In the COGENT (Clopidogrel and the Optimization of Gas- trointestinal Events) study,42 omeprazole was compared with placebo in 3627 patients starting dual antiplatelet therapy with aspirin and clopidogrel. No difference was found in the primary composite cardiovascular endpoint between clopi- dogrel plus omeprazole and clopidogrel plus placebo (HR: 1.02), but GI bleeding complications were reduced.42 CO- GENT had several shortcomings (see Online Data Supple- ment), and more controlled, randomized clinical trial data are needed to address the clinical impact of conjunctive therapy with clopidogrel and PPIs. The FDA communication on an ongoing safety review of clopidogrel bisulfate14 advises that healthcare providers should reevaluate the need for starting or continuing treatment with a PPI, including omeprazole, in patients taking clopidogrel. The FDA notes there is no evidence that other drugs that reduce stomach acid, such as H2 blockers or antacids, interfere with the antiplatelet activity of clopidogrel. Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke. Healthcare providers should reevaluate the need for starting or continuing treatment with a PPI, including omepra- zole (over the counter), in patients taking clopidogrel. Patients taking clopidogrel should consult their healthcare provider if they are currently taking or considering taking a PPI, including omeprazole.14 The ACCF has released a statement on the use of PPI agents in combination with clopidogrel. The expert consen- sus statement does not prohibit the use of PPI agents in appropriate clinical settings, yet highlights the potential risks and benefits from use of PPI agents in combination with 3.2.3.1.6. Glycoprotein IIb/IIIa Receptor Antagonists. The efficacy of glycoprotein (GP) IIb/IIIa inhibitor therapy has been well established during PCI procedures and in patients with UA/NSTEMI, particularly among high-risk patients such as those with elevated troponin biomarkers, those with diabetes, and those undergoing revascularization.44 54 The preponderance of the evidence supporting the use of GP IIb/IIIa inhibitor therapy predated the trials that established the benefits of clopidogrel, early invasive therapy, and contemporary medical treatments in patients with UA/NSTEMI. These studies sup- ported the upstream use of a GP IIb/IIIa inhibitor as a second agent in combination with aspirin for dual antiplatelet therapy in patients with UA/NSTEMI, especially in high-risk subsets such as those with an initial elevation in cardiac troponins, those with diabetes, and in those undergoing revascularization.47,48,50 52,55 These studies did not directly test in a randomized fashion the selection of an oral thienopyridine versus an intravenous (IV) GP IIb/IIIa inhibitor as the second antiplatelet agent in UA/NSTEMI. Contemporary clinical trials have therefore been needed to define the optimal timing of initiation of GP IIb/IIIa inhibitor therapy in patients with UA/NSTEMI, whether upstream (at presentation and before angiography) or deferred (at the time of angiography/PCI), and its optimal application (whether routine, selective, or provisional) and to clarify the relative benefit and risk of GP IIb/IIIa inhibitor therapy as a third antiplatelet agent in combination with aspirin and a thienopyridine. The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non ST-Segment Elevation Acute Coronary Syndrome) trial56 tested the hypothesis that a strategy of early routine administration of the GP IIb/IIIa inhibitor eptifibatide would be superior to delayed provisional administration in reducing ischemic complications among high-risk patients with UA/NSTEMI. The study investigators enrolled 9492 patients who presented within 24 hours of an episode of ischemic rest discomfort of at least 10 minutes duration. The study subjects were randomized within 8 to 12 hours after presentation and assigned to an invasive treatment strategy no sooner than the next calendar day. To qualify as having high-risk UA/NSTEMI, the subjects were required to have at least 2 of the following: ST-segment depression or transient ST-segment elevation, elevated biomarker levels (creatine kinase myocardial band or troponin), or age 60 years. The study subjects were randomized in a double-blind design to receive either early routine administration of eptifibatide (double bolus followed by standard infusion) or delayed provisional eptifibatide at the time of PCI. Eptifibatide infusion was given for 18 to 24 hours after PCI in both groups. For patients who underwent PCI, the total duration of the infusion was 96 hours. For patients who did not receive PCI for whatever reason, the duration of infusion was 96 hours. The study infusion was stopped 2 hours before surgery for those undergoing CABG. Early clopidogrel was allowed at the inves- tigators discretion (75% intended early use), and if used, a loading dose of 300 mg was recommended. For patients begin- ning clopidogrel during PCI (intended in 25% of study subjects, but actually implemented in 11%), a dose of 600 mg was permitted. Randomization to 1 of 3 antithrombotic regimens was stratified according to the intention of the investigator to admin- ister early clopidogrel (ie, at or before randomization).56 The primary endpoint (a 30-day composite of all-cause death, MI, recurrent ischemia requiring urgent revasculariza- tion, or thrombotic bailout at 96 hours) occurred in 9.3% of patients in the early therapy arm versus 10.0% of patients in the provisional GP IIb/IIIa inhibitor therapy arm (OR: 0.92; cause death or MI within 30 days) event rates were 11.2% versus 12.3% (OR: 0.89; 95% CI: 0.79 to 1.01; P 0.08). Early routine eptifibatide administration was associated with a greater risk of TIMI major hemorrhage (2.6% versus 1.8%; P 0.02). Severe or moderate bleeding, as defined by the GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) criteria, also occurred more commonly in the early eptifibatide group (7.6% versus 5.1%; P 0.001). Rates of red blood cell transfusion were 8.6% and 6.7% in the early-eptifibatide and delayed-eptifibatide groups, respectively (P 0.001). There were no significant interactions with respect to prespecified baseline characteris- tics, including early clopidogrel administration, and the pri- mary or secondary efficacy endpoints. In a subgroup analysis, early administration of eptifibatide in patients who underwent PCI was associated with numerically fewer ischemic events. A second contemporary study, the ACUITY (Acute Cath- eterization and Urgent Intervention Triage Strategy) trial,57 examined in part the optimal strategy for the use of GP IIb/IIIa inhibitors in moderate- and high-risk ACS patients undergoing early invasive therapy. A total of 9207 patients were randomized to 1 of 3 antithrombin regimens: unfractionated heparin (UFH) or enoxaparin plus GP IIb/IIIa inhibitor therapy; bivalirudin plus GP IIb/IIIa inhibitor therapy; or bivalirudin alone. Patients assigned to the heparin (UFH or enoxaparin) plus GP IIb/IIIa inhibitor therapy or to the bivalirudin plus GP IIb/IIIa inhibitor therapy were also randomized to immediate upstream routine GP IIb/IIIa inhibitor therapy or deferred selective use of GP IIb/IIIa inhibitor therapy at the time of PCI. A clopidogrel loading dose of 300 mg was required in all cases no later than 2 hours after PCI, and provisional GP IIb/IIIa inhibitor use was permitted before angiography in the deferred group for severe breakthrough ischemia. The composite ischemic endpoint oc- curred in 7.1% of the patients assigned to upstream administra- tion and in 7.9% of patients assigned to deferred selective thus the noninferiority hypothesis was not achieved. Major bleeding was lower in the deferred-use group versus the up- stream group (4.9% to 6.1%; P 0.001 for noninferiority and P 0.009 for superiority). Although early GP IIb/IIIa inhibitor therapy as dual antiplatelet therapy also reduced complications after PCI, supporting its continued role in patients undergoing PCI,49,53,54,56,58 these 2 most recent studies56,57 more strongly support a strategy of selective rather than routine upstream use of GP IIb/IIIa inhibitor therapy as part of triple antiplate- let therapy. Data from EARLY ACS56 highlight the potential bleeding risks of upstream use of a GP IIb/IIIa inhibitor as part of triple antiplatelet therapy. The use of a GP IIb/IIIa inhibitor should be undertaken when the risk-benefit ratio suggests a potential benefit for the patient. The use of these agents as part of triple antiplatelet therapy may therefore not be supported when there is a concern for increased bleeding risk or in non high-risk subsets such as those with a normal baseline troponin level, those without diabetes, and those aged 75 years, in whom the potential benefit may be significantly offset by the potential risk of bleeding (Tables 2 and 3). 3.3. Initial Invasive Versus Initial Conservative Strategies: Recommendations (See Table 4, and Appendixes 5 and 6 for supplemental information.) 3.3.3.1. Timing of Invasive Therapy Among initially stabilized patients with UA/NSTEMI for whom an early invasive strategy of coronary angiography is chosen, optimal timing of angiography has not been well defined. Early or immediate catheterization with revascularization of unstable coronary lesions may prevent ischemic events that would oth- erwise occur during medical therapy. Conversely, pretreatment with intensive antithrombotic therapy may diminish thrombus burden and passivate unstable plaques, improving the safety of percutaneous revascularization and reducing the risk of peripro- cedural ischemic complications. Three trials have compared different strategies of early versus delayed intervention in patients with UA/NSTEMI and form the basis of the updated recommendations in this guideline. The ISAR-COOL (Intracoronary Stenting with Antithrom- botic Regimen Cooling-Off) trial122 carried out at 2 hospitals between 2000 and 2002 randomized 410 patients with unstable chest pain and either electrocardiographic ST-segment depres- sion or elevated troponin levels to undergo coronary angiogra- phy within 6 hours of presentation (median 2.4 hours) or after 3 to 5 days (median 86 hours) of antithrombotic pretreatment.122 Patients with large MI, defined by ST-segment elevation or creatine kinase myocardial band isoenzyme activity 3 times normal, were excluded. Underlying medical therapy in both treatment arms included aspirin, clopidogrel, UFH, and tiro- fiban. By 30 days follow-up, the primary endpoint of death or large MI (defined by new electrocardiographic Q waves, left bundle-branch block, or creatine kinase myocardial band eleva- tion 5 times normal) occurred in 11.6% of patients randomized to delayed catheterization versus 5.9% of those in the early angiography group (P 0.04). Differences between treatment groups were observed exclusively in the period before catheter- ization, with identical event rates in the 2 arms after angiogra- phy. Although providing evidence that a strategy of cooling- off for 3 to 5 days before angiography does not improve outcome in this setting, the findings of this trial were limited because of the small sample size and the prolonged delay before angiography in the medical pretreatment arm. Information more relevant to contemporary practice pat- terns was provided in the 2009 publication of the large-scale multicenter TIMACS (Timing of Intervention in Acute Cor- onary Syndromes) trial,107 which compared early versus delayed angiography and intervention in patients with non Jneid et al 2012 UA/NSTEMI Focused Update 885 Table 2. Recommendations for Antiplatelet Therapy 2012 Focused Update Recommendations 2012 Comments Class I 1. Aspirin should be administered to UA/NSTEMI patients as soon as possible after hospital presentation and continued indefinitely in patients who tolerate it.59 66 (Level of Evidence: A) 2011 recommendation remains current. 2. A loading dose followed by daily maintenance dose of either clopidogrel13,67,68 (Level of Evidence: B), prasugrel* (in PCI-treated patients)7 (Level of Evidence: C), or ticagrelor 9 (Level of Evidence: C) should be administered to UA/NSTEMI patients who are unable to take aspirin because of hypersensitivity or major GI intolerance. modified (included prasugrel and ticagrelor). 3. Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected (Appendix 6) should receive dual antiplatelet therapy on presentation.13,16,45,69 (Level of Evidence: A) Aspirin should be initiated on presentation.59,61 66 (Level of Evidence: A) The choice of a second antiplatelet therapy to be added to aspirin on presentation includes 1 of the following (note that there are no data for therapy with 2 concurrent P2Y12 receptor inhibitors, and this is not recommended in the case of aspirin allergy): modified (included ticagrelor). Before PCI: Clopidogrel13,16 (Level of Evidence: B); or Ticagrelor 9 (Level of Evidence: B); or An IV GP IIb/IIIa inhibitor.45,50,51,70,71 (Level of Evidence: A) IV eptifibatide and tirofiban are the preferred GP IIb/IIIa inhibitors.50,51 (Level of Evidence: B) At the time of PCI: Clopidogrel if not started before PCI13,16 (Level of Evidence: A); or Prasugrel*7 (Level of Evidence: B); or Ticagrelor 9 (Level of Evidence: B); or An IV GP IIb/IIIa inhibitor.46,50,51 (Level of Evidence: A) 4. For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, clopidogrel or ticagrelor (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for up to 12 months.9,10,13 (Level of Evidence: B) modified (included ticagrelor and changed duration of therapy to up to 12 months ). 5. For UA/NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, heart failure, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed.55,72 (Level of Evidence: A) Either an IV GP IIb/IIIa inhibitor (eptifibatide or tirofiban46,50,51 Level of Evidence: A ), clopidogrel (loading dose followed by daily maintenance dose13 Level of Evidence: B ), or ticagrelor (loading dose followed by daily maintenance dose9 Level of Evidence: B ) should be added to aspirin and anticoagulant therapy before diagnostic angiography (upstream). (Level of Evidence: C) modified (included ticagrelor). 6. A loading dose of P2Y12 receptor inhibitor therapy is recommended for UA/NSTEMI patients for whom PCI is planned. One of the following regimens should be used: modified (included ticagrelor and changed loading dose of clopidogrel and associated level of evidence to be concordant with 2011 PCI guideline75). a. Clopidogrel 600 mg should be given as early as possible before or at the time of PCI32,73,74 (Level of Evidence: B) or b. Prasugrel* 60 mg should be given promptly and no later than 1 hour after PCI once coronary anatomy is defined and a decision is made to proceed with PCI7 (Level of Evidence: B) or c. Ticagrelor 180 mg should be given as early as possible before or at the time of PCI.9 (Level of Evidence: B) 7. The duration and maintenance dose of P2Y12 receptor inhibitor therapy should be as follows: 2011 recommendation modified (included ticagrelor; a footnote added pertaining to recommended aspirin maintenance dose). a. In UA/NSTEMI patients undergoing PCI, either clopidogrel 75 mg daily,13,16 prasugrel* 10 mg daily,7 or ticagrelor 90 mg twice daily9 should be given for at least 12 months. (Level of Evidence: B) b. If the risk of morbidity because of bleeding outweighs the anticipated benefits afforded by P2Y12 receptor inhibitor therapy, earlier discontinuation should be considered. (Level of Evidence: C) Class IIa 1. For UA/NSTEMI patients in whom an initial conservative strategy is selected and who have recurrent ischemic discomfort with aspirin, a P2Y12 receptor inhibitor (clopidogrel or ticagrelor), and anticoagulant therapy, it is reasonable to add a GP IIb/IIIa inhibitor before diagnostic angiography. (Level of Evidence: C) modified ( clopidogrel replaced with P2Y12 receptor inhibitor [clopidogrel or ticagrelor]). 2. For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to omit administration of an IV GP IIb/IIIa inhibitor if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 hours earlier than planned catheterization or PCI.57,76,77 (Level of Evidence: B) 2011 recommendation remains current. (Continued) ST-segment elevation ACS. Patients were included if they presented within 24 hours of onset of unstable ischemic symptoms with advanced age ( 60 years), elevated cardiac biomarkers, or ischemic electrocardiographic changes, and were randomized to undergo angiography as rapidly as possible and within 24 hours of randomization (median 14 hours) versus after a minimum delay of 36 hours (median 50 hours). Anticoagulation included aspirin, clopidogrel in 80% of patients, heparin or fondaparinux, and GP IIb/IIIa inhibitors in 23% of patients. Although the trial was initially powered for enrollment of 4000 patients to detect a 25% reduction in the primary endpoint of death, new MI, or stroke at 6 months, the steering committee chose to terminate enrollment at 3031 patients because of recruitment chal- lenges. Among the overall trial population, there was only a nonsignificant trend toward a reduced incidence of the primary clinical endpoint, from 11.3% in the delayed inter- vention group to 9.6% in the early intervention arm (HR for early intervention: 0.85; 95% CI: 0.68 to 1.06; P 0.15). However, a prospectively defined secondary endpoint of death, MI, or refractory ischemia was significantly reduced by early intervention from 12.9% to 9.5% (HR: 0.72; 95% CI: 0.58 to 0.89; P 0.003), mainly because of a difference in the incidence of refractory ischemia (3.3% versus 1.0% in the delayed versus early intervention arms, respectively; P 0.001). The occurrence of refractory ischemia was asso- ciated with a 4-fold increase in risk of subsequent MI. Moreover, significant heterogeneity was observed in the primary endpoint when stratified according to a prespecified estimation of baseline risk according to the GRACE (Global Registry of Acute Coronary Events) score. Patients in the highest tertile of the GRACE risk score ( 140) experienced a sizeable and significant reduction in the incidence of the primary ische- Table 2. Continued 2012 Focused Update Recommendations 2012 Comments Class IIb 1. For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, it may be reasonable to add eptifibatide or tirofiban to anticoagulant and oral antiplatelet therapy.50,51 (Level of Evidence: B) 2007 recommendation remains current. 2. Prasugrel* 60 mg may be considered for administration promptly upon presentation in patients with UA/NSTEMI for whom PCI is planned, before definition of coronary anatomy if both the risk for bleeding is low and the need for CABG is considered unlikely.7,8,78 (Level of Evidence: C) 2011 recommendation remains current. 3. The use of upstream GP IIb/IIIa inhibitors may be considered in high-risk UA/NSTEMI patients already receiving aspirin and a P2Y12 receptor inhibitor (clopidogrel or ticagrelor) who are selected for an invasive strategy, such as those with elevated troponin levels, diabetes, or significant ST-segment depression, and who are not otherwise at high risk for bleeding.50,51,55,56,58 (Level of Evidence: B) modified ( clopidogrel replaced with P2Y12 receptor inhibitor [clopidogrel or ticagrelor]). 4. In patients with definite UA/NSTEMI undergoing PCI as part of an early invasive strategy, the use of a loading dose of clopidogrel of 600 mg, followed by a higher maintenance dose of 150 mg daily for 6 days, then 75 mg daily may be reasonable in patients not considered at high risk for bleeding.32 (Level of Evidence: B) 2011 recommendation remains current. Class III: No Benefit 1. Abciximab should not be administered to patients in whom PCI is not planned.46,71 (Level of Evidence: A) 2007 recommendation remains current. 2. In UA/NSTEMI patients who are at low risk for ischemic events (eg, TIMI risk score 2) or at high risk of bleeding and who are already receiving aspirin and a P2Y12 receptor inhibitor, upstream GP IIb/IIIa inhibitors are not recommended.56,57,78 (Level of Evidence: B) modified ( clopidogrel replaced with P2Y12 receptor inhibitor ). Class III: Harm 1. In UA/NSTEMI patients with a prior history of stroke and/or TIA for whom PCI is planned, prasugrel* is potentially harmful as part of a dual antiplatelet therapy regimen.7 (Level of Evidence: B) 2011 recommendation remains current. *Patients weighing 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once-daily maintenance dose. Consideration should be given to lowering the maintenance dose to 5 mg in patients who weigh 60 kg, although the effectiveness and safety of the 5-mg dose have not been studied prospectively. For post-PCI patients, a daily maintenance dose should be given for at least 12 months for patients receiving DES and up to 12 months for patients receiving BMS unless the risk of bleeding outweighs the anticipated net benefit afforded by a P2Y12 receptor inhibitor. Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. In patients age 75 years, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit except in high-risk situations (patients with diabetes or a history of prior myocardial infarction), in which its effect appears to be greater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. When possible, discontinue prasugrel at least 7 days before any surgery.8 Additional risk factors for bleeding include body weight 60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, or chronic use of nonsteroidal anti-inflammatory drugs).8 The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.11 Ticagrelor s benefits were observed irrespective of prior therapy with clopidogrel. 9 When possible, discontinue ticagrelor at least 5 days before any surgery.12 Issues of patient compliance may be especially important. Consideration should be given to the potential and as yet undetermined risk of intracranial hemorrhage in patients with prior stroke or TIA. Applies to patients who were not treated chronically with these medications. BMS indicates bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; GI, gastrointestinal; GP, glycoprotein; IV, intravenous; PCI, percutaneous coronary intervention; TIA, transient ischemic attack; TIMI, Thrombolysis In Myocardial Infarction; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Jneid et al 2012 UA/NSTEMI Focused Update 887 Table 3. Recommendations for Additional Management of Antiplatelets and Anticoagulants 2012 Focused Update Recommendations 2012 Comments Class I 1. For UA/NSTEMI patients in whom an initial conservative strategy is selected and no subsequent features appear that would necessitate diagnostic angiography (recurrent symptoms/ischemia, heart failure, or serious arrhythmias), a stress test should be performed.72 (Level of Evidence: B) modified (included ticagrelor, and duration of antiplatelet therapy changed to up to 12 months ). a. If, after stress testing, the patient is classified as not at low risk, diagnostic angiography should be performed.55,72 (Level of Evidence: A) b. If, after stress testing, the patient is classified as being at low risk, the instructions noted below should be followed in preparation for discharge55,72: 1. Continue aspirin indefinitely.61,63,64 (Level of Evidence: A) 2. Continue clopidogrel or ticagrelor* for up to 12 months.9,10,13 (Level of Evidence: B) 3. Discontinue IV GP IIb/IIIa inhibitor if started previously.50,51 (Level of Evidence: A) 4. Continue UFH for 48 hours66,79 (Level of Evidence: A) or administer enoxaparin80 82 (Level of Evidence: A) or fondaparinux83 (Level of Evidence: B) for the duration of hospitalization, up to 8 days, and then discontinue anticoagulant therapy. 2. For UA/NSTEMI patients in whom CABG is selected as a postangiography management strategy, the instructions noted below should be followed. 2011 recommendation remains current. a. Continue aspirin.84 90 (Level of Evidence: A) b. See Class I, #3, in this section. c. Discontinue IV GP IIb/IIIa inhibitor (eptifibatide or tirofiban) 4 hours before CABG.84,88,91 (Level of Evidence: B) d. Anticoagulant therapy should be managed as follows: 1. Continue UFH.80,92 94 (Level of Evidence: B) 2. Discontinue enoxaparin 12 to 24 hours before CABG and dose with UFH per institutional practice.80,92 94 (Level of Evidence: B) 3. Discontinue fondaparinux 24 hours before CABG and dose with UFH per institutional practice.95,96 (Level of Evidence: B) 4. Discontinue bivalirudin 3 hours before CABG and dose with UFH per institutional practice.97,98 (Level of Evidence: B) 3. In patients taking a P2Y12 receptor inhibitor in whom CABG is planned and can be delayed, it is recommended that the drug be discontinued to allow for dissipation of the antiplatelet effect13 (Level of Evidence: B). The period of withdrawal should be at least 5 days in patients receiving clopidogrel13,45,99 (Level of Evidence: B) or ticagrelor*12 (Level of Evidence: C) and at least 7 days in patients receiving prasugrel 8 (Level of Evidence: C) unless the need for revascularization and/or the net benefit of the P2Y12 receptor inhibitor therapy outweighs the potential risks of excess bleeding.100 (Level of Evidence: C) modified (included ticagrelor). 4. For UA/NSTEMI patients in whom PCI has been selected as a postangiography management strategy, the instructions noted below should be followed: modified ( thienopyridine replaced with P2Y12 receptor inhibitor ). a. Continue aspirin.61,63,64 (Level of Evidence: A) b. Administer a loading dose of a P2Y12 receptor inhibitor if not started before diagnostic angiography.9,68,74,101 103 (Level of Evidence: A) c. Discontinue anticoagulant therapy after PCI for uncomplicated cases.80,82,104 106 (Level of Evidence: B) 5. For UA/NSTEMI patients in whom medical therapy is selected as a management strategy and in whom no significant obstructive coronary artery disease on angiography was found, antiplatelet and anticoagulant therapy should be administered at the discretion of the clinician (Level of Evidence: C). For patients in whom evidence of coronary atherosclerosis is present (eg, luminal irregularities or intravascular ultrasound-demonstrated lesions), albeit without flow-limiting stenoses, long-term treatment with aspirin and other secondary prevention measures should be prescribed. (Level of Evidence: C) 2007 recommendation remains current. 6. For UA/NSTEMI patients in whom medical therapy is selected as a management strategy and in whom coronary artery disease was found on angiography, the following approach is recommended: modified (included ticagrelor). a. Continue aspirin.61,63,64 (Level of Evidence: A) b. Administer a loading dose of clopidogrel or ticagrelor* if not given before diagnostic angiography.9,13 (Level of Evidence: B) c. Discontinue IV GP IIb/IIIa inhibitor if started previously.50,51,57,107 (Level of Evidence: B) (Continued) Table 3. Continued 2012 Focused Update Recommendations 2012 Comments d. Anticoagulant therapy should be managed as follows: 1. Continue IV UFH for at least 48 hours or until discharge if given before diagnostic angiography66,79,80 (Level of Evidence: A) 2. Continue enoxaparin for duration of hospitalization, up to 8 days, if given before diagnostic angiography.80 82,96 (Level of Evidence: A) 3. Continue fondaparinux for duration of hospitalization, up to 8 days, if given before diagnostic angiography.83 (Level of Evidence: B) 4. Either discontinue bivalirudin or continue at a dose of 0.25 mg/kg per hour for up to 72 hours at the physician s discretion if given before diagnostic angiography.77,108,109 (Level of Evidence: B) 7. For UA/NSTEMI patients in whom a conservative strategy is selected and who do not undergo angiography or stress testing, the instructions noted below should be followed: modified (included ticagrelor; duration of antiplatelet therapy changed to up to 12 months ). a. Continue aspirin indefinitely.61,63,64 (Level of Evidence: A) b. Continue clopidogrel or ticagrelor* for up to 12 months.9,13,67,110 (Level of Evidence: B) c. Discontinue IV GP IIb/IIIa inhibitor if started previously.50,51 (Level of Evidence: A) d. Continue UFH for 48 hours66,79 (Level of Evidence: A) or administer enoxaparin80 82 (Level of Evidence: A) or fondaparinux83 (Level of Evidence: B) for the duration of hospitalization, up to 8 days, and then discontinue anticoagulant therapy. 8. For UA/NSTEMI patients in whom an initial conservative strategy is selected and in whom no subsequent features appear that would necessitate diagnostic angiography (recurrent symptoms/ischemia, heart failure, or serious arrhythmias), LVEF should be measured.55,111 114 (Level of Evidence: B) 2007 recommendation remains current. Class IIa 1. For UA/NSTEMI patients in whom PCI has been selected as a postangiography management strategy, it is reasonable to administer an IV GP IIb/IIIa inhibitor (abciximab, eptifibatide, or tirofiban) if not started before diagnostic angiography, particularly for troponin-positive and/or other high-risk patients.55,58 (Level of Evidence: A) 2011 recommendation remains current. 2. For UA/NSTEMI patients in whom PCI is selected as a management strategy, it is reasonable to omit administration of an IV GP IIb/IIIa inhibitor if bivalirudin was selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 hours earlier.55,57 (Level of Evidence: B) 2007 recommendation remains current. 3. If LVEF is less than or equal to 0.40, it is reasonable to perform diagnostic angiography.111 114 (Level of Evidence: B) 2007 recommendation remains current. 4. If LVEF is greater than 0.40, it is reasonable to perform a stress test.111 (Level of Evidence: B) 2007 recommendation remains current. Class IIb 1. Platelet function testing to determine platelet inhibitory response in patients with UA/NSTEMI (or, after ACS and PCI) on P2Y12 receptor inhibitor therapy may be considered if results of testing may alter management.115 119 (Level of Evidence: B) modified ( thienopyridine replaced with P2Y12 receptor inhibitor ). 2. Genotyping for a CYP2C19 loss of function variant in patients with UA/NSTEMI (or, after ACS and with PCI) on P2Y12 receptor inhibitor therapy might be considered if results of testing may alter management.19 22,25,27,120 (Level of Evidence: C) modified ( thienopyridine replaced with P2Y12 receptor inhibitor ). Class III: No Benefit 1. IV fibrinolytic therapy is not indicated in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block.121 (Level of Evidence: A) 2007 recommendation remains current. *The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.11 The benefits of ticagrelor were observed irrespective of prior therapy with clopidogrel.9 When possible, discontinue ticagrelor at least 5 d before any surgery.12 Issues of patient compliance may be especially important. Consideration should be given to the potential and as yet undetermined risk of intracranial hemorrhage in patients with prior stroke or TIA. Patients weighing 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once-daily maintenance dose. Consideration should be given to lowering the maintenance dose to 5 mg in patients who weigh 60 kg, although the effectiveness and safety of the 5-mg dose have not been studied prospectively. For post-PCI patients, a daily maintenance dose should be given for at least 12 mo for patients receiving DES and up to 12 months for patients receiving BMS unless the risk of bleeding outweighs the anticipated net benefit afforded by a P2Y12 receptor inhibitor. Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. In patients age 75 y, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit except in high-risk situations (patients with diabetes or a history of prior MI), in which its effect appears to be greater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. When possible, discontinue prasugrel at least 7 d before any surgery.8 Additional risk factors for bleeding include body weight 60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, or chronic use of nonsteroidal anti-inflammatory drugs).8 ACS indicates acute coronary syndrome; BMS, bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; GP, glycoprotein; IV, intravenous; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIA, transient ischemic attack; UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction; and UFH, unfractionated heparin. Jneid et al 2012 UA/NSTEMI Focused Update 889 0.89; P 0.006), whereas no difference in outcome (6.7% versus 7.6% in the delayed and early groups, respectively; HR: 1.12; 95% CI: 0.81 to 1.56; P 0.48) was observed among patients in the lower 2 risk tertiles (GRACE score 140).107 Results of the TIMACS trial suggested superior outcome among patients managed by early rather than delayed inter- vention in the setting of UA/NSTEMI, although the reduction in the primary endpoint did not reach statistical significance for the overall trial population. Nevertheless, refractory is- chemia was reduced by an early approach, as were the risks of death, MI, and stroke among patients at the highest tertile of ischemic risk as defined by the GRACE risk score.107 To assess whether a more aggressive strategy of very early intervention, analogous to the standard of primary PCI for STEMI, would lead to improved outcomes in patients with non ST-elevation ACS, the ABOARD (Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes) study investigators123 compared angiography and intervention per- formed immediately on presentation with intervention carried out on the next working day. A total of 352 patients with unstable ischemic symptoms, ECG changes, or troponin elevation were randomized at 13 hospitals to immediate (at a median 70 minutes after enrollment) versus delayed (at a median 21 hours) angiography and revascularization. Back- ground antithrombotic therapy consisted of aspirin, clopi- dogrel with a loading dose of 300 mg, abciximab during PCI, and the anticoagulant of the investigator s choice. The primary trial endpoint was peak troponin I value during the hospitalization period. Immediate intervention conferred no advantage with regard to the primary endpoint (median troponin I value 2.1 versus 1.7 ng/mL in the immediate and delayed intervention groups, respectively), nor was there even a trend toward improved outcome in the prespecified clinical secondary endpoint of death, MI, or urgent revascu- larization by 1 month (13.7% versus 10.2% in the immediate and delayed intervention groups, respectively; P 0.31).123 These 3 trials,107,122,123 taken together with earlier studies, do provide support for a strategy of early angiography and inter- vention to reduce ischemic complications in patients who have been selected for an initial invasive strategy, particularly among those at high risk (defined by a GRACE score 140), whereas a more delayed approach is reasonable in low- to intermediate- risk patients. The early time period in this context is consid- ered to be within the first 24 hours after hospital presentation, although there is no evidence that incremental benefit is derived by angiography and intervention performed within the first few hours of hospital admission. The advantage of early intervention was achieved in the context of intensive background antithrom- botic therapy (Table 4). 5. Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care 5.2. Long-Term Medical Therapy and Secondary Prevention 5.2.1. Convalescent and Long-Term Antiplatelet Therapy: Recommendations (See Table 5 and Appendix 3 for supplemental information.) Table 4. Recommendations for Initial Invasive Versus Initial Conservative Strategies 2012 Focused Update Recommendations 2012 Comments Class I 1. An early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) is indicated in UA/NSTEMI patients who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures).124,125 (Level of Evidence: B) 2007 recommendation remains current. 2. An early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events (see 20074 Table 11 and 2007 Sections 2.2.6 and 3.4.3).55,72,111 (Level of Evidence: A) 2007 recommendation remains current. Class IIa 1. It is reasonable to choose an early invasive strategy (within 12 to 24 hours of admission) over a delayed invasive strategy for initially stabilized high-risk patients with UA/NSTEMI.* For patients not at high risk, a delayed invasive approach is also reasonable.107 (Level of Evidence: B) 2011 recommendation remains current. Class IIb 1. In initially stabilized patients, an initially conservative (ie, a selectively invasive) strategy may be considered as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events (see 20074 Table 11 and Sections 2.2.6 and 3.4.3), including those who are troponin positive.111,126 (Level of Evidence: B) The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference. (Level of Evidence: C) 2007 recommendation remains current. Class III: No Benefit 1. An early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) is not recommended in patients with extensive comorbidities (eg, liver or pulmonary failure, cancer), in whom the risks of revascularization and comorbid conditions are likely to outweigh the benefits of revascularization. (Level of Evidence: C) 2007 recommendation remains current. 2. An early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) is not recommended in patients with acute chest pain and a low likelihood of ACS. (Level of Evidence: C) 2007 recommendation remains current. 3. An early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) should not be performed in patients who will not consent to revascularization regardless of the findings. (Level of Evidence: C) 2007 recommendation remains current. *Immediate catheterization/angiography is recommended for unstable patients. ACS indicates acute coronary syndrome; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Table 5. Recommendations for Convalescent and Long-Term Antiplatelet Therapy 2012 Focused Update Recommendations 2012 Comments Class I 1. For UA/NSTEMI patients treated medically without stenting, aspirin* should be prescribed indefinitely60,61,63,64 (Level of Evidence: A); clopidogrel (75 mg per day) or ticagrelor (90 mg twice daily) should be prescribed for up to 12 months.9,10,14 (Level of Evidence: B) modified (included ticagrelor and footnote added pertaining to recommended aspirin maintenance dose). 2. For UA/NSTEMI patients treated with a stent (BMS or DES), aspirin should be continued indefinitely. (Level of Evidence: A) The duration and maintenance dose of P2Y12 receptor inhibitor therapy should be as follows: modified (included the term P2Y12 receptor inhibitor and altered aspirin dosing and duration of therapy after stent deployment). a. Clopidogrel 75 mg daily,16 prasugrel 10 mg daily,7 or ticagrelor 90 mg twice daily9 should be given for at least 12 months in patients receiving DES and up to 12 months for patients receiving BMS.9,13,16 (Level of Evidence: B) b. If the risk of morbidity because of bleeding outweighs the anticipated benefits afforded by P2Y12 receptor inhibitor therapy, earlier discontinuation should be considered. (Level of Evidence: C) 3. Clopidogrel 75 mg daily13,67 (Level of Evidence: B), prasugrel 10 mg daily (in PCI-treated patients)7 (Level of Evidence: C), or ticagrelor 90 mg twice daily9 (Level of Evidence: C) should be given to patients recovering from UA/NSTEMI when aspirin is contraindicated or not tolerated because of hypersensitivity or GI intolerance (despite use of gastroprotective agents such as PPIs).42,68 modified (included prasugrel and ticagrelor; deleted ticlopidine). Class IIa 1. After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses.32,33,90,127,128 (Level of Evidence: B) modified (changed wording and aspirin dose to be concordant with the 2011 PCI guideline75). Class IIb 1. For UA/NSTEMI patients who have an indication for anticoagulation, the addition of warfarin may be reasonable to maintain an INR of 2.0 to 3.0. 129 138 (Level of Evidence: B) 2007 recommendation remains current. 2. Continuation of a P2Y12 receptor inhibitor beyond 12 months may be considered in patients following DES placement. (Level of Evidence: C) modified (changed time period to be concordant with 2011 PCI guideline75 and replaced clopidogrel and prasugrel with P2Y12 receptor inhibitor ). Class III: No Benefit 1. Dipyridamole is not recommended as an antiplatelet agent in post-UA/NSTEMI patients because it has not been shown to be effective.90,139,140 (Level of Evidence: B) 2011 recommendation remains current. *For aspirin-allergic patients, use either clopidogrel or ticagrelor alone (indefinitely) or try aspirin desensitization. Note that there are no data for therapy with 2 concurrent P2Y12 receptor inhibitors, and this is not recommended in the case of aspirin allergy. The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.11 Ticagrelor s benefits were observed irrespective of prior therapy with clopidogrel.9 When possible, discontinue ticagrelor at least 5 d before any surgery.12 Issues of patient compliance may be especially important. Consideration should be given to the potential and as yet undetermined risk of intracranial hemorrhage in patients with prior stroke or TIA. Patients weighing 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10-mg once-daily maintenance dose. Consideration should be given to lowering the maintenance dose to 5 mg in patients who weigh 60 kg, although the effectiveness and safety of the 5-mg dose have not been studied prospectively. For post-PCI patients, a daily maintenance dose should be given for at least 12 mo for patients receiving DES and up to 12 mo for patients receiving BMS unless the risk of bleeding outweighs the anticipated net benefit afforded by a P2Y12 receptor inhibitor. Do not use prasugrel in patients with active pathological bleeding or a history of TIA or stroke. In patients age 75 y, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding and uncertain benefit except in high-risk situations (patients with diabetes or a history of prior myocardial infarction), in which its effect appears to be greater and its use may be considered. Do not start prasugrel in patients likely to undergo urgent CABG. When possible, discontinue prasugrel at least 7 d before any surgery.8 Additional risk factors for bleeding include body weight 60 kg, propensity to bleed, and concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, or chronic use of nonsteroidal anti-inflammatory drugs).8 Continue aspirin indefinitely and warfarin longer term as indicated for specific conditions such as atrial fibrillation; LV thrombus; or cerebral, venous, or pulmonary emboli. An INR of 2.0 to 2.5 is preferable while given with aspirin and a P2Y12 receptor inhibitor, especially in older patients and those with other risk factors for bleeding. For UA/NSTEMI patients who have mechanical heart valves, the INR should be at least 2.5 (based on type of prosthesis). BMS indicates bare-metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; GI, gastrointestinal; INR, international normalized ratio; LV, left ventricular; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; TIA, transient ischemic attack; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Jneid et al 2012 UA/NSTEMI Focused Update 891 5.2.6. Warfarin Therapy: Recommendations (See Table 6.) 6. Special Groups 6.2. Diabetes Mellitus: Recommendations (See Table 7.) 6.2.1.1. Intensive Glucose Control As detailed in the 2004 STEMI guideline,153 2007 UA/ NSTEMI guideline revision,4 and 2009 STEMI and PCI focused update,154 randomized trial evidence supported use of insulin infusion to control hyperglycemia. A clinical trial of intensive versus conventional glucose control in critically ill patients raised uncertainty about the optimal level to target when achieving glucose control. NICE-SUGAR (Normogly- caemia in Intensive Care Evaluation Survival Using Glu- cose Algorithm Regulation), a large international randomized trial (n 6104) of adults admitted to the intensive care unit with either medical or surgical conditions, compared inten- sive glucose control (target glucose range, 81 to 108 mg/dL) with conventional glucose control (to achieve a glucose level of 180 mg/dL, with reduction and discontinuation of insulin if the blood glucose level dropped below 144 mg/dL).149 Time-weighted glucose levels achieved were 115 18 mg/dL in the intensive group versus 144 23 mg/dL in the conven- tional group. The risk of death was increased at 90 days in the 95% CI: 1.02 to 1.08; P 0.02; number needed to harm 38). The result remained the same after adjusting for potential confounders. There were significantly more episodes of treatment-related hypoglycemia in the intensely managed group (6.8% versus 0.5%; P 0.001), although the contribu- tion of hypoglycemia to excess mortality is uncertain.149,150 Overall, the hospital course and proximate causes of death were similar in the 2 groups. Excess deaths in the intensive management group were predominantly of cardiovascular causes (absolute difference: 5.8%; P 0.02). More patients in the intensive group than in the conventional group were treated with corticosteroids. Because NICE-SUGAR149 enrolled critically ill medical and surgical patients, the degree to which its results can be extrapolated to the management of patients with UA/ NSTEMI is unclear. Although recent data from a small, mechanistic clinical trial155 suggest that glucose control may reduce inflammation and improve left ventricular ejection fraction in patients with acute MI, it remains uncertain whether acute glucose control will improve patient outcomes. A consensus statement by the American Association of Clinical Endocrinologists and the American Diabetes Asso- ciation157 summarized that although hyperglycemia is asso- ciated with adverse outcomes after acute MI, reduction of glycemia per se and not necessarily the use of insulin is Table 6. Recommendations for Warfarin Therapy 2012 Focused Update Recommendations 2012 Comments Class I 1. Use of warfarin in conjunction with aspirin and/or P2Y12 receptor inhibitor therapy is associated with an increased risk of bleeding, and patients and clinicians should watch for bleeding, especially GI, and seek medical evaluation for evidence of bleeding.7,9,13,14,141 144 (Level of Evidence: A) modified ( thienopyridine replaced with P2Y12 receptor inhibitor ). Class IIb 1. Warfarin either without (INR 2.5 to 3.5) or with low-dose aspirin (81 mg per day; INR 2.0 to 2.5) may be reasonable for patients at high coronary artery disease risk and low bleeding risk who do not require or are intolerant of P2Y12 receptor inhibitor therapy.145,146 (Level of Evidence: B) modified ( thienopyridine replaced with P2Y12 receptor inhibitor ). 2. Targeting oral anticoagulant therapy to a lower INR (eg, 2.0 to 2.5) might be reasonable in patients with UA/NSTEMI managed with aspirin and a P2Y12 inhibitor. (Level of Evidence: C) New recommendation GI indicates gastrointestinal; INR, international normalized ratio; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Table 7. Recommendations for Diabetes Mellitus 2012 Focused Update Recommendations 2012 Comments Class I 1. Medical treatment in the acute phase of UA/NSTEMI and decisions on whether to perform stress testing, angiography, and revascularization should be similar in patients with and without diabetes mellitus.55,72,81,147 (Level of Evidence: A) 2007 recommendation remains current. Class IIa 1. For patients with UA/NSTEMI and multivessel disease, CABG with use of the internal mammary arteries can be beneficial over PCI in patients being treated for diabetes mellitus.148 (Level of Evidence: B) 2007 recommendation remains current. 2. PCI is reasonable for UA/NSTEMI patients with diabetes mellitus with single-vessel disease and inducible ischemia.55 (Level of Evidence: B) 2007 recommendation remains current. 3. It is reasonable to use an insulin-based regimen to achieve and maintain glucose levels less than 180 mg/dL while avoiding hypoglycemia* for hospitalized patients with UA/NSTEMI with either a complicated or uncomplicated course.149 152 (Level of Evidence: B) 2011 recommendation remains current. *There is uncertainty about the ideal target range for glucose necessary to achieve an optimal risk-benefit ratio. CABG indicates coronary artery bypass graft; PCI, percutaneous coronary intervention; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. associated with improved outcomes. It remains unclear, however, whether hyperglycemia is a marker of underlying health status or is a mediator of complications after acute MI. Noniatrogenic hypoglycemia has also been associated with adverse outcomes and is a predictor of higher mortality. There is a clear need for a well-designed, definitive random- ized trial of target-driven glucose control in UA/NSTEMI patients with meaningful clinical endpoints so that glucose treatment thresholds and glucose targets can be determined. Until such a trial is completed, and on the basis of the balance of current evidence,157 159 the writing group concluded that it was prudent to change the recommendation for the use of insulin to control blood glucose in UA/NSTEMI from a more stringent to a more moderate target range in keeping with the recent 2009 STEMI and PCI focused update (Class IIa, LOE: B)154 and recommend treatment for hyperglycemia 180 mg/dL while avoiding hypoglycemia. The writing group believed that the 2007 recommendation4 regarding long-term glycemic control targets failed to reflect recent data casting doubt on a specific ideal goal for the management of diabetes in patients with UA/NSTEMI. Diabetes is another characteristic associated with high risk for adverse outcomes after UA/NSTEMI. The 2007 UA/ NSTEMI guidelines4 state that patients with diabetes are at high risk and in general should be treated similarly to patients with other high-risk features. However, the 2012 writing group noted that diabetes was not listed as a high-risk feature for which an invasive strategy was specifically preferred, in contrast to the inclusion of chronic kidney disease (CKD) and diabetes mellitus as characteristics favoring an invasive approach in the 2007 European Society of Cardiology guide- lines for management of UA/NSTEMI.160 To revisit this question for diabetes, the writing group reviewed results of the published analysis of patients with diabetes in the FRISC-II (FRagmin and Fast Revascularization during InSta- bility in Coronary artery disease) trial.72 Overall, the FRISC- II trial demonstrated a benefit with invasive management compared with conservative management in patients with UA/NSTEMI. There were similar reductions in the risk of MI/death at 1 year in the diabetic subgroup randomized to an invasive strategy (OR: 0.61; 95% CI: 0.36 to 1.04) compared with patients who did not have diabetes randomized to an invasive strategy (OR: 0.72; 95% CI: 0.54 to 0.95). The risk of death was also reduced by randomization to an invasive strategy among patients with diabetes (OR: 0.59; 95% CI: 0.94). Subgroup analysis of the TACTICS-TIMI-18 (Treat Angina with aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy Thrombolysis In Myocar- dial Infarction 18) study in patients with diabetes, available in abstract form, was consistent with this finding.161 Thus, diabetes, as well as the often concurrent comorbidity of CKD (Section 6.5, Chronic Kidney Disease: Recommendations), is not only a high-risk factor but also benefits from an invasive approach. Accordingly, diabetes has been added to the list of characteristics for which an early invasive strategy is gener- ally preferred (Appendix 6). 6.5. Chronic Kidney Disease: Recommendations (See Table 8, and Online Data Supplement.) 6.5.1. Angiography in Patients With CKD Since the 2007 UA/NSTEMI Guidelines were published,4 several larger randomized trials have been published that reported no difference in contrast-induced nephropathy (CIN) when iodixanol was compared with various other low- osmolar contrast media (LOCM).170 173 These and other randomized trials comparing isosmolar iodixanol with LOCM have been summarized in 2 mutually supportive and complementary meta-analyses involving 16 trials in 2763 patients174 and 25 trials in 3260 patients,175 respectively. When more recent trials were combined with the older studies, the data supporting a reduction in CIN favoring iodixanol were no longer significant (summary RR: 0.79; CI: 0.61 to 1.04; P 0.10,175 respectively). However, subanal- yses showed variations in relative renal safety by specific LOCM: A reduction in CIN was observed when iodixanol was compared to ioxaglate, the only ionic LOCM (RR: 0.58; 95% CI: 0.37 to 0.92; P 0.022174), and to iohexol, a nonionic no difference was noted in comparisons of iodixanol with iopamidol, iopromide, or ioversol,174 and a single trial fa- vored iomeprol.170 A pooled comparison of iodixanol with all nonionic LOCM other than iohexol indicated equivalent Table 8. Recommendations for Chronic Kidney Disease 2012 Focused Update Recommendations 2012 Comments Class I 1. Creatinine clearance should be estimated in UA/NSTEMI patients and the doses of renally cleared medications should be adjusted according to the pharmacokinetic data for specific medications.162,163 (Level of Evidence: B) 2011 recommendation remains current. 2. Patients undergoing cardiac catheterization with receipt of contrast media should receive adequate preparatory hydration.164,165 (Level of Evidence: B) 2011 recommendation remains current. 3. Calculation of the contrast volume to creatinine clearance ratio is useful to predict the maximum volume of contrast media that can be given without significantly increasing the risk of contrast-associated nephropathy.166,167 (Level of Evidence: B) 2011 recommendation remains current. Class IIa 1. An invasive strategy is reasonable in patients with mild (stage 2) and moderate (stage 3) CKD.162,163,168,169 (Level of Evidence: B) (There are insufficient data on benefit/risk of invasive strategy in UA/NSTEMI patients with advanced CKD 2011 recommendation remains current. CKD indicates chronic kidney disease; and UA/NSTEMI, unstable angina/non ST-elevation myocardial infarction. Jneid et al 2012 UA/NSTEMI Focused Update 893 were consistent regardless of ancillary preventive therapies (hydration, acetylcysteine), route of administration (IV or intra-arterial), age, sex, dose, or preexisting CKD or diabetes. Of further interest, findings were similar in the 8 studies (n 1793 patients) performed in the setting of coronary angiography.174 A more recent study comparing iodixanol versus iopamidol provides additional supportive evidence.176 However, even these clinical inferences must be tempered by the relative paucity of head-to-head trials comparing CIN rates among the various contrast media and the variability in results (eg, for iohexol versus other low-osmolar compara- tors).177 180 Furthermore, the assumption that a transient rise in serum creatinine after 24 to 48 hours is a reliable predictor of the more serious but somewhat delayed development of renal failure requiring hospitalization or dialysis has been challenged. A nationwide Swedish survey181 of hospitaliza- tions for renal failure after coronary procedures in 57 925 patients found that this risk was paradoxically higher with iodixanol (1.7%) than ioxaglate (0.8%) or iohexol (0.9%; P 0.001). Although the result was observational, hence subject to selection bias, it persisted in analyses of high-risk patient subsets (patients with diabetes, prior history of renal failure), in multivariable analysis, and in hospitals crossing over from ioxaglate to iodixanol. Iodixanol s greater viscosity was speculated but not demonstrated to be a possible mech- anism for the observed effect. Thus, an overall summary of the current database, updated since previous guideline rec- ommendations,4 is that strength and consistency of relation- ships between specific isosmolar or low-osmolar agents and CIN or renal failure are not sufficient to enable a guideline statement on selection among commonly used low-osmolar and isosmolar media. Instead, the writing group recommends focusing on operator conduct issues shown to be important to protect patients, that is, 1) proper patient preparation with hydration, and 2) adjustment of maximal contrast dose to each patient s renal function and other clinical characteristics. With respect to patient preparation, the writing group re- viewed several trials addressing the optimal preparatory regimen of hydration and pharmacotherapy. The basic principle of hydration follows from experimental studies and clinical expe- rience, with isotonic or half-normal saline alone being the historical gold standards.164,165,182 184 More recently, sodium bicarbonate has been tested as the hydrating solution. Some trials have reported superiority of sodium bicarbonate over saline in preventing CIN.185 188 Similarly, some have reported a benefit of N-acetylcysteine administration as adjunctive therapy to hydra- tion,185,189 whereas others have not.190,191 Thus, although the writing group found the evidence compelling for adequate hydration preparatory to angiography with contrast media, it found the evidence insufficient to recommend a specific regimen. With respect to limitation of contrast dose by renal func- tion, mounting evidence points to renal-function specific limits on maximal contrast volumes that can be given without significantly increasing the baseline risk of provoking CIN. In a contemporary study, Laskey et al studied 3179 consecutive patients undergoing PCI and found that a contrast volume to creatinine clearance ratio 3.7 was a significant and inde- pendent predictor of an early and abnormal increase in serum creatinine.166 In an earlier trial, administration of a contrast volume of 5 mL body weight (kg)/serum creatinine (mg/ dL), applied to 16 592 patients undergoing cardiac catheter- ization, was associated with a 6-fold increase in the likelihood of patients developing CIN requiring dialysis.167 Patients with CKD are consistently underrepresented in randomized controlled trials of cardiovascular disease.192 The impact of an invasive strategy has been uncertain in this group. The SWEDEHEART (Swedish Web-System for En- hancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Ther- apies) study included a cohort of 23 262 patients hospitalized for NSTEMI in Sweden between 2003 and 2006 who were age 80 years.169 This contemporary nationwide registry of nearly all consecutive patients examined the distribution of CKD and the use of early revascularization after NSTEMI and evaluated whether early revascularization (by either PCI or CABG) within 14 days of admission for NSTEMI altered outcomes at all stages of kidney function. In SWEDEHEART, all-cause mortality was assessed at 1 year and was available in 99% of patients. Moderate or more advanced CKD (estimated glomerular filtration rate ) was present in 5689 patients (24.4%). After multivariable adjustment, the 1-year mortality in the overall cohort was 36% lower with early P 0.001).169 The magnitude of the difference in 1-year mortality was similar in patients with normal eGFR (early revascularization versus medically treated: 1.9% versus 10%; 95% CI: 0.52 to 0.80; P 0.001), and moderate CKD [eGFR 95% CI: 0.54 to 0.86; P 0.001). The benefit of an invasive therapy was not evident in patients with severe CKD stage 4 ] (22% versus 41%; HR: stage 5 kidney failure [eGFR 15 mL/min per 1.73 m2 or to 3.09; P 0.150). Early revascularization was associated with increased 1-year survival in UA/NSTEMI patients with mild to moderate CKD, but no association was observed in those with severe or end-stage kidney disease.169 The findings from SWEDEHEART are limited by their nonrandomized nature and the potential for selection bias despite the intricate multivariable adjustment.169 On the other hand, SWEDEHEART captured unselected patients with more comor- bidities and is therefore more reflective of real-world patients. Recently, a collaborative meta-analysis of randomized con- trolled trials that compared invasive and conservative treatments in UA/NSTEMI was conducted to estimate the effectiveness of early angiography in patients with CKD.168 The meta-analysis demonstrated that an invasive strategy was associated with a significant reduction in rehospitalization (RR: 0.76; 95% CI: 0.66 to 0.87; P 0.001) at 1 year compared with conservative strategy. The meta-analysis did not show any significant differ- ences with regard to all-cause mortality (RR: 0.76; 95% CI: 0.49 P 0.22), and the composite of death/nonfatal MI (RR: 0.79; Our recommendation is that an early invasive strategy (ie, diagnostic angiography with intent to perform revasculariza- tion) is a reasonable strategy in patients with mild and moderate CKD. Clinicians should exercise judgment in all populations with impaired kidney function when considering whether to implement an invasive strategy. Such implemen- tation should be considered only after careful assessment of the risks, benefits, and alternatives for each individual patient. The observational data with regard to patients with mild to severe CKD also support the recognition that CKD is an underappreciated high-risk characteristic in the UA/NSTEMI population. The increased risk of mortality associated with mild, moderate, and severe CKD remains evident across stud- ies.162,163,168,193 Indeed, the risks of short- and long-term mortal- ity are increased as the gradient of renal dysfunction wors- ens.162,168,193 The optimal role of early revascularization in this heterogeneous population of patients remains an important topic of research and investigation as discussed earlier in this update. 7. Conclusions and Future Directions 7.1. Quality of Care and Outcomes for UA/NSTEMI: Recommendation (See Table 9.) 7.1.1. Quality Care and Outcomes The development of regional systems of UA/NSTEMI care is a matter of utmost importance.196,198,199 This includes encouraging the participation of key stakeholders in collaborative efforts to evaluate care using standardized performance and quality- improvement measures, such as those endorsed by the ACC and the AHA for UN/NSTEMI.199 Standardized quality-of-care data registries designed to track and measure outcomes, complica- tions, and adherence to evidence-based processes of care for UA/NSTEMI are also critical: programs such as the NCDR (National Cardiovascular Data Registry) ACTION Registry- GWTG, the AHA s Get With The Guidelines (GWTG) quality- improvement program, and those performance-measurement systems required by The Joint Commission and the Centers for Medicare and Medicaid Services.194,201 203 More recently, the AHA has promoted its Mission: Lifeline initiative, which was developed to encourage closer cooperation and trust among prehospital emergency services personnel and cardiac care professionals.194 The evaluation of UA/NSTEMI care delivery across traditional care-delivery boundaries with these tools and other resources is imperative to identify systems problems and enable the application of modern quality-improvement methods, such as Six Sigma, to make necessary improve- ments.195,197,200,204 The quality-improvement data coming from registries like the ACTION-GTWG may prove pivotal in ad- dressing opportunities for quality improvement at the local, regional, and national level, including the elimination of health- care disparities and conduct of comparative effectiveness research. President and Staff American College of Cardiology Foundation William A. Zoghbi, MD, FACC, President Thomas E. Arend, Jr, Esq, CAE, Interim Chief Staff Officer William J. Oetgen, MD, MBA, FACC, Senior Vice President, Science and Quality Charlene May, Senior Director, Science and Clinical Policy American College of Cardiology Foundation/American Heart Association Lisa Bradfield, CAE, Director, Science and Clinical Policy Sue Keller, BSN, MPH, Senior Specialist, Evidence-Based Medicine Ezaldeen Ramadhan III, Specialist, Science and Clinical Policy American Heart Association Gordon F. Tomaselli, MD, FAHA, President Nancy Brown, Chief Executive Officer Rose Marie Robertson, MD, FAHA, Chief Science Officer Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice President, Office of Science Operations Judy L. 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