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Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA

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1 Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA
STEMI-WRAP on Evidence-Based Management of STEMI: The Emergency Department Perspective Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA Professor and Chair, Emergency Medicine, Pennsylvania Hospital University of Pennsylvania Health System Philadelphia

2 STEMI Accounts for 15-20% of cases of ACS seen in ED; UA/NSTEMI (collectively, NSTE ACS) account for majority High-visibility diagnosis because of its high morbidity and mortality, patient and family fears and expectations, and intensity of monitoring by observers inside and outside the hospital—QI, payors, JCAHO, P4P

3 STEMI Pathophys: STEMI is caused by complete obstruction of an epicardial vessel, which causes angina or anginal equivalent and diagnostic ECG changes of ST-segment elevation Recognition of STEMI, which by GLs should occur within 10 minutes of ED arrival, launches the ED-cardiology team on a fast-moving track that demands prompt stabilization, evidence-based medical management, and quick decisions regarding reperfusion therapy Dx of STEMI is clinical + electrocardiographic and DOES NOT require assessment of cardiac markers

4 STEMI STEMI typically result from fissure or frank rupture of an atherosclerotic plaque Stimulates local activation of: platelets coagulation cascade complement Platelet aggregate forms over site of plaque injury and as it matures (fibrinogen→fibrin) causes complete obstruction of distal flow. To the extent that collateral flow downstream is lacking, ischemia quickly ensues and infarction starts to occur within minutes

5 STEMI Pharmacologic therapy in STEMI is therefore directed at this triad of abnormal activity: Platelet activation—anti-activation and anti-aggregation ASA and clopidogrel GPIs Coagulation activation—anticoagulants Complement activation—anti-inflammatories ? Statins In preparation for reperfusion therapy by lysis or angiography and primary PCI

6 Guidelines for STEMI diagnosis and management
complex disease state with broad ranges of presentation and a multitude of therapeutic options Many important and pertinent clinical studies Information overload! Need evidence-based guidelines to promote consistency of care and resulting better outcomes

7 Guidelines for STEMI management
ACC/AHA Joint Task Force: 1990, 1996, 1999 Last comprehensive update in 2004 Widely read, lots of interest Clear evidence scoring, sensible recommendations, temporal sequencing “soup to nuts” Recapitulation, interpretation, and promulgation for upstream providers in Annals of Emergency Medicine

8 Guidelines for STEMI management
ACC/AHA Joint Task Force: presented “focused update” in December 2007 “focus” (from upstream perspective) on reperfusion strategies and opportunities to minimize delays to reperfusion Beta blockers Choices of anticoagulants New recommendations regarding clopidogrel

9 Applying Classification of Recommendations
Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Class IIb Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Risk ≥ Benefit No additional studies needed Procedure/Treatment should NOT be per-formed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL should is recommended is indicated is useful/effective/ beneficial is reasonable can be useful/effective/ beneficial is probably recommended or indicated may/might be considered may/might be reasonable usefulness/effectiveness is unknown /unclear/uncertain or not well established is not recommended is not indicated should not is not useful/effective/ beneficial may be harmful

10 “The Guidelines” Weighing the Evidence
Weight of evidence grades: = Data from many large, randomized trials = Data from fewer, smaller randomized trials, careful analyses of nonrandomized studies, observational registries = Expert consensus The weight of evidence is graded on three levels A, B, and C, with an emphasis on randomized clinical trials. A- the data is obtained from many large randomized clinical trials B-the data is obtained from fewer, smaller randomized clinical trials or there is careful analyses of nonrandomized studies including observational studies C-the weakest evidence of all is supplies by expert consensus or opinion Many standard medical practices carry a weight of “C” and were never exposed to a randomized trial (e.g. supplying oxygen).

11 Time Delays and 30 Day Outcome in STEMI
Loss of benefit per hour of delay 1.6±0.6 lives per 1000 patients 40 3000 14,000 45,000 patients in placebo controlled lytic trials. 30 12,000 9000 Lives saved/1000 patients 20 10 7000 6 12 18 24 Hours from onset of symptoms to randomization Collins. NEJM. 1997;336:847.

12 Time Delays and 30 Day Outcome in STEMI: Primary PCI (NRMI-2)
Cannon C, et al. JAMA 2000;283:

13 Time Delays and 30 Day Outcome in STEMI: Primary PCI (NRMI-2)
Cannon C, et al. JAMA 2000;283:

14 Prehospital Issues EMS Chest Pain Evaluation & Treatment
Emphasis on early defibrillation; AEDs; 911 dispatchers training & use of national protocols; 12-lead ECGs Chest Pain Evaluation & Treatment Emphasis on giving chewable ASA, unless contraindicated & prehospital ECG & checklist Prehospital Fibrinolysis Upgraded to a Class IIa (Level B) Recommendation although not particularly likely in most systems Prehospital Destination Protocols Where to transport STEMI patients: a plan must be in place Special considerations Cardiogenic Shock Fibrinolytic contraindicated The prehospital section is highlighted on this slide. Review slide and emphasize each bullet. Review prehospital commentary on EMS-early chain of survival, chest pain evaluation and TX. Exec Summary, pg Pre Hospital Fibrinolysis: Class IIa 1. Establishment of a prehospital fibrinolysis protocol is reasonable in 1) settings in which physicians are present in the ambulance or in 2) well-organized EMS systems with full-time paramedics who have 12-lead ECGs in the field with transmission capability, paramedic initial and ongoing training in ECG interpretation and STEMI treatment, online medical command, a medical director with training/experience in STEMI management, and an ongoing continuous quality-improvement program. (Level of Evidence: B) From page 6-7 Executive Summary: “Randomized controlled trials of fibrinolytic therapy have demonstrated the benefit of initiating fibrinolytic therapy as early as possible after onset of ischemic-type chest discomfort (Figure 1). It appears reasonable to expect that if fibrinolytic therapy could be started at the time of prehospital evaluation, a greater number of lives could be saved. Prehospital fibrinolysis is reasonable in those settings in which physicians are present in the ambulance or prehospital transport times are more than 60 minutes in high-volume (more than 25,000 runs per year) EMS systems. Other considerations for implementing a prehospital fibrinolytic service include the ability to transmit ECGs, paramedic initial and ongoing training in ECG interpretation and myocardial infarction (MI) treatment, online medical command, a medical director with training/experience in management of STEMI, and full-time paramedics.”

15 Patients Transported by EMS After Calling 9-1-1
Hospital Fibrinolysis: Door-to-needle within<30 min Call 911 Call Fast EMS Triage Plan Not PCI Capable Hospital EMS on-scene Encourage 12-lead ECG Consider prehospital fibrinolytic if capable and EMS-to-needle < 30 min Onset of STEMI Symptoms 9-1-1 EMS Dispatch Interhospital Transfer PPCI: Door-to-balloon within<90 min PCI Capable Hospital Goals EMS on scene EMS transport Patient Dispatch EMS transport:EMS to Balloon within 90 min 5’ after sx onset Within 8 min Patient self-transport: Hospital Door-to-Balloon within 90 min 1 min Total ischemic time: Within 120 min*

16 ACC/AHA 2007 STEMI Focused Update: Acute Medical Therapy
General treatment measures Aspirin, nitrates, oxygen, analgesicsa (morphine) Infarct size limitation β-blockers (not for acute use in patients with evidence of heart failure) Reperfusion Thrombolysis (within 30 min) or primary PCI (within 90 min) Anticoagulant and antiplatelet therapy UFH or enoxaparin or fondaparinuxb Clopidogrel 75 mg/d added to aspirin for patients undergoing fibrinolysis; 300 mg loading dose for patients <75 y who receive fibrinolytic therapy or who do not receive reperfusion therapy If PCI: clopidogrel, GP IIb/IIIa inhibitors This slide reflects the acute therapy recommendations from the ACC/AHA STEMI 2007 focused update.1 The 2004 ACC/AHA STEMI guidelines2 should be consulted for policy on clinical areas not covered by the focused update. General measures for the treatment of STEMI include morphine, nitrates, oxygen, and aspirin.1,2 Patients routinely taking NSAIDs (except for aspirin), both nonselective as well as COX-2 selective agents, before STEMI should have those agents discontinued at the time of presentation with STEMI because of the increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use.1 Oral -blocker therapy should be initiated in the first 24 hours for STEMI patients who do not have any of the following: (1) signs of heart failure, (2) evidence of a low output state, (3) increased risk for cardiogenic shock, or (4) other relative contraindications to -blockade.1 Reperfusion options include primary percutaneous coronary intervention (PCI) or coronary thrombolysis. Primary PCI is the preferred option if the patient presents more than 3 hours after symptom onset.1,2 Recommended anticoagulant therapies include unfractionated heparin (UFH) or enoxaparin or fondaparinux.1 Bivalirudin may be used in patients treated previously with UFH. Because of the risk of catheter thrombosis, fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered.1 Clopidogrel 75 mg/d is recommended in combination with aspirin for patients undergoing fibrinolysis.1 In patients less than 75 years of age who receive fibrinolytic therapy or who do not receive reperfusion therapy, it is reasonable to administer an oral loading dose of clopidogrel 300 mg. Glycoprotein IIb/IIIa inhibitors and clopidogrel are recommended as adjunctive therapy in PCI.1 a Patients routinely taking NSAIDs (except for aspirin), both nonselective as well as COX-2 selective agents, before STEMI should have those agents discontinued at the time of presentation with STEMI because of the increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use. b Because of the risk of catheter thrombosis, fondaparinux should not be used as the sole anticoagulant to support PCI. An additional anticoagulant with anti-IIa activity should be administered. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol. 2004;44:e1-e211. .

17 Reperfusion Therapy for STEMI
2007 ACC/AHA STEMI Focused Update Reperfusion Therapy for STEMI Class I Modified Recommendations STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 minutes of first medical contact as a systems goal (Level of Evidence: A) STEMI patients presenting to a hospital without PCI capability and who cannot be transferred to a PCI center and undergo PCI within 90 minutes of first medical contact should be treated with fibrinolytic therapy within 30 minutes of hospital presentation as a systems goal unless fibrinolytic therapy is contraindicated (Level of Evidence: B) The 2007 focused update of the ACC/AHA guidelines for the management of patients with ST-segment elevation myocardial infarction (STEMI) list reperfusion therapy as a Class I recommendation. The guidelines state that STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 minutes of the first medical contact as a systems goal (Level of Evidence: A). STEMI patients presenting to a hospital without PCI capability and who cannot be transferred to a PCI center and undergo PCI within 90 minutes of first medical contact should be treated with fibrinolytic therapy within 30 minutes of hospital presentation as a systems goal unless fibrinolytic therapy is contraindicated (Level of Evidence: B). These goals should not be understood as ideal times but rather as the longest times that should be considered acceptable for a given system. Systems that are able to achieve even more rapid times for treatment of patients with STEMI should be encouraged. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

18 Determine Whether Fibrinolysis or PCI Is Preferred
No Preference for Either Strategy If Presentation Is 3 hr and There Is No Delay in Invasive Strategy However, fibrinolysis generally preferred when Invasive strategy not an option Vascular access difficulties No access to skilled PCI lab Delay to invasive strategy Prolonged transport Door-to-balloon time >90 min >1 hr vs fibrinolysis (fibrin-specific agent) now The goal of therapy – restoring blood flow to the obstructed artery – is the same, whether fibrinolysis or PCI is used. This slide outlines the clinical circumstances that drive therapeutic decision-making. The earlier fibrinolytic therapy is begun the better, because their clot busting efficacy diminishes over time. The window of opportunity for the use of these agents is 3 hours. Fibrinolytic therapy within the first 2 hours (especially the first hour) can occasionally abort MI and dramatically reduce mortality. The choice of which approach to implement is also based on practical considerations, such as transport time and receiving hospital capabilities. Generally, patients with STEMI who present to hospitals unable to intervene with PCI within 90 minutes should undergo fibrinolysis, which can be more rapidly administered. If transport time is lengthy, fibrinolytic agents (which may be administered by EMS personnel) should be used. Adapted with permission from Antman EM, et al. J Am Coll Cardiol. 2004;44: Photo courtesy of ACC/AHA guidelines for STEMI slide set. Slides&parsedquery+&x+10&y=5. Accessed January 10, 2008. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol. 2004;44:

19 Determine Whether Fibrinolysis or PCI Is Preferred (cont.)
No Preference for Either Strategy If Presentation Is 3 hr and There Is No Delay in Invasive Strategy However, invasive strategy generally preferred when Skilled PCI lab is available with surgical backup Door-to-balloon time <90 min High risk from STEMI Cardiogenic shock*, Killip class ≥III Contraindications to fibrinolysis, including increased risk of bleeding and ICH Late presentation >3 hr from symptom onset Diagnosis of STEMI is in doubt PCI is the preferred approach in settings where a skilled PCI lab is available within 90 minutes, the risk of death is increased due to cardiogenic shock, fibrinolysis is contraindicated due to increased risk of bleeding and intracranial hemorrhage, the 3-hour window of fibrinolytic efficacy has closed, or the diagnosis of STEMI is unclear. Importantly, although PCI is a less time dependent strategy than fibrinolysis, the time from symptom onset to balloon inflation significantly correlates with 1-year mortality. Several consensus panels, including the ACC/AHA and the European Society of Cardiology, recommend a target goal of medical contact-to-balloon or door-to-balloon time within 90 minutes. The goal for patients with STEMI is to get them into treatment fast. Optimally, fibrinolytic therapy should be provided within 30 minutes and PCI within 90 minutes. In the real-world, external circumstances (transport delays) and individual patient presentation (cardiogenic shock) may dictate the choice of treatment used. *PCI strongly preferred, but if immediate PCI not available/transfer for PCI delayed and presentation ≤3 hours, treat with fibrinolytic therapy and transfer to a skilled PCI lab. Adapted from Antman EM, et al. J Am Coll Cardiol. 2004;44: Photo courtesy of ACC/AHA guidelines for STEMI slide set. Slides&parsedquery+&x+10&y=5. Accessed January 10, 2008. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol. 2004;44:

20 Primary PCI vs Thrombolysis in STEMI: Quantitative Analysis (23 RCTs
Primary PCI vs Thrombolysis in STEMI: Quantitative Analysis (23 RCTs*, N=7739) 25 Short-term outcomes (4–6 wk) PCI Thrombolytic therapy P<.0001 20 P<.0001 15 Frequency, % P=.0002 P<.0001 P=.032 10 5 P<.0001 This meta-analysis encompassed 23 trials in which 3872 patients with STEMI were randomized to primary percutaneous transluminal coronary angioplasty (PTCA) and 3867 patients were randomized to thrombolytic therapy. Stents were used in 12 of the 23 trials and in 8 trials GP IIb/IIIa inhibitors were used. Results indicated that the incidence of every short-term clinical outcome of interest was significantly higher in patients receiving thrombolytic agents than it was in those who underwent primary PTCA. Results with PTCA continued to be superior to those with thrombolysis during long-term follow-up and were independent of the type of thrombolytic agent used (76% received a fibrin-specific agent rather than streptokinase) and whether or not the patient was transferred to primary PTCA. The criterion for time to treatment was 6 h or less in nine of the trials, 12 h in 13 trials, and up to 36 h in the SHOCK trial. Death Nonfatal MI Recurrent Ischemia Hemor- rhagic Stroke Major Bleed Death, Nonfatal Reinfarction, or Stroke *The criterion for time to treatment was 6 h or less in 9 of the trials, h in 13 trials, and up to 36 h in the SHOCK trial. Adapted with permission from Keeley EC, et al. Lancet. 2003;361:13-20. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13-20.

21 NRMI: Advantage of PCI Compared With Fibrinolysis Decreases as PCI-Related Delay Increases
2.0 Odds of Death With Fibrinolysis 1.5 PCI Better 1.25 1.0 0.8 Fibrinolysis Better In a cohort of 192,509 patients from 645 National Registry of Myocardial Infarction hospitals, the multivariate adjusted odds of death were the same for fibrinolytic therapy or percutaneous coronary intervention (PCI) when the PCI-related delay was 114 minutes (95% CI, minutes; P<.001). In this adjusted analysis, the association of increasing PCI-related delay (increasing door-to-balloon–door-to-needle time), with increasing mortality remained significant (P<.001). The interaction of treatment with fibrinolytic therapy and door-to-balloon–door-to-needle time was also significant (P<.001). This suggests that the benefit of one treatment over another varied depending on increasing door-to-balloon–door-to-needle time. 0.5 60 75 90 105 114 135 150 165 180 PCI-Related Delay (door-to-balloon–door-to-needle time), min Adapted with permission from Pinto DS, et al. Circulation. 2006;114: Pinto DS, Kirtane AJ, Nallamothu BK, et al. Hospital delays in reperfusion for ST-elevation myocardial infarction: implications when selecting a reperfusion strategy. Circulation. 2006;114:

22 Door to Balloon (D2B): An Alliance for Quality Campaign
Door to Balloon (D2B) Campaign—joint program of ACC, AHA, and other health organizations Aims to increase percentage of AMI patients who receive primary angioplasty within 90 minutes of hospital presentation to 75%; current figures indicate only 35% achieve this goal D2B implementation kit contains 6 evidence-based strategies for reducing door-to-balloon times In January 2006, the ACC formed a work group to help develop a national initiative to address D2B times, and the D2B initiative was formally launched in November 2006 at the American Heart Association annual meeting. The ACC is collaborating with a number of strategic partners to advance the D2B initiative. The goal of the D2B campaign is to achieve a door-to-balloon time of ≤90 minutes for at least 75% of nontransfer primary PCI patients with STEMI in all participating hospitals performing primary PCI. The D2B campaign focuses on hospitals that perform primary PCI on STEMI patients and aims to provide the hospitals with evidence-based strategies, supporting tools, and educational resources to lower D2B times. The program recognizes that reducing D2B times is a complex challenge requiring the coordination of EMTs, ED staff, cardiologists and other team members. D2B: An Alliance for Quality Web site. Accessed December 27, 2007. D2B: An Alliance for Quality. D2B Web site. Accessed December 27, 2007.

23 Mean reduction in door-to-balloon time (min)*
Door to Balloon (D2B): An Alliance for Quality Campaign Strategies Associated With a Significant Reduction in DTB Time Strategy Mean reduction in door-to-balloon time (min)* Having emergency medicine physicians activate the cath lab 8.2 Having a single call to a central page operator activate the cath lab 13.8 Having the ED activate the cath lab while patient is still en route 15.4 Expecting staff to arrive at the cath lab within 20 minutes after page 19.3 Having an attending cardiologist always on site 14.6 Having staff in the ED and cath lab use and receive real-time feedback 8.6 The Door to Balloon (D2B): An Alliance for Quality campaign is built on 6 evidence-based strategies compiled from a review of the literature, including this study by Bradley et al. The researchers surveyed 365 hospitals to identify factors that reduce door-to-balloon time, looking specifically at 28 strategies. Of these, a multivariate analysis identified 6 strategies that were significantly associated with a faster door-to-balloon time, as listed on this slide. However, despite the effectiveness of the strategies, only a minority of the hospitals surveyed used them. *P<.05 for all. Bradley EH, et al. N Engl J Med. 2006;355: Bradley EH, Herrin J, Wang Y, et al. Strategies for reducing the door-to-balloon time in acute myocardial infarction. N Engl J Med. 2006;355:

24 Anticoagulants as Ancillary Therapy to Reperfusion Therapy
2007 ACC/AHA STEMI Focused Update Anticoagulants as Ancillary Therapy to Reperfusion Therapy New Class I Recommendation Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy for a minimum of 48 hours and preferably for the duration of the index hospitalization, up to 8 days (regimens other than UFH are recommended if anticoagulant therapy is given for more than 48 hours because of the risk of heparin-induced thrombocytopenia with prolonged UFH treatment) Anticoagulants regimens with established efficacy include: UFH Enoxaparin Fondaparinux According to the 2007 focused update of the ACC/AHA 2004 STEMI guidelines, the following are new class I recommendations for anticoagulant therapy: Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy for a minimum of 48 hours and preferably for the duration of the index hospitalization, up to 8 days (regimens other than UFH are recommended if anticoagulant therapy is given for more than 48 hours because of the risk of heparin-induced thrombocytopenia with prolonged UFH treatment) Anticoagulants regimens with established efficacy include unfractionated heparin (UFH), enoxaparin, and fondaparinux. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

25 2007 ACC/AHA STEMI Focused Update
Anticoagulants Modified Class IIa Recommendation It is reasonable for patients with STEMI who do not undergo reperfusion therapy to be treated with anticoagulant therapy (non-UFH regimen) for the duration of the index hospitalization, up to 8 days (Level of Evidence: B). Convenient strategies that can be used include those with LMWH (Level of Evidence: C) or fondaparinux (Level of Evidence: B) using the same dosing regimens as for patients who receive fibrinolytic therapy The 2007 focused update to the ACC/AHA 2004 STEMI guidelines also included the following modified class IIa recommendation: It is reasonable for patients with STEMI who do not undergo reperfusion therapy to be treated with anticoagulant therapy (non-UFH regimen) for the duration of the index hospitalization, up to 8 days (Level of Evidence: B). Convenient strategies that can be used include those with LMWH (Level of Evidence: C) or fondaparinux (Level of Evidence: B) using the same dosing regimens as for patients who receive fibrinolytic therapy. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

26 Main Results From ExTRACT–TIMI 25
Primary End Point: Death or nonfatal re-MI by 30 days Main Secondary End Point: Death, nonfatal re-MI, or urgent revascularization by 30 days UFH 12.0 15 UFH 14.5 12 9.9 12 11.7 9 ENOX ENOX 9 6 RR=0.83 P<.001 % RR=0.81 P<.001 % 6 3 3 RR=0.88 P=.02 The EXTRACT-TIMI 25 trial included patients with ST-segment elevation MI within 6 hours who were lytic eligible. Patients received one of the standard lytics (tenecteplase, tissue plasminogen activator, reteplase, or streptokinase) per the treating physician’s choice. All patients received aspirin. In a double-blind, double-dummy fashion, patients also received either enoxaparin or unfractionated heparin (UFH). UFH was dosed according to the guidelines for weight-adjusted dosing and maximum levels. It was to be given for at least 48 hours and then could be continued at the physician's discretion. This was done in a double-blind fashion so that the patients who were actually getting enoxaparin had an intravenous infusion of placebo. Enoxaparin, on the other hand, was continued through hospital discharge, and included a 30 mg IV bolus for patients under the age of 75 years and then the standard 1 mg/kg every 12 hours while in hospital. For patients at least 75 years of age, who have been seen in some trials to have an increased risk of bleeding, the bolus was omitted and only 75% of the full dose was given as their standard dose. As is typical for patients with poor creatinine clearance, the dosing was switched to once a day instead of twice a day. The primary efficacy end point was death or nonfatal MI. The primary safety end point was TIMI major hemorrhage. The graph on the left shows the primary end point with a highly significant (P<.001) 17% reduction in the relative risk of death or nonfatal recurrent MI in an intention-to-treat analysis. As shown, the curves begin to separate early and then separate more widely beginning after the first 48 hours. There is, however, a reduction of events in the enoxaparin group even during the first 48 hours. The graph on the right shows the major secondary end point: a triple end point of death, nonfatal reinfarction, or urgent revascularization due to recurrent ischemia. The same pattern is again seen in that the absolute reduction is greater with enoxaparin, a nearly 3% absolute and a 19% relative risk reduction. These results were also highly significant (P<.001). At the 48-hour time point, shown by the dotted line on the graph, there is a 12% significant (P=.02) risk reduction. During this time period, unfractionated heparin was mandated in all patients. The mean duration was approximately 48 hours for the IV study drug. Thus, half of the patients received drug for 48 hours and half of the patients continued longer. On the other hand, enoxaparin was continued in the hospital, which became an average of just under 7 days. During this extended time period, a clear advantage of continuing anticoagulation was seen compared with administration for only about 2 days overall. The rates of TIMI major bleeding, including intracranial hemorrhage (ICH), at 30 days were 1.4% in the UFH group and 2.1% in the enoxaparin group (P<.001). The rates of ICH were 0.7% in the UFH group and 0.8% in the enoxaparin group (P=.14). 5 10 15 20 25 30 5 10 15 20 25 30 Days Days Major bleeding at 30 days: 1.4% with UFH vs 2.1% with enoxaparin (P<.001) ICH: 0.7% for UFH vs 0.8% for enoxaparin (P=.14) Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354: Antman EM, Morrow DA, McCabe CH, et al, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:

27 (No increase in nonfatal ICH) Nonfatal TIMI Major Bleed
ExTRACT–TIMI 25: For Every 1000 Patients Treated With Enoxaparin vs UFH 4 5 (No increase in nonfatal ICH) -5 Events/1000 Patients -6 -7 -10 This slide illustrates the net effect per every 1000 patients treated with enoxaparin versus unfractionated heparin. As shown, for every 1000 patients treated with enoxaparin there would be a reduction of 15 events—a large absolute effect for preventing recurrent MI. An additional 7 per 1000 patients would be prevented from having urgent revascularization, and 6 deaths per 1000 patients would be prevented. Four patients per every 1000 would develop a nonfatal TIMI major bleed, with no increase in nonfatal intracranial hemorrhage. -15 -15 Nonfatal reMI Urgent Revasc. Nonfatal TIMI Major Bleed -20 Death Antman EM, et al. N Engl J Med. 2006;354: Adapted with permission from clinicaltrialresults.org. Antman EM, Morrow DA, McCabe CH, et al, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:

28 OASIS-6 Trial: Study Design
12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial) Randomized. Blinded. Factorial. 28% female; mean age, 62 years; mean follow-up, 3-6 months Stratum 1 (No UFH) n=5658 Stratum 2 (UFH) n=6434 Fondaparinux n=2823 2.5 mg/day for up to 8 days or hospital discharge Placebo n=2835 Fondaparinux n=3213 2.5 mg/day for up to 8 days or hospital discharge UFH n=3221 The clinical data for fondaparinux in ST-segment-elevation MI comes from the Sixth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-6) trial. The objective of the trial was to evaluate the effects of fondaparinux compared with the usual control, either unfractionated heparin or placebo, when initiated early and then given for up to eight days, in an extended duration of anticoagulant therapy. The patients were separated into stratum one, where the control group felt that that the unfractionated heparin was not indicated, and thus fondaparinux was compared with placebo. In stratum two, the patients in the active group were treated with unfractionated heparin as compared with fondaparinux. A PCI sub-study assessed the efficacy in both strata in the setting of primary PCI for STEMI. There were 12,092 patients enrolled in the trial from 447 hospitals in 41 countries. The patients were enrolled between September 2003 and January This slide illustrates the trial design and number of patients enrolled in each of the two strata. The trial used a factorial design, but in stratum one if the physician did not feel unfractionated heparin was indicated, the fondaparinux 2.5 mg a day up through hospital discharge or day eight was compared to placebo. The majority of patients in the trial did not get antithrombin as control. In stratum two, fondaparinux was compared to unfractionated heparin. It should be noted that of the patients treated with UFH, 75% received UFH for less than 48 hours versus a 7-8 day course of fondaparinux. The primary endpoint was the composite of death or reinfarction at 30 days. Primary end point: composite of death or reinfarction at 30 days Secondary end point: composite of death or reinfarction at 9 days and at final follow-up Yusuf S, et al. JAMA. 2006;295: Adapted with permission from Yusuf S, Mehta SR, Chrolavicius S, et al. for the OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:

29 OASIS-6 Trial: Results 14% Reduction in Death/MI at 30 days: Stratum 1 (No UFH Indicated) P<.05 Reduction in Death/MI: Stratum 2 (UFH Indicated) P=NS p=0.97 12% 10% 8% 6% 4% 2% 0% 11.2% Fondaparinux Placebo UFH 8.3% 8.7% 15% Primary End Point: Death/Reinfarction (%) P=.008 P=.003 12% 9% 6% 3% 0% 9.7% 11.2% 7.4% 8.9% 13.4% 14.8% 30 days 9 days 3-6 months Fondaparinux (n=6036) Control (n=6056) Frequency The overall results are shown on the left of this slide. The primary endpoint was reduced from 11.2% for control (either placebo or unfractionated heparin) to 9.7% with fondaparinux, a highly significant P value of This was also seen at the earlier time point of 9 days and at the later follow-up of three to six months. There were some differences at the 30 day time period in the results by strata. A significant difference in stratum one (fondaparinux vs placebo) was seen with an absolute 3% reduction in death or MI, whereas in patients who had unfractionated heparin in the control group, there was a nonsignificant difference that went from 8.7% for unfractionated heparin down to 8.3% for fondaparinux. The risk of bleeding is also shown on this slide. When all cases were analyzed, there were no differences seen in bleeding. However, there was a trend toward lower bleeding with fondaparinux in stratum one, as compared with placebo. This reduction in bleeding in the fondaparinux group versus placebo currently defies a rational explanation. In stratum 2 (fondaparinux vs UFH) there was no difference in bleeding. Severe Bleeding at 9 Days Fonda- Placebo/UFH HR P All cases 1.0% 1.3% 0.77 .13 Stratum 1 vs placebo 1.6% 0.63 .06 Stratum 2 vs UFH 1.1% 0.95 .82 Yusuf S, et al. JAMA. 2006;295: Adapted with permission from clinicaltrialresults.org. Yusuf S, Mehta SR, Chrolavicius S, et al. for the OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:

30 OASIS-6: PCI Substudy at 30 Days
Primary End Point of Death or MI in Primary PCI Cohort (%) P=.04 8% Guiding catheter thrombosis in the primary PCI cohort occurred more often with fondaparinux compared with control (n=22 vs n=0, P<.001) 6.0% 6% 4.9% 4% 2% In the subgroup of patients undergoing primary PCI (during which intravenous heparin was used in all patients in the control group and in only 21% in the fondaparinux group), there was no benefit in receiving fondaparinux compared with the control group (6.0% vs 4.9%, respectively; P=.04). In addition, guiding catheter thrombosis occurred more often in the fondaparinux group compared with the control group (22 vs 0 patients, respectively; P<.001). 0% Fondaparinux Control Yusuf S, et al. JAMA. 2006;295: Adapted with permission from Yusuf S, Mehta SR, Chrolavicius S, et al, for the OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:

31 HORIZONS AMI: Bivalirudin vs Heparin + GP IIb/IIIa for Primary PCI in STEMI
Heparin + GP IIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 20 Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ .0001 Psup = .006 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ .0001 Psup ≤ .0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] Psup = 1.00 15 12.1 30-day event rates (%) 10 9.2 8.3 5 5.5 5.4 The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS AMI) trial evaluated bivalirudin vs heparin plus glycoprotein IIb/IIIa inhibitors in more than 3600 STEMI patients undergoing primary PCI. Patients undergoing planned primary PCI for acute MI were randomized to bivalirudin (n=1800) or glycoprotein IIb/IIIa inhibitors (n=1802). Investigators were aware of treatment assignments in this single-blind, prospective study. There were 2 co-primary end points: net adverse clinical events and non-CABG major bleeding. Net adverse clinical events was defined as a composite of major adverse cardiovascular events (death, reinfarction, stroke, or ischemic target vessel revascularization), and non-CABG major bleeding at 30 days. Major adverse cardiovascular events at 30 days was the major secondary end point. The primary end point—net adverse clinical events (death, reinfarction, stroke, or ischemic target vessel revascularization, plus non-CABG major bleeding at 30 days)— was significantly lower in the bivalirudin monotherapy group (9.2%) than in the GP IIb/IIIa inhibitor + UFH group (12.1%) (P=.006). Major bleeding significantly decreased in the bivalirudin group, as well (4.9% vs 8.3% for GP IIb/IIIa inhibitor + UFH; P<.001). There were no significant differences between the two groups in terms of major adverse cardiovascular events (P=1). 4.9 1 end point 1 end point Net adverse clinical events Major bleedinga MACEb aNot related to CABG; bMACE = All-cause death, reinfarction, ischemic TVR or stroke. Stone GW, et al. Presented at: Transcatheter Cardiovascular Therapeutics 2007; October 20-25, 2007; Washington, DC. Stone GW, for the HORIZONS AMI Investigators. A prospective, randomized comparison of bivalirudin vs heparin plus glycoprotein IIb/IIIa inhibitors during primary angioplasty in acute myocardial infarction: 30 day results. Presented at: Transcatheter Cardiovascular Therapeutics 2007; October 20-25, 2007; Washington, DC.

32 2007 ACC/AHA STEMI Focused Update
Thienopyridines New Class I Recommendation Clopidogrel 75 mg per day orally should be added to aspirin in patients with STEMI regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy. Treatment with clopidogrel should continue for at least 14 days 2004 Class I Recommendation (remains current) In patients taking clopidogrel in whom CABG is planned, the drug should be withheld for at least 5 days, and preferably for 7 days, unless the urgency for revascularization outweighs the risks of excess bleeding According to the 2007 focused update of the ACC/AHA 2004 STEMI guidelines, the following are new class I recommendations for thienopyridines: Clopidogrel 75 mg per day orally should be added to aspirin in patients with STEMI regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy. Treatment with clopidogrel should continue for at least 14 days. The following class I recommendation from the 2004 STEMI guidelines remains current: In patients taking clopidogrel in whom CABG is planned, the drug should be withheld for at least 5 days, and preferably for 7 days, unless the urgency for revascularization outweighs the risks of excess bleeding. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

33 Thienopyridines (cont.)
2007 ACC/AHA STEMI Focused Update Thienopyridines (cont.) New Class IIa Recommendations In patients less than 75 years of age who receive fibrinolytic therapy or who do not receive reperfusion therapy, it is reasonable to administer an oral loading dose of clopidogrel 300 mg (No data are available to guide decision making regarding an oral loading dose in patients 75 years of age or older) Long-term maintenance therapy (eg, 1 year) with clopidogrel (75 mg per day orally) is reasonable in STEMI patients regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy According to the 2007 focused update of the ACC/AHA 2004 STEMI guidelines, the following are new class IIa recommendations for thienopyridines: In patients less than 75 years of age who receive fibrinolytic therapy or who do not receive reperfusion therapy, it is reasonable to administer an oral loading dose of clopidogrel 300 mg. (No data are available to guide decision making regarding an oral loading dose in patients 75 years of age or older.) Long-term maintenance therapy (eg, 1 year) with clopidogrel (75 mg per day orally) is reasonable in STEMI patients regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

34 CLARITY- TIMI 28 Trial: Study Design
Double-blind, randomized, placebo-controlled trial in 3491 patients, aged yrs, with STEMI <12 hours Fibrinolytic, ASA, Heparin Randomized Clopidogrel 300 mg + 75 mg qd Placebo Study Drug The CLopidogrel as Adjunctive ReperfusIon TherapY – Thrombolysis In Myocardial Infarction (CLARITY TIMI) 28 investigators hypothesized that the addition of clopidogrel to standard fibrinolytic regimens that include aspirin would improve infarct-related artery patency and decrease ischemic complications. Effects on mortality alone were assessed in the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT). CLARITY TIMI-28 was a double-blind, randomized, placebo-controlled trial conducted in 3,491 patients. Inclusion criteria were age 18 to 75 years and ST-elevation MI within 12 hours of symptom onset. All patients were to receive a standard fibrinolytic regimen, including aspirin. For those receiving a fibrin-specific lytic (eg, TNK, rPA, tPA), either unfractionated or low–molecular-weight heparin was administered. Patients were then randomized to receive clopidogrel with a loading dose of 300 mg followed by 75 mg daily thereafter or placebo. Per protocol, all patients were to undergo coronary angiography 2 to 8 days after the start of study medication. The prespecified primary end point was an occluded infarct-related artery, defined as TIMI flow grade 0 or 1, or death or MI by the time of angiography, the latter two of which served as a surrogate for failed reperfusion and/or reocclusion of the artery. Study medication was discontinued after angiography, and for patients undergoing PCI, it was recommended that they receive open-label clopidogrel with a loading dose. Patients were followed for 30 days for clinical events. Vital status was ascertained in 99.9% of the trial population. Primary end point: Occluded artery (TIMI flow grade 0/1) or death/MI by time of angio Coronary Angiogram (2-8 days) Open-label clopidogrel per MD in both groups 30-day clinical follow-up Sabatine MS, et al. N Engl J Med. 2005;352: Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:

35 CLARITY–TIMI 28: Clopidogrel 300 mg/75 mg qd vs Placebo With Thrombolysis for STEMI (n = 3491)
Primary End Point: Occluded Artery (or Death/MI Through Angio/HD) CV Death, MI, RI  Urg Revasc 5 10 15 20 25 36% Odds Reduction 21.7 Days End Point, % 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio: 0.80 (95% CI, ) P=.03 20% 15.0 Occluded Artery or Death/MI, % The Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 study was a double-blind, randomized, placebo-controlled trial conducted in 3491 patients, 18 to 75 years of age, who presented with STEMI within 12 hours of symptom onset. All patients were to receive a standard fibrinolytic regimen, including aspirin. For those receiving a fibrin-specific lytic (eg, tenecteplase [TNK], reteplase [rPA], tissue-type plasminogen activator [tPA]), either unfractionated heparin or low-molecular-weight heparin was administered. Patients were then randomized to receive clopidogrel (a 300-mg loading dose followed by 75 mg daily thereafter) or placebo. Per protocol, all patients were to undergo coronary angiography 2 to 8 days after the start of study medication. The prespecified primary end point was a composite of an occluded infarct-related artery (defined by a TIMI flow grade of 0 or 1) on angiography or death or recurrent MI before angiography, the latter 2 of which served as a surrogate for failed reperfusion and/or reocclusion of the artery. Study medication was discontinued after angiography, and it was recommended that patients undergoing PCI receive open-label clopidogrel with a loading dose. Patients were followed for 30 days for clinical events. Vital status was ascertained in 99.9% of the trial population. The occurrence of the primary end point of occluded artery, death, or MI was reduced by 36% when clopidogrel was added (left figure). There was a 20% reduction in the clinical end points of cardiovascular death, MI, or recurrent ischemia leading to the need for urgent revascularization (right figure), which was noted early on and continued through the 30-day time period. n=1752 n=1739 Clopidogrel Placebo P <.001 Adapted with permission from Sabatine MS, et al. N Engl J Med. 2005;352: Sabatine MS, Cannon CP, Gibson CM, for the CLARITY–TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:

36 Notes: COMMIT: Trial Design
COMMIT included a 2 x 2 factorial design with independent comparisons of clopidogrel versus placebo (plus usual care) and metoprolol versus placebo (plus usual care). For the clopidogrel part of the trial, the primary purpose was to evaluate the efficacy and safety of clopidogrel as part of standard therapy (including ASA) in patients (N=45,852) presenting within 24 hours of the onset of the symptoms of suspected MI with suspected ECG abnormalities (ST elevation, ST depression, or left bundle-branch block). The two coprimary end points for the COMMIT trial are death and the combined end point of the first occurrence of death, MI, or stroke during initial hospitalization (within 28 days or until hospital discharge, whichever came first). A total of 55% of patients in COMMIT received thrombolytics. COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Addition of clopidogrel to aspirin in patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:

37 COMMIT/CCS-2: Effect of Clopidogrel 75 mg qd vs Placebo (n = 45,852)
Death, Re-MI, or Stroke Death in the Hospital Placebo + ASA: 2310 events (10.1%) Placebo + ASA: deaths (8.1%) 9 8 7 6 5 4 3 2 1 7 6 5 4 3 2 1 Clopidogrel + ASA: 2121 events (9.2%) Clopidogrel + ASA: 1726 deaths (7.5%) 9% (SE 3) relative risk reduction (P=.002) 7% (SE 3) relative risk reduction (P=.03) Event, % Mortality, % The COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial)/CCS-2 (Second Chinese Cardiac Study), a collaboration between the UK Oxford Clinical Trials Unit and Chinese investigators, involved 45,852 patients with an MI (either ST-segment change or left bundle-branch block) within 24 hours of symptom onset. Patients undergoing primary percutaneous coronary intervention or at high risk of bleeding were excluded. The study randomized patients to treatment with clopidogrel 75 mg once daily for the duration of hospital stay (mean 16 days) or placebo. All patients received aspirin 162 mg daily. The two primary end points were the composite of death, reinfarction, or stroke and death from any cause at hospital discharge, both of which were significantly reduced. As shown in the figure on the left, allocation to clopidogrel produced a 9% reduction (P=.002) in death, reinfarction, or stroke. Predischarge deaths (shown in the figure on the right) were reduced by 7% (P=.03) in the clopidogrel group. 7 14 21 28 7 14 21 28 Days Since Randomization (up to 28 days) Days Since Randomization (up to 28 days) a All patients received aspirin 162 mg/d. SE = standard error. Adapted with permission from COMMIT Collaborative Group. Lancet. 2005;366: Chen ZM, Jiang LX, Chen YP, et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:

38 CLARITY–TIMI 28 and COMMIT/CCS-2: Intracranial Hemorrhage and Major Bleeding
Clopidogrel n=1733 (%) Placebo n=1719 (%) P Value ICH 8 (0.5) 12 (0.7) .38 Major Bleeding 23 (1.3) 19 (1.1) .64 30-day Major Bleeding 33 (1.9) 30 (1.7) .80 COMMIT-CCS-22 n=22,961 (%) n=22,891 (%) 55 (0.2) 56 (0.2) .90 134 (0.6) 125 (0.5) .59 In CLARITY-TIMI 28, there was no significant excess in TIMI major or minor bleeding and no excess intracranial hemorrhage. 30-day major bleeding also did not show a significant excess in bleeding. Not shown on the slide, in patients undergoing coronary artery bypass grafting, treatment with clopidogrel was not associated with an excess of major bleeding, even in those patients who underwent surgery within 5 days of discontinuation of study medication. Similarly, in COMMIT, the benefits of clopidogrel treatment were not associated with an increased risk of major bleeding or ICH. 1. Sabatine MS, et al. N Engl J Med. 2005;352: Chen Z, et al. Lancet. 2005;366: Sabatine MS, Cannon CP, Gibson CM, et al, for the CLARITY–TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352: Chen ZM, Jiang LX, Chen YP, et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:

39 COMMIT/CCS-2: Metoprolol Results
End Point (%) Metoprolol, n=22,929 Placebo, n=22,923 P Death, reinfarction, or cardiac arrest 9.4 9.9 .10 All-cause mortality 7.7 7.8 .69 Reinfarction 2.0 2.5 .001 Ventricular fibrillation 2.5 3.0 .001 The COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial), also known as the CCS-2 (Second Chinese Cardiac Study), separately studied the effect of IV -blockers early in the course of acute MI followed by an oral -blocker. The study included more than 45,000 patients with suspected acute MI, defined as ST-segment changes or left bundle-branch block on electrocardiogram. Patients were randomized within 24 hours of symptom onset to receive metoprolol up to 15 mg IV over 15 minutes followed by the oral drug at 200 mg/day or matching placebo. Patients in shock or with a systolic blood pressure of <100 mm Hg, a heart rate of <50 beats per minute, or a grade II to III atrioventricular block were excluded. The primary end points for the metoprolol randomization were total mortality and the composite of death, reinfarction, or ventricular fibrillation or cardiac arrest before hospital discharge or out to 4 weeks, whichever came first. The mean follow-up and treatment time was 16 days. As shown on the slide, neither of the primary end points was significantly reduced by metoprolol treatment. Allocation to metoprolol reduced the risk of in-hospital reinfarction and ventricular fibrillation but increased the risk of cardiogenic shock, especially during the first day or so after admission. The risk of shock was concentrated in higher-risk patients, such as those already compromised by hypotension or heart failure. Lower-risk patients and those who received thrombolytics tended to gain the most from -blockade. The study suggests that early -blockade should not be given routinely in acute MI, but should be targeted according to patient risk features. Other cardiac arrest 3.0 2.8 .14 Cardiogenic shock 5.0 3.9 <.00001 COMMIT = ClOpidogrel & Metoprolol in Myocardial Infarction Trial. Adapted with permission from Chen ZM, et al. Lancet. 2005;366: Chen ZM, Pan HC, Chen YP, et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:

40 Implications for the ED
Lytics are underused, even when preference for PPCI is accepted Lytic therapy can be optimized with proper use of adjunctive medications Enoxaparin Clopidogrel Beta blockers should be used appropriately

41 2007 ACC/AHA STEMI Focused Update
-Blockers Modified Class I Recommendation Oral -blocker therapy should be initiated in the first 24 hours for patients who do not have any of the following: Signs of heart failure Evidence of a low output state Increased riska for cardiogenic shock Other relative contraindications to -blockade (PR interval >0.24 second, second- or third-degree heart block, active asthma, or reactive airway disease) According to the 2007 focused update of the ACC/AHA 2004 STEMI guidelines, the following is a new class I recommendation: Oral -blocker therapy should be initiated in the first 24 hours for patients who do not have any of the following: signs of heart failure, evidence of a low-output state, increased risk for cardiogenic shock, or other relative contraindications to -blockade, such as a PR interval greater than 0.24 seconds, second- or third-degree heart block, active asthma, or reactive airway disease. a Risk factors for cardiogenic shock: age >70 years, systolic blood pressure <120 mm Hg, sinus tachycardia >110 bpm or heart rate <60 bpm, and increased time since onset of symptoms of STEMI. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

42 2007 ACC/AHA STEMI Focused Update
-Blockers (cont.) New Class III Recommendation IV -blockers should not be administered to STEMI patients who have any of the following: Signs of heart failure Evidence of a low output state Increased riska for cardiogenic shock, Other relative contraindications to -blockade (PR interval >0.24 second, second- or third-degree heart block, active asthma, or reactive airway disease) According to the 2007 focused update of the ACC/AHA 2004 STEMI guidelines, the following is a new class III recommendation: Intravenous -blockers should not be administered to STEMI patients who have any of the following: signs of heart failure, evidence of a low-output state, increased risk for cardiogenic shock, or other relative contraindications to -blockade, such as a PR interval greater than 0.24 seconds, second- or third-degree heart block, active asthma, or reactive airway disease. a Risk factors for cardiogenic shock: age >70 years, systolic blood pressure <120 mm Hg, sinus tachycardia >110 bpm or heart rate <60 bpm, and increased time since onset of symptoms of STEMI. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

43 Anticoagulants as Ancillary Therapy to Reperfusion Therapy in PCI
2007 ACC/AHA STEMI Focused Update Anticoagulants as Ancillary Therapy to Reperfusion Therapy in PCI New Class I Recommendation For patients undergoing PCI after having received an anticoagulant regimen, the following dosing recommendations should be followed: For prior treatment with UFH, administer additional boluses of UFH as needed to support the procedure, taking into account whether GP IIb/IIIa receptor antagonists have been administered. Bivalirudin may also be used in patients treated previously with UFH For prior treatment with enoxaparin, if the last SC dose was administered within the prior 8 hours, no additional enoxaparin should be given; if the last SC dose was administered at least 8 to 12 hours earlier, an IV dose of 0.3 mg per kg of enoxaparin should be given For prior treatment with fondaparinux, administer additional IV treatment with an anticoagulant possessing anti-IIa activity, taking into account whether GP IIb/IIIa receptor antagonists have been administered The 2007 focused update to the ACC/AHA 2004 STEMI guidelines also included the following new class I recommendation: For patients undergoing PCI after having received an anticoagulant regimen, the following dosing recommendations should be followed: For prior treatment with UFH, administer additional boluses of UFH as needed to support the procedure, taking into account whether GP IIb/IIIa receptor antagonists have been administered. Bivalirudin may also be used in patients treated previously with UFH For prior treatment with enoxaparin, if the last SC dose was administered within the prior 8 hours, no additional enoxaparin should be given; if the last SC dose was administered at least 8 to 12 hours earlier, an IV dose of 0.3 mg per kg of enoxaparin should be given For prior treatment with fondaparinux, administer additional IV treatment with an anticoagulant possessing anti-IIa activity, taking into account whether GP IIb/IIIa receptor antagonists have been administered Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 19, 2007.

44 2007 ACC/AHA STEMI Focused Update
PCI After Fibrinolysis or for Patients Not Undergoing Primary Reperfusion Modified Class IIb Recommendation PCI of a hemodynamically significant stenosis in a patent infarct artery >24 hours after STEMI may be considered as part of an invasive strategy New Class III Recommendation PCI of a totally occluded infarct artery >24 hours after STEMI is not recommended in asymptomatic patients with 1- or 2-vessel disease if they are hemodynamically and electrically stable and do not have evidence of severe ischemia According to the 2007 focused update of the ACC/AHA 2004 STEMI guidelines, PCI of a hemodynamically significant stenosis in a patent infarct artery greater than 24 hours after STEMI may be considered as part of an invasive strategy. This is a modified Class IIb recommendation, Level of Evidence: B. PCI of a totally occluded infarct artery greater than 24 hours after STEMI is not recommended in asymptomatic patients with 1- or 2-vessel disease if they are hemodynamically and electrically stable and do not have evidence of severe ischemia. This is a new Class III recommendation, Level of Evidence: B. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 27, 2007.

45 Antiplatelet Therapy: Clopidogrel
2007 ACC/AHA/SCAI PCI Focused Update Antiplatelet Therapy: Clopidogrel Modified Class I Recommendations A loading dose of clopidogrel, generally 600 mg, should be administered before or when PCI is performed In patients undergoing PCI within 12 to 24 hours of receiving fibrinolytic therapy, a clopidogrel oral loading dose of 300 mg may be considered According to the 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention, a loading dose of clopidogrel, generally 600 mg, should be administered before or when PCI is performed. In patients undergoing PCI within 12 to 24 hours of receiving fibrinolytic therapy, a clopidogrel oral loading dose of 300 mg may be considered. King SB III, et al. J Am Coll Cardiol. doi: /j.jacc King SB III, Smith SC Jr, Hirshfeld JW Jr, Jacobs AK, Morrison DA, Williams DO focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008:51. Accessed January 15, 2008.

46 Antiplatelet Therapy: Clopidogrel (cont.)
2007 ACC/AHA/SCAI PCI Focused Update Antiplatelet Therapy: Clopidogrel (cont.) Modified Class IIa Recommendation If clopidogrel is given at the time of the procedure, supplementation with GP IIb/IIIa receptor antagonists can be beneficial Class IIa Recommendation (No Change) For patients with an absolute 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 According to the 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention, if clopidogrel is given at the time of the procedure, supplementation with GP IIb/IIIa inhibitors can be beneficial. This recommendation has been modified from the 2005 PCI guideline update. For patients with an absolute 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/III inhibitors, administered at the time of PCI. This recommendation has not changed from the 2005 PCI guideline update. King SB III, et al. J Am Coll Cardiol. doi: /j.jacc King SB III, Smith SC Jr, Hirshfeld JW Jr, Jacobs AK, Morrison DA, Williams DO focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008:51. Accessed January 15, 2008.

47 DES vs BMS in STEMI: Meta-analysis Primary Efficacy End Point: Reintervention
13.3% 13.3% Kastrati and coworkers conducted a meta-analysis of 8 randomized trials comprising 2786 patients to compare the efficacy and safety of drug-eluting stents (DES) vs bare-metal stents (BMS) in patients with acute STEMI. DES consisted of paclitaxel-eluting stents in 2 of the trials and sirolimus-eluting stents in 4 other trials; in the remaining 2 trials, a 3-arm design was used including both paclitaxel-eluting stents and sirolimus-eluting stents. The primary efficacy end point of the meta-analysis was the need for reintervention (target lesion revascularization). Use of DES was associated with a 62% reduction in the hazard of reintervention compared with BMS. The advantage of DES was notable within the first month after stent implantation and continued to increase thereafter. The figure on the left shows the number of patients who experienced reintervention according to the treatment group, with the hazard ratio for each of the trials. Overall, the use of DES was associated with a hazard ratio of 0.38 for reintervention (95% CI, ), P <.001, compared with the use of BMS. The figure on the right shows 1-year probability curves for reintervention in the 2 treatment arms. An early and continuous separation of the curves is readily visible. The probability of reintervention was 5.0% in the DES group compared with 13.3% in the BMS group. 5.0% 5.0% Reintervention = target lesion revascularization. Reproduced with permission from Kastrati A, et al. Eur Heart J. 2007;28: Kastrati A, Dibra A, Spaulding C, et al. Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. Eur Heart J. 2007;28:

48 DES vs BMS in STEMI: Meta-analysis Primary Safety End Point: Stent Thrombosis
The primary safety end point of the meta-analysis was stent thrombosis. No significant difference in the risk of stent thrombosis was found in patients treated with DES compared with BMS. The figure on the left shows the number of patients who experienced stent thrombosis according to the treatment group, with the hazard ratio for each of the trials. The hazard ratio for stent thrombosis was 0.80 (95% CI, ), P = .43. The figure on the right shows 1-year curves of stent thrombosis probability for the 2 treatment groups. The probability of stent thrombosis was 1.6% in the DES group vs 2.2% in the BMS group. Three stent thromboses occurred after 1 year: 2 in the DES group and 1 in the BMS group. Reproduced with permission from Kastrati A, et al. Eur Heart J. 2007;28: Kastrati A, Dibra A, Spaulding C, et al. Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. Eur Heart J. 2007;28:

49 Antiplatelet Therapy for Post-PCI Patients Class I Recommendations
2007 ACC/AHA STEMI Focused Update Antiplatelet Therapy for Post-PCI Patients Class I Recommendations PCI without stenting ASA mg/d indefinitely and Clopidogrel 75 mg/d for at least 14 d Bare-metal stent ASA mg/d for at least 1 mo, mg/d indefinitely Clopidogrel 75 mg/d for at least 1 mo, ideally up to 1 y Drug-eluting stent ASA mg/d for at least 3 (sirolimus) to 6 (paclitaxel) mo, mg/d indefinitely Clopidogrel 75 mg/d for at least 1 y For all post-PCI nonstented patients: Aspirin (75 to 162 mg per day) should be prescribed indefinitely (Class I, level of evidence: B). For aspirin-allergic patients, use clopidogrel alone (indefinitely) or try aspirin desensitization Clopidogrel (75 mg per day) should be prescribed for at least 14 days (Class I, level of evidence: B) For patients treated with bare-metal stents: Aspirin (162 to 325 mg per day) should be prescribed for at least 1 month (Class I, level of evidence: B), then continued indefinitely at a a dose of 75 to 162 mg per day (Class I, level of evidence: A) Clopidogrel (75 mg per day) should be prescribed for a minimum of 1 month and ideally for up to 1 year (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks) (Class I, level of evidence: B) For patients treated with drug-eluting stents: Aspirin (162 to 325 mg per day) should be prescribed for at least 3 months after sirolimus-eluting stent implantation and 6 months after paclitaxel-eluting stent implantation, then continued indefinitely at a dose of 75 to 162 mg per day (Class I, level of evidence: B) Clopidogrel 75 mg daily should be given for at least 12 months to all post-PCI patients receiving drug-eluting stents (Class I, level of evidence: B) Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 27, 2007.

50 Secondary Prevention: Clopidogrel
2007 ACC/AHA STEMI Focused Update Secondary Prevention: Clopidogrel New Class I Recommendation For all STEMI patients not undergoing stenting (medical therapy alone or PTCA without stenting), treatment with clopidogrel should continue for at least 14 days New Class IIa Recommendation Long-term maintenance therapy (eg, 1 year) with clopidogrel (75 mg per day orally) is reasonable in STEMI patients regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy According to the 2007 focused update of the ACC/AHA 2004 STEMI guidelines, for all STEMI patients not undergoing stenting (medical therapy alone or PTCA without stenting), treatment with clopidogrel should continue for at least 14 days. This a new Class I recommendation, level of evidence: B. Long-term maintenance therapy (eg, 1 year) with clopidogrel (75 mg per day orally) is reasonable in STEMI patients regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion therapy. This is a new Class IIa recommendation, level of evidence: C. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 27, 2007.

51 Secondary Prevention: Additional Recommendations
2007 ACC/AHA STEMI Focused Update Secondary Prevention: Additional Recommendations Smoking cessation At each visit, every tobacco user and family members who smoke should be advised to quit (Class I, B) Exposure to environmental tobacco smoke at work and at home should be avoided (Class I, B) Statin goal LDL-C <100 mg/dL (Class I, A) Consider LDL-C <70 mg/dL (Class IIa, A) Daily physical activity 30 min/d, min 5 d/wk (Class I, B) Annual influenza immunization (Class I, B) The slide shows revised recommendations for secondary prevention of STEMI. The 2007 goal for smoking is complete cessation and no exposure to environmental tobacco smoke (Class I, level of evidence: B). Clopidogrel 75 mg per day should be added to aspirin in patients with STEMI for at least 14 days whether patients undergo reperfusion with fibrinolysis or do not receive reperfusion therapy (ie, all post-PCI nonstented STEMI patients). Statins, in the absence of contraindications, regardless of baseline LDL-C and diet modification, should be given to post-STEMI patients, including postrevascularization patients. (Class I, level of evidence: A). For hospitalized patients, lipid-lowering medications should be initiated before discharge (Class I, level of evidence: A). For STEMI patients with LDL-C ≥100 mg per dL, cholesterol-lowering therapy should be initiated or intensified to achieve an LDL-C of <100 mg per dL. Further titration to <70 mg per dL is reasonable. Adding plant stanol/sterols (2 g per day) and/or viscous fiber (greater than 10 g per day) is reasonable to further lower LDL-C. If triglycerides are greater than or equal to 200 mg per dL, non-HDL-C should be less than 130 mg per dL. Other changes include the addition of recommended physical activity and a new recommendation for an annual influenza vaccination. Antman E, et al. J Am Coll Cardiol. doi: /j.jacc Antman EM, Hand M, Armstrong PW, et al focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Developed in Collaboration With the Canadian Cardiovascular Society. Endorsed by the American Academy of Family Physicians). J Am Coll Cardiol. 2008:51. Accessed December 27, 2007.

52 Conclusion: STEMI Optimal medical care of STEMI begins in the prehospital setting, continues in the ED, and culminates in a prompt and informed decision about reperfusion strategy. Optimal outcomes in STEMI can be achieved only with a multidisciplinary approach. The ACC/AHA GLs invest initial decisionmaking authority in the emergency physician.

53 Summary Acute therapy in STEMI focuses on reperfusion and antithrombotic therapy – new ACC/AHA guidelines provide current recommendations Long-term treatment involves aggressive multifactorial lifestyle modification and both antithrombotic and anti-ischemic therapies Acute therapy in STEMI focuses on reperfusion and antithrombotic therapy. Reasonable options for hospitals without on-site PCI capability include Fibrinolytic therapy (goal: door-to-needle time ≤30 minutes) Code 30! Transfer for primary PCI if fibrinolysis is contraindicated (goal: door-to-balloon time ≤90 minutes) Code 90! Transfer for rescue PCI if reperfusion with lytic fails No clinical benefit for facilitated PCI has been seen to date Clopidogrel in combination with aspirin results in significant further improvements in the outcomes of patients with STEMI (CLARITY–TIMI 28/COMMIT).


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