patients who have undergone 4. A loading dose of clopidogrel,* generally 1. A loading dose of thienopyridine is recommended for STEMI patients for Modified recommendation diagnostic cardiac catheterization 600 mg, should be administered before whom PCI is planned. Regimens should be 1 of the following: (changed text).
and for whom PCI is planned, or when PCI is performed. (Level of a. At least 300 to 600 mg of clopidogrel† should be given as early as clopidogrel should be started and Evidence: C) In patients undergoing PCI possible before or at the time of primary or nonprimary PCI. (Level of continued for at least 1 month within 12 to 24 hours of receiving Evidence: C) after bare metal stent fibrinolytic therapy, a clopidogrel oral b. Prasugrel 60 mg should be given as soon as possible for primary implantation and for several loading dose of 300 mg may be PCI.26,27 (Level of Evidence: B) months after drug-eluting stent considered. (Level of Evidence: C) c. For STEMI patients undergoing nonprimary PCI, the following
implantation (3 months for regimens are recommended: sirolimus, 6 months for (i) If the patient has received fibrinolytic therapy and has been given paclitaxel) and for up to 12 clopidogrel, clopidogrel should be continued as the thienopyridine months in patients who are not of choice (Level of Evidence: C); at high risk for bleeding. (Level (ii) If the patient has received fibrinolytic therapy without a of Evidence: B) thienopyridine, a loading dose of 300 to 600 mg‡ of clopidogrel should be given as the thienopyridine of choice (Level of Evidence: C); (iii) If the patient did not receive fibrinolytic therapy, either a loading dose of 300 to 600 mg of clopidogrel should be given or, once the coronary anatomy is known and PCI is planned, a loading dose of 60 mg of prasugrel should be given promptly and no later than 1 hour after the PCI.26,27 (Level of Evidence: B) 5. For all post-PCI stented patients receiving 2. The duration of thienopyridine therapy should be as follows: Modified recommendation a DES, clopidogrel 75 mg daily should be a. In patients receiving a stent (BMS or drug-eluting stent [DES]) during (pertains to STEMI and given for at least 12 months if patients PCI for ACS, clopidogrel 75 mg daily†27–29 (Level of Evidence: B) or are not at high risk of bleeding. For prasugrel 10 mg daily§27 (Level of Evidence: B) should be given for post-PCI patients receiving a BMS, at least 12 months; 关NSTEMI兴 based on clopidogrel should be given for a b. If the risk of morbidity because of bleeding outweighs the anticipated TRITON-TIMI 38).
minimum of 1 month and ideally up to benefit afforded by thienopyridine therapy, earlier discontinuation 12 months (unless the patient is at should be considered. (Level of Evidence: C) increased risk of bleeding; then it should be given for a minimum of 2 weeks).
(Level of Evidence: B) 2007 STEMI Update, Section 9 2. In patients taking clopidogrel in 3. In patients taking a thienopyridine in whom CABG is planned and can Modified recommendation whom CABG is planned, the drug be delayed, it is recommended that the drug be discontinued to allow (added prasugrel).
should be withheld for at least 5 for dissipation of the antiplatelet effect. (Level of Evidence: C) The days and preferably for 7 days period of withdrawal should be at least 5 days in patients receiving unless the urgency for clopidogrel2,30 (Level of Evidence: B) and at least 7 days in patients revascularization outweighs the receiving prasugrel†27 (Level of Evidence: C), unless the need for risks of excess bleeding. (Level revascularization and/or the net benefit of the thienopyridine outweighs of Evidence: B) the potential risks of excess bleeding.31 (Level of Evidence: C) Class IIa
2004 STEMI Guidelines, Section 2007 PCI Update, Table 14 1. If clopidogrel is given at the time of Deleted recommendation procedure, supplementation with GP IIb/IIIa receptor antagonists can be beneficial. (Level of Evidence: B) 2. For patients with an absolute Deleted recommendation contraindication to aspirin, it is reasonable to give a 300-mg to 600-mg loading dose of clopidogrel, administered at least 6 hours before PCI, and/or GP IIb/IIIa antagonists, administered at the time of PCI. (Level of Evidence: C) Class IIb
2004 STEMI Guidelines, Section 2007 PCI Update, Table 14 1. Continuation of clopidogrel therapy 1. Continuation of clopidogrel or prasugrel§ beyond 15 months may be Modified recommendation beyond 1 year may be considered in considered in patients undergoing DES placement.27 (Level of Evidence: C) (changed text).
patients undergoing DES placement.
(Level of Evidence: C) Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Comments (All Modified Recommendations Are for STEMI Recommendations PCI Recommendations 2009 Joint STEMI/PCI Focused Update Recommendations Patients With ACS) Class III
1. In STEMI patients with a prior history of stroke and transient ischemic New recommendation attack for whom primary PCI is planned, prasugrel is not recommended as part of a dual-antiplatelet therapy regimen. (Level of Evidence: C) *Available data for prasugrel use are for PCI for acute coronary syndrome (ACS) and not elective PCI. Recommendations for elective PCI with clopidogrel use are not being updated in this guideline focused update.
†The optimum loading dose of clopidogrel has not been established. Randomized trials establishing its efficacy and providing data on bleeding risks used a loading dose of 300 mg orally followed by a daily oral dose of 75 mg.26,27 Higher oral loading doses such as 600 mg or more than 900 mg36 of clopidogrel more rapidly inhibitplatelet aggregation and achieve a higher absolute level of inhibition of platelet aggregation, but the additive clinical efficacy and safety of higher oral loading doseshave not been rigorously established. The necessity for giving a loading dose of clopidogrel before PCI is driven by the pharmacokinetics of clopidogrel, for whichseveral hours are required to achieve desired levels of platelet inhibition. For post-PCI patients receiving a stent (BMS or DES), a daily maintenance dose should begiven for at least 12 months and for up to 15 months unless the risk of bleeding outweighs the anticipated net benefit afforded by a thienopyridine.
‡Clopidogrel loading dose after fibrinolytic therapy: For patients given fibrin- and non–fibrin-specific fibrinolytic drugs who are undergoing PCI within 24 hours, 300 mg; for patients given a fibrin-specific fibrinolytic undergoing PCI after more than 24 hours, 300 to 600 mg; for patients given a non–fibrin-specific fibrinolyticundergoing PCI between 24 and 48 hours, 300 mg; for patients given a non–fibrin-specific fibrinolytic undergoing PCI after 48 hours, 300 to 600 mg.
§Patients weighing ⬍60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once-daily maintenance dose. Consideration should be given to lowering the maintenance dose to 5 mg in patients who weigh ⬍60 kg. The effectiveness and safety of the 5-mg dose havenot been studied prospectively. For post-PCI patients receiving a stent (BMS or DES), a daily maintenance dose should be given for at least 12 months and for upto 15 months unless the risk of bleeding outweighs the anticipated net benefit afforded by a thienopyridine. Do not use prasugrel in patients with active pathologicalbleeding or a history of transient ischemic attack or stroke. In patients ⱖ75 years of age, prasugrel is generally not recommended because of the increased risk offatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or a history of prior MI) in which its effect appears to begreater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. When possible, discontinue prasugrel at least 7 days beforeany surgery. Additional risk factors for bleeding include body weight ⬍60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding(eg, warfarin, heparin, fibrinolytic therapy, or chronic use of nonsteroidal anti-inflammatory drugs).
1.32; 95% CI 1.03 to 1.68, P⫽0.03), which represented an A post hoc analysis suggested there were 3 subgroups of increase in the relative rate of major bleeding of 32%. From the ACS patients who did not have a favorable net clinical benefit standpoint of safety, prasugrel was associated with an in- (defined as the rate of death due to any cause, nonfatal MI, crease of 35 TIMI major and non– coronary artery bypass nonfatal stroke, or non–CABG-related nonfatal TIMI major graft bleeds (number needed to harm⫽167).27 Also, greater bleeding) from the use of prasugrel or who had net harm: rates of life-threatening bleeding were evident in the prasug- Patients with a history of stroke or transient ischemic attack rel group than in the clopidogrel group: 1.4% versus 0.9%, (TIA) before enrollment had net harm from prasugrel (HR respectively (HR for prasugrel 1.52; 95% CI 1.08 to 2.13; 1.54; 95% CI 1.02 to 2.32; P⫽0.04), patients 75 years of age P⫽0.01), which included nonfatal bleeding (1.1% versus and older had no net benefit from prasugrel (HR 0.99; 95% CI 0.9%; HR for prasugrel 1.25; 95% CI 0.87 to 1.81; 0.81 to 1.21; P⫽0.92); and patients with a body weight of less P⫽0.23) and fatal bleeding (0.4% versus 0.1%; HR for than 60 kg had no net benefit from prasugrel (HR 1.03; 95% prasugrel 4.19; 95% CI 1.58 to 11.11; P⫽0.002). In the CI 0.69 to 1.53; P⫽0.89). In both treatment groups, patients few patients who underwent coronary artery bypass graft with at least 1 of these risk factors had higher rates of (CABG), TIMI major bleeding through 15 months was also bleeding than those without them.27 A pharmacokinetic anal- greater with prasugrel than with clopidogrel (13.4% versus ysis showed greater exposure to the active metabolite of 3.2%, respectively; HR for prasugrel 4.73; 95% CI 1.90 to prasugrel for patients who weighed less than 60 kg and who 11.82; P⬍0.001).27 Despite the increase in bleeding, the were 75 years old or older.38 net clinical-benefit end point, which included all-cause The US Food and Drug Administration (FDA) approved mortality, ischemic events, and major bleeding events, prasugrel in July 2009 and incorporated the aforementioned favored prasugrel.27 subgroup findings into its labeling by citing a contraindica- Prasugrel showed superior efficacy in major prespecified tion against prasugrel use in patients with a history of TIA or subgroups in the overall ACS population. The benefit tended to stroke and active pathological bleeding. The FDA further be greater among the 3146 patients with diabetes (12.2% of recommends that consideration be given to lowering the whom had the primary end point in the prasugrel group versus maintenance dose of prasugrel to 5 mg in patients who weigh 17.0% in the clopidogrel group; HR 0.70; 95% CI 0.58 to 0.85; less than 60 kg, with a note that the effectiveness and safety P⬍0.001) than among the 10 462 patients without diabetes of the 5-mg dose have not been studied prospectively to date.
(9.2% of whom had the primary end point in the prasugrel group The FDA labeling information includes a general warning versus 10.6% in the clopidogrel group; HR 0.86; 95% CI 0.76 to against the use of prasugrel in patients older than 75 years of 0.98; P⫽0.02). The rate of definite or probable stent thrombosis age because of concerns of an increased risk of fatal and was significantly reduced in the prasugrel group compared with intracranial bleeding and uncertain benefit, except in high- the clopidogrel group, as noted.27 risk situations (patients with diabetes or a history of prior December 1, 2009
MI), in which case its effect appears to be greater and its use Determination of patient groups that should be considered may be considered.37 for continuation of dual-antiplatelet treatment beyond 12 In focusing specifically on patients with STEMI, the months is based on patient-level factors (eg, age, history of primary composite end point of cardiovascular death, nonfa- bleeding) and lesion characteristics (eg, bifurcation, small- tal MI, or nonfatal stroke was significantly reduced in patients diameter vessel).28 assigned to prasugrel at 30 days compared with patients who In previous studies of patients with prior stroke or TIA, use received clopidogrel (6.5% versus 9.5%; HR 0.68; 95% CI of dual-antiplatelet therapy has been associated with an 0.54 to 0.87; P⫽0.0017), and this trend persisted to 15 increased risk of adverse outcomes, notably intracranial months (HR 0.79; 95% CI 0.65 to 0.97; P⫽0.0221).13 bleeding, compared with single-antiplatelet therapy. In the Furthermore, in the STEMI group, the key secondary end MATCH (Management of Atherothrombosis With Clopi- point of cardiovascular death, MI, or urgent TVR was dogrel in High-Risk Patients With TIA or Stroke) trial40 in significantly reduced with prasugrel at 30 days (P⫽0.0205) which patients with prior stroke or TIA and additional risk and 15 months (P⫽0.0250).13 At 30 days and 15 months, the factors (n⫽7599) were allocated to clopidogrel 75 mg or individual end points of cardiovascular death and MI, as well combination therapy with clopidogrel 75 mg plus ASA 75 mg as stent thrombosis, were reduced with prasugrel.13 per day, there was no significant benefit of combination The interaction testing for efficacy and safety showed no therapy compared with clopidogrel alone in reducing the significant difference in bleeding risk regardless of the type primary outcome of the composite of ischemic stroke, MI, of ACS (eg, UA/NSTEMI versus STEMI). Thus, the STEMI vascular death, or rehospitalization due to ischemic events, or results for efficacy and safety are consistent with the main any of the secondary outcomes. The risk of major hemorrhage results of the trial. In a post hoc analysis of patients with was significantly increased in the combination-therapy group anterior MI, event rates at 15 months for the primary end compared with those given clopidogrel alone, with a 1.3% point were lower with prasugrel (9.8% for prasugrel versus absolute increase in life-threatening bleeding. Although clo- 16.3% for clopidogrel; HR 0.57; 95% CI 0.42 to 0.78; pidogrel plus ASA is recommended over ASA alone for P⫽0.0003). In patients with nonanterior MI, treatment effects patients with ACS,41–43 the results of MATCH do not suggest did not differ for the primary end point (10.1% for prasugrel a similar risk-benefit ratio for stroke and TIA survivors. The versus 9.9% for clopidogrel; HR 1.02; 95% CI 0.78 to 1.34; AHA/American Stroke Association's Guidelines for Preven- P⫽0.8749). The test for heterogeneity of the effect of tion of Stroke in Patients With Ischemic Stroke or Transient prasugrel was significant (P⫽0.0053), which suggests that Ischemic Stroke contain a Class III recommendation for the the benefit might vary by the location of the MI. Data were use of ASA in combination with clopidogrel in patients with consistent in both the primary and secondary PCI prior stroke or TIA.44 On the other hand, a post hoc analysis from the CHARISMA (Clopidogrel for High Atherothrom- The writing group weighed the current data regarding the botic Risk and Ischemic Stabilization, Management, and use of thienopyridine therapy in patients who remain hospi- Avoidance) trial, which included 9478 patients, suggested talized after STEMI and are candidates for CABG and that patients with documented prior MI, ischemic stroke, or retained the 2007 focused update recommendation of empiric symptomatic peripheral artery disease derive benefit from discontinuation of clopidogrel therapy for at least 5 days and dual-antiplatelet therapy with clopidogrel plus ASA.45 Al- at least 7 days in patients receiving prasugrel before planned though MATCH and CHARISMA did not involve STEMI patients, the writing group recommended weighing the ben- Platelet function testing to determine the degree of platelet efits and risks of prescribing clopidogrel and ASA in patients with a recent history of TIA or stroke. Given prasugrel's 39 may be used, and if platelet function has normalized, CABG may be performed at an earlier time. Additionally, other greater tendency to cause intensive inhibition of plateletaggregation in general and the findings of increased levels of strategies of platelet inhibition (GP IIb/IIIa receptor antagonists) bleeding compared with clopidogrel in this population, the may be used if recurrent ischemia is a concern during the waiting use of prasugrel as part of a dual-antiplatelet therapy regimen period for CABG. Ultimately, the patient's clinical status will in patients with prior stroke or TIA is contraindicated.37 determine the risk-to-benefit ratio of CABG compared withawaiting restoration of platelet function.
3.1.1. Additional Thienopyridine Information The results of TRITON-TIMI 38 influenced dosing recom- Although clopidogrel in combination with ASA has been mendations for loading and chronic thienopyridine therapy shown to reduce recurrent coronary events in the posthospi- with prasugrel. Sixty milligrams of prasugrel is now recom- talized ACS population,32,43,46 the response to clopidogrel mended as a loading dose for primary PCI in STEMI. For varies among patients, and clopidogrel resistance has been secondary PCI in those patients who have recurrent ischemia observed.43 Information is accumulating about the variations or other reasons for planned intervention during their course in the antiplatelet effect of clopidogrel in patients with of treatment, 60 mg of prasugrel may be given after the loss-of-function alleles in the gene encoding CYP450 coronary anatomy has been identified (to avoid dosing those 2C19.32,46–50 These patients form a subgroup in which failure patients who require CABG) either before, during, or within of clopidogrel effectiveness has been linked to adverse 1 hour of PCI.27 Furthermore, 10 mg of prasugrel may be clinical outcomes.30,47–51 In TRITON-TIMI 38 and 3 of the used in addition to ASA for chronic dual-antiplatelet cohort studies,47,49,52 patients who were carriers of a reduced- function CYP450 2C19 allele had significantly lower levels Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
of the active metabolite of clopidogrel, diminished platelet MIs, with deaths and nonfatal strokes being similar, bleeding inhibition, and increased rates of cardiovascular events (eg, was increased in the prasugrel group.27 In addition, the death, MI, stroke), including stent thrombosis,53 compared comparison of the 2 drugs is based on a single large trial.
with the extensive metabolizers.54 In another cohort study Also, the loading dose of clopidogrel in TRITON-TIMI 38 with 2208 patients,50 the increased event rate was observed was lower than is currently recommended in these guidelines.
only in poor metabolizers. (Prasugrel has a higher level of Furthermore, there are some emerging studies that suggest inhibition of platelet aggregation than clopidogrel and a more there may be some patients who are resistant to clopidogrel, rapid onset of action.55 Its metabolism is not affected by the but there is little information about the use of strategies to 2C19 allele variant.56) select patients who might do better with prasugrel. There is Accordingly, the effective clopidogrel dose for an individ- not yet experience with the use of prasugrel in routine ual undergoing PCI for STEMI may not be known. A large community practice. As a result, the writing group believes randomized trial57 is attempting to determine whether adjust- that there is some uncertainty regarding the net benefit and ment of clopidogrel therapy on the basis of platelet function risks of 1 drug over another for a given patient. Consider- testing with a point-of-care assay safely improves outcomes ations of efficacy in the prevention of thrombosis and risk of after PCI with DES. As noted in the drug dosing table an adverse effect related to bleeding, as well as experience (Appendix 4), the current recommended loading dose for with a given medication, may best guide decisions about the clopidogrel is uncertain. In addition, a period of several hours choice of thienopyridine for individual patients.
is required to metabolize clopidogrel to its active metabolite, 3.2. Proton Pump Inhibitors and Dual-Antiplatelet
which leaves a window of time during which there is a Therapy for ACS
reduced level of effectiveness even in responders.
Proton pump inhibitors (PPIs) are often prescribed prophy- With regard to clopidogrel loading for PCI after a patient lactically when clopidogrel is started, to prevent gastrointes- has received fibrinolytic therapy, there are no studies that tinal complications such as ulceration and related bleeding59 have formally tested a 600-mg (or higher) clopidogrel loading due to dual-antiplatelet therapy, in particular ASA and dose administered with fibrinolytic treatment. The only study clopidogrel.32 Coupled with concern about the gastrointesti- that tested any clopidogrel dose with a fibrinolytic was the nal precautions, there has been increased emphasis on the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion prevention of premature discontinuation of dual-antiplatelet Therapy–Thrombolysis in Myocardial Infarction 28) study, therapy, particularly in patients who have received a stent which randomized 3491 patients 75 years of age and younger (BMS or DES), for whom 12 months of antiplatelet therapy is who were receiving fibrinolytic therapy within 12 hours of recommended.28 PPI medications* have been found to inter- STEMI to clopidogrel (300-mg oral loading dose; 75-mg oral fere with the metabolism of clopidogrel.34 daily maintenance dose) or placebo.58 As described in the Although there are studies that show a pharmacodynamic 2007 STEMI focused update,4 patients who received clopi- interaction on ex vivo platelet function testing, to date there are dogrel had a reduced rate of an occluded infarct artery, no convincing randomized clinical trial data for an important accomplished by preventing infarct-related reocclusion rather clinical drug– drug interaction. Retrospective claims-based re- than by facilitating early reperfusion.
ports suggesting clinical harm, some detailed below, may be When considering a loading dose of clopidogrel for PCI after confounded by different baseline characteristics and lack of a patient has received a fibrinolytic agent, the available level of compliance data. There have been retrospective reports of evidence is limited (Level of Evidence: C), and consensus adverse cardiovascular outcomes (eg, readmission for ACS) opinion suggests it is dependent on how many hours have when the antiplatelet regimen of clopidogrel and ASA is elapsed since fibrinolytic therapy was administered before PCI.
accompanied by PPIs, assessed as a group, compared with the For patients who have received any fibrinolytic agent and use of this regimen without a PPI.32–34,60 In a retrospective subsequently proceed to PCI within 24 hours, a dose of 300 mg cohort study from the Veterans Affairs' medical records and of clopidogrel as a loading dose is suggested. If the patient pharmacy database, concomitant clopidogrel and PPI therapy received a fibrin-specific fibrinolytic agent and then proceeds to (with omeprazole, rabeprazole, lansoprazole, or pantoprazole) at PCI after 24 hours has elapsed, a loading dose of 300 to 600 mg any time point during follow-up of 8205 patients discharged for may be considered. If at least 48 hours has elapsed after ACS was associated with an increased risk of death or rehospi- treatment with a non–fibrin-specific fibrinolytic agent, a dose of talization for ACS.32 Other post hoc study analyses50,61 and a 300 to 600 mg may be considered.
retrospective data analysis from the NHLBI Dynamic Registry62 Prasugrel has not been studied in patients who have in which PPIs were assessed as a class in combination with a received fibrinolytic therapy. Thus, for STEMI patients un- clopidogrel and an ASA regimen have not found an effect of PPI dergoing nonprimary PCI who received prior fibrinolytic therapy on the clinical effect of clopidogrel in ACS patients, therapy without a thienopyridine, only a loading dose with clopidogrel should be given as the thienopyridine of choice.
Some studies have suggested that adverse cardiovascular 3.1.2. Choice of Thienopyridine for PCI in STEMI outcomes with the combination of clopidogrel and a PPI are The guidelines do not endorse explicitly one of the thienopy-ridines over the other. There were several reasons for this *PPIs include omeprazole, lansoprazole, pantoprazole, rabeprazole, and es- decision. Although the composite efficacy end point favored omeprazole (which are all available by prescription). Omeprazole is also sold prasugrel, driven predominantly by a difference in nonfatal over the counter for frequent heartburn.66 December 1, 2009
explained by the individual PPI, in particular the use of a PPI was 6%.67 The writing committee concluded that additional that inhibits CYP450 2C19, which includes omeprazole, data, notably randomized controlled clinical trial data that lansoprazole, and rabeprazole. The PPI omeprazole notably have been peer reviewed and published, are needed before an has been reported to significantly decrease the inhibitory official recommendation can be made about the use of dual effect of clopidogrel on platelet aggregation.63,64 One study antiplatelet therapy with PPIs in the setting of ACS.
reported that the PPI pantoprazole was not associated withrecurrent MI among patients receiving clopidogrel, possibly 4. Recommendations for the Use of
because of its lack of inhibition of CYP450 2C19.33 Other studies have examined the thienopyridine agent (See Table 4 and Appendix 4.) prescribed with the PPI. One open-label drug study evaluated 4.1. Parenteral Anticoagulants
the effects of the PPI lansoprazole on the pharmacokinetics Parenteral anticoagulants include intravenous UFH, bivaliru- and pharmacodynamics of prasugrel and clopidogrel in din, enoxaparin, and fondaparinux. Bivalirudin was briefly healthy subjects given single doses of prasugrel (60 mg) and cited in the 2007 STEMI focused update. The HORIZONS- clopidogrel (300 mg) with and without concurrent lansopra- AMI trial, which was reported subsequently, was a prospec- zole 30 mg per day. The data suggest that inhibition of tive, open-label, randomized, multicenter, international trial platelet aggregation was reduced in patients who took the that included 3602 patients with STEMI undergoing primary combination of clopidogrel and lansoprazole, whereas it was PCI. Patients were randomized to treatment with UFH plus a unaffected after a prasugrel dose.56 GP IIb/IIIa receptor antagonist or to bivalirudin alone (with Another study35 assessed the association of PPIs with the provisional abciximab or double-bolus eptifibatide). The pharmacodynamics and clinical efficacy of clopidogrel and primary efficacy end point was a composite of net adverse prasugrel, based on populations from 2 randomized trials, the clinical events, including major bleeding plus MACE, a PRINCIPLE (Prasugrel In Comparison to Clopidogrel for composite of cardiovascular death, reinfarction, TVR for Inhibition of Platelet Activation and Aggregation) TIMI-44 ischemia, and stroke within 30 days. Bivalirudin alone trial65 and the TRITON-TIMI 38 trial.27 The findings indi-cated that first, PPI treatment attenuated the pharmacody- resulted in a lower incidence of net adverse clinical events at namic effects of clopidpgrel and, to a lesser extent, those of 30 days (9.2% versus 12.1%; RR 0.76; 95% CI 0.63 to 0.92; prasugrel. Secondly, PPI treatment did not affect the clinical P⫽0.005; NNT⫽34) and at 1 year (15.7% versus 18.3%, HR outcome of patients given clopidogrel or prasugrel. This 0.84; 95% CI 0.71 to 0.98; P⫽0.3).9 The difference was finding was true for all PPIs that were studied, including driven by a significant decrease in major bleeding complica- omeprazole and pantoprazole.
tions with bivalirudin at 30 days (4.9% versus 8.3%, The FDA communication concerning an ongoing safety P⫽0.001; number needed to harm⫽33) and 1 year (5.8% review of clopidogrel bisulfate66 advises that healthcare versus 9.2%, P⫽0.001). There was a statistically significant providers avoid the use of clopidogrel in patients with 1% increase in stent thrombosis (n⫽17) within the first 24 impaired CYP2C19 function due to known genetic varia- hours with bivalirudin but no subsequent difference (1.3% tion or due to drugs that inhibit CYP2C19 activity. The versus 0.3%, P⬍0.001). More deaths at 30 days occurred FDA notes that there is no evidence that other drugs that after major bleeding (n⫽26) than after reinfarction (n⫽10) or reduce stomach acid, such as H2 blockers or antacids, definite stent thrombosis (n⫽5).9 Treatment with bivalirudin interfere with the antiplatelet activity of clopidogrel.
resulted in significantly lower 30-day rates of death due to Further research with thienopyridines and PPI combina- cardiac causes (1.8% versus 2.9%; RR 0.62; 95% CI 0.40 to tions, particularly drugs that are not dependent on CYP450 0.95; P⫽0.03) and death due to all causes (2.1% versus 3.1%; 2C19, is needed. Consideration may be given to the use of H2 RR 0.66; 95% CI 0.44 to 1.00; P⫽0.047 compared with UFH antagonists as an alternative to PPIs in the setting of dual- plus GP IIb/IIIa inhibitors). At 1 year, MACE rates were antiplatelet therapy, although they cannot be relied on to identical, but there was a decrease in all-cause mortality with protect as well as PPIs, and there are few data about their use bivalirudin (3.4% versus 4.8%, P⫽0.03).68 with ASA.59 The FAMOUS (Famotidine for the Prevention of Concerns about the trial include its open-label design and Peptic Ulcers in Users of Low-Dose Aspirin) trial, a phase II, the administration of UFH before randomization in 66% of double-blind, randomized, placebo-controlled trial, found that patients in the bivalirudin arm and 76% of patients in the among patients with a history of coronary heart disease, UFH plus GP IIb/IIIa receptor antagonist arm. Only 615 diabetes mellitus, or cerebrovascular disease who were taking patients received bivalirudin monotherapy, and only 60% of low-dose ASA, 12 weeks of famotidine 20 mg twice daily patients in the trial received a 600-mg clopidogrel loading (n⫽204) compared with placebo twice daily (n⫽200) was dose. Major bleeding as defined in the publication included beneficial in reducing the incidence of peptic ulcer or hematomas of 5 cm, intracranial hemorrhage, and bleeding esophagitis during follow-up endoscopy at 12 weeks. The rate that required surgery. Additionally, the study put forth a of occurrence of a gastric ulcer at endoscopy at 12 weeks was composite primary end point that combined efficacy and 3.4% in the famotidine group versus 15% in the placebo safety. Although there were no statistically significant inter- group (P⫽0.0002), duodenal ulcer occurred in 0.5% versus actions at 30 days between the treatment assignment and 8.5% (P⫽0.0045), and erosive esophagitis was seen in 4.4% preprocedural UFH use or clopidogrel loading dose with versus 19% (P⬍0.0001), respectively. Of note, in the famo- respect to MACE or major bleeding, the occurrence of an tidine group, clopidogrel use was 19% and dipyridamole use increase in early stent thrombosis with bivalirudin and the Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Recommendations for the Use of Parenteral Anticoagulants
2009 Joint STEMI/PCI Focused Update STEMI Recommendations PCI Recommendations 2007 STEMI Update, Section 8 2007 PCI Guideline Update, Table 13 2. For patients undergoing PCI after having 1. For patients undergoing PCI after having received 1. For patients proceeding to primary Modified recommendation. (Bivalirudin received an anticoagulant regimen, the an anticoagulant regimen, the following dosing PCI who have been treated with was added as an acceptable following dosing recommendations should recommendations should be followed: ASA and a thienopyridine, anticoagulant for primary PCI; text a. For prior treatment with UFH, administer recommended supportive about UFH was modified to a. For prior treatment with UFH, additional boluses of UFH as needed to support anticoagulant regimens include the mention activated clotting time administer additional boluses of UFH the procedure, taking into account whether GP levels. Information on enoxaparin as needed to support the procedure, IIb/IIIa receptor antagonists have been a. For prior treatment with UFH, and fondaparinux was not taking into account whether GP IIb/IIIa administered. (Level of Evidence: C) Bivalirudin additional boluses of UFH should receptor antagonists have been may also be used in patients treated previously be administered as needed to administered. (Level of Evidence: C) with UFH. (Level of Evidence: C) maintain therapeutic activated these drugs were unchanged.) Bivalirudin may also be used in b. For prior treatment with enoxaparin, if the last clotting time levels, taking into patients treated previously with UFH. subcutaneous dose was administered at least 8 account whether GP IIb/IIIa (Level of Evidence: C) to 12 hours earlier, an IV (intravenous) dose of receptor antagonists have been b. For prior treatment with enoxaparin, if 0.3 mg/kg of enoxaparin should be given; if the administered. (Level of the last subcutaneous dose was last subcutaneous dose was administered within Evidence: C) administered within the prior 8 hours, the prior 8 hours, no additional enoxaparin b. Bivalirudin is useful as a no additional enoxaparin should be should be given. (Level of Evidence: B) supportive measure for primary given; if the last subcutaneous dose c. For prior treatment with fondaparinux, administer PCI with or without prior treatment was administered at least 8 to 12 additional intravenous treatment with an with UFH.9 (Level of hours earlier, an intravenous dose of anticoagulant possessing anti-IIa activity, taking Evidence: B) 0.3 mg per kg of enoxaparin should into account whether GP IIb/IIIa receptor be given. (Level of Evidence: B) antagonists have been administered. (Level of c. For prior treatment with fondaparinux, Evidence: C) administer additional intravenous treatment with an anticoagulant possessing anti-IIa activity taking into account whether GP IIb/IIIa receptor antagonists have been administered.
(Level of Evidence: C) Class IIa
1. In STEMI patients undergoing PCI New recommendation who are at high risk of bleeding, bivalirudin anticoagulation is reasonable.9 (Level of Evidence: B) excess bleeding with UFH and GP IIb/IIIa inhibitors may be PCI.4 These terms are no longer used for the recommenda- related to the degree of platelet inhibition and antithrombin tions in this update so that the contemporary therapeutic activity associated with these treatment doses.
choices that lead to reperfusion as part of the treatment of A preliminary report suggested that the use of bivalirudin patients presenting with STEMI can be described without alone (P⫽0.005) and a lower loading dose of clopidogrel these potentially misleading labels.
(300 versus 600 mg; P⫽0.01) were independent predictors of A brief review of facilitated PCI, however, is needed. This acute and subacute stent thrombosis rates, respectively.69 strategy involves full- or half-dose fibrinolytic therapy with Probability values for secondary end points may not have or without a GP IIb/IIIa receptor antagonist, followed by been adjusted for multiple looks.
immediate PCI. Two studies addressed this issue: ASSENT-4 Therefore, the writing group now considers bivalirudin PCI (Assessment of the Safety and Efficacy of a New useful for primary PCI in STEMI whether or not the patient Treatment Strategy With Percutaneous Coronary Interven- received pretreatment with UFH. The risk of acute stent tion),70 which was described in detail in the 2007 PCI and thrombosis associated with bivalirudin appeared to be miti- STEMI focused updates, and FINESSE,71 which was a gated by the prior use of UFH and the risk of subacute stent randomized, double-blind clinical trial of 2452 patients ran- thrombosis by the use of a 600-mg loading dose of clopi- domized within 6 hours of symptom onset to receive reduced- dogrel. These data should be confirmed by prospective dose reteplase plus abciximab followed by PCI (combination- facilitated PCI), abciximab alone followed by PCI 5. Recommendations for Triage and Transfer
(abciximab-facilitated PCI), or placebo (primary PCI).
ASSENT-4 patients treated with fibrinolytic therapy (See Table 5 and Appendix 5.) before PCI had increased rates of adverse outcomes,including in-hospital death (6% versus 3%). The investi- 5.1. Triage and Transfer for PCI
gators theorized that suboptimal antithrombotic therapy 5.1.1. STEMI Patients Who Are Candidates for Reperfusion (ie, the lack of a heparin infusion after bolus administra- The 2007 STEMI Focused Update describes several strate- tion, no upfront loading dose of clopidogrel, and prohibi- gies for reperfusion, among them facilitated PCI and rescue tion of IIb/IIIa use except for bailout) and a short time December 1, 2009
Recommendations for Triage and Transfer for PCI
2009 Joint STEMI/PCI Focused Update Recommendations 1. Each community should develop a STEMI system of care that follows New recommendation standards at least as stringent as those developed for the AHA'snational initiative, Mission: Lifeline, to include the following: ongoing multidisciplinary team meetings that include emergency medical services, non–PCI-capable hospitals/STEMI referralcenters, and PCI-capable hospitals/STEMI receiving centers toevaluate outcomes and quality improvement data; a process for prehospital identification and activation; destination protocols for STEMI receiving centers; transfer protocols for patients who arrive at STEMI referral centers who are primary PCI candidates, are ineligible for fibrinolyticdrugs, and/or are in cardiogenic shock. (Level of Evidence: C) Class IIa
1. It is reasonable for high-risk* patients who receive fibrinolytic New recommendation therapy as primary reperfusion therapy at a non–PCI-capable facility to be transferred as soon as possible to a PCI-capable facility wherePCI can be performed either when needed or as a pharmacoinvasivestrategy. Consideration should be given to initiating a preparatoryantithrombotic (anticoagulant plus antiplatelet) regimen before andduring patient transfer to the catheterization laboratory.14,15 (Level ofEvidence: B) Class IIb
(From 2007 STEMI Update, Section 5) 1. Facilitated PCI using regimens other than full-dose 1. Patients who are not at high risk who receive fibrinolytic therapy as fibrinolytic therapy might be considered as a primary reperfusion therapy at a non–PCI-capable facility may be reperfusion strategy when all of the following are considered for transfer as soon as possible to a PCI-capable facility (changed text).
present: a. Patients are at high risk, b. PCI is not where PCI can be performed either when needed or as a immediately available within 90 minutes, and c.
pharmacoinvasive strategy. Consideration should be given to Bleeding risk is low (younger age, absence of initiating a preparatory antithrombotic (anticoagulant plus antiplatelet) poorly controlled hypertension, normal body regimen before and during patient transfer to the catheterization weight). (Level of Evidence: C) laboratory. (Level of Evidence: C) (From 2007 STEMI Update, Section 6) 1. A strategy of coronary angiography with intent to Deleted recommendation perform PCI in the absence of 1 or more of the above Class I or IIa indications might be reasonable in moderate- and high-risk patients, but its benefits and risks are not well established.
The benefits of rescue PCI are greater the earlierit is initiated after the onset of ischemicdiscomfort. (Level of Evidence: C) *High risk was defined in the CARESS-in-AMI15 study as STEMI patients with ⱖ1 high-risk feature (extensive ST-segment elevation, new-onset left bundle-branch block, previous MI, Killip class ⬎2, or left ventricular ejection fraction ⱕ35% for inferior MIs; anterior MI alone with ⱖ2 mm of ST elevation in ⱖ2 leads also qualifiedthe patient as being at high risk). It was defined in TRANSFER-AMI14 as ⱖ2 mm of ST-segment elevation in 2 anterior leads or ST elevation of at least 1 mm in inferiorleads with at least 1 of the following: systolic blood pressure ⬍100 mm Hg, heart rate ⬎100 bpm, Killip class II to III, ⱖ2 mm of ST-segment depression in the anteriorleads, or ⱖ1 mm of ST elevation in right-sided lead V4 indicative of right ventricular involvement.
from fibrinolytic therapy to PCI contributed in part to the difference would be significant if the trial had been allowed adverse clinical outcomes.
to continue to its planned completion.
FINESSE8 showed that neither PCI preceded by abciximab The indications for rescue PCI have been defined by a and reteplase nor PCI preceded by abciximab alone was combination of clinical and electrocardiographic clues that an superior to abciximab used at the time of PCI among patients infarct artery has not reperfused. These are relief of pain and presenting within 4 hours of medical contact. Neither the resolution of ST-segment elevation. Although complete relief primary end point (a composite of death due to all causes, of pain and complete resolution of ST elevation are reason- ventricular function more than 48 hours after randomization, ably predictive of reperfusion after fibrinolytic therapy, this is cardiogenic shock, and congestive heart failure during the not a common occurrence. In the 2007 STEMI Focused first 90 days after randomization) nor mortality was signifi- Update, the writing committee held that at 90 minutes after cantly different among the groups. Although the study was initiation of fibrinolytic therapy, if there was less than 50% terminated early because of recruitment challenges, there was ST-segment resolution in the lead that showed the greatest less than a 2% chance that the primary treatment group degree of ST elevation at presentation, then fibrinolytic Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
therapy had likely failed to reperfuse the patient.4 If the who had at least 1 high-risk feature (greater than or equal to judgment was made that fibrinolytic therapy had not resulted 2 mm of ST-segment elevation in 2 anterior leads, systolic in reperfusion after 90 minutes, then PCI performed at that blood pressure less than 100 mm Hg, heart rate higher than time was labeled rescue PCI.
100 bpm, Killip class II to III, 2 mm or more of ST-segment The 2007 STEMI Focused Update4 recommended rescue depression in the anterior leads, or 1 mm or more of ST PCI in the following cases: Fibrinolytic-treated STEMI pa- elevation in right-sided lead V4 indicative of right ventricular tients meeting high-risk criteria (ie, cardiogenic shock [less involvement for inferior MIs; anterior MI alone with 2 mm or than 75 years of age, Class I; 75 years of age or older, Class more of ST-segment elevation in 2 or more leads also IIa]); hemodynamic or electrical instability; persistent ische- qualified) and who were treated with fibrinolytic therapy mic symptoms; and for certain moderate- and high-risk were randomized to a pharmacoinvasive strategy (immediate patients who did not strictly meet the above criteria (Class transfer for PCI within 6 hours of fibrinolytic therapy) or to IIb). These recommendations were based on results of the standard treatment after fibrinolytic therapy, which included REACT (Rescue Angioplasty Versus Conservative Treat- rescue PCI as required for ongoing chest pain and less than ment of Repeat Thrombolysis) trial74 which showed a clear 50% resolution of ST elevation at 60 to 90 minutes or benefit of rescue PCI (over repeated doses of fibrinolytics or hemodynamic instability. Standard-treatment patients who medical management) in moderate- to high-risk patients with did not require rescue PCI remained at the initial hospital for failed reperfusion, as well as a meta-analysis of 8 rescue PCI at least 24 hours, and coronary angiography within the first 2 trials (including REACT).73–76 The 2007 focused update weeks was encouraged.
acknowledged that the expected benefits of rescue PCI are All patients received standard-dose tenecteplase, ASA, and greater the earlier it is initiated after the onset of ischemic either UFH or enoxaparin. Clopidogrel loading (300 mg for patients 75 years of age or younger and 75 mg for those older Two new trials have helped inform this update: The than 75 years of age) was strongly encouraged in all study CARESS-in-AMI trial and the TRANSFER-AMI trial.
patients. GP IIb/IIIa receptor antagonists were administered CARESS-in-AMI15 studied 600 STEMI patients 75 years of at the PCI-capable hospitals according to standard practice at age or younger with at least 1 high-risk feature (extensive the institution. The primary end point of the trial was the ST-segment elevation, new-onset left bundle-branch block, 30-day composite of the first occurrence of death, reinfarc- previous MI, Killip class greater than 2, or left ventricular tion, recurrent ischemia, new or worsening heart failure, and ejection fraction 35% or less) who were treated initially at cardiogenic shock.
non-PCI hospitals with half-dose reteplase, abciximab, hep- The median time to administration of tenecteplase from arin, and ASA within 12 hours of symptom onset.3 All onset of symptoms was approximately 2 hours in both groups, patients were randomized to immediate transfer for PCI or to whereas the median time from tenecteplase administration to standard treatment with transfer for rescue PCI if needed. PCI catheterization was 2.8 hours in the pharmacoinvasive group was performed in 85.6% of patients in the immediate PCI and 32.5 hours in the standard-treatment group. Coronary group, and rescue PCI was performed in 30.3% of the angiography was performed in 98.5% versus 88.7% and PCI standard treatment/transfer for rescue PCI group. There was a in 84.9% versus 67.4% of the pharmacoinvasive and shorter median time from fibrinolytic therapy to transfer to a standard-treatment groups, respectively.
PCI-capable center in the immediate versus the rescue PCI The primary end point of the trial occurred in 11.0% of the group (110 versus 180 minutes, P⬍0.0001). Antiplatelet pharmacoinvasive group compared with 17.2% of the therapy with ASA and clopidogrel was used less frequently in standard-treatment group (RR 0.64; 95% CI 0.47 to 0.84; the standard care/rescue arm than in the early intervention P⫽0.004). Importantly, the incidence of TIMI major and group. The primary outcome (composite of all-cause mortal- minor bleeding and GUSTO (Global Use of Strategies to ity, reinfarction, and refractory myocardial ischemia within Open Occluded Coronary Arteries)77 moderate and severe 30 days of randomization) occurred significantly less often bleeding was not different between groups, although there (4.4% versus 10.7%, P⫽0.004) in the immediate PCI group was a higher incidence of GUSTO mild bleeding in the than in the standard care/rescue PCI group (NNT⫽17). There pharmacoinvasive group (13.0% compared with 9.0% in the were no significant differences in the rates of major bleeding standard-treatment group, P⫽0.036). The authors concluded at 30 days (3.4% versus 2.3%, P⫽0.47) or stroke (0.7% that after treatment with fibrinolytic therapy in STEMI versus 1.3%, P⫽0.50) between groups. These results suggest patients presenting to hospitals without PCI capability, trans- that high-risk STEMI patients treated at non-PCI hospitals fer to a PCI center to undergo coronary angiography and PCI with a preparatory pharmacological strategy of half-dose should be initiated immediately without waiting to determine fibrinolytic therapy, abciximab, heparin, and ASA have whether reperfusion has occurred. These results lend further improved outcomes when transferred immediately to a PCI support to the routine, early transfer of high-risk, fibrinolytic- facility rather than when medical therapy is continued with treated patients to a PCI center for early PCI supported by transfer for rescue PCI only if there is evidence of failed contemporary antiplatelet and antithrombotic therapy.
On the basis of this evidence, a pathway has been sug- The TRANSFER-AMI study14 further tested the pharma- gested for the care of STEMI patients that has been divided coinvasive strategy concept in high-risk STEMI patients.
into those patients presenting to a PCI-capable facility and Accordingly, 1059 patients who presented to a non–PCI- those presenting to a non–PCI-capable facility (Appendix 5).
capable hospital within 12 hours of symptom onset of STEMI Those seen at a PCI-capable facility should be moved December 1, 2009
expeditiously to the catheterization laboratory, with appropri- facility in that community should have an agreed-upon plan ate antithrombotic therapy for catheterization and PCI if for how STEMI patients are to be treated. This includes appropriate. There has been discussion about whether the which hospitals should receive STEMI patients from emer- recommended door-to-balloon time (or first medical contact– gency medical services units capable of obtaining diagnostic to-balloon time) should be greater than 90 minutes, with the ECGs, management at the initial receiving hospital, and recognition that in certain patients, the mortality advantage of written criteria and agreements for expeditious transfer of primary PCI compared with fibrinolytic therapy is maintained patients from non–PCI-capable to PCI-capable facilities.82 with more prolonged door-to-balloon times.78 However, the The development of regional systems of STEMI care is a writing groups continue to believe that the focus should be on matter of utmost importance.83,84 This includes encouraging developing systems of care to increase the number of patients the participation of key stakeholders in collaborative efforts with timely access to primary PCI rather than extending the to evaluate care using standardized performance and quality acceptable window for door-to-balloon time.79 Moreover, in a improvement measures, such as those endorsed by the ACC study of 43 801 patients with STEMI undergoing primary and the AHA for ACS.85 Standardized quality-of-care data PCI within the National Cardiovascular Data Registry, any registries designed to track and measure outcomes, compli- delay in time to reperfusion after arrival at the hospital was cations, and adherence to evidence-based processes of care associated with a higher adjusted risk of in-hospital mortality for ACS are also critical: programs such as the National in a continuous, nonlinear fashion (30 minutes⫽3.0%, 60 Cardiovascular Data Registry ACTION Registry, the AHA's minutes⫽3.5%, 90 minutes⫽4.3%, 120 minutes⫽5.6%, 150 "Get With The Guidelines" quality improvement program, minutes⫽7.0%, and 180 minutes⫽8.4%; P⬍0.001).80 Rather and those performance-measurement systems required by the than accepting a 90-minute door-to-balloon benchmark for Joint Commission and the Centers for Medicare and Medic- primary PCI, these data suggest an as-soon-as-possible aid Services.86–89 More recently, the AHA has promoted its "Mission: Lifeline" initiative, which was developed to en- Those patients presenting to a non–PCI-capable facility courage closer cooperation and trust among prehospital emer- should be triaged to fibrinolytic therapy or immediate transfer gency services, and cardiac care professionals.90 The evalu- for PCI. This decision will depend on multiple clinical ation of STEMI care delivery across traditional care-delivery observations that allow judgment of the mortality risk of the boundaries with these tools and other resources is imperative STEMI, the risk of fibrinolytic therapy, the duration of the to identify systems problems and to enable the application of symptoms when first seen, and the time required for transport modern quality improvement methods, such as Six Sigma, to to a PCI-capable facility.3 If primary PCI is chosen, the make necessary improvements.70,91–93 patient will be transferred for PCI. If fibrinolytic therapy ischosen, the patient will receive the agent(s), and a judgment 6. Recommendations for Intensive Glucose Control
as to whether the patient is high risk or not will be made. If high risk, the patient should receive appropriate antithrom- botic therapy and be moved immediately to a PCI-capablefacility for diagnostic catheterization and consideration of 6.1. Intensive Glucose Control
PCI. If not high risk, the patient may be moved to a As detailed in the 2004 STEMI guideline and the 2007 PCI-capable facility after receiving antithrombotic therapy or UA/NSTEMI guideline revision, randomized trial evidence may be observed in the initial facility.
supported the use of insulin infusion to control hyperglyce- Patients best suited for transfer for PCI are those STEMI mia.3,97 A recently published randomized clinical trial of patients who present with high-risk features, those with high intensive versus conventional glucose control in critically ill bleeding risk from fibrinolytic therapy, and patients pres- patients raised uncertainty regarding the optimal level to enting late, that is, more than 4 hours after onset of symp- target when achieving glucose control. NICE-SUGAR, a toms. The decision to transfer is a judgment made after large, international randomized trial (n⫽6104) of adults consideration of the time required for transport and the admitted to the intensive care unit with either medical or capabilities of the receiving hospital.2,5 Patients best suited surgical conditions, compared intensive glucose control (tar- for fibrinolytic therapy are those who present early after get glucose range 81 to 108 mg/dL) with conventional symptom onset with low bleeding risk. After fibrinolytic glucose control (to achieve a glucose level less than 180 therapy, if the patient is not at high risk, transfer to a mg/dL, with reduction and discontinuation of insulin if the PCI-capable facility may be considered, especially if symp- blood glucose level dropped below 144 mg/dL).16 Time- toms persist and failure to reperfuse is suspected.
weighted glucose levels achieved were 115⫾18 mg/dL in the The duration of symptoms should continue to serve as a intensive glucose control group versus 144⫾23 mg/dL in the modulating factor in selecting a reperfusion strategy for conventional glucose control group. The risk of death was STEMI patients. Although patients at high risk (eg, those increased at 90 days in the intensive glucose control group by with congestive heart failure, shock, and contraindications to 2.6% (27.5% versus 24.9%; odds ratio 1.14; 95% CI 1.02 to fibrinolytic therapy) are best served with timely PCI, "inor- 1.08; P⫽0.02; number needed to harm⫽38). The result dinate delays between the time from symptom onset and remained the same after adjustment for potential confounders.
effective reperfusion with PCI may prove deleterious, espe- There were significantly more episodes of treatment-related cially among the majority of STEMI patients at relatively low hypoglycemia in the intensely managed group (6.8% versus risk" (p 1299).81 Accordingly, each community and each 0.5%, P⫽0.001), although the contribution of hypoglycemia Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Recommendations for Intensive Glucose Control in STEMI
2004/2005/2007 Recommendations: 2004 STEMIGuidelines 2009 Joint STEMI/PCI Focused Update Recommendations 1. An insulin infusion to normalize blood glucose Recommendation is no longer current.
is recommended for patients with STEMI and See 2009 Class IIa complicated courses. (Level of Evidence: B) recommendation #1.
Class IIa
1. It is reasonable to use an insulin-based regimen to achieve New recommendation and maintain glucose levels less than 180 mg/dL whileavoiding hypoglycemia* for patients with STEMI with eithera complicated or uncomplicated course.16,94–96 (Level ofEvidence: B) 1. During the acute phase (first 24 to 48 hours) Recommendation is no longer current.
of the management of STEMI in patients with See 2009 Class IIa hyperglycemia, it is reasonable to administer recommendation #1.
an insulin infusion to normalize blood glucoseeven in patients with an uncomplicatedcourse. (Level of Evidence: B) *There is uncertainty about the ideal target range for glucose necessary to achieve an optimal risk-benefit ratio.
to excess mortality is uncertain.94,98 Overall, the hospital 7.1. Thrombus Aspiration
course and proximate causes of death were similar in the 2 Since the publication of the last STEMI and PCI focused groups. Excess deaths in the intensive-control group were updates, 2 new trials of manual thrombus aspiration have been predominantly due to cardiovascular causes (absolute differ- published. TAPAS was a single-center, unblinded, randomized ence 5.8%; P⫽0.02). More patients in the intensive-control clinical trial that compared 2 catheter-based reperfusion strate- group than in the conventional-control group were treated gies in 1071 patients with STEMI.17,102 Before coronary angiog- raphy, patients were randomized to manual thrombus aspiration Because NICE-SUGAR enrolled critically ill medical and before PCI (55.1% by direct stenting, 28.6% by balloon angio- surgical patients, the degree to which its results can be plasty followed by stenting, 10.1% by PCI without thrombus extrapolated to the management of patients with STEMI is aspiration) or conventional PCI with balloon angioplasty fol- unclear. Although recent data from a small, mechanistic lowed by stenting. BMS were implanted in 92% of PCI clinical trial28,29,98 suggest that glucose control may reduce procedures. All patients were treated with ASA, 600 mg of inflammation and improve left ventricular ejection fraction in clopidogrel, UFH, and abciximab unless contraindicated. TIMI patients with acute myocardial infarction (AMI), whether it myocardial blush grade 0 or 1 occurred in 17.1% of patients with will improve patient outcomes remains uncertain.
thrombus aspiration and 26.3% of those with conventional PCI A consensus statement by the American Association of (P⬍0.001). Complete resolution of ST-segment elevation oc- Clinical Endocrinologists and the American Diabetes Asso- curred in 56.6% and 44.2%, respectively (P⬍0.001). Death, ciation99 summarized that "although hyperglycemia is asso- reinfarction, and TVR rates at 30 days were not significantly ciated with adverse outcomes after AMI, reduction of glyce- different (6.8% versus 9.4%).17 However, at 1 year, rates of mia per se, and not necessarily the use of insulin, is associated cardiac death (3.6% versus 6.7%, P⫽0.02) and cardiac death or with improved outcomes. It remains unclear, however, nonfatal reinfarction (5.6% versus 9.9%, P⫽0.009) were lower whether hyperglycemia is a marker of underlying health with thrombus aspiration. Low myocardial blush grade and status or is a mediator of complications after AMI. Noniatro- incomplete ST-segment resolution were associated with clinical genic hypoglycemia has also been associated with adverseoutcomes and is a predictor of higher mortality" (p 1120).
There is a clear need for a well-designed, definitive random- EXPIRA was a smaller (n⫽175) randomized clinical trial ized trial of target-driven glucose control in STEMI that has that also compared thrombus aspiration with conventional meaningful clinical end points to determine glucose treatment PCI, but only in patients with TIMI flow 0/1.18 TIMI thresholds and glucose targets. Until such a trial is completed, myocardial blush grade of 2 or more (88% versus 60%, and based on the balance of current evidence,99–101 the writinggroup concluded that it was prudent to change the recommen- Recommendation for Thrombus Aspiration During PCI
dation for the use of insulin to control blood glucose in STEMI for STEMI
from a Class I to a Class IIa recommendation (Level of Evidence: 2009 Joint STEMI/PCI Focused Update B) and to recommend treatment for hyperglycemia greater than 180 mg/dL while avoiding hypoglycemia.
Class IIa
7. Recommendation for Thrombus Aspiration
1. Aspiration thrombectomy is reasonable for New recommendation During PCI for STEMI
patients undergoing primary PCI.17,18,102(Level of Evidence: B) December 1, 2009
Recommendations for the Use of Stents in STEMI
2009 Joint STEMI/PCI Focused Update Class IIa
1. It is reasonable to use a DES as an alternative to a New recommendation BMS for primary PCI in STEMI.11,105 (Level ofEvidence: B)* Class IIb
2007 PCI Guideline Update, Table 16 1. A DES may be considered for clinical and anatomic settings 1. A DES may be considered for clinical and anatomic Modified recommendation (level of in which the effectiveness/safety profile appears favorable settings† in which the efficacy/safety profile appears evidence changed from C to B).
but has not been fully confirmed by clinical trials. (Level of favorable.106–109 (Level of Evidence: B) Evidence: C) *Consideration for the use of stents (DES or BMS) in STEMI should include the ability of the patient to comply with prolonged dual-antiplatelet therapy, the bleeding risk in patients undergoing chronic oral anticoagulation, and the possibility that the patient may need surgery during the ensuing year.28 †For example, small vessels, long lesions, or diabetes mellitus. This recommendation applies to primary and nonprimary PCI patients with STEMI.
P⬍0.001) and 90-minute ST-segment resolution greater than cautiously. Additionally, duration of clopidogrel therapy was 70% (64% versus 39%, P⬍0.001) occurred more frequently longer in the DES group.
in the thrombus aspiration group. Infarct size measured by More recently, several relatively small randomized clinical contrast-enhanced magnetic resonance imaging in 75 patients trials have shown an inconsistent efficacy for DES over BMS at 3 months was significantly reduced only in the thrombus in primary PCI. Three meta-analyses of these trials have aspiration group.
concluded that there were no differences in death, MI, or stent Both of these trials, as well as a meta-analysis by Bavry et thrombosis rates, but TVR rates were decreased with al103 and a large pooled analysis of randomized trials,104 DES.115–117 Variably included were 12 studies that differed in support the use of aspiration thrombectomy for STEMI. In trial design, inclusion criteria, end-point definitions, stent developing a recommendation for the role of routine aspira- types, duration of clopidogrel treatment, and type of tion thrombectomy, however, it is noteworthy that TAPAS follow-up (angiographic versus clinical). They were limited was a study of routine thrombus aspiration versus no throm- by sample size and duration of follow-up and by usually bus aspiration rather than a study of routine thrombus requiring angiographic documentation of stent thrombosis, aspiration versus selective thrombus aspiration. It is not which may have underestimated its true incidence.
known whether a strategy of selective thrombus aspiration in The HORIZONS-AMI trial randomized, in a 3-to-1 ratio, patients with a large thrombus burden might be superior to no 3006 patients to DES or BMS.9,68,105 There was no differ- thrombus aspiration or equivalent to routine thrombus aspi- ence in the 12-month composite safety end point of death, ration. Clinically, it is reasonable to assume that this strategy reinfarction, stroke, or stent thrombosis. The rates of can be useful in STEMI patients with short ischemic times ischemia-driven TVR and target-lesion revascularization and large thrombus burden. It may not be helpful in STEMI were significantly lower in the DES group (5.8% versus patients with long ischemic times, side branches with small 8.7% and 4.5% versus 7.5%, respectively; NNT⫽33 at 1 infarct territories, or lesions with low thrombus burden.
year), as was the 13-month binary restenosis rate (10.0%versus 22.9%).
8. Recommendations for the Use of Stents
In summary, there appears to be no difference between BMS and DES in mortality or MI rates and no difference in stent thrombosis risk. The major advantage of DES over BMS 8.1. Stent Selection for STEMI
is a small reduction in TVR rates. Given cost considerations, Primary PCI is generally the preferred reperfusion strategy it could be argued that selective use of DES to prevent for patients with STEMI.110 Compared with balloon angio- restenosis and TVR in high-risk patients (ie, patients with plasty, routine BMS implantation during primary PCI de- diabetes) and in high-risk lesions (longer and smaller- creases risk for TVR and possibly reduces MI rates but does diameter stents) could be recommended,118 as it has been for not reduce mortality rates.111,112 elective PCI. The greatest challenge in selecting patients for Two-year data from the Massachusetts registry113 from DES implantation, however, is determining in an emergency 1221 propensity score–matched pairs of DES and BMS situation whether the patient is a candidate for prolonged patients demonstrated a reduction in mortality and TVR rates thienopyridine therapy. As with elective procedures, DES with DES in primary PCI, and an analysis from the New York should be avoided in the presence of financial barriers to State registry114 found a reduction in mortality rates but not continuing prolonged dual-antiplatelet therapy, social barriers TVR rates with DES. These reports were limited to patients that may limit patient compliance, or medical issues that treated before 2005, so they represent the earliest experience involve bleeding risks or the need for invasive or surgical with DES, in which selection bias may have influenced stent procedures in the following year that would interrupt anti- choice and off-label use may have been pursued more platelet therapy.
Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Recommendation for Angiography in Patients With Chronic Kidney Disease
2004/2005/2007 Recommendation: 2007 PCIGuidelines Update, Table 9 2009 PCI Focused Update Recommendation 2. In chronic kidney disease patients undergoing 1. In patients with chronic kidney disease undergoing angiography Modified recommendation angiography, isosmolar contrast agents are who are not undergoing chronic dialysis, either an isosmolar (changed text).
indicated and are preferred. (Level of Evidence: A) contrast medium19,119 (Level of Evidence: A) or alow-molecular-weight contrast medium other than ioxaglate oriohexol is indicated.19 (Level of Evidence: B) PCI Focused Update Section
the only ionic LOCM (RR 0.58, CI 0.37 to 0.92, P⫽0.02124),and with iohexol, a nonionic LOCM (RR 0.19 to 0.38, 9. Recommendation for Angiography in Patients
P⬍0.01124,125), but no difference was noted in comparisons of With Chronic Kidney Disease
iodixanol with iopamidol, iopromide, or ioversal,124 and a single trial favored iomeprol.123 A pooled comparison of 9.1. Angiography in Patients With Chronic
iodixanol with all nonionic LOCM other than iohexol indi- cated equivalent safety (RR 0.97; CI 0.72 to 1.32, Patients with chronic kidney disease (CKD) with or without P⫽0.86125). Results were consistent regardless of ancillary diabetes who undergo angiography are at high risk for a preventive therapies (hydration, acetylcysteine), route of contrast-induced nephropathy (CIN). At issue is the selection administration (intravenous or intra-arterial), age, sex, dose, of a contrast agent to minimize this risk. The 2007 UA/ or preexisting CKD or diabetes. Of further interest, findings NSTEMI guideline recommended that in patients with were similar in the 8 studies (n⫽1793 patients) performed in chronic kidney disease undergoing angiography, "isosmolar the setting of coronary angiography.124 contrast agents are indicated and are preferred (Level of These more recent observations indicate that the CIN risk Evidence: A)" (p e112).97 In patients with CKD or CKD and of contrast media cannot be attributed to osmolarity alone, but diabetes mellitus who are undergoing angiography, isosmolar that ionicity and other and unknown characteristics of spe- contrast material was shown to lessen the rise in creatinine.
cific agents may play a role. Thus, the updated evidence base This was based on evidence up to mid-2007 that suggested suggests that the recommended choices of contrast media that isosmolar agents also reduced the risk of CIN in both a during coronary angiography be expanded to either isosmolar moderate-sized randomized clinical trial (RECOVER [Renal media or LOCM other than ioxaglate or iohexol.
Toxicity Evaluation and Comparison Between Visipaque(Iodixanol) and Hexabrix (Ioxaglate) in Patients With Renal 10. Recommendations for Use of Fractional
Insufficiency Undergoing Coronary Angiography]) that com- Flow Reserve
pared iodixanol with ioxaglate119 and a meta-analysis of 16 smaller, earlier clinical trials.120 10.1. Fractional Flow Reserve
However, in mid-2007, a major US randomized trial of Coronary angiography is often performed in clinical situa- contrast agents in patients with CAD and an estimated tions in which preprocedural functional testing has not been glomerular filtration rate of 20 to 59 mL/min who were obtained. Additionally, in the setting of multivessel disease, undergoing angiography, the CARE study, was published.
the need to treat individual stenosis is often difficult to CARE compared the low-osmolar agent iopamidol and the determine. Although revascularization of ischemia-producing isosmolar agent iodixanol and found no difference in the lesions improves patient outcomes, the clinical benefits of primary end point (serum creatinine increase of 0.5 mg/dL or revascularization of stenotic but non–ischemia-producing le- higher over baseline) between iopamidol (4.4%) and iodixa- sions are less clear. Intraprocedural assessment of the func- nol (6.7%, P⫽0.39).19 tional significance of individual stenosis may help define the Since then, several larger randomized trials have been optimal revascularization strategy.
published that reported no difference in CIN when iodixanol The objective of the FAME trial20 was to compare clinical was compared with various other low-osmolar contrast media outcomes after PCI on the basis of conventional angiographic (LOCM).19,121–123 These and other randomized trials compar- determination of lesion severity versus fractional flow reserve ing isosmolar iodixanol with LOCM have been summarized (FFR) combined with angiography in patients with multivessel in 2 mutually supportive and complementary meta-analyses disease. This prospective, randomized, multicenter trial included involving 16 trials in 2763 patients124 and 25 trials in 3260 1005 patients selected from 1905 screened patients at 20 medical patients,125 respectively. When more recent trials were com- centers who were randomized to either angiography-guided or bined with the older studies, trends in CIN favoring iodixanol FFR-guided (for lesions with FFR less than or equal to 0.80) were no longer significant (summary RR 0.79; 95% CI 0.56 PCI. Before randomization, lesions that required PCI were to 1.12; P⫽0.29; summary RR 0.80; CI 0.61 to 1.04; P⫽0.10, prespecified on the basis of the angiographic appearance. Pa- respectively).124,125 However, subanalyses showed variations tients assigned to angiography-guided PCI had all identified in relative renal safety by specific LOCM: A reduction in CIN lesions treated with DES, whereas those assigned to FFR-guided was observed when iodixanol was compared with ioxaglate, PCI had only identified lesions with an FFR of 0.80 or less December 1, 2009
Table 10.
Recommendations for Use of Fractional Flow Reserve
2004/2005/2007 Recommendation: 2005 PCIGuideline, Section 5.6.2.
2009 PCI Focused Update Recommendations Class IIa
1. It is reasonable to use intracoronary physiologic 1. Coronary pressure (fractional flow reserve 关FFR兴) or Doppler Modified recommendation (level of measurements (Doppler ultrasound, fractional velocimetry can be useful to determine whether PCI of a evidence changed from B to A flow reserve) in the assessment of the effects of specific coronary lesion is warranted. FFR or Doppler for FFR; C for Doppler).
intermediate coronary stenoses (30% to 70% velocimetry can also be useful as an alternative to luminal narrowing) in patients with anginal performing noninvasive functional testing (eg, when the symptoms. Coronary pressure or Doppler functional study is absent or ambiguous) to determine velocimetry may also be useful as an alternative whether an intervention is warranted. It is reasonable to to performing noninvasive functional testing (eg, use intracoronary physiological measurements (coronary when the functional study is absent or pressure 关FFR兴20,126–137 关Level of Evidence: A兴 or Doppler ambiguous) to determine whether an velocimetry 关Level of Evidence: C兴) in the assessment of intervention is warranted. (Level of Evidence: B) the effects of intermediate coronary stenoses (30% to 70%luminal narrowing) in patients with anginal symptoms.
Class III
1. Routine assessment with intracoronary 1. Routine assessment with intracoronary physiological Modified recommendation physiologic measurements such as Doppler measurements such as coronary pressure (FFR) or Doppler ultrasound or fractional flow reserve to assess ultrasound to assess the severity of angiographic disease in the severity of angiographic disease in patients concordant vascular distribution in patients with angina and with a positive, unequivocal noninvasive a positive, unequivocal noninvasive functional study is not functional study is not recommended. (Level of recommended. (Level of Evidence: C) Evidence: C) treated with DES. The primary end point of the trial was the rate Evidence B recommendation for patients who are not eligible of death, nonfatal MI, and repeat revascularization at 1 year.
for CABG. Thus, it has been recommended that CABG still No difference was evident in the number of intended be considered the standard of care for left main CAD.147–149 lesions to be treated per patient (2.7⫾0.9 versus 2.8⫾1.0, Several studies comparing CABG to PCI, however, indi- P⫽0.34) in the angiography- and FFR-guided groups, respec- cated that the advantage of CABG consists primarily of fewer tively. In the FFR group, 37% of lesions had an FFR greater repeat revascularizations.139,149–155 The study by Brener et than 0.80. Evaluation of ischemia, as defined by an FFR less al156 indicates no significant mortality difference between than 0.80, resulted in fewer lesions receiving stents (2.7⫾1.2 PCI and CABG after 3 years of follow-up. Longer-term versus 1.9⫾1.3, P⬍0.001). At 1 year, the composite event follow-up is needed.
rate was 18.3% in the angiography-guided group compared The present focused update specifically addresses the with 13.2% in the FFR-guided group (P⫽0.02).
findings of SYNTAX, an unblinded, randomized clinical trial The results of the FAME trial suggest that identification of that assigned patients with 3-vessel and/or left main CAD to ischemia-producing lesions by use of systematic assessment an initial treatment strategy of CABG or PCI.21 The primary of FFR in patients undergoing multivessel PCI is associated prespecified end point for the 1800 enrolled patients was the with improved clinical outcomes compared with angio- composite of death, stroke, and myocardial revascularization graphic assessment alone. Further evidence is needed regard- determined at 12 months. Prespecified stratification occurred ing the added value of assessing FFR in lesions with greater for diabetes mellitus and left main CAD. Ninety-seven than 90% stenosis.
percent of CABG patients received at least 1 arterial graft.
In SYNTAX, for the subgroup with left main CAD, there 11. Recommendations for PCI for Unprotected
were no significant differences in the incidence of the Left Main Coronary Artery Disease
composite end point (death, MI, stroke, or repeat revascular- ization) between the 2 groups (PCI 15.8% versus CABG13.7%, P⫽0.44), although rates of repeat revascularization 11.1. Unprotected Left Main Coronary Artery Disease
were higher (11.8% versus 6.5%, P⫽0.02) and rates of stroke Although listed as a Class III indication in the 2003 guideline were lower (0.3% versus 2.7%, P⫽0.01) in the PCI group.21 on the management of chronic stable angina,145 PCI of an Left main stented patients with limited CAD (lower SYNTAX unprotected left main coronary artery has increased in fre- score) displayed a trend toward fewer adverse events at 12 quency.146 Early studies (listed in Appendix 6) involved short months than did similar patients assigned to CABG. Specifi- follow-up periods, which gave CABG a disadvantage, be- cally, MACE in patients with isolated left main CAD oc- cause the apparent benefits of surgery over PCI in other curred in 8.5% with CABG versus 7.1% with PCI, and in settings have not typically been fully evident until 1 to 5 years 13.2% with CABG versus 7.5% with PCI in patients with left after the procedure. In the ACC/AHA/SCAI 2005 guideline main CAD and disease of 1 other vessel. In contrast, MACE update for PCI, the performance of PCI for left main CAD is with CABG versus PCI were numerically less frequent in given a Class III, Level of Evidence C recommendation if the patients with disease of the left main coronary artery and patient is eligible for CABG and a Class IIa, Level of disease of 2 other vessels (14.4% versus 19.8%) and in Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Table 11.
Recommendations for PCI for Unprotected Left Main Coronary Artery Disease
2009 PCI Focused Update Recommendations Class IIa
2005 PCI Guideline, Section 6.3.4.
1. It is reasonable that patients undergoing PCI to Deleted recommendation (no longer unprotected left main coronary obstructions be followed up with coronary angiographybetween 2 and 6 months after PCI. (Level ofEvidence: C) Class IIb
1. PCI of the left main coronary artery with stents as an New recommendation alternative to CABG may be considered in patientswith anatomic conditions that are associated with alow risk of PCI procedural complications and clinicalconditions that predict an increased risk of adversesurgical outcomes.*21,138,139 (Level of Evidence: B) Class III
2005 PCI Guideline, Section 5.1 PCI is not recommended in patients with 关. . 兴 Modified recommendation (bullet "f" from f. Left main disease and eligibility for CABG.
Section 5.1 and bullet "e" from (Level of Evidence: C) Sections 5.2. and 5.3. are no longer 2005 PCI Guideline, Sections 5.2, 5.3 current; see 2009 Class IIb PCI is not recommended in patients with 关. . 兴 recommendation #1).
e. Left main disease and eligibility for CABG.
(Level of Evidence: C) *Stenting for unprotected left main CAD is relatively more favorable for patients with isolated left main coronary artery lesions or left main coronary artery plus single-vessel disease,21 for patients with ostial or mid left main coronary artery lesions,138,140–144 and for patients with factors (such as severe lung disease, priorthoracic surgery, or poor bypass graft targets) that would make CABG a high-risk procedure or unlikely to be successful. Conversely, CABG surgery for unprotectedleft main CAD may be relatively more favorable for patients with left main CAD plus multivessel disease,21 distal/bifurcation left main coronary artery lesions,138,140–144or low surgical risk with a good chance of technical success.
patients with both left main CAD and 3 other vessels with left main and 2- or 3-vessel disease compared with involved (15.4% versus 19.3%).21 patients with left main and no other vessel or 1-vessel disease These data from a post hoc subgroup analysis in SYNTAX had higher rates of MACE, it is recommended that PCI to left must be interpreted with caution for several reasons. The number main lesions be limited to patients without significant mul- of patients with isolated left main (or left main plus single tivessel disease. Second, because of the narrow margin for vessel) CAD was relatively small, and the differences in out- error, operators undertaking PCI of left main coronary lesions comes were not statistically significant. Furthermore, SYNTAX should be experienced and backed by highly competent reported outcomes at 1 year, and longer follow-up is needed support staff and surgeons.157 Although routine use of intra- before left main PCI (in patients who are otherwise surgical vascular ultrasound has been advocated by some authors for candidates) should become standard clinical practice. Moreover, the evaluation of left main lesions, there is no definitive because the overall study did not reach its primary end point, evidence at present that this technique improves out-comes.138,157 Finally, not all left main lesions respond equally subset analyses are less robust; because noninferiority was not well to PCI. Bifurcation lesions are technically more chal- proven in this cohort, specific information for each subgroup is lenging138 and have higher rates of restenosis.140,141,143,144 In of an observational nature and is hypothesis-generating.
contrast, results of PCI of ostial or mid-body left main On the basis of the evidence in aggregate, prior to and coronary lesions more closely approximate the results of within the present focused update, the writing group has CABG, even with respect to the need for subsequent proce- modified the class of recommendation for PCI to unprotected dures.142 The best case for PCI as an alternative to CABG for left main coronary from Class III to Class IIb, now citing the left main CAD is in ostial and mid-body lesions without Level of Evidence as B. The writing group noted 3 important additional multivessel disease.
caveats in classifying unprotected left main CAD as a Class The writing group discussed the previous Class IIa recom- IIb indication. First, patients undergoing PCI in cohort or mendation for follow-up between 2 and 6 months with randomized studies represent merely a subset of all patients coronary angiography. They focused on the inability of with left main CAD. Because only certain left main coronary angiography to predict a situation that might be prone to lesions are amenable to PCI, the Class IIb indication is acute, sudden stent thrombosis, as well as the risk associated intended to apply only to those left main lesions that are with angiography in a patient who has undergone placement suitable for PCI. The primary conclusion of SYNTAX is that of a left main stent. In view of these factors, the writing group PCI failed to be shown to be noninferior to CABG in left decided that the Class IIa recommendation for angiographic main and triple-vessel disease. Because patients in SYNTAX follow-up should be omitted from the guidelines.
December 1, 2009
Table 12.
Recommendations for the Timing of Angiography and Antiplatelet Therapy in UA/NSTEMI
2009 PCI Focused Update Recommendations 1. Patients with definite or likely UA/NSTEMI selected for an invasive approach should receive New recommendation dual-antiplatelet therapy.158,159 (Level of Evidence: A) Aspirin should be initiated on presentation.158,159(Level of Evidence: A) Clopidogrel (before or at the time of PCI)158,159 (Level of Evidence: A) orprasugrel (at the time of PCI)27 (Level of Evidence: B) is recommended as a second antiplatelet agent.
Class IIa
1. It is reasonable for initially stabilized high-risk patients with UA/NSTEMI* (GRACE 关Global Registry of New recommendation Acute Coronary Events兴 risk score greater than 140) to undergo an early invasive strategy within 12to 24 hours of admission. For patients not at high risk, an early invasive approach is alsoreasonable.22,23 (Level of Evidence: B) *Immediate catheterization/angiography is recommended for unstable patients.
12. Recommendations for the Timing
to early intervention; major bleeding occurred in 3.1% of of Angiography and Antiplatelet Therapy
patients in the early invasive group and 3.5% in the delayed in UA/NSTEMI
invasive group.
Overall in TIMACS, early intervention trended to be superior to delayed intervention in preventing the composite 12.1. Timing of Angiography
of death, MI, or stroke (primary end point), but the difference A routine invasive strategy in UA/NSTEMI patients with was not statistically significant.23 However, early intervention high-risk features has been associated with improved out- reduced the composite of death, MI, or refractory ischemia comes, but the optimal timing of intervention has not been (the secondary end point) and, in high-risk patients, was well established. Early intervention might prevent ischemic superior to a delayed invasive strategy. The trial was under- events that could occur while the patient awaits a delayed powered to discern a clinically meaningful 15% advantage to procedure. Alternatively, with intensive antithrombotic ther- early invasive therapy for the primary end point, with apy with a delay for up to a few days, procedure-related recruitment stopped at 3000 because of recruitment and complications might be avoided by intervening on a more funding challenges. This provided a power of 80% to detect stable, "passivated" plaque. Although one study has sug- a risk reduction of 28% in the primary end point. Subgroup gested greater benefit with relatively early intervention,106 the analysis (high-risk subset) of this overall negative trial was evidence base for a definitive recommendation on timing isweak. Thus, the question of when to intervene in UA/ not robust and must be viewed cautiously.
NSTEMI has not been answered conclusively. Given this Taken together with the earlier ISAR-COOL (Intracoro- uncertainty, the TIMACS investigators23 undertook a large, nary Stenting With Antithrombotic Regimen Cooling Off) multicenter randomized trial to determine whether a strategy study,106 the favorable secondary end-point results, the sub- of early coronary angiography and intervention was superior group analysis in patients at higher risk, and the lack of a to a delayed strategy in patients with UA/NSTEMI assigned safety issue with early therapy, TIMACS suggests the fol- to an invasive approach.
lowing conclusions: an early invasive strategy within 12 to 24 TIMACS randomly assigned 3031 non–ST-elevation ACS hours (median 14 hours) is preferred in high-risk patients and patients to routine early intervention (coronary angiography may be chosen in patients at low to intermediate risk at the within 24 hours) or to delayed intervention (coronary angiogra- physician's or institution's preference (eg, efficiency and cost phy at 36 hours or more). The primary outcome was the savings), whereas a more delayed approach may be beneficial composite of death, MI, or stroke at 6 months, and a prespecified in low- to intermediate-risk patients.23 In contrast, results secondary outcome was death, MI, or refractory ischemia.23 from the recent ABOARD (Angioplasty to Blunt the rise Of Coronary angiography was performed at a median of 14 hours troponin in Acute coronary syndromes Randomized for an in the early-intervention group and 50 hours in the delayed- immediate or Delayed intervention) trial160 indicate that an intervention group. At 6 months, 9.7% of patients in the immediate invasive strategy (median time 1.1 hour) in UA/ early-intervention group experienced a primary outcome versus NSTEMI is not associated with further incremental benefit.
11.4% in the delayed-intervention group (HR 0.85; 95% CI 0.68 Typically, early versus delayed angiography is defined to 1.06; P⫽0.15). Death, MI, or refractory ischemia was reduced with reference to a 12- to 48-hour time window. The by 28% in favor of early intervention (9.6% versus 13.1%; HR ISAR-COOL study106 supports an earlier compared with a 0.72; 95% CI 0.58 to 0.89; P⫽0.002). Prespecified analyses more delayed time to angiography, but the data supporting showed that early intervention improved the primary outcome in this general timing suggestion are limited.
the one third of patients at highest risk (HR 0.65; 95% CI 0.48to 0.88), as determined by a GRACE (Global Registry of Acute 12.2. Timing of GP IIb/IIIa Receptor Antagonist Therapy
Coronary Events) risk score greater than 140, but not in the two in UA/NSTEMI Patients Undergoing Angiography
thirds at low to intermediate risk (HR 1.14; 95% CI 0.82 to 1.58; The optimal timing of initiation of GP IIb/IIIa receptor P for heterogeneity⫽0.01). There were no safety issues related antagonist therapy in patients with UA/NSTEMI (ie, whether Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
to administer therapy upstream on presentation or later at the the use of eptifibatide at PCI (39% of patients in the delayed, time of angiography/PCI) and the optimal application of this provisional group), EARLY ACS does not contradict the benefit therapy (ie, whether routine, selective, or provisional) have of GP IIb/IIIa therapy over placebo in UA/NSTEMI in previous not been resolved. The 2007 ACC/AHA Guidelines for the studies. Rather, its findings relate specifically to the timing of Management of Patients With UA/NSTEMI recommend that such therapy and selective versus routine use.
patients with definite or likely UA/NSTEMI selected for an In another similar study, ACUITY (Acute Catheterization invasive approach should receive ASA and either clopidogrel and Urgent Intervention Triage strategY), superiority of early or a GP IIb/IIIa receptor antagonist before angiography GP IIb/IIIa therapy also was not found, but investigators (Class I, Level of Evidence: A).97 They further state that it is could not exclude as much as a 29% benefit with GP IIb/IIIa reasonable to initiate both clopidogrel and a GP IIb/IIIa therapy nor show noninferiority of delayed administration. In receptor antagonist, especially in the setting of delays to addition, drug exposure before angiography was much shorter angiography, high-risk features, or recurrent ischemic discom- (4 hours), which might substantially diminish the opportunity fort (Class IIa, Level of Evidence: B). The 2007 European for differential efficacy.161 Society of Cardiology guidelines recommend early dual- The results of the EARLY ACS study are similar to a antiplatelet therapy with ASA and clopidogrel (Class I), with the meta-analysis of 6 prior large, randomized trials of GP IIb/IIIa addition of a GP IIb/IIIa receptor antagonist for those patients therapy versus placebo in non–ST-elevation ACS in which an with the specific high-risk features of an elevated troponin level, invasive strategy was not mandated, which showed a relative ST-segment depression, or diabetes (Class IIa).163 reduction in death/MI of 9% (CI 2% to 16%).162 In those patients The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in who underwent PCI, the RR reduction was a more robust 23% Patients With Non–ST-Segment Elevation Acute Coronary Syn- (CI 8% to 36%). This finding also was consistent with EARLY drome) trial22 tested the hypothesis that a strategy of early, ACS. Both studies found no benefit in troponin-negative pa- routine administration of the GP IIb/IIIa receptor antagonist tients. The investigators ascribed the less than expected benefit eptifibatide would be superior to delayed, provisional adminis- of early GP IIb/IIIa therapy in EARLY ACS to convergence of tration in reducing ischemic complications among high-risk eptifibatide use in the 2 arms at the time of PCI and more patients. EARLY ACS enrolled 9492 non–ST-segment eleva- aggressive contemporary cotherapies compared with earlier tion ACS (UA/NSTEMI) patients who presented within 24 studies, including frequent use of clopidogrel, low-molecular- hours of an episode of ischemic rest discomfort and who were weight heparin, and statins. A further caution is the lack of assigned to an invasive treatment strategy no sooner than the follow-up for several years.
next calendar day (amended later to at least 12 hours but less Despite a lack of clarity from the overall and subgroup than 96 hours after randomization). Eligibility required at least 2 of results, an argument can be made against the routine upstreamuse of GP IIb/IIIa therapy in all non–ST-elevation ACS the following features: ST-segment depression or transient ST- patients intended for an invasive strategy. In particular, those segment elevation, an elevated biomarker (creatine kinase-MB or with a normal baseline troponin level and those over the age troponin), and age of 60 years or older (amended to include patients of 75 years, in whom there was no evidence for benefit but 50 to 59 years with known vascular disease). The key primary end who showed an increased risk of bleeding, might be ex- point was all-cause death, MI, recurrent ischemia that required cluded. On the other hand, findings in those with a positive urgent revascularization, or thrombotic bailout at 96 hours. The key troponin at baseline and those with diabetes, although not secondary efficacy end point was all-cause death or MI within 30 definitive in EARLY ACS alone, trend positively and are in days. Safety end points included major hemorrhage and transfu- line with previous results. The EARLY ACS trial showed no sions through 120 hours after randomization. The study was significant benefit in the composite outcome comparing early powered to detect 22.5% and 15% relative reductions in the primary versus delayed eptifibatide as defined by the study. Thus, at and key secondary end points, respectively.
this time, a high-risk group that would clearly benefit from The primary end point occurred in 9.3% of patients in the the early administration of eptifibatide upstream before car- early therapy arm versus 10.0% of patients in the provisional diac catheterization has not been identified. Early GP IIb/IIIa GP IIb/IIIa therapy arm (odds ratio 0.92; 95% CI 0.80 to 1.06; therapy in patient groups continues to appear reasonable if P⫽0.23). Secondary end-point event rates were 11.2% versus they are judged clinically to be at high risk of thrombotic 12.3% (odds ratio 0.89; CI 0.79 to 1.01; P⫽0.08). Early, events relative to bleeding risk.
routine eptifibatide administration occurred at the cost of agreater risk of TIMI major hemorrhage (2.6% versus 1.8%, P⫽0.02). Moderate and less severe bleeding also occurredmore commonly. Rates of red cell transfusion were 8.6% and American College of Cardiology Foundation
6.7%, respectively (P⫽0.001).
John C. Lewin, MD, Chief Executive OfficerCharlene May, Senior Director, Science and Clinical Policy EARLY ACS represents a large, carefully executed trial with Lisa Bradfield, CAE, Associate Director, Science and Clinical Policy potentially important implications; however, these results are Leigh Maltese, Specialist, Science and Clinical Policy best taken in the context of previous major trials. As a single Debjani Mukherjee, MPH, Associate Director, Evidence-Based Medicine trial, EARLY ACS does not establish the superiority of early Erin A. Barrett, Senior Specialist, Science and Clinical Policy versus delayed, provisional eptifibatide in non–ST-elevation American Heart Association
ACS. A trend toward fewer recurrent ischemic complications Nancy Brown, Chief Executive Officer was noted at 30 days, but this was counterbalanced by more Rose Marie Robertson, MD, FACC, FAHA, Chief Science Officer frequent episodes of bleeding and need for transfusions. Given Judy Bezanson, DSN, CNS, RN, Senior Science and Medicine Advisor December 1, 2009
Appendix 1.
Author Relationships With Industry and Other Entities—ST-Elevation Myocardial Infarction
or Other Financial Frederick G.
Tulane University School of Abbott; Bristol-Myers Squibb Professor of Medicine; Agency for Healthcare Quality—Health Science Brigham and Women's Sanofi-aventis; Eli Lilly Accumetrics; Amgen, Inc; AstraZeneca Pharmaceuticals; Bayer Healthcare; Beckman Coulter; Biosite; Bristol-Myers Squibb Pharmaceutical Research Institute; CV Therapeutics; Daiichi-Sankyo*; Eli Lilly*; GlaxoSmithKline; Inotek Pharmaceuticals Corp; Integrated Therapeutics Corp; Merck; Millennium Pharmaceuticals; National Institutes of Health; Novartis Pharmaceuticals; Nuvelo; Ortho Clinical Diagnostics; Pfizer; Roche Diagnostics Corp; Roche Diagnostics GmbH; Sanofi-aventis*; Sanofi-Synthelabo Recherche; Schering-Plough Research Institute Boehringer Ingelheim; Michigan—Professor of Daiichi-Sankyo; Eli Lilly; Eli Lilly; Novartis; Atlantic Health—Chief Medical Officer and Vice President of Quality University of Michigan —Associate Professor, Dept. of Family Medicine New York University School Bayer HealthCare AG; Eli Lilly; Johnson & of Medicine—Clinical Chief Johnson Pharmaceutical Research & Development; Millennium Pharmaceuticals; Schering-Plough Research Institute Yale University School of Centers for Medicare and Medicaid Services* Hines, Jr. Professor of Medicine and Epidemiology and Public Health Virginia Commonwealth University Health System—Professor and Chair, Dept. of Emergency Georgetown University Hospital—Professor of University of South Boehringer Ingelheim; Anoxic Encephalopathy, Florida—Professor and Genentech; National 2006; Acute Stroke Director, USF Stroke Association for Continuing 2006–2007; Carotid Endarterectomy, 2006 Center for Cardiovascular Medicine—Professor of Medicine; Director This table represents the relationships of committee members with industry that were reported at the Task Force on Practice Guidelines meeting and updated in conjunction with all meetings. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% or more of the voting stock or share of the business entity or ownership of $10 000 or more of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. A relationship is considered to be modest if it is less than significant under the preceding definition. Relationships noted in this table are modest unless otherwise noted.
*Significant (greater than $10 000) relationship.
Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Appendix 2.
Author Relationships With Industry and Other Entities—Percutaneous Coronary Intervention
or Other Financial Center for Cardiovascular Science Smith, Jr, Chair and Medicine—Professor of Medicine; Director Saint Joseph's Heart and Vascular Abbott; AngelMed; BG III, Co-Chair Intermountain Medical Center—Associate Chief of Daiichi-Sankyo; Eli University of Texas Medical Abbott; BSCI; Cordis; Center—Professor of Medicine Volcano Therapeutics Geisinger Medical Director, Cardiac Cath Lab Boston University School of Medicine—Professor of Medicine; Accumetrics; Cordis; Boston University Medical Research Institute Catheterization Laboratories and Duke Clinical Research Institute, Duke University Medical Center—Professor of Medicine; aventis*; Merck*; Director, Cardiovascular Research Cleveland Clinic Foundation, Dept.
ICON Plc; Medlogics; of Cardiovascular Brigham and Women's Hospital Boston Biomedical Volcano Therapeutics DSMB indicates data and safety monitoring board; SCAI, Society for Cardiovascular Angiography and Interventions.
This table represents the relationships of committee members with industry that were reported at the Task Force on Practice Guidelines meeting and updated in conjunction with all meetings. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% or more of the voting stockor share of the business entity or ownership of $10 000 or more of the fair market value of the business entity, or if funds received by the person from the businessentity exceed 5% of the person's gross income for the previous year. A relationship is considered to be modest if it is less than significant under the precedingdefinition. Relationships noted in this table are modest unless otherwise noted.
*Significant (greater than $10 000) relationship.
December 1, 2009
Appendix 3.
Reviewer Relationships With Industry and Other Entities—2009 STEMI and PCI Focused Updates
or Other Financial Eli Lilly*; Ischemix LLC Boehringer Ingelheim (Canada) Ltd*; Eli Lilly*; Portola Pharmaceuticals Inc*; Sanofi-aventis Canada Inc*; Schering-Plough Research Institute*; Uppsala Clinical Research Center and Christopher E.
Practice Guidelines Board of Governors United Health Care Biophysical*; Paragon antithrombotic therapy Board of Trustees for an individual with Boston Scientific*; Medtronic*; The Medicines Co* Bayer; Boehringer Ingelheim; Exeter CME; Johnson & Johnson; King Roche; Sanofi-aventis Boston Scientific; Interventional Council Interventional Council Bristol-Myers Squibb; Cogentus; Eisai*; Eli Squibb; Daiichi-Sankyo; Eli Lilly; Johnson & Johnson; Heartscape*; Johnson & Medtronic; Novartis; Johnson; The Medicines Co; Momenta; Portola; Board of Governors Interventional Council Board of Governors Practice Guidelines Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Appendix 3.
or Other Financial Abbott Vascular; Boston Boston Scientific Boston Scientific Practice Guidelines AstraZeneca; Baxter; AstraZeneca; Baxter; Bayer; Bristol-Myers Bristol-Myers Squibb*; Research Institute Squibb; Daiichi-Sankyo; Eli GlaxoSmithKline*; The Lilly; Johnson & Johnson; Medicines Co; Merck*; Medtronic; Ostuka Maryland Research Institute; Pfizer; Schering-Plough*; WebMD* Bayer Healthcare AG; Eli Lilly; GlaxoSmithKline; Johnson & Johnson Pharmaceutical Practice Guidelines Research & Development; Schering-Plough Research Board of Governors Bristol-Myers Squibb Canada*; Eli Lilly Canada; Medtronic Canada*; Pfizer Canada*; Sanofi-aventis Canada*; Schering-Plough Canada*; Sepracor Pharmaceuticals, Inc Board of Governors Board of Governors 2009, deposition for plaintiff: air embolism Board of Governors Interventional Council Sharon-Lise T.
December 1, 2009
Appendix 3.
or Other Financial Abbott Vascular; Baxter Abbott Vascular; AstraZeneca; Healthcare; Boehringer Baxter Healthcare; Berlex Labs/Bayer HealthCare; Therapeutics; NicOx; Pfizer; Boehringer Ingelheim; Cardium Therapeutics; CV Therapeutics; Labs; GlaxoSmithKline; Merck; Novartis; Pfizer; Reliant Schering-Plough; The Medicines Co; Viron Charanjit S.
Interventional Council Interventional Council Boston Biomedical Abbott Vascular; Boston Associates*; CR Bard*; Scientific; Medtronic Davol*; Lab Coat*; TherOx* Abbott Vascular*; Eli Lilly*; AstraZeneca; Boston Gilead Sciences*; Merck*; Scientific; Genzyme; Gilead Sciences; Medtronic; Eli Lilly*; GlaxoSmithKline*; Johnson & Johnson*; Merck Sharpe & Dohme*; The Medicines Co*; NIH*; Pfizer*; Roche*; Sanofi-aventis*; Astellas Healthcare*; GE GE Healthcare*; Molecular Molecular Insight Healthcare*; King Insight Pharmaceuticals* ACCF indicates American College of Cardiology Foundation; AHA, American Heart Association; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institutes of Health; and SCAI, Society for Cardiovascular Angiography and Interventions.
This table represents the relationships of peer reviewers with industry and other entities that were reported by authors to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process.
The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interestrepresents ownership of 5% or more of the voting stock or share of the business entity or ownership of $10 000 or more of the fair market value of the businessentity, or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. A relationship is considered to bemodest if it is less than significant under the preceding definition. Relationships in this table are modest unless otherwise noted.
*Significant (greater than $10 000) relationship.
Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Appendix 4.
Dosing Table for Antiplatelet and Anticoagulant Therapy Discussed in This Focused Update to Support PCI in STEMI
Patient Received Initial Medical Treatment (With an Patient Did Not Receive Initial Medical Anticoagulant and/or Treatment (With an Anticoagulant Comments: All Patients to Receive Fibrinolytic Therapy) and/or Fibrinolytic Therapy) ASA (162–325 mg) Glycoprotein IIb/IIIa ReceptorAntagonists (Section 2) Of uncertain benefit LD of 0.25 mg/kg IV bolus Continue for up to 12 hours at the MD of 0.125 mcg/kg per minute discretion of the physician.9,11 (maximum 10 mcg/min) (Class IIa,LOE: A) Of uncertain benefit LD of 180 mcg/kg IV bolus followed 10 Double bolus recommended to support minutes later by second IV bolus of PCI in STEMI as the recommended adult dosage of eptifibatide in MD of 2.0 mcg/kg per minute, started patients with normal renal after first bolus; reduce infusion by 50% in patients with estimated Infusion should be continued for 12 to creatinine clearance ⬍50 mL/min 18 hours at the discretion of the (Class IIa, LOE: B) Of uncertain benefit LD of 25 mcg/kg IV bolus Increased dosing over previous MD of IV infusion of 0.1 mcg/kg per min; reduce rate of infusion by 50% Continue for up to 18 hours at the in patients with estimated creatinine discretion of the physician.12 clearance ⬍30 mL/min (Class IIa,LOE: B) Thienopyridines (Section 3) If 600 mg given orally, then no LD 300–600 mg orally Optimum LD has not been established.
additional treatment MD of 75 mg orally per day (Class I, Dose for patients ⬎75 years of age A second LD of 300 mg may has not been established.
be given orally to There is a recommended duration of supplement a prior LD of therapy for all post-PCI patients 300 mg (Class I, LOE: C) receiving a BMS or DES.
Period of withdrawal before surgery should be at least 5 days.
(For full explanations, see footnote.) No data are available to guide LD of 60 mg orally There is no clear need for treatment MD of 10 mg orally per day (Class I, with prasugrel before PCI.
MD of 5 mg orally per day in special Special dosing for patients ⬍60 kg or ⬎75 years of age.
There is a recommended duration of therapy for all post-PCI patientsreceiving a DES.
Contraindicated for use in patients with prior history of TIA or stroke.
(For full explanations, see footnote.) Parenteral Anticoagulants(Section 4) For patients who have received 0.75 mg/kg bolus, 1.75 mg/kg per hour Bivalirudin may be used to support PCI UFH, wait 30 minutes, then and STEMI with or without give 0.75 mg/kg bolus, then previously administered UFH with 1.75 mg/kg per hour the addition of 600 mg of infusion (Class I, LOE: B) clopidogrel.9 In STEMI patientsundergoing PCI who are at high riskof bleeding, bivalirudinanticoagulation is reasonable.9 December 1, 2009
Appendix 4.
Patient Received Initial Medical Treatment (With an Patient Did Not Receive Initial Medical Anticoagulant and/or Treatment (With an Anticoagulant Comments: All Patients to Receive Fibrinolytic Therapy) and/or Fibrinolytic Therapy) ASA (162–325 mg) IV GP IIb/IIIa planned: target IV GP IIb/IIIa planned: 50–70 U/kg bolus ACT 200–250 seconds to achieve an ACT of 200–250 No IV GP IIb/IIIa planned: target ACT 250–300 No IV GP IIb/IIIa planned: 70–100 U/kg seconds for HemoTec, bolus to achieve target ACT of 300–350 seconds for 250–300 seconds for HemoTec, Hemochron (Class I, LOE: C) 300–350 seconds for Hemochron(Class I, LOE: C) ACT indicates activated clotting time; BMS, bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; GP, glycoprotein; IV, intravenous; LD, loading dose; LOE, level of evidence; MACE, major adverse cardiac events; MD, maintenance dose; PCI, percutaneous coronary intervention; STEMI, ST-elevationmyocardial infarction; TIA, transient ischemic attack; and UFH, unfractionated heparin.
*This list is in alphabetical order and is not meant to indicate a particular therapy preference. This drug table does not make recommendations for combinations of listed drugs. It is only meant to indicate approved dosages if a drug is chosen for a given situation.
†The optimum LD of clopidogrel has not been established. Randomized trials establishing its efficacy and providing data on bleeding risks used an LD of 300 mg orally followed by a daily oral dose of 75 mg.26,27 Higher oral LDs such as 600 mg or more than 900 mg36 of clopidogrel more rapidly inhibit platelet aggregation andachieve a higher absolute level of inhibition of platelet aggregation, but the additive clinical efficacy and safety of higher oral LD have not been rigorously established.
For post-PCI patients receiving a DES, a daily MD should be given for at least 12 months unless the risk of bleeding outweighs the anticipated net benefit affordedby a thienopyridine. For post-PCI patients receiving a BMS, an MD should be given for a minimum of 1 month28 and ideally up to 12 months (unless the risk of bleedingoutweighs the anticipated net benefit afforded by a thienopyridine; then it should be given for a minimum of 2 weeks). The necessity for giving an LD of clopidogrelbefore PCI is driven by the pharmacokinetics of clopidogrel, for which a period of several hours is required to achieve desired levels of platelet inhibition. Patientswho have a reduced-function CYP2C19 allele have significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rateof MACE, including stent thrombosis.53 In STEMI patients taking clopidogrel for whom CABG is planned and can be delayed, it is reasonable to discontinue theclopidogrel to allow for dissipation of the antiplatelet effect, unless the urgency for revascularization and/or the net benefit of clopidogrel outweighs the potential risksof excess bleeding. The period of withdrawal should be at least 5 days in patients receiving clopidogrel.30 Clopidogrel LD after fibrinolytic therapy: For patients givenfibrin- and non–fibrin-specific fibrinolytic drugs who are undergoing PCI within 24 hours, 300 mg; for patients given a fibrin-specific fibrinolytic undergoing PCI aftermore than 24 hours, 300 to 600 mg; for patients given a non–fibrin-specific fibrinolytic undergoing PCI between 24 and 48 hours, 300 mg; for patients given anon–fibrin-specific fibrinolytic undergoing PCI after 48 hours, 300 to 600 mg.
‡Patients weighing ⬍60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once-daily MD. Consider lowering the MD to 5 mg in patients who weigh ⬍60 kg. The effectiveness and safety of the 5-mg dose have not been studied prospectively. For post-PCI patientsreceiving a DES, a daily MD should be given for at least 12 and up to 15 months unless the risk of bleeding outweighs the anticipated net benefit afforded by athienopyridine. Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. In patients ⱖ75 years of age, prasugrel is generallynot recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit, except in high-risk situations (patients with diabetes or ahistory of prior MI) for which its effect appears to be greater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. Whenpossible, discontinue prasugrel at least 7 days before any surgery. Additional risk factors for bleeding include body weight ⬍60 kg, propensity to bleed, concomitantuse of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, or chronic use of nonsteroidal antiinflammatory drugs).
Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
Appendix 5.
Triage and Transfer for PCI
who is a candidate Initially seen at a Initially seen at a Send to Cath Lab Initial treatment with fibrinolytic therapy reperfusion strategy* (Class I, LOE: A) (Class I, LOE: A) (Class I, LOE: A) Transfer to a PCI Transfer to a PCI Preparatory antithrombotic (anticoagulant plus antiplatelet) regimen early diagnostic (Class IIb, LOE: angio and possible C), especially if (Class IIa, LOE: B) symptoms persist High-risk patients (Class I, LOE: B) Angio indicates angiography; CABG, coronary artery bypass graft surgery; Cath Lab, catheterization laboratory; LOE, level of evidence; PCI, percutaneous coronary intervention; and STEMI, ST-elevation myocardial infarction.
Each community and each facility in that community should have an agreed-on plan for how STEMI patients are to be treated that includes which hospitals should receive STEMI patients from emergency medical services units capable of obtaining diagnostic electrocardiograms, management at the initial receiving hospital, andwritten criteria and agreements for expeditious transfer of patients from non–PCI-capable to PCI-capable facilities. Consideration should be given to initiating apreparatory pharmacological regimen as soon as possible in preparation for and during patient transfer to the catheterization laboratory. The optimal regimen is notyet established, although published studies (see text for details) have used various combinations of the following: anticoagulant, oral antiplatelet agents, intravenousantiplatelet.
*Time since onset of symptoms; risk of STEMI; risks associated with fibrinolytic therapy; time required for transport to a skilled PCI laboratory.
Appendix 6.
Outcomes of PCI Versus CABG for Unprotected Left Main Coronary Artery Disease
Type of Study, Years of Recruitment Short-Term Results Long-Term Results Chieffo et al,141 2006 Cohort, 2002–2004 In-hospital outcomes for PCI versus CABG: 1-Year adjusted ORs for PCI versus CABG: Death: 0% versus 2.1%; P⫽NS Death or MI: 0.26; 95% CI 0.078–0.597; P⫽0.0005 MI: 9.3% versus 26.1%; P⫽0.0009 Death, MI, or stroke: 0.385; 95% CI 0.180–0.819; Stroke: 0% versus 2%; P⫽NS Revascularization: 4.2; 95% CI 1.486–14.549; P⫽0.005 Lee et al,151 2006 Cohort, 2003–2005 30-Day outcomes for PCI versus CABG: 1-Year follow-up for PCI versus CABG: Death: 2% versus 5%; P⫽NS Death: 4% versus 15%; P⫽0.2 MI: 0% versus 2%; P⫽NS Death, MI, stroke: 4% versus 21%; HR⫽4.4; 95% CI Stroke: 0% versus 8%; P⫽0.03 Revascularization: 13.3% versus 5.5%; P⫽0.2 versus 2%; P⬍0.01 Palmerini et al,152 2006 Cohort, 2002–2005 30-Day outcomes for PCI versus CABG: 1- to 2-Year follow-up for PCI and CABG: Death: 3.2% versus 4.5%; P⫽NS Death: 13.4% versus 12.3%; 95% CI 0.51–1.77; MI: 4.5% versus 1.9%; P⫽NS Revascularization: 0.6% versus 0.6%; MI: 8.3% versus 4.5%; 95% CI 0.21–1.32; P⫽0.17 Revascularization: 2.6% versus 25.5%; 95% CI Buszman et al,150 2008 Randomized, 2001–2004 30-Day outcomes for PCI versus CABG: 1-Year follow-up for PCI versus CABG: Death: 0% versus 0% Death: 2% versus 8%; P⫽NS MI: 2% versus 4%; P⫽NS MI: 2% versus 6%; P⫽NS MACE: 2% versus 14%; 95% CI Revascularization: 30% versus 10%; 95% CI MACE: 32% versus 26%; 95% CI 0.85–1.38; P⫽NS December 1, 2009
Appendix 6.
Type of Study, Years of Recruitment Short-Term Results Long-Term Results Sanmartin et al,154 Cohort, 2000–2005 At 30 days for PCI versus CABG: At 1 year, for PCI versus CABG: Death: 2.1% versus 6.1%; P⫽0.17 Death: 5.2% versus 8.4%; P⫽0.37 MI: 0% versus 1.3%; P⫽0.44 versus 9.0%; P⫽0.03 Repeat revascularization: 5.2% versus 0.8%; P⫽0.02Death/MI/stroke/revascularization: 10.4% versus 11.4%; P⫽0.5 Brener et al,156 2008 Cohort with matched CABG controls, At 3 years, outcomes for PCI versus CABG: Death: 20% versus 15%; P⫽0.14 Seung et al,139 2008 Matched cohort, 2000–2006 At 3 years, HRs for PCI versus CABG: Death: 1.18; HR⫽1.18; 95% CI 0.77–1.80; P⫽0.45Death/MI/stroke: 1.10; HR⫽1.10; 95% CI 0.75–1.62; Revascularization: 4.76; HR⫽4.76; 95% CI White et al,155 2008 Cohort, 2003–2007 At 30 months, HRs for PCI versus CABG: Death: 1.93; 95% CI 0.89–4.19; P⫽0.10 Serruys et al,21 2009 Randomized, 2005–2007 At 1 year, HRs for PCI versus CABG: Death/MI/CVA/revascularization: 15.8 versus 13.7; CABG indicates coronary artery bypass graft surgery; CI, confidence interval; CVA, cerebrovascular accident; HR, hazard ratio; MACE, major adverse cardiac events; MI, myocardial infarction; NS, not significant; OR, odds ratio; RR, relative risk; and PCI, percutaneous coronary intervention.
When possible, 95% CIs reported were provided for RR, OR, or HR calculations along with probability values.
9. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358: 1. ACCF/AHA Task Force on Practice Guidelines. Methodologies and Policies from the ACCF/AHA Task Force on Practice Guidelines.
10. Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percu- pdfs/methodology.pdf. Accessed August 1, 2009.
taneous coronary intervention after clopidogrel loading: a randomized 2. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 double-blind trial. Circulation. 2009;119:1933– 40.
guideline update for percutaneous coronary intervention: a report of the 11. Valgimigli M, Campo G, Percoco G, et al. Comparison of angioplasty American College of Cardiology/American Heart Association Task with infusion of tirofiban or abciximab and with implantation of Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to sirolimus-eluting or uncoated stents for acute myocardial infarction: the Update the 2001 Guidelines for Percutaneous Coronary Intervention).
MULTISTRATEGY randomized trial. JAMA. 2008;299:1788 –99.
J Am Coll Cardiol. 2006;47:e1–121.
12. Van't Hof AW, Ten Berg J, Heestermans T, et al. Prehospital initiation 3. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for of tirofiban in patients with ST-elevation myocardial infarction the management of patients with ST-elevation myocardial infarction: a undergoing primary angioplasty (On-TIME 2): a multicentre, double- report of the American College of Cardiology/American Heart Asso- blind, randomised controlled trial. Lancet. 2008;372:537– 46.
ciation Task Force on Practice Guidelines (Committee to Revise the 13. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared 1999 Guidelines for the Management of Patients with Acute Myocardial with clopidogrel in patients undergoing percutaneous coronary inter- Infarction). J Am Coll Cardiol. 2004;44:e1– e211.
vention for ST-elevation myocardial infarction (TRITON-TIMI 38): 4. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of double-blind, randomised controlled trial. Lancet. 2009;373:723–31.
the ACC/AHA 2004 Guidelines for the Management of Patients With 14. Cantor WJ, Fitchett D, Borgundvaag B, et al. Routine early angioplasty ST-Elevation Myocardial Infarction: a report of the American College of after fibrinolysis for acute myocardial infarction. N Engl J Med. 2009; Cardiology/American Heart Association Task Force on Practice Guide- lines: 2007 Writing Group to Review New Evidence and Update the 15. Di Mario C, Dudek D, Piscione F, et al. Immediate angioplasty versus ACC/AHA 2004 Guidelines for the Management of Patients With standard therapy with rescue angioplasty after thrombolysis in the ST-Elevation Myocardial Infarction. J Am Coll Cardiol. 2008;51: Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI): an open, prospective, randomised, mul- 5. King SB III, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 Focused Update ticentre trial. Lancet. 2008;371:559 – 68.
of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous 16. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360: Coronary Intervention: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (2007 17. Svilaas T, Vlaar PJ, van der Horst I, et al. Thrombus aspiration during Writing Group to Review New Evidence and Update the ACC/ primary percutaneous coronary intervention. N Engl J Med. 2008;358: AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Inter- vention). J Am Coll Cardiol. 2008;51:172–209.
18. Sardella G, Mancone M, Bucciarelli-Ducci C, et al. Thrombus aspiration 6. Gurm H, Tamhane U, Meier P, et al. A comparison of abciximab and during primary percutaneous coronary intervention improves myo- small molecule glycoprotein IIb/IIIa inhibitors in patients undergoing cardial reperfusion and reduces infarct size: the EXPIRA (throm- primary percutaneous coronary intervention: a meta-analysis of contem- bectomy with export catheter in infarct-related artery during primary porary randomized controlled trials. Circ Cardiovasc Intervent. 2009;2: percutaneous coronary intervention) prospective, randomized trial. J Am Coll Cardiol. 2009;53:309 –15.
7. De Luca G, Ucci G, Cassetti E, et al. Benefits from small molecule 19. Solomon RJ, Natarajan MK, Doucet S, et al. Cardiac Angiography in administration as compared with abciximab among patients with Renally Impaired Patients (CARE) study: a randomized double-blind ST-segment elevation myocardial infarction treated with primary angio- trial of contrast-induced nephropathy in patients with chronic kidney plasty: a meta-analysis. J Am Coll Cardiol. 2009;53:1668 –73.
disease. Circulation. 2007;115:3189 –96.
8. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients 20. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus with ST-elevation myocardial infarction. N Engl J Med. 2008;358: angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213–24.
Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
21. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary 42. Mehta SR, Yusuf S. The Clopidogrel in Unstable angina to prevent intervention versus coronary-artery bypass grafting for severe coronary Recurrent Events (CURE) trial programme; rationale, design and artery disease. N Engl J Med. 2009;360:961–72.
baseline characteristics including a meta-analysis of the effects of thien- 22. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provi- opyridines in vascular disease. Eur Heart J. 2000;21:2033– 41.
sional eptifibatide in acute coronary syndromes. N Engl J Med. 2009; 43. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with 360:2176 –90.
clopidogrel and aspirin followed by long-term therapy in patients 23. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive undergoing percutaneous coronary intervention: the PCI-CURE study.
intervention in acute coronary syndromes. N Engl J Med. 2009;360: 44. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke 24. Wagner GS, Macfarlane P, Wellens H, et al. AHA/ACCF/HRS recom- in patients with ischemic stroke or transient ischemic attack: a statement mendations for the standardization and interpretation of the electrocar- for healthcare professionals from the American Heart Association/ diogram: part VI: acute ischemia/infarction: a scientific statement from American Stroke Association Council on Stroke. Stroke. 2006;37: the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of 45. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial Cardiology Foundation; and the Heart Rhythm Society. J Am Coll infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49:1982– 8.
25. Hamm C. ON-TIME-2. Ongoing-Tirofiban In Myocardial Infarction 46. Lau WC, Gurbel PA. The drug-drug interaction between proton pump evaluation 1 year follow-up. Available at: www.clinicaltrialresults.org/ inhibitors and clopidogrel. CMAJ. 2009;180:699 –700.
slides/OnTime2-Orlando.ppt. Accessed March 30, 2009.
47. Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 poly- 26. Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel morphism in young patients treated with clopidogrel after myocardial compared with clopidogrel in patients with acute coronary syndromes: infarction: a cohort study. Lancet. 2009;373:309 –17.
design and rationale for the TRial to assess Improvement in Therapeutic 48. Roden DM, Stein CM. Clopidogrel and the concept of high-risk phar- Outcomes by optimizing platelet InhibitioN with prasugrel Thromboly- sis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006; 49. Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of- function polymorphism and stent thrombosis following percutaneous 27. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopi- coronary intervention. Eur Heart J. 2009;30:916 –22.
dogrel in patients with acute coronary syndromes. N Engl J Med.
50. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med.
28. Grines CL, Bonow RO, Casey DE Jr, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary 51. Mega J, Thakuria JV, Cannon CP, Sabatine MS. Sequence variations in artery stents: a science advisory from the American Heart Association, CYP metabolism genes and cardiovascular outcomes following American College of Cardiology, Society for Cardiovascular treatment with clopidogrel: insights from the CLARITY-TIMI 28 Angiography and Interventions, American College of Surgeons, and genomic study. Available at: http://content.onlinejacc.org/cgi/reprint/51/ American Dental Association, with representation from the American 10_Suppl_A/A178.pdf. Accessed May 25, 2009.
College of Physicians. J Am Dent Assoc. 2007;138:652–5.
52. Giusti B, Gori AM, Marcucci R, et al. Relation of cytochrome P450 29. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet 2C19 loss-of-function polymorphism to occurrence of drug-eluting inhibition after a 600-mg loading dose of clopidogrel in a large, un- coronary stent thrombosis. Am J Cardiol. 2009;103:806 –11.
selected cohort of candidates for percutaneous coronary intervention.
53. Mega J, Close S, Wiviott S, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354 – 62.
30. Plavix (clopidogrel bisulfate) [package insert]. Bridgewater, NJ: 54. Aspirin for the prevention of cardiovascular disease. Available at: Bristol-Myers Squibb Sanofi-aventis. Sanofi-aventis, 2009.
31. Kim JH, Newby LK, Clare RM, et al. Clopidogrel use and bleeding after detaildocuments/250601.pdf?cs⫽&s⫽PL. Accessed May 26, 2009.
coronary artery bypass graft surgery. Am Heart J. 2008;156:886 –92.
55. Michelson AD, Frelinger AL III, Braunwald E, et al. Pharmacodynamic 32. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes asso- assessment of platelet inhibition by prasugrel vs. clopidogrel in the ciated with concomitant use of clopidogrel and proton pump inhibitors TRITON-TIMI 38 trial. Eur Heart J. 2009;30:1753– 63.
following acute coronary syndrome. JAMA. 2009;301:937– 44.
56. Small DS, Farid NA, Payne CD, et al. Effects of the proton pump 33. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics drug interaction between proton pump inhibitors and clopidogrel.
of prasugrel and clopidogrel. J Clin Pharmacol. 2008;48:475– 84.
CMAJ. 2009;180:713– 8.
57. Price MJ, Berger PB, Angiolillo DJ, et al. Evaluation of individualized 34. Stanek E. Medco study: PPIs reduce clopidogrel efficacy post-stenting.
clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS 1130am/. Accessed July 29, 2009.
trial. Am Heart J. 2009;157:818 –24.
35. O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic 58. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to effect and clinical efficacy of clopidogrel and prasugrel with or without aspirin and fibrinolytic therapy for myocardial infarction with a proton-pump inhibitor: an analysis of two randomised trials. Lancet.
ST-segment elevation. N Engl J Med. 2005;352:1179 – 89.
2009;374:989 –97.
59. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 36. Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading expert consensus document on reducing the gastrointestinal risks of doses according to vasodilator-stimulated phosphoprotein phosphoryla- antiplatelet therapy and NSAID use: a report of the American College of tion index decrease rate of major adverse cardiovascular events in Cardiology Foundation Task Force on Clinical Expert Consensus Doc- patients with clopidogrel resistance: a multicenter randomized pro- uments. J Am Coll Cardiol. 2008;52:1502–17.
spective study. J Am Coll Cardiol. 2008;51:1404 –11.
60. Aubert RE, Epstein RS, Teagarden JR, et al. Proton pump inhibitors 37. Prasugrel [drug label]. Indianapolis, Ind: Eli Lilly and Co., 2009.
effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes 38. Wrishko RE, Ernest CS, Small DS, et al. Population pharmacokinetic Study. Circulation. 2008;118:S-815. Abstract.
analyses to evaluate the influence of intrinsic and extrinsic factors on 61. Dunn SP, Macaulay TE, Brennan DM, et al. Baseline proton pump exposure of prasugrel active metabolite in TRITON-TIMI 38. J Clin inhibitor use is associated with increased cardiovascular events with and Pharmacol. 2009;49:984 –98.
without the use of clopidogrel in the CREDO trial. Circulation. 2008; 39. Michelson AD. Platelet function testing in cardiovascular diseases. Cir- culation. 2004;110:e489 –93.
62. Ramirez JF, Selzer F, Chakaprani R. Proton pump inhibitor and clopi- 40. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel dogrel combination is not associated with adverse clinical outcomes compared with clopidogrel alone after recent ischaemic stroke or after PCI: the NHLBI Dynamic Registry. J Am Coll Cardiol 2009;53: transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331–7.
63. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the 41. Jneid H, Bhatt DL, Corti R, et al. Aspirin and clopidogrel in acute antiplatelet action of clopidogrel associated with aspirin: the ran- coronary syndromes: therapeutic insights from the CURE study. Arch domized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study.
Intern Med. 2003;163:1145–53.
J Am Coll Cardiol. 2008;51:256 – 60.
December 1, 2009
64. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors 85. Krumholz HM, Anderson JL, Bachelder BL, et al. ACC/AHA 2008 on the antiplatelet effects of clopidogrel. Thromb Haemost. 2009;101: performance measures for adults with ST-elevation and non–ST- elevation myocardial infarction: a report of the American College of 65. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high Cardiology/American Heart Association Task Force on Performance loading- and maintenance-dose clopidogrel in patients with planned Measures (Writing Committee to Develop Performance Measures for percutaneous coronary intervention: the Prasugrel in Comparison to ST-Elevation and Non-ST-Elevation Myocardial Infarction). Circu- Clopidogrel for Inhibition of Platelet Activation and Aggregation- lation. 2008;118:2596 – 648.
Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116: 86. American Heart Association. Get With The Guidelines. Available at: 66. US Food and Drug Administration. Clopidogrel (Marketed as Plavix) Accessed June 10, 2009.
and Omeprazole (Marketed as Prilosec): Drug Interaction. Available at: 87. Measure Comparison (Inpatient Hospital Quality Measures). Available forHumanMedicalProducts/ucm190848.htm. Accessed November 17, June 10, 2009.
67. Taha AS, McCloskey C, Prasad R, et al. Famotidine for the prevention 88. National Cardiovascular Data Registry. Action Registry – GWTG.
of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled Accessed June 10, 2009.
trial. Lancet. 2009;374:119 –25.
89. The Joint Commission. Acute Myocardial Infarction Core Measure Set.
68. Mehran R, Brodie B, Cox DA, et al. The Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial: study design and rationale. Am Heart J.
Core⫹Measure⫹Set.htm. Accessed June 10, 2009.
2008;156:44 –56.
90. American Heart Association. Mission: lifeline. Available at: http:// 69. Dangas GD, Lansky AJ, Brodie BR. Predictors of Stent Thrombosis After Primary Angioplasty in Acute Myocardial Infarction: The June 10, 2009.
HORIZONS-AMI Trial. Available at: http://www.cardiosource.com/ 91. Henry TD, Sharkey SW, Burke MN, et al. A regional system to provide rapidnewssummaries/summary.asp?SumID⫽406. Accessed August 3, timely access to percutaneous coronary intervention for ST-elevation myocardial infarction. Circulation. 2007;116:721– 8.
70. ASSENT-4 PCI Investigators. Primary versus tenecteplase-facilitated 92. Le May MR, So DY, Dionne R, et al. A citywide protocol for primary percutaneous coronary intervention in patients with ST-segment ele- PCI in ST-segment elevation myocardial infarction. N Engl J Med.
vation acute myocardial infarction (ASSENT-4 PCI): randomised trial.
2008;358:231– 40.
Lancet. 2006;367:569 –78.
93. Ting HH, Rihal CS, Gersh BJ, et al. Regional systems of care to 71. Ellis SG, Armstrong P, Betriu A, et al. Facilitated percutaneous coronary optimize timeliness of reperfusion therapy for ST-elevation myocardial intervention versus primary percutaneous coronary intervention: design infarction: the Mayo Clinic STEMI Protocol. Circulation. 2007;116: and rationale of the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial. Am Heart J. 2004;147:E16.
94. Kosiborod M, Inzucchi SE, Goyal A, et al. Relationship between spon- 72. Deleted in proof.
taneous and iatrogenic hypoglycemia and mortality in patients hospi- 73. Alp NJ, Gershlick AH, Carver A, et al. Rescue angioplasty for failed talized with acute myocardial infarction. JAMA. 2009;301:1556 – 64.
thrombolysis in older patients: insights from the REACT trial. Int 95. Malmberg K, Norhammar A, Wedel H, et al. Glycometabolic state at J Cardiol. 2008;125:254 –7.
admission: important risk marker of mortality in conventionally treated 74. Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty patients with diabetes mellitus and acute myocardial infarction: after failed thrombolytic therapy for acute myocardial infarction. N Engl long-term results from the Diabetes and Insulin-Glucose Infusion in J Med. 2005;353:2758 – 68.
Acute Myocardial Infarction (DIGAMI) study. Circulation. 1999;99: 75. Collet JP, Montalescot G, Le May M, et al. Percutaneous coronary intervention after fibrinolysis: a multiple meta-analyses approach 96. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin according to the type of strategy. J Am Coll Cardiol. 2006;48:1326 –35.
therapy in the medical ICU. N Engl J Med. 2006;354:449 – 61.
76. Wijeysundera HC, Vijayaraghavan R, Nallamothu BK, et al. Rescue 97. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 angioplasty or repeat fibrinolysis after failed fibrinolytic therapy for guidelines for the management of patients with unstable angina/non–ST- ST-segment myocardial infarction: a meta-analysis of randomized trials.
elevation myocardial infarction: a report of the American College of J Am Coll Cardiol. 2007;49:422–30.
Cardiology/American Heart Association Task Force on Practice 77. Lincoff AM, Califf RM, Van de Werf F, et al. Mortality at 1 year with Guidelines (Writing Committee to Revise the 2002 Guidelines for the combination platelet glycoprotein IIb/IIIa inhibition and reduced-dose Management of Patients With Unstable Angina/Non ST-Elevation Myo- fibrinolytic therapy vs conventional fibrinolytic therapy for acute myo- cardial Infarction). J Am Coll Cardiol. 2007;50:e1–157.
cardial infarction: GUSTO V randomized trial. JAMA. 2002;288: 98. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA. 2008;300: 78. Pinto DS, Kirtane AJ, Nallamothu BK, et al. Hospital delays in reper- fusion for ST-elevation myocardial infarction: implications when 99. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Asso- selecting a reperfusion strategy. Circulation. 2006;114:2019 –25.
ciation of Clinical Endocrinologists and American Diabetes Association 79. Antman EM. Time is muscle: translation into practice. J Am Coll consensus statement on inpatient glycemic control. Diabetes Care. 2009; Cardiol. 2008;52:1216 –21.
32:1119 –31.
80. Rathore SS, Curtis JP, Chen J, et al. Association of door-to-balloon time 100. Deedwania P, Kosiborod M, Barrett E, et al. Hyperglycemia and acute and mortality in patients admitted to hospital with ST elevation myo- coronary syndrome: a scientific statement from the American Heart cardial infarction: national cohort study. BMJ. 2009;338:b1807.
Association Diabetes Committee of the Council on Nutrition, Physical 81. Armstrong PW, Westerhout CM, Welsh RC. Duration of symptoms is Activity, and Metabolism. Anesthesiology. 2008;109:14 –24.
the key modulator of the choice of reperfusion for ST-elevation myo- 101. Marfella R, Di Filippo C, Portoghese M, et al. Tight glycemic control cardial infarction. Circulation. 2009;119:1293–303.
reduces heart inflammation and remodeling during acute myocardial 82. Jacobs AK, Antman EM, Faxon DP, et al. Development of systems of infarction in hyperglycemic patients. J Am Coll Cardiol. 2009;53: care for ST-elevation myocardial infarction patients: executive summary. Circulation. 2007;116:217–30.
102. Vlaar PJ, Svilaas T, van der Horst I, et al. Cardiac death and reinfarction 83. Jacobs AK. Regional systems of care for patients with ST-elevation after 1 year in the Thrombus Aspiration during Percutaneous coronary myocardial infarction: being at the right place at the right time. Circu- intervention in Acute myocardial infarction Study (TAPAS): a 1-year lation. 2007;116:689 –92.
follow-up study. Lancet. 2008;371:1915–20.
84. Bonow RO, Masoudi FA, Rumsfeld JS, et al. ACC/AHA classification 103. Bavry AA, Kumbhani DJ, Bhatt DL. Role of adjunctive thrombectomy of care metrics: performance measures and quality metrics: a report of and embolic protection devices in acute myocardial infarction: a com- the American College of Cardiology/American Heart Association Task prehensive meta-analysis of randomized trials. Eur Heart J. 2008;29: Force on Performance Measures. J Am Coll Cardiol. 2008;52:2113–7.
2989 –3001.
Kushner et al
2009 Focused Updates: STEMI and PCI Guidelines
104. Burzotta F, De Vita M, Gu YL, et al. Clinical impact of thrombectomy mediate stenosis on the basis of coronary pressure measurement. J Am in acute ST-elevation myocardial infarction: an individual patient-data Coll Cardiol. 1998;31:841–7.
pooled analysis of 11 trials. Eur Heart J. 2009;30:2193–203.
127. Berger A, Botman KJ, MacCarthy PA, et al. Long-term clinical outcome 105. Stone GW, Lansky AJ, Pocock SJ, et al. Paclitaxel-eluting stents versus after fractional flow reserve-guided percutaneous coronary intervention bare-metal stents in acute myocardial infarction. N Engl J Med. 2009; in patients with multivessel disease. J Am Coll Cardiol. 2005;46: 360:1946 –59.
106. Neumann FJ, Kastrati A, Pogatsa-Murray G, et al. Evaluation of pro- 128. Botman KJ, Pijls NH, Bech JW, et al. Percutaneous coronary inter- longed antithrombotic pretreatment (‘cooling-off‘ strategy) before inter- vention or bypass surgery in multivessel disease? A tailored approach vention in patients with unstable coronary syndromes: a randomized based on coronary pressure measurement. Catheter Cardiovasc Interv.
controlled trial. JAMA. 2003;290:1593–9.
2004;63:184 –91.
107. Marroquin OC, Selzer F, Mulukutla SR, et al. A comparison of 129. Caymaz O, Fak AS, Tezcan H, et al. Correlation of myocardial frac- bare-metal and drug-eluting stents for off-label indications. N Engl tional flow reserve with thallium-201 SPECT imaging in intermediate- J Med. 2008;358:342–52.
severity coronary artery lesions. J Invasive Cardiol. 2000;12:345–50.
108. Garg P, Normand SL, Silbaugh TS, et al. Drug-eluting or bare-metal 130. Chamuleau SA, Meuwissen M, Koch KT, et al. Usefulness of fractional stenting in patients with diabetes mellitus: results from the Massa- flow reserve for risk stratification of patients with multivessel coronary chusetts Data Analysis Center Registry. Circulation. 2008;118:2277– 85.
artery disease and an intermediate stenosis. Am J Cardiol. 2002;89: 109. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350: 131. Christou MA, Siontis GC, Katritsis DG, et al. Meta-analysis of frac- tional flow reserve versus quantitative coronary angiography and non- 110. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intrave- invasive imaging for evaluation of myocardial ischemia. Am J Cardiol.
nous thrombolytic therapy for acute myocardial infarction: a quantitative 2007;99:450 – 6.
review of 23 randomised trials. Lancet. 2003;361:13–20.
132. Costa MA, Sabate M, Staico R, et al. Anatomical and physiologic 111. Zhu MM, Feit A, Chadow H, et al. Primary stent implantation compared assessments in patients with small coronary artery disease: final results with primary balloon angioplasty for acute myocardial infarction: a of the Physiologic and Anatomical Evaluation Prior to and After Stent meta-analysis of randomized clinical trials. Am J Cardiol. 2001;88: Implantation in Small Coronary Vessels (PHANTOM) trial. Am Heart J.
2007;153:296 –7.
112. Nordmann AJ, Hengstler P, Harr T, et al. Clinical outcomes of primary 133. Courtis J, Rodes-Cabau J, Larose E, et al. Comparison of medical stenting versus balloon angioplasty in patients with myocardial treatment and coronary revascularization in patients with moderate infarction: a meta-analysis of randomized controlled trials. Am J Med.
coronary lesions and borderline fractional flow reserve measurements.
2004;116:253– 62.
Catheter Cardiovasc Interv. 2008;71:541– 8.
113. Mauri L, Silbaugh TS, Garg P, et al. Drug-eluting or bare-metal stents 134. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow for acute myocardial infarction. N Engl J Med. 2008;359:1330 – 42.
reserve to assess the functional severity of coronary-artery stenoses.
114. Hannan EL, Racz M, Walford G, et al. Drug-eluting versus bare-metal N Engl J Med. 1996;334:1703– 8.
stents in the treatment of patients with ST-segment elevation myocardial 135. Verna E, Lattanzio M, Ghiringhelli S, et al. Performing versus deferring infarction. JACC Cardiovasc Interv. 2008;1:129 –35.
coronary angioplasty based on functional evaluation of vessel stenosis 115. Pasceri V, Patti G, Speciale G, et al. Meta-analysis of clinical trials on by pressure measurements: a clinical outcome study. J Cardiovasc Med use of drug-eluting stents for treatment of acute myocardial infarction.
(Hagerstown). 2006;7:169 –75.
Am Heart J. 2007;153:749 –54.
136. Yanagisawa H, Chikamori T, Tanaka N, et al. Correlation between 116. Kastrati A, Dibra A, Spaulding C, et al. Meta-analysis of randomized thallium-201 myocardial perfusion defects and the functional severity of trials on drug-eluting stents vs. bare-metal stents in patients with acute coronary artery stenosis as assessed by pressure-derived myocardial myocardial infarction. Eur Heart J. 2007;28:2706 –13.
fractional flow reserve. Circ J. 2002;66:1105–9.
117. De Luca G, Stone GW, Suryapranata H, et al. Efficacy and safety of 137. Yanagisawa H, Chikamori T, Tanaka N, et al. Application of pressure- drug-eluting stents in ST-segment elevation myocardial infarction: a derived myocardial fractional flow reserve in assessing the functional meta-analysis of randomized trials. Int J Cardiol. 2009;133:213–22.
severity of coronary artery stenosis in patients with diabetes mellitus.
118. Van de Werf F. Drug-eluting stents in acute myocardial infarction.
Circ J. 2004;68:993– 8.
N Engl J Med. 2006;355:1169 –70.
119. Jo SH, Youn TJ, Koo BK, et al. Renal toxicity evaluation and com- 138. Park SJ, Hong MK, Lee CW, et al. Elective stenting of unprotected left parison between visipaque (iodixanol) and hexabrix (ioxaglate) in main coronary artery stenosis: effect of debulking before stenting and patients with renal insufficiency undergoing coronary angiography: the intravascular ultrasound guidance. J Am Coll Cardiol. 2001;38:1054-60.
RECOVER study: a randomized controlled trial. J Am Coll Cardiol.
139. Seung KB, Park DW, Kim YH, et al. Stents versus coronary-artery 2006;48:924 –30.
bypass grafting for left main coronary artery disease. N Engl J Med.
120. McCullough PA, Bertrand ME, Brinker JA, et al. A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast 140. Chieffo A, Stankovic G, Bonizzoni E, et al. Early and mid-term results media. J Am Coll Cardiol. 2006;48:692–9.
of drug-eluting stent implantation in unprotected left main. Circulation.
121. Kuhn MJ, Chen N, Sahani DV, et al. The PREDICT study: a randomized double-blind comparison of contrast-induced nephropathy after low- or 141. Chieffo A, Morici N, Maisano F, et al. Percutaneous treatment with isoosmolar contrast agent exposure. AJR Am J Roentgenol. 2008;191: drug-eluting stent implantation versus bypass surgery for unprotected left main stenosis: a single-center experience. Circulation. 2006;113: 122. Rudnick MR, Davidson C, Laskey W, et al. Nephrotoxicity of iodixanol versus ioversol in patients with chronic kidney disease: the Visipaque 142. Chieffo A, Park SJ, Valgimigli M, et al. Favorable long-term outcome Angiography/Interventions with Laboratory Outcomes in Renal Insuffi- after drug-eluting stent implantation in nonbifurcation lesions that ciency (VALOR) Trial. Am Heart J. 2008;156:776 – 82.
involve unprotected left main coronary artery: a multicenter registry.
123. Thomsen HS, Morcos SK, Erley CM, et al. The ACTIVE Trial: com- Circulation. 2007;116:158 – 62.
parison of the effects on renal function of iomeprol-400 and 143. Kim YH, Dangas GD, Solinas E, et al. Effectiveness of drug-eluting iodixanol-320 in patients with chronic kidney disease undergoing stent implantation for patients with unprotected left main coronary artery abdominal computed tomography. Invest Radiol. 2008;43:170 – 8.
stenosis. Am J Cardiol. 2008;101:801– 6.
124. Reed M, Meier P, Tamhane UU, et al. The relative renal safety of 144. Takagi T, Stankovic G, Finci L, et al. Results and long-term predictors iodixanol compared with low-osmolar contrast media: a meta-analysis of adverse clinical events after elective percutaneous interventions on of randomized controlled trials. JACC Cardiovasc Interv. 2009;2: unprotected left main coronary artery. Circulation. 2002;106:698 –702.
145. Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline 125. Heinrich MC, Haberle L, Muller V, et al. Nephrotoxicity of iso-osmolar update for the management of patients with chronic stable angina– iodixanol compared with nonionic low-osmolar contrast media: meta- summary article: a report of the American College of Cardiology/ analysis of randomized controlled trials. Radiology. 2009;250:68 – 86.
American Heart Association Task Force on Practice Guidelines (Com- 126. Bech GJ, De Bruyne B, Bonnier HJ, et al. Long-term follow-up after mittee on the Management of Patients With Chronic Stable Angina).
deferral of percutaneous transluminal coronary angioplasty of inter- J Am Coll Cardiol. 2003;41:159 – 68.
December 1, 2009
146. Huang HW, Brent BN, Shaw RE. Trends in percutaneous versus surgical 155. White A, Kedia G, Mirocha J, et al. Comparison of coronary artery revascularization of unprotected left main coronary stenosis in the drug- bypass surgery and percutaneous drug-eluting stent implantation for eluting stent era: a report from the American College of Cardiology- treatment of left main coronary artery stenosis. JACC Cardiovasc Interv.
National Cardiovascular Data Registry (ACC-NCDR). Catheter Car- 2008;1:236 – 45.
diovasc Interv. 2006;68:867–72.
156. Brener SJ, Galla JM, Bryant R III, et al. Comparison of percutaneous versus surgical revascularization of severe unprotected left main 147. Baim DS, Mauri L, Cutlip DC. Drug-eluting stenting for unprotected left coronary stenosis in matched patients. Am J Cardiol. 2008;101:169 –72.
main coronary artery disease: are we ready to replace bypass surgery? 157. Kereiakes DJ, Faxon DP. Left main coronary revascularization at the J Am Coll Cardiol. 2006;47:878 – 81.
crossroads. Circulation. 2006;113:2480 – 4.
148. Brinker J. The left main facts: faced, spun, but alas too few. J Am Coll 158. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to Cardiol. 2008;51:893– 8.
aspirin in patients with acute coronary syndromes without ST-segment 149. Taggart DP, Kaul S, Boden WE, et al. Revascularization for unprotected elevation. N Engl J Med. 2001;345:494 –502.
left main stem coronary artery stenosis stenting or surgery. J Am Coll 159. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a 150. Buszman PE, Kiesz SR, Bochenek A, et al. Acute and late outcomes of randomized controlled trial. JAMA. 2002;288:2411–20.
160. Montalescot G. Angioplasty to Blunt the rise Of troponin in Acute unprotected left main stenting in comparison with surgical revascular- coronary syndromes Randomized for an immediate or Delayed inter- ization. J Am Coll Cardiol. 2008;51:538 – 45.
vention. Available at: http://www.theheart.org/article/954535.do.
151. Lee MS, Kapoor N, Jamal F, et al. Comparison of coronary artery Accessed August 3, 2009.
bypass surgery with percutaneous coronary intervention with drug- 161. Stone GW, Bertrand ME, Moses JW, et al. Routine upstream initiation eluting stents for unprotected left main coronary artery disease. J Am vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute Coll Cardiol. 2006;47:864 –70.
coronary syndromes: the ACUITY Timing trial. JAMA. 2007;297: 152. Palmerini T, Marzocchi A, Marrozzini C, et al. Comparison between coronary angioplasty and coronary artery bypass surgery for the 162. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein treatment of unprotected left main coronary artery stenosis (the Bologna IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all Registry). Am J Cardiol. 2006;98:54 –9.
major randomised clinical trials. Lancet. 2002;359:189 –98.
163. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis 153. Rodes-Cabau J, Deblois J, Bertrand OF, et al. Nonrandomized com- and treatment of non–ST-segment elevation acute coronary syndromes.
parison of coronary artery bypass surgery and percutaneous coronary Eur Heart J. 2007;28:1598 – 660.
intervention for the treatment of unprotected left main coronary arterydisease in octogenarians. Circulation. 2008;118:2374 – 81.
KEY WORDS: ACCF/AHA practice guidelines 䡲 focused update 䡲 154. Sanmartin M, Baz JA, Claro R, et al. Comparison of drug-eluting stents ST-elevation myocardial infarction 䡲 percutaneous coronary intervention versus surgery for unprotected left main coronary artery disease.
䡲 thienopyridines 䡲 parenteral anticoagulants 䡲 antiplatelet therapy 䡲 Am J Cardiol. 2007;100:970 –3.
glycoprotein IIb/IIIa receptor antagonists

Source: http://www.interventor.ru/ru/downloads/AHA-2009-guideline.pdf

revistargo.com.br

ORIGINAL ORIGINAL Non-surgical periodontal therapy for the treatment of chronic periodontitis Terapia periodontal não-cirúrgica no tratamento da periodontite crônica Mari Raquel Botlender TROJAHN1 Robert Carvalho da SILVA2 Júlio César JOLY2 The aim of this split-mouth controlled study was to compare the clinical benefits of administering subgingival 10% Doxycycline (test group)

weblaw.ch

Prof. Daniel Kraus - Liste des publications, conférences et cours donnés Précis de propriété intellectuelle (avec Nathalie Tissot et Vincent Salvadé), éd. Stämpfli A paraître en 2014 Le droit d'auteur des planificateurs (avec Blaise Carron, Mélanie Krüsi et Yann Férolles), éd. Schulthess (version allemande : 2014 ; version française : 2015)