Acute Coronary Syndromes: Selective vs Early Invasive Strategies

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1 Acute Coronary Syndromes: Selective vs Early Invasive Strategies WilliamE.Boden,MD,FACCandVipulGupta,MBBS,MPH Division of Cardiovascular Medicine, University at Buffalo Schools of Medicine and Public Health, Division of Cardiology, Buffalo General Hospital (Boden), Buffalo, New York; Division of Cardiology, Department of Medicine, University at Buffalo Schools of Medicine and Public Health (Gupta), Buffalo, New York Address for correspondence: William E. Boden, MD, FACC Division of Cardiology Buffalo General Hospital 100 High Street Buffalo, NY Recommendations in the 2007 update of the American College of Cardiology/American Heart Association guidelines for patients with non ST-elevation myocardial infarction (NSTEMI) provide considerable latitude regarding treatment choices and care pathways. Nevertheless, as accumulating evidence leads to increased recommendations for early invasive strategies, more patients are likely to receive care that falls short of recommendations. While tailoring pharmacotherapy to optimize the risk/benefit ratio for individual patients remains essential, it becomes increasingly important that care paradigms be prospectively defined. To facilitate this goal, we examined key differences between the 2002 and 2007 guidelines and explored data underlying changed recommendations for periprocedural pharmacotherapy. Introduction Updated guidelines for patients with unstable angina and non ST-elevation myocardial infarction (UA/NSTEMI) from the American College of Cardiology and American Heart Association (ACC/AHA) 1 are based on evidence from multiple clinical trials; however, optimal strategies are as yet undetermined, partly because the guidelines provide broad latitude in defining optimal care. Adapting the guidelines into institutional care paradigms will facilitate physician choices. Current Guidelines Risk Stratification: Estimating risk is critical in selecting site of care (coronary care unit, monitored step-down unit, outpatient) and optimal therapeutic approach, including pharmacologic therapy. 1 Implementation of guideline recommendations for early risk stratification permits guidelineconsistent downstream treatment. The guidelines categorize signs and symptoms of acute coronary syndrome (ACS) into high, intermediate, or low likelihood of ACS overlapping coronary artery disease; and high, intermediate, or low risk of death or nonfatal myocardial infarction (MI) in patients with confirmed NSTEMI. 1 Reflecting evidence for a direct, positive relationship between elevated levels of biomarkers of myocardial necrosis and increased risk for death, the new guidelines give a class I recommendation to measure cardiac markers, preferably troponin, in patients with chest discomfort consistent with ACS. (Troponin values on which to base decisions vary by hospital and are assay-dependent.) Patients with negative cardiac biomarkers within 6 hours of symptom onset should be reassessed 8 to hours after onset. 1 For patients presenting within 6 hours of onset, assessment of early (myoglobin) plus late (troponin) markers of cardiac Received: May 13, 2009 Accepted with revision: July 15, 2009 injury may be considered; alternatively, a 2-hour change in creatine kinase-mb (CK-MB) fraction in conjunction with a 2-hour change in troponin or myoglobin, plus CK-MB or troponin at baseline and 90 minutes, can be considered. 1 The guidelines suggest using risk stratification models, such as the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), Thrombolysis in Myocardial Infarction (TIMI), or Global Registry of Acute Coronary Events (GRACE) scores, to determine treatment in patients with possible ACS, 1 noting that patients with higher risk scores demonstrate greater benefit from more aggressive therapies (eg, low-molecular-weight heparin, glycoprotein IIb/IIIa inhibition). 1 Management Strategies Initial risk estimation (particularly via biomarkers of myocardial necrosis) in the emergency department guides downstream care. The 2002 guidelines categorized strategies as early invasive and early conservative and recommended (class I/A) that patients with high-risk features (recurrent ischemia despite medication, elevated troponin I or T levels, new ST-segment depression, recurrent ischemia with coronary heart failure symptoms, high-risk stress test findings, left ventricular dysfunction, hemodynamic instability, percutaneous coronary intervention [PCI] within 6 months, prior coronary artery bypass grafting [CABG]) undergo diagnostic angiography and revascularization within 48 hours of arrival. 2 Either strategy was recommended for patients without these indicators. The 2007 guidelines outline an early invasive strategy (EIS; patients receiving pharmacologic therapy undergo coronary angiography within 4 to 24 hours of admission) and a selectively invasive strategy (SIS; invasive evaluation Clin. Cardiol. 32, 11, (2009) 621

2 Reviews continued only if patients do not respond to intensive medical management or have objective evidence of ongoing ischemia). 1 An EIS is indicated in patients with refractory angina or hemodynamic or electrical instability without serious comorbidities or procedural contraindications, and in initially stabilized patients with elevated risk for clinical events. 1 An EIS may be considered in patients with chronic renal insufficiency (as determined by the Modification of Diet in Renal Disease equation for estimating glomerular filtration rate; values < 60 ml/min per 1.73 m 2 body surface area are considered abnormal). 3 An SIS may be used in those with elevated risk for clinical events (including elevated troponins), according to physician and patient preference. 1 The 2007 guidelines demonstrate preference for EIS (class I) over selectively invasive/medical management (class IIb), based on evidence from meta-analyses and trials indicating better overall outcomes with EIS. 1,4 7 Ametaanalysis of 7 trials enrolling a total of 8375 patients found 25% lower all-cause mortality at 2-year follow-up among patients who underwent EIS vs conservative treatment (P = 0.001; Figure 1), and 17% lower risk for nonfatal MI (P = 0.0). 6 Differences in risk for death and nonfatal MI were not statistically significant until after 24 months. 6 These results must be interpreted cautiously, as the studies spanned a significant period of time during which best-treatment practices varied. The Invasive vs Conservative Treatment in Unstable Coronary Syndromes (ICTUS) study suggested that EIS is Study FRISC-II TRUCS TIMI-18 VINO RITA-3 ISAR-COOL ICTUS Deaths, n Invasive Conservative Follow-up, months Overall RR (95% CI) 0.75 ( ) Favors Favors early invasive conservative therapy therapy Figure 1. Relative risk of all-cause mortality for early invasive vs conservative therapy. Reprinted with permission from Bavry et al. 6 Abbreviations: FRISC-II, Fragmin and Fast Revascularization During Instability in Coronary Disease; ICTUS, Invasive Versus Conservative Treatment in Unstable Coronary Syndromes; ISAR-COOL, Intracoronary Stenting with Antithrombotic Regimen Cooling Off; RITA-3, Randomized Intervention Trial of Unstable Angina-3; RR, relative risk; TIMI-18, Thrombolysis In Myocardial Infarction-18; TRUCS, Treatment of Refractory Unstable Angina in Geographically Isolated Areas Without Cardiac Surgery; VINO, Value of First Day Coronary Angiography/Angioplasty in Evolving Non-ST Segment Elevation Myocardial Infarction not superior to SIS. 8 In ICTUS, 00 patients with symptoms of ischemia that were increasing or occurred at rest, ischemic changes on electrocardiography, or documented history of coronary artery disease and elevated troponin T levels were randomly assigned to EIS or SIS. All patients received 300 mg aspirin at randomization and 75 mg/day indefinitely, plus enoxaparin (1 mg/kg; maximum, 80 mg twice daily) for 48 hours. Early clopidogrel (300-mg loading dose followed by 75 mg/d) was recommended after its 2002 approval for ACS. The primary end point was a composite of death, recurrent MI, and rehospitalization for angina within 1 year of randomization. 8 The estimated 1-year cumulative event rate for the primary end point was 22.7% (EIS patients) vs 21.2% (SIS patients; P = 0.33; Figure 2). However, the cumulative MI risk was significantly higher among the EIS group (15.0% vs 10.0%; P = 0.005), while the rehospitalization risk was significantly lower (7.4% vs 10.9%; P = 0.04). 8 Results showed few statistically significant differences at 1 year. Whether longer follow-up would have revealed a difference remains an open question. Recent trials to determine the optimal timing of EIS include the randomized, multicenter Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial, in which 3031 patients received EIS (coronary angiography within 24 h after randomization) or delayed intervention (coronary angiography 36 h after randomization). 9 Though no significant difference was seen for the 6-month primary end point of death, new MI, or stroke, a reduced rate of the 6 month secondary outcome of death, new MI, or refractory ischemia (9.5% vs.9%; P = 0.003) was seen in the EIS group. High risk EIS patients (GRACE score > 140) had a significantly lower rate of the primary outcome (13.9% vs 21.0%; P = 0.006). No difference was seen in outcomes of EIS performed within 6 hours, 6 to hours, or after Cumulative event rate (%) No. at risk Early invasive strategy Selectively invasive strategy Months Early invasive strategy Selectively invasive strategy Figure 2. Kaplan-Meier estimates of cumulative rate of the composite primary end point. (Copyright 2005 Massachusetts Medical Society. All rights reserved.) Reprinted with permission from de Winter et al. 8 All rights reserved Clin. Cardiol. 32, 11, (2009)

3 hours, indicating no benefit for very early intervention, although confidence limits were wide. The Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes Randomized for an Immediate or Delayed Intervention (ABOARD) trial randomly assigned 352 patients with non ST-segment elevation (NSTE) ACS and TIMI flow grade 3 to immediate or next-day PCI. 10 Median time to PCI was 1.10 hours in the immediate group and hours in the next-day group. Although early intervention did not reduce the risk of MI, patients in the immediate PCI group had significantly shorter hospital stays (median 55 h vs 77 h; P < 0.001). The preponderance of data indicating superior outcomes with EIS together with the class IIb recommendation for conservative management suggest a preference for EIS in most patients. In TIMACS, patients at higher risk showed greater benefit from EIS, suggesting that accurate risk stratification is of major importance in choosing optimal treatment. Results from ABOARD showed little additional benefit from immediate PCI, and data from ICTUS indicate that conservative management remains a viable option, based on physician and patient preference. Recommendations for Pharmacotherapy As with previous guidelines, the new pharmacotherapy recommendations are not immutable requirements, partly because multiple options permit tailoring treatment to individual risk-benefit profiles. Anticoagulant Therapy: Anticoagulants for patients with ACS include indirect antithrombin agents (unfractionated heparin [UFH], low-molecular-weight heparins, factor Xa inhibitors) and direct thrombin inhibitors (Table 1). 11 Inconsistent trial designs make comparisons difficult. In 2002, enoxaparin was recommended over UFH unless CABG was planned within 24 hours. 2 The 2007 guidelines recommend, similarly, that anticoagulant therapy be added to antiplatelet therapy in UA/NSTEMI patients as soon as possible. 1 For patients undergoing EIS, current guidelines recommend UFH or enoxaparin (class I/A) and, more recently, fondaparinux or bivalirudin (class I/B). For those undergoing SIS, enoxaparin, UFH, and fondaparinux have class I recommendations. For SIS patients with increased bleeding risk, fondaparinux is preferred; either enoxaparin or fondaparinux is preferable to UFH unless CABG is planned within 24 hours. 1 The ability to tailor therapy to the individual patient is an advantage attendant upon these multiple options. Antiplatelet Therapy: Changes in recommendations for antiplatelet therapy are summarized in Table New Evidence: Bivalirudin: The new recommendation for bivalirudin in patients undergoing EIS stems from results of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. This prospective, open-label, randomized study compared heparin plus a glycoprotein IIb/IIIa inhibitor; bivalirudin plus a glycoprotein IIb/IIIa inhibitor; and bivalirudin alone in patients with moderaterisk or high-risk ACS undergoing EIS. Although methodologic approaches (particularly bleeding definition) present issues in interpreting results, this trial suggests that for the composite ischemia end point, bivalirudin alone is noninferior to heparin plus a glycoprotein IIb/IIIa inhibitor (7.8% vs 7.3%; P = 0.01) and is associated with significantly Table 1. Antithrombotic Therapy Recommendations in NSTEMI (2002 and 2007 Guidelines a ) Agent 2002 Guidelines Class/Level 2007 Guidelines Class/Level UFH Initiate for treatment I/A EIS: initiate I/A SIS: initiate I/A Enoxaparin Initiate for treatment; preferred over UFH I/A EIS:initiate I/A SIS: initiate I/A IIa/A SIS: preferred over UFH Fondaparinux Not rated EIS: initiate I/B SIS: initiate SIS w/increased bleeding risk: initiate SIS: preferred over UFH I/B I/B Bivalirudin Not rated EIS: initiate I/B Abbreviations: EIS, early invasive management strategy; NSTEMI, non-st-segment elevation myocardial infarction; SIS, selectively invasive management strategy; UFH, unfractionated heparin. Reprinted with permission from Pollack et al. 11 a American College of Cardiology/American Heart Association guidelines. Clin. Cardiol. 32, 11, (2009) 623

4 Reviews continued Table 2. Antiplatelet Therapy Recommendations in NSTEMI (2002 and 2007 Guidelines a ) Agent 2002 Guidelines Class/Level 2007 Guidelines Class/Level ASA Initiate promptly I/A Initiate promptly I/A Clopidogrel Initiate promptly in ASA-allergic pts I/A Initiate promptly in ASA-allergic pts; give LD I/A Initiate promptly in NSTEMI, give LD I/A EIS: initiate with LD ASAP or SM GPI I/A Hold if CABG planned 5 7 d I/B Hold if CABG planned 5 7 d. SIS: Initiate w/ld ASAP; SIS w/later high risk: initiate with LD ASAP or give SM GPI I/B SM GPI Initiate if catheterization and PCI are planned I/A EIS: initiate or give LD clopidogrel I/A EIS: initiate and give LD clopidogrel Initiate as MM in high risk pts IIa/A SIS with later high risk: initiate upstream IIa/C Initiate w/asa, anticoagulation, clopidogrelifcatheterization + PCI planned EIS: Omit upstream GPI if pt receives bivalirudin mg clopidogrel < 6 h before catheterization + PCI Initiate as MM in non-high risk pts when catheterization and PCI not planned IIb/A Large-molecule GPI Initiate if catheterization and PCI are planned I/A EIS: initiate I/A Inappropriate for MM if no PCI by < 24 h III/A Inappropriate for MM if no PCI by < 24 h III/A Abbreviations: ASA, aspirin; ASAP, as soon as possible; CABG, coronary artery bypass graft; GPI, glycoprotein IIb/IIIa inhibitor; LD, loading dose; MM, medical management; NSTEMI, non ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; pts, patients; SM, small-molecule. Reprinted with permission from Pollack et al. 11 a American College of Cardiology/American Heart Association guidelines. less major bleeding (3.0% vs 5.7%; P < 0.001; Figure 3). Among patients not receiving a thienopyridine (n = 3304) vs those who did (n = 5753) before angiography or PCI, the composite ischemic end point was considerably higher with bivalirudin alone vs heparin plus glycoprotein IIb/IIIa inhibition (9.1% vs 7.1%; P = 0.054). These data suggest caution when administering bivalirudin alone in high-risk patients with delay to angiography and with early ischemic discomfort after an initial antithrombotic strategy. Guidelines recommend that these patients receive either glycoprotein IIb/IIIa inhibition or a thienopyridine before angiography, regardless of whether a bivalirudin-based or heparin-based strategy is used. 1 This approach is supported by results of the ACUITY Timing trial, in which more patients receiving deferred glycoprotein IIb/IIIa inhibitors experienced ischemic events (7.9%, vs 7.1% in the upstream group; P for noninferiority = 0.44), 13 and the ACUITY PCI substudy, in which patients receiving bivalirudin with no thienopyridine before PCI had a 2.8% increased rate of the ischemic end point vs similar patients in the heparin plus glycoprotein IIb/IIIa inhibitor group. 14 New Evidence: Enoxaparin: Results from the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial provided support for enoxaparin or UFH in patients undergoing EIS. 15 High-risk patients (n = 9978) with NSTEMI received aspirin ( mg/d) or clopidogrel (75 mg/d), plus either enoxaparin (1 mg/kg every h) or UFH (60 U/kg bolus, maximum 5000 U; initial infusion, U/kg/h, up to 1000 U/h). Results for the primary end point (a composite of 30-d death or nonfatal MI) 15 were similar, occurring in 14.0% of those given enoxaparin and 14.5% of those given UFH. A significant increase in TIMI major bleeding was seen among patients receiving enoxaparin (9.1% vs 7.6%; P = 0.008). 15 Mortality was similar between groups. 16 New Evidence: Fondaparinux: The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS- 5) trial compared fondaparinux, a factor Xa inhibitor, with enoxaparin in patients with high-risk NSTEMI. 16 Patients were randomly assigned to receive enoxaparin (1 mg/kg twice daily or once daily if creatinine clearance was < 30 ml/min) plus UFH if PCI was to be performed > 6 hours after the last enoxaparin dose, or fondaparinux (2.5 mg once daily), with additional fondaparinux at PCI. 17 Results for the primary composite end point (death, MI, or refractory ischemia at 9 d) showing fondaparinux to be 624 Clin. Cardiol. 32, 11, (2009)

5 Patients experiencing outcome (%) Composite ischemia UFH or enoxaparin plus GP IIb/IIIa Major bleeding Net clinical outcome Bivalirudin alone Figure 3. Outcomes in the ACUITY Trial. 11 Abbreviations: GP IIb/IIIa, glycoprotein IIb/IIIa; UFH, unfractionated heparin. noninferior to enoxaparin (5.8% vs 5.7%) supported a class IB recommendation for fondaparinux in patients undergoing EIS. Patients receiving fondaparinux had significantly lower rates of major bleeding (2.2%) vs enoxaparin (4.1%; P < 0.001). The net clinical outcome the combined ischemic end point and major bleeding significantly favored fondaparinux (7.3% vs 9.0%; P < 0.001). 11 Patients who receive fondaparinux upstream must receive an additional anticoagulant with antithrombin activity at the time of PCI. Thus, any early choice to use fondaparinux must be communicated to the interventional team. 17 New Evidence: Aspirin and Clopidogrel: Use of aspirin and clopidogrel 21 in patients with NSTEMI is well supported by clinical trials. It is less clear whether higher loading doses of clopidogrel (600 or 900 mg) increase efficacy without substantially increasing bleeding; guidelines currently recommend the 300-mg dosage. 1 New Evidence: Glycoprotein IIb/IIIa Inhibitors: Use of glycoprotein IIb/IIIa inhibitors in patients with ACS is supported by evidence from multiple clinical trials Significant new data informing the 2007 guidelines emanated from the Intracoronary Stenting and Antithrombotic Regimen Rapid Early Action for Coronary Treatment (ISAR-REACT) trials, in which glycoprotein IIb/IIIa inhibitors conferred the greatest benefit in patients at higher risk. In these studies, lowrisk to intermediate-risk 25 and high-risk 26 patients received abciximab or placebo (with background aspirin and heparin plus, in accord with contemporary practice, clopidogrel loading). In ISAR-REACT, 30 day incidence of death, MI, or target-vessel revascularization was similar in both treatment groups. 25 However, in ISAR-REACT 2, high-risk patients receiving abciximab had a 25% reduced risk; rates of major and minor bleeding were similar between groups, 26 and the efficacy advantage remained at 1-year follow-up. 27 Notably, abciximab benefit was largely seen in the 52% of patients with elevated troponin levels (> 0.03µg/L). In the recent Early Glycoprotein IIb/IIIa Inhibition in Non ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, 28 in which patients were stratified for clopidogrel administration, early glycoprotein IIb/IIIa inhibition with eptifibatide showed no benefit over delayed provisional administration in EARLY ACS, though selected subgroups of patients may be considered for early use. Conclusions Evidence supports increased EIS use among patients with UA/NSTEMI, especially in patients at high risk. In the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry of almost high-risk patients with NSTEMI, 29 the EIS group had a 4.7% rate of in-hospital death or MI vs 8.9% in the non-eis group. However, only 44.8% of patients underwent early cardiac catheterization within 48 hours of presentation (per 2002 guidelines for invasive management). The 2007 guidelines suggest that patients undergo coronary angiography between 4 and 24 hours after admission; therefore, the percentage of patients receiving care falling short of guideline recommendations will likely increase. While the multiple treatment options for UA/NSTEMI permit tailoring pharmacotherapy to optimize individual patients risk/benefit ratio, in practical application, defining treatment regimens prospectively is important. Acknowledgment Editorial assistance was provided by Rina Kleege, MS. This assistance was funded by Schering-Plough. References 1. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-st-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction). JAm Coll Cardiol. 2007;50:e1 e Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-st-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Clin. Cardiol. 32, 11, (2009) 625

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