Although overall major bleeding was not increased with ticagrelor, a modest increase in major bleeding and non pro- cedure-related bleeding occurred in the subgroup of patients who did not undergo CABG (major bleeding: 4.5% versus 2.3%; P=0.05); however, there was no difference in blood transfusion or fatal bleeding.305 Side effects unique to ticagre- lor include dyspnea (which occurs in up to 15% of patients within the first week of treatment but is rarely severe enough to cause discontinuation of treatment)293 and bradycardia. The benefit of ticagrelor over clopidogrel was limited to patients taking 75 mg to 100 mg of aspirin.290 The short half-life requires twice-daily administration, which could potentially result in adverse events in non-compliant patients, particularly after stent implantation. When possible, ticagrelor should be discontinued at least 5 days before surgery.306 Although ticagrelor has not been studied in the absence of aspirin, its use in aspirin-intolerant patients is a reasonable alternative. Intravenous GP IIb/IIIa Receptor Inhibitors The small molecule GP IIb/IIIa receptor antagonists, tirofiban and eptifibatide, bind reversibly to the GP IIb/IIIa receptor. Because the drug-to-receptor ratio is high, platelet infusion is not effective in cases of severe bleeding after use of eptifiba- tide or tirofiban, and they must be cleared from the circulation to reduce bleeding. In contrast, with abciximab, the drug-to- receptor ratio is low, and platelet infusion may be effective. Several large RCTs evaluated the impact of GP IIb/IIIa receptor inhibitors in patients with NSTE-ACS who were committed to an invasive strategy.295,296,306 TheACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial evaluated unfractionated heparin (UFH) versus bivalirudin with or without GP IIb/IIIa inhibitors.295,307 The rates of composite ischemia (death, MI, unplanned revascularization) in patients who received bivalirudin alone compared with those who received UFH plus GP IIb/IIIa inhibitors were similar (9% ver- Fewer patients experienced major bleeding with bivalirudin alone than did with heparin plus GP IIb/IIIa inhibitors (4% versus 7%; relative risk [RR]: 0.52; 95% confi- The ACUITY Timing trial evaluated the benefit of upstream GP IIb/IIIa receptor antagonist compared with its deferred use, testing the hypothesis that earlier administration of GP IIb/IIIa inhibitors in patients destined for PCI would be superior.308 Composite ischemia at 30 days occurred in 7.9% of patients assigned to deferred use compared with 7.1% assigned to upstream admin- riority; P=0.13 for superiority). Deferred GP IIb/IIIa inhibitors reduced the 30-day rates of major bleeding compared with Similar results were reported by the EARLYACS investigators, who evaluated eptifibatide given upstream versus delayed, provisional admin- istration in >9000 patients with NSTE-ACS.295 The compos- ite endpoint of death, MI, recurrent ischemia requiring urgent revascularization, or thrombotic complications occurred in 9.3% of patients in the early-eptifibatide group compared with 10% in the delayed-eptifibatide group (odds ratio [OR]: 0.92; As in the ACUITY Timing trial, the early-eptifibatide group had significantly higher rates of bleeding and red cell transfusions.295,308 Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e367 4.3.2. Initial Parenteral Anticoagulant Therapy in Patients With Definite NSTE-ACS: Recommendations See Table 7 for a summary of recommendations regarding antiplatelet/anticoagulant therapy in patients with definite or likely NSTE-ACS and Online Data Supplement 16 for addi- tional information on combined oral anticoagulant therapy and antiplatelet therapy in patients with definite NSTE-ACS. Class I 1. In patients with NSTE-ACS, anticoagulation, in ad- dition to antiplatelet therapy, is recommended for all patients irrespective of initial treatment strategy. Treatment options include: Enoxaparin: 1 mg/kg subcutaneous (SC) every 12 hours (reduce dose to 1 mg/kg SC once daily in patients with creatinine clearance [CrCl] <30 mL/min), continued for the duration of hos- pitalization or until PCI is performed. An initial intravenous loading dose of 30 mg has been used in selected patients.133,136,309 (Level of Evidence: A) Bivalirudin: 0.10 mg/kg loading dose followed by 0.25 mg/kg per hour (only in patients managed with an early invasive strategy), continued until diagnostic angiography or PCI, with only provi- sional use of GP IIb/IIIa inhibitor, provided the patient is also treated with DAPT.292,293,310,311 (Level of Evidence: B) Fondaparinux: 2.5 mg SC daily, continued for the duration of hospitalization or until PCI is per- (Level of Evidence: B) If PCI is performed while the patient is on fondaparinux, an additional anticoagulant with anti-IIa activity (either UFH or bivalirudin) should be administered because of the risk of catheter (Level of Evidence: B) UFH IV: initial loading dose of 60 IU/kg (maxi- mum 4000 IU) with initial infusion of 12 IU/kg per hour (maximum 1000 IU/h) adjusted per activated partial thromboplastin time to maintain therapeu- tic anticoagulation according to the specific hospi- tal protocol, continued for 48 hours or until PCI is (Level of Evidence: B) 4.3.2.1. Low-Molecular-Weight Heparin LMWHs have a molecular weight approximately one third that of UFH and have balanced anti-Xa and anti-IIa activity. LMWHs are readily absorbed after subcutaneous administration and have less platelet activation.323 The anticoagulant activity of LMWH does not require routine monitoring. The dose of enoxaparin is 1 mg/kg SC every 12 hours for NSTE-ACS; an initial intravenous loading dose of 30 mg has been used in selected patients. In the presence of impaired renal function (CrCl <30 mL per minute), which is a common finding in older patients, the dose should be reduced to 1 mg/kg SC once daily, and strong consideration should be given to UFH as an alternative. Calculation of CrCl is prudent in patients considered for enoxaparin therapy. In the ESSENCE trial, in patients with UA or non Q-wave MI, the rates of recurrent ischemic events and invasive diagnostic and therapeutic procedures were significantly reduced by enoxaparin therapy in the short term, and benefit was sustained at 1 year.324 In the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) trial of high-risk patients with NSTE-ACS treated with an early invasive strategy, there was no significant difference in death or MI at 30 days between those randomized to enoxapa- rin versus UFH. There was more TIMI major bleeding in those treated with enoxaparin without statistically significant increase in GUSTO severe bleeding or transfusion. Some of the increased bleeding may have been related to patients randomized to enoxa- parin who received additional UFH at the time of PCI.325,326 The direct thrombin inhibitor bivalirudin is administered intra- venously. Bivalirudin was evaluated in the ACUITY trial, a randomized open-label trial, in 13819 moderate- to high-risk patients with NSTE-ACS with a planned invasive strategy. Three treatment arms were tested, including UFH or LMWH with a GP IIb/IIIa receptor inhibitor, bivalirudin with a GP IIb/IIIa receptor inhibitor, or bivalirudin alone. The majority of patients received clopidogrel (300 mg) before interven- tion, in addition to aspirin, anticoagulants, and GP IIb/IIIa inhibitors. Bivalirudin alone was noninferior to the standard UFH/LMWH combined with GP IIb/IIIa inhibitor (composite there was a significantly lower rate of major bleeding with The anticoagulant effect of bivalirudin can be monitored in the catheterization laboratory by the activated clotting time. Fondaparinux is a synthetic polysaccharide molecule and the only selective inhibitor of activated factor X available for clinical use. Fondaparinux is well absorbed when given sub- cutaneously and has a half-life of 17 hours, enabling once- daily administration. Because it is excreted by the kidneys, it is contraindicated if CrCl is <30 mL per minute. Monitoring of anti-Xa activity is not required, and fondaparinux does not affect usual anticoagulant parameters such as activated partial thromboplastin time or activated clotting time. In NSTE-ACS, the dose of fondaparinux is 2.5 mg SC administered daily and continued for the duration of hospitalization or until PCI is per- In the OASIS (Organization to Assess Strategies in Ischemic Syndromes)-5 study, patients with NSTE-ACS were randomized to receive 2.5 mg SC fondaparinux daily or enoxaparin 1 mg/kg SC twice daily for 8 days. The inci- dence of the primary composite ischemic endpoint at 9 days was similar between fondaparinux and enoxaparin, but major bleeding was significantly less frequent with fondaparinux. To avert catheter thrombosis when fondaparinux is used alone in patients undergoing PCI, an anticoagulant with anti-IIa activ- ity is also administered.313 315 One regimen is 85 IU/kg of UFH loading dose at the time of PCI (reduced to 60 IU/kg if a GP IIb/IIIa inhibitor is used concomitantly).314 4.3.2.4. Unfractionated Heparin Studies supporting the addition of a parenteral anticoagulant to aspirin in patients with NSTE-ACS were performed primar- ily on patients with a diagnosis of unstable angina in the era before DAPT and early catheterization and revascularization. See Section 5.1.2.1 for recommendations at the time of PCI. In general, those studies found a strong trend for reduction in composite adverse events with the addition of parenteral UFH to aspirin therapy.316 322 Clinical trials indicate that a weight-adjusted dosing regi- men of UFH can provide more predictable anticoagulation327 than a fixed initial dose (eg, 5000 IU loading dose, 1000 IU/h initial infusion). The recommended weight-adjusted regimen is an initial loading dose of 60 IU/kg (maximum 4000 IU) and an initial infusion of 12 IU/kg/h (maximum 1000 IU/h), adjusted using a standardized nomogram. Argatroban, a direct thrombin inhibitor, is indicated for pro- phylaxis or treatment of thrombosis in patients with heparin- induced thrombocytopenia, including those undergoing PCI.328 Steady state plasma concentrations are achieved in 1 to 3 hours after intravenous administration. Because of its hepatic metab- olism, argatroban can be used in patients with renal insuffi- ciency. The usual dose is 2 mcg/kg per minute by continuous intravenous infusion, adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times baseline (but not >100 s). 4.3.3. Fibrinolytic Therapy in Patients With Definite NSTE-ACS: Recommendation Class III: Harm 1. In patients with NSTE-ACS (ie, without ST-elevation, true posterior MI, or left bundle-branch block not known to be old), intravenous fibrinolytic therapy should not be used.93,329 (Level of Evidence: A) There is no role for fibrinolytic therapy in patients with NSTE- ACS. Fibrinolysis with or without subsequent PCI in patients with NSTE-ACS was evaluated by the Fibrinolytic Trialists and There was no benefit for mortality or MI. Intracranial hemorrhage and fatal and nonfatal MI occurred more frequently in patients treated with fibrinolytic therapy. See Online Data Supplement 17 for additional informa- tion on parenteral anticoagulant and fibrinolytic therapy in patients with definite NSTE-ACS. 4.4. Ischemia-Guided Strategy Versus Early Invasive Strategies See Figure 3 for the management algorithm for ischemia- guided versus early invasive strategy. 4.4.1. General Principles Two treatment pathways have emerged for all patients with NSTE-ACS. The invasive strategy triages patients to an inva- sive diagnostic evaluation (ie, coronary angiography). In contrast, the initial ischemia-guided strategy calls for an inva- sive evaluation for those patients who 1) fail medical therapy (refractory angina or angina at rest or with minimal activity despite vigorous medical therapy), 2) have objective evidence of ischemia (dynamic electrocardiographic changes, myo- cardial perfusion defect) as identified on a noninvasive stress test, or 3) have clinical indicators of very high prognostic risk (eg, high TIMI or GRACE scores). In both strategies, patients should receive optimal anti-ischemic and antithrombotic medical therapy as outlined in Section 4.1. A subgroup of patients with refractory ischemic symptoms or hemodynamic or rhythm instability are candidates for urgent coronary angi- ography and revascularization. 4.4.2. Rationale and Timing for Early Invasive Strategy This strategy seeks to rapidly risk stratify patients by assess- ing their coronary anatomy. The major advantages of invasive therapy when appropriate are 1) the rapid and definitive nature of the evaluation, 2) the potential for earlier revascularization in appropriate patients that might prevent occurrence of fur- ther complications of ACS that could ensue during medical therapy, and 3) facilitation of earlier discharge from a facility. 4.4.2.1. Routine Invasive Strategy Timing The optimal timing of angiography has not been conclusively defined. In general, 2 options have emerged: early invasive (ie, within 24 hours) or delayed invasive (ie, within 25 to 72 hours). In most studies using the invasive strategy, angiogra- phy was deferred for 12 to 72 hours while antithrombotic and anti-ischemic therapies were intensified.138,332 337 The concept of deferred angiography espouses that revascularization may be safer once plaque is stabilized with optimal antithrombotic and/or anti-ischemic therapies. Conversely, early angiography facilitates earlier risk stratification and consequently speeds revascularization and discharge but can place greater logistic demands on a healthcare system. 4.4.3. Rationale for Ischemia-Guided Strategy The ischemia-guided strategy seeks to avoid the routine early use of invasive procedures unless patients experience refractory or recurrent ischemic symptoms or develop hemo- dynamic instability. When the ischemia-guided strategy is chosen, a plan for noninvasive evaluation is required to detect severe ischemia that occurs at a low threshold of stress and to promptly refer these patients for coronary angiography and revascularization as indicated. The major advantage offered by the ischemia-guided strategy is that some patients con- ditions stabilize during medical therapy and will not require coronary angiography and revascularization. Consequently, the ischemia-guided strategy may potentially avoid costly and possibly unnecessary invasive procedures. 4.4.4. Early Invasive and Ischemia-Guided Strategies: Recommendations Class I 1. An urgent/immediate invasive strategy (diagnostic angiography with intent to perform revascularization if appropriate based on coronary anatomy) is indi- cated in patients (men and women ) with NSTE-ACS who have refractory angina or hemodynamic or elec- trical instability (without serious comorbidities or contraindications to such procedures).42,44,138,338 (Level of Evidence: A) 2. An early invasive strategy (diagnostic angiography with intent to perform revascularization if appropri- ate based on coronary anatomy) is indicated in ini- tially stabilized patients with NSTE-ACS (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events (Table 8).42,44,138,333,334,338,339 (Level of Evidence: B) See Section 7.7 for additional information on women. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e369 Class IIa 1. It is reasonable to choose an early invasive strategy (within 24 hours of admission) over a delayed inva- sive strategy (within 25 to 72 hours) for initially sta- bilized high-risk patients with NSTE-ACS. For those not at high/intermediate risk, a delayed invasive ap- proach is reasonable.139 (Level of Evidence: B) Class IIb 1. In initially stabilized patients, an ischemia-guid- ed strategy may be considered for patients with Figure 3. Algorithm for Management of Patients With Definite or Likely NSTE-ACS.* *See corresponding full-sentence recommendations and their explanatory footnotes. In patients who have been treated with fondaparinux (as upfront therapy) who are undergoing PCI, an additional anticoagulant with anti-IIa activity should be administered at the time of PCI because of the risk of catheter thrombosis. ASA indicates aspirin; CABG, coronary artery bypass graft; cath, catheter; COR, Class of Recommendation; DAPT, dual antiplatelet therapy; GPI, glycoprotein IIb/IIIa inhibitor; LOE, Level of Evidence; NSTE-ACS, non ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; pts, patients; and UFH, unfractionated heparin. NSTE-ACS (without serious comorbidities or contra- indications to this approach) who have an elevated risk for clinical events.333,334,338 (Level of Evidence: B) 2. The decision to implement an ischemia-guided strat- egy in initially stabilized patients (without serious comorbidities or contraindications to this approach) may be reasonable after considering clinician and patient preference. (Level of Evidence: C) Class III: No Benefit 1. An early invasive strategy (ie, diagnostic angiogra- phy with intent to perform revascularization) is not recommended in patients with: a. Extensive comorbidities (eg, hepatic, renal, pulmo- nary failure; cancer), in whom the risks of revascular- ization and comorbid conditions are likely to outweigh thebenefitsofrevascularization.(LevelofEvidence:C) b. Acute chest pain and a low likelihood of ACS who are troponin-negative (Level of Evidence: C), espe- (Level of Evidence: B) have con- cluded that a strategy of routine invasive therapy is generally superior to an ischemia-guided strategy or selectively invasive approach. One study reported that the routine invasive strategy resulted in an 18% relative reduction in death or MI, including a significant reduction in MI alone.341 The routine invasive arm was associated with higher in-hospital mortality (1.8% versus 1.1%), but this disadvantage was more than compensated for by a significant reduction in mortality between discharge and the end of follow-up (3.8% versus 4.9%). The invasive strategy was also associated with less angina and fewer rehospitalizations. Patientsundergoingroutineinvasivetreatmentalsohadimproved quality of life. In an analysis of individual patient data340 that reported 5-year outcomes from the FRISC (Framingham and Fast Revascularization During Instability in Coronary Artery ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes) trial,338 and RITA (Randomized Trial of a Conservative Treatment Strategy Versus an Interventional Treatment Strategy in Patients with Unstable to a routine invasive strategy experienced cardiovascular death or nonfatal MI versus 17.9% of patients (475 of 2746) in the selective invasive strategy (HR: 0.81; 95% CI: 0.71 to 0.93; P=0.002). The most marked treatment effect was on MI (10.0% routine invasive strategy versus 12.9% selective invasive strat- egy), and there were consistent trends for fewer cardiovascular mortality (HR: 0.90; 95% CI: 0.77 to 1.05). There were abso- lute reductions of 2.0% to 3.8% in cardiovascular death or MI in the low- and intermediate-risk groups and an 11.1% absolute risk reduction in the highest-risk patients. The invasive strategy demonstrated its greatest advantage in the highest-risk stratum of patients with no significant benefit on mortality over the noninvasive approach in moderate- and low-risk patients.342 An ischemia-guided strategy has been used with favorable results in initially stabilized patients with NSTE-ACS at elevated risk for clinical events, including those with positive troponin levels.338 One limitation of these studies is the absence of adherence to optimal medical therapy in non-invasively treated patients dur- ing long-term management. In addition, in FRISC-II, invasive management was delayed and patients with markedly positive stress tests (up to 2.9-mm exercise-induced ST depression) were randomized to noninvasive or invasive therapy.338 See Online Data Supplement 18 for additional information on comparison of early invasive strategy and ischemia-guided strategy. 4.4.4.1. Comparison of Early Versus Delayed Angiography In some studies, early angiography and coronary intervention have been more effective in reducing ischemic complications than delayed interventions, particularly in patients at high risk (defined by a GRACE score >140).139,336 A more delayed strategy is also reasonable in low- to intermediate-risk patients. The advantage of early intervention was achieved in the context of intensive back- ground antithrombotic and anti-ischemic therapy. However, this question was also assessed by a meta-analysis of 11 trials (7 RCTs Meta-analysis of the RCTs was inconclusive for a survival benefit of the early invasive strategy (OR:0.83[95%CI:0.64to1.09];P=0.180),andtherewere no sig- nificant differences in MI or major bleeding; a similar result was found with the observational studies. These data are limited by the small sample size of the individual trials, low event rates, inconsis- tency in timing of intervention, and heterogeneous patient profiles. See Online Data Supplement 19 for additional information on comparison of early versus delayed angiography. Table 8. Factors Associated With Appropriate Selection of Early Invasive Strategy or Ischemia-Guided Strategy in Patients With NSTE-ACS Immediate invasive (within 2 h) Refractory angina Signs or symptoms of HF or new or worsening mitral regurgitation Hemodynamic instability Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy Sustained VT or VF Ischemia-guided strategy Low-risk score (eg, TIMI [0 or 1], Low-risk Tn-negative female patients Patient or clinician preference in the absence of high-risk features Early invasive (within 24 h) None of the above, but GRACE risk score >140 Temporal change in Tn (Section 3.4) New or presumably new ST depression Delayed invasive (within None of the above but diabetes mellitus Renal ) Reduced LV systolic function (EF <0.40) Early postinfarction angina PCI within 6 mo Prior CABG GRACE risk score 109 140; TIMI score 2 CABG indicates coronary artery bypass graft; EF, ejection fraction; GFR, glo merular filtration rate; GRACE, Global Registry of Acute Coronary Events; HF, heart failure; LV, left ventricular; NSTE-ACS, non ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarc tion; Tn, troponin; VF, ventricular fibrillation; and VT, ventricular tachycardia. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e371 4.4.5. Subgroups: Early Invasive Strategy Versus Ischemia- Guided Strategy The TACTICS-TIMI (Treat Angina With Tirofiban and Determine Cost of Therapy With an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction) 18 trial demonstrated a reduction in the 6-month endpoint of death or MI in older adults with ACS.138 Controversy exists over revas- cularization treatment differences between men and women with ACS. The FRISC-II trial showed a benefit of revascu- larization in men for death or MI that was not observed for In contrast, death, MI, or rehospitalization rates were reduced for both men and women in TACTICS-TIMI RITA-3 showed that the routine strategy of invasive evaluation resulted in a beneficial effect in high-risk men that was not seen in women.342 A meta-analysis suggests that in NSTE-ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end- point of death, MI, or rehospitalization.141,345,346 In contrast, an ischemia-guided strategy is preferred in low-risk women.141 Another collaborative meta-analysis of randomized trials reported that an early invasive strategy yielded similar RR reductions in overall cardiovascular events in patients with and without diabetes mellitus.347 However, an invasive strat- egy appeared to reduce recurrent nonfatal MI to a greater extent in patients with diabetes mellitus. 4.4.6. Care Objectives Coronary angiography is designed to provide detailed infor- mation about the size and distribution of coronary vessels, the location and extent of atherosclerotic obstruction, and the suitability for revascularization. The LV angiogram, usually performed with coronary angiography, provides an assess- ment of the extent of focal and global LV dysfunction and of the presence and severity of coexisting disorders (eg, valvular or other associated lesions). Patients with NSTE-ACS can be divided into risk groups on the basis of their initial clinical presentation. The TIMI, PURSUIT, and GRACE scores are useful tools for assigning risk to patients with NSTE-ACS. Risk stratification identifies patients who are most likely to benefit from subsequent revascularization. Patients with left main disease or multivessel CAD with reduced LV function are at high risk for adverse outcomes and are likely to benefit from CABG. Clinical evaluation and noninvasive testing aid in the identification of most patients at high risk because they often have 1 of the following high-risk features: advanced age (>70 years of age), prior MI, revascularization, ST devia- tion, HF, depressed resting LV function (ie, LVEF 0.40) on noninvasive study, or noninvasive stress test findings, includ- ing magnetic resonance imaging.348 Any of these risk factors or diabetes mellitus may aid in the identification of high-risk patients who could benefit from an invasive strategy. Some patients with NSTE-ACS are not in the very high- risk group and do not have findings that portend a high risk for adverse outcomes. They are not likely to receive the same degree of benefit from routine revascularization afforded to high-risk patients, and an invasive study is optional for those at lower risk and can be safely deferred pending further clinical evidence. Decisions about coronary angiography in patients who are not at high risk according to findings on clinical examination and noninvasive testing can be individualized on the basis of patient preferences and/or symptoms. 4.5. Risk Stratification Before Discharge for Patients With an Ischemia-Guided Strategy of NSTE-ACS: Recommendations Class I 1. Noninvasive stress testing is recommended in low- and intermediate-risk patients who have been free of ischemia at rest or with low-level activity for a mini- (Level of Evidence: B) 2. Treadmill exercise testing is useful in patients able to exercise in whom the ECG is free of resting ST changes that may interfere with interpretation.349 352 (Level of Evidence: C) 3. Stress testing with an imaging modality should be used in patients who are able to exercise but have ST changes on resting ECG that may interfere with in- terpretation. In patients undergoing a low-level ex- ercise test, an imaging modality can add prognostic (Level of Evidence: B) 4. Pharmacological stress testing with imaging is rec- ommended when physical limitations preclude ad- equate exercise stress. (Level of Evidence: C) 5. A noninvasive imaging test is recommended to evalu- ate LV function in patients with definite ACS.349 352 (Level of Evidence: C) The management of patients with NSTE-ACS requires con- tinuous risk stratification. Important prognostic information is derived from initial assessment, the patient s course during the early days of management, and the response to anti-ischemic and antithrombotic therapy. The choice of stress test is based on the patient s resting ECG and ability to exercise, local expertise, and available technologies. The exercise intensity of the treadmill test (low level or symptom-limited) is used at the discretion of the attending clinician based on individ- ual patient assessment. For invasively managed patients with residual nonculprit lesions, additional evaluation may be indi- cated to ascertain the significance of such lesions. Refer to the PCI CPG for additional details.26 4.5.1. Noninvasive Test Selection The goals of noninvasive testing in patients with a low or intermediate likelihood of CAD and high-risk patients who did not have an early invasive strategy are to detect ischemia and estimate prognosis. This information guides further diag- nostic steps and therapeutic measures. Because of its simplicity, lower cost, and widespread famil- iarity with its performance and interpretation, the standard low- level exercise electrocardiographic stress test remains the most reasonable test in patients who are able to exercise and who have a resting ECG that is interpretable for ST shifts. There is evidence that imaging studies are superior to exercise elec- trocardiographic evaluation in women for diagnosis of CAD.350 However, for prognostic assessment in women, treadmill exer- cise testing has provided comparable results to stress imag- Patients with an electrocardiographic pattern that would interfere with interpretation of the ST segment (baseline ST abnormalities, bundle-branch block, LV hypertrophy with ST-T changes, intraventricular conduction defect, paced rhythm, pre-excitation, and digoxin) should have an exercise test with imaging. Patients who are unable to exercise should have a pharmacological stress test with imaging. Low- and intermedi- ate-risk patients with NSTE-ACS may undergo symptom-lim- ited stress testing, provided they have been asymptomatic and clinically stable at 12 to 24 hours for those with UA and 2 to 5 days for patients at similar risk with NSTEMI.349 The optimal testing strategy in women is less well defined than in men. 4.5.2. Selection for Coronary Angiography In contrast to noninvasive tests, coronary angiography provides detailed structural information for assessment of prognosis and appropriate management. When combined with LV angi- ography, it also provides an assessment of global and regional LV function. Coronary angiography is usually indicated in patients with NSTE-ACS who have recurrent symptoms or ischemia despite adequate medical therapy or who are at high risk as categorized by clinical findings (HF, serious ventricular arrhythmias), noninvasive test findings (significant LV dysfunc- tion with EF <0.40, large anterior or multiple perfusion defects or wall motion abnormalities on echocardiography, high-risk Duke treadmill score 11), high-risk TIMI or GRACE scores, or markedly elevated troponin levels. Patients with NSTE-ACS who have had previous PCI or CABG should also be considered for early coronary angiography, unless prior coronary angiog- raphy data indicate that no further revascularization is feasible. The general indications for coronary angiography and revascularization should be tempered by individual patient characteristics and preferences (a patient-centered approach). Patient and clinician judgments about risks and benefits are important for patients who might not be candidates for cor- onary revascularization, such as very frail older adults and those with serious comorbid conditions (eg, severe hepatic, pulmonary, or renal failure; active or inoperable cancer). See Online Data Supplement 20 for additional information on risk stratification. 5. Myocardial Revascularization Recommendations about coronary artery revascularization indications, benefits, and choice of revascularization proce- dure (PCI or CABG) for all anatomic subsets have been pub- lished in the 2011 PCI CPG,26 and the 2012 stable ischemic heart disease CPG and its 2014 focused The main difference between management of patients with stable ischemic heart disease and NSTE-ACS is a stronger impetus for revascularization in those with NSTE- ACS. Myocardial ischemia in ACS may progress to MI and is potentially life threatening. In addition, in patients with ACS, angina (including recurrent angina) is more likely to be reduced by revascularization than by medical therapy.26 A heart team approach to revascularization deci- sions, involving an interventional cardiologist and cardio- thoracic surgeon, is used in patients with unprotected left main or complex CAD. Calculation of SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) and STS scores is reasonable in these patients to guide the choice of revascularization.23,26,355 Factors that influence the choice of revascularization pro- cedure include the extent and complexity of CAD; short-term risk and long-term durability of PCI; operative mortality (which can be estimated by the STS score); diabetes mellitus; CKD; completeness of revascularization; LV systolic dys- function; previous CABG; and the ability of the patient to tol- erate and comply with DAPT. In general, the greater the extent and complexity of the multivessel disease, the more com- pelling the choice of CABG over multivessel PCI.23,26,356 358 In patients with NSTE-ACS, PCI of a culprit unprotected left main coronary artery lesion is an option if the patient is not a candidate for CABG.23,26 See Online Data Supplements 21 and 22 for additional information on myocardial revascularization. 5.1. Percutaneous Coronary Intervention 5.1.1. PCI General Considerations: Recommendation Class IIb 1. A strategy of multivessel PCI, in contrast to cul- prit lesion only PCI, may be reasonable in pa- tients undergoing coronary revascularization as part of treatment for NSTE-ACS.330,359 364 (Level of Evidence: B) Approximately half of all PCI procedures are performed in patients with UA or NSTEMI, and approximately 32% to 40% of patients with NSTE-ACS will undergo PCI.365 As discussed previously, in patients with NSTE-ACS, a strategy of early angiography and revascularization (primarily with PCI) results in lower rates of recurrent UA, recurrent reho- spitalization, MI, and death.366,367 Although PCI of a noncul- prit lesion is not advocated in patients with STEMI,26 there is less agreement on whether nonculprit lesions should undergo intervention at the time of culprit-lesion PCI for NSTE-ACS. but not all,330 comparing culprit lesion only PCI with multivessel PCI (eg, PCI of multiple vessels performed at the same time) in patients with NSTE-ACS did not find an increased risk of MACE with multivessel PCI and found a reduction in the need for repeat revascularization. However, the data consist predominantly of post hoc analysis of nonrandomized data with variable duration of follow-up. This question has not been resolved and is an area of current investigation. 5.1.2. PCI Antiplatelet and Anticoagulant Therapy 5.1.2.1. Oral and Intravenous Antiplatelet Agents: Recommendations Class I 1. Patients already taking daily aspirin before PCI should take 81 mg to 325 mg non enteric-coated as- pirin before PCI.26,368 370 (Level of Evidence: B) 2. Patients not on aspirin therapy should be given non enteric- coated aspirin 325 mg as soon as possible be- (Level of Evidence: B) 3. After PCI, aspirin should be continued indefinitely at a dose of 81 mg to 325 mg daily.27,288,371 (Level of Evidence: B) Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e373 4. A loading dose of a P2Y12 receptor inhibitor should be given before the procedure in patients undergoing PCI with stenting.26,293,302,331,372 375 (Level of Evidence:A) Options include: (Level of Evidence: B) or (Level of Evidence: B) or (Level of Evidence: B) 5. In patients with NSTE-ACS and high-risk features (eg, elevated troponin) not adequately pretreated with clopidogrel or ticagrelor, it is useful to adminis- ter a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-dose bolus tirofiban) at the time (Level of Evidence: A) 6. In patients receiving a stent (bare-metal stent or drug-eluting stent [DES]) during PCI for NSTE- inhibitor therapy should be given for at Options include: a. (Level of Evidence: B) or b. Prasugrel#: 10 mg daily302 (Level of Evidence: B) or c. Ticagrelor : 90 mg twice daily293 (Level of Evidence: B) Class IIa 1. It is reasonable to choose ticagrelor over clopido- grel for P2Y12 inhibition treatment in patients with NSTE-ACS treated with an early invasive strategy and/or coronary stenting.293,294 (Level of Evidence: B) 2. It is reasonable to choose prasugrel over clopidogrel treatment in patients with NSTE-ACS who undergo PCI who are not at high risk of bleeding (Level of Evidence: B) 3. In patients with NSTE-ACS and high-risk features (eg, elevated troponin) treated with UFH and ad- equately pretreated with clopidogrel, it is reasonable to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-bolus dose tirofi- ban) at the time of PCI.195,383,384 (Level of Evidence: B) 4. After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance dos- (Level of Evidence: B) 5. If the risk of morbidity from bleeding outweighs the anticipated benefit of a recommended duration of inhibitor therapy after stent implantation, ear- lier discontinuation (eg, <12 months) of P2Y12 inhibi- tor therapy is reasonable.330 (Level of Evidence: C) Class IIb 1. Continuation of DAPT beyond 12 months may be considered in patients undergoing stent implanta- tion. (Level of Evidence: C) Class III: Harm 1. Prasugrel should not be administered to patients with a prior history of stroke or transient ischemic (Level of Evidence: B) Comprehensive recommendations on the use of antiplatelet and anticoagulant therapy in patients with NSTE-ACS under- going PCI are given in the 2011 PCI CPG.26 Aspirin reduces the frequency of ischemic complications after PCI and is ideally administered at least 2 hours, and preferably 24 hours, before DAPT, consisting of aspirin and a P2Y12 inhibitor, in patients treated with coronary stents reduces the risk of stent thrombosis and composite ischemic events.296,331,372 375,389,390 Compared with a loading dose of 300 mg of clopidogrel, a load- ing dose of 600 mg of clopidogrel in patients undergoing PCI achieves greater platelet inhibition with fewer low responders and decreases the incidence of MACE.376 378 In patients with ACS who have undergone coronary stenting, treatment with prasugrel or ticagrelor, compared with treatment with clopi- dogrel, results in a greater reduction in composite ischemic events and the incidence of stent thrombosis, although at a risk of increased non CABG bleeding.293,302 The optimal dura- tion of DAPT therapy in patients treated with DES is not well However, aspirin is continued indefinitely in all patients managed with a bare-metal stent or DES, and DAPT is an option for >12 months in patients who have received a DES. This determination should balance the risks of stent thrombo- sis and ischemic complications versus bleeding and should be jointly made by the clinician and the patient. Loading and short-term maintenance doses of clopi- dogrel were studied in CURRENT OASIS (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Organization to Assess Strategies in Ischemic Syndromes) 7, which demonstrated a potential benefit of higher-dose clopidogrel (600-mg loading dose, 150 mg daily for 6 days, 75 mg daily thereafter) in patients with NSTE-ACS under- going an invasive management strategy.292,391 Although the failed to demonstrate a significant difference in the primary endpoint between the clopidogrel and aspirin groups (4.2% versus 4.4%), the PCI subset (n=17263) showed significant differences in the clopidogrel arm.391 Notably, the higher-dose clopidogrel therapy increased major bleeding in the entire group (2.5% versus 2.0%; P=0.012) and the PCI subgroup (1.1% versus 0.7%; P=0.008). In addition, during the period of several hours required for conversion of clopi- dogrel to its active metabolite, there is reduced effectiveness. However, efficacy is restored following conversion. Patients undergoing PCI who have previously received a loading dose of 300 mg of clopidogrel and are on a 75-mg daily maintenance dose should receive another 300-mg There are no data appropriate for prasugrel because this drug is administered before PCI. For ticagrelor, there are no data on additional loading. 5.1.2.2. GP IIb/IIIa Inhibitors: Recommendations Class I 1. In patients with NSTE-ACS and high-risk features (eg, elevated troponin) who are not adequately pretreated #Patients should receive a loading dose of prasugrel, provided that they were not pretreated with another P2Y12 receptor inhibitor. The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.290 with clopidogrel or ticagrelor, it is useful to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus ep- tifibatide, or high-dose bolus tirofiban) at the time of (Level of Evidence: A) Class IIa 1. In patients with NSTE-ACS and high-risk features (eg, elevated troponin) treated with UFH and ad- equately pretreated with clopidogrel, it is reasonable to administer a GP IIb/IIIa inhibitor (abciximab, double-bolus eptifibatide, or high-dose bolus tirofi- ban) at the time of PCI.195,383 (Level of Evidence: B) GP IIb/IIIa receptor antagonist therapy in patients with NSTE-ACS undergoing PCI reduced the incidence of com- posite ischemic events, primarily through a decrease in documented MI, although in some trials this is counter- balanced by an increased rate of bleeding.193,195,310,379 382,392 Most, but not all, randomized trials of the use of GP IIb/IIIa inhibitor were conducted in the era before clopidogrel Abciximab, double-bolus eptifiba- tide, and high-bolus dose tirofiban result in a high degree of platelet inhibition, reduce ischemic complications in patients undergoing PCI, and appear to afford comparable angio- graphic and clinical outcomes.26 As trials of the GP IIb/IIIa inhibitors generally excluded patients at high risk of bleed- ing, recommendations for the use of GP IIb/IIIa inhibitors are best understood as applying to patients not at high risk of bleeding complications. Although GP IIb/IIIa inhibitors were used in 27% and 55% of patients, respectively, in the PLATO (Platelet Inhibition and Patient Outcomes) and TRITON studies of ticagrelor and prasugrel, there are insufficient (and no RCT data) from which to make specific recommendations about GP IIb/IIIa inhibitor use in patients treated with either of these P2Y12 inhibitors. See Online Data Supplement 21 for additional information on GP IIb/IIIa inhibitors. 5.1.2.3. Anticoagulant Therapy in Patients Undergoing PCI: Recommendations Class I 1. An anticoagulant should be administered to patients with NSTE-ACS undergoing PCI to reduce the risk of intracoronary and catheter thrombus formation. (Level of Evidence: C) 2. Intravenous UFH is useful in patients with NSTE- ACS undergoing PCI. (Level of Evidence: C) 3. Bivalirudin is useful as an anticoagulant with or without prior treatment with UFH in patients with NSTE-ACS undergoing PCI.310,394 398 (Level of Evi- dence: B) 4. An additional dose of 0.3 mg/kg IV enoxaparin should be administered at the time of PCI to pa- tients with NSTE-ACS who have received fewer than 2 therapeutic subcutaneous doses (eg, 1 mg/kg SC) or received the last subcutaneous enoxaparin (Level of Evi- dence: B) 5. If PCI is performed while the patient is on fondaparinux, an additional 85 IU/kg of UFH should be given intravenously immediately before PCI be- cause of the risk of catheter thrombosis (60 IU/kg IV if a GP IIb/IIIa inhibitor used with UFH dosing based on the target-activated clotting time).26,313 315,404 (Level of Evidence: B) 6. In patients with NSTE-ACS, anticoagulant therapy should be discontinued after PCI unless there is a compelling reason to continue such therapy. (Level of Evidence: C) Class IIa 1. In patients with NSTE-ACS undergoing PCI who are at high risk of bleeding, it is reasonable to use bivali- rudin monotherapy in preference to the combination of UFH and a GP IIb/IIIa receptor antagonist.310,396 (Level of Evidence: B) Class IIb 1. Performance of PCI with enoxaparin may be reason- able in patients treated with upstream subcutaneous enoxaparin for NSTE-ACS.26,309,399 402,405,406 (Level of Evidence: B) Class III: Harm 1. Fondaparinux should not be used as the sole an- ticoagulant to support PCI in patients with NSTE- ACS due to an increased risk of catheter thrombo- (Level of Evidence: B) Anticoagulant therapy prevents thrombus formation at the site of arterial injury, on the coronary guide wire, and in the catheters used for PCI.26,407 With rare exceptions, all PCI studies have used some form of anticoagulant at the time Intravenous UFH and bivalirudin both have Class I recommendations in patients undergoing PCI in the 2011 Patients who have received multiple doses of subcutaneously-administered enoxaparin who undergo PCI within 8 hours of the last subcutaneous dose generally have received adequate anticoagulation to undergo PCI, but the degree of anticoagulation may diminish 8 to 12 hours after the last subcutaneous dose. In such patients, as well as in patients who have received fewer than 2 subcutaneous doses of enoxaparin, the addition of enoxaparin (0.3 mg/kg IV) at the time of PCI provides additional anticoagulation and has become standard practice.26,309,399 403 Patients who undergo PCI >12 hours after the last subcutaneous dose of enoxa- parin are usually treated with full-dose de novo anticoagu- lation with an established regimen (eg, full-dose UFH or bivalirudin). Fondaparinux as the sole anticoagulant during PCI has been associated with catheter thrombosis, and use of an anticoagulant with anti-IIa activity is recommended when patients treated with fondaparinux undergo PCI.313 315 One suggested regimen is UFH 85 IU/kg IV if no GP IIb/IIIa inhibitor is used and 60 IU/kg IV if a GP IIb/IIIa inhibitor is used with UFH dosing based on the target-activated clotting Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e375 5.2. Timing of Urgent CABG in Patients With NSTE-ACS in Relation to Use of Antiplatelet Agents: Recommendations Class I 1. Non enteric-coated aspirin (81 mg to 325 mg daily) should be administered preoperatively to patients (Level of Evidence: B) 2. In patients referred for elective CABG, clopidogrel and ticagrelor should be discontinued for at least (Level of Evidence: B) and prasugrel for at least 7 days before surgery.8,414 (Level of Evidence: C) 3. In patients referred for urgent CABG, clopidogrel and ticagrelor should be discontinued for at least 24 hours to reduce major bleeding.8,412,415 417 (Level of Evidence: B) 4. In patients referred for CABG, short-acting intrave- nous GP IIb/IIIa inhibitors (eptifibatide or tirofiban) should be discontinued for at least 2 to 4 hours before and abciximab for at least 12 hours be- fore to limit blood loss and transfusion.389 (Level of Evidence: B) Class IIb 1. In patients referred for urgent CABG, it may be reasonable to perform surgery less than 5 days after clopidogrel or ticagrelor has been discontinued and less than 7 days after prasugrel has been discontin- ued. (Level of Evidence: C) In-hospital CABG is performed in 7% to 13% of patients hospitalized with NSTE-ACS.420 422 Approximately one third of patients with NSTEMI undergo CABG within 48 hours of In these patients, CABG was performed at a median time of 73 hours after admission (interquartile In-hospital mortality in patients with NSTEMI undergoing CABG is approximately 3.7%.421 Recommendations for management of patients treated with oral and intravenous antiplatelet agents who undergo CABG are given in the 2011 CABG CPG.23 Preoperative aspirin reduces operative morbidity and mortality, and CABG can be performed safely in patients on aspirin therapy with only a modest increase in bleeding risk.23,408 410 The use of inhibitors in patients with NSTE-ACS is associated with an increase in post CABG bleeding and the need for Although it is recommended that clopidogrel and ticagrelor be discontinued at least 5 days before surgery and prasugrel at least 7 days before surgery in patients referred for elective CABG,23,411 413 the timing of CABG in patients with NSTE-ACS treated with a P2Y12 should reflect a balance of the potential increase in bleeding against the potential benefits of not delaying sur- gery 5 to 7 days. The risk of major bleeding complications is increased when CABG is performed <24 hours after dis- continuation of clopidogrel.23,416,417 In patients who undergo CABG 1 to 4 days after discontinuation of clopidogrel, it appears that the incidence of life-threatening bleeding is not significantly increased, but an increase in blood transfusions is In the TRITON-TIMI 38 trial,302 the inci- dence of CABG-related major bleeding was higher in patients treated with prasugrel than in patients treated with clopido- In the PLATO trial, the rates of major bleeding and transfusion requirements were similar between patients treated with ticagrelor and patients treated with clopidogrel.294 The more rapid recovery of platelet function in pharmacokinetic Table 9. Dosing of Parenteral Anticoagulants During PCI Drug* In Patients Who Have Received Prior Anticoagulant Therapy In Patients Who Have Not Received Prior Anticoagulant Therapy Enoxaparin For prior treatment with enoxaparin, if last SC dose was administered 8 12 h earlier or if <2 therapeutic SC doses of enoxaparin have been administered, an IV dose of enoxaparin 0.3 mg/kg should be given 0.5 mg/kg-0.75 mg/kg IV loading dose If the last SC dose was administered within prior 8 h, no additional enoxaparin should be given Bivalirudin For patients who have received UFH, wait 30 min, then give 0.75 mg/kg IV loading dose, then 1.75 mg/kg/h IV infusion 0.75 mg/kg loading dose, 1.75 mg/kg/h IV infusion For patients already receiving bivalirudin infusion, give additional loading dose 0.5 mg/kg and increase infusion to 1.75 mg/kg/h during PCI Fondaparinux For prior treatment with fondaparinux, administer additional IV treatment with anticoagulant possessing anti-IIa activity, considering whether GPI receptor antagonists have been administered N/A UFH IV GPI planned: additional UFH as needed (eg, 2000 5000 U) to achieve ACT of 200 250 s IV GPI planned: 50 70 U/kg loading dose to achieve ACT of No IV GPI planned: additional UFH as needed (eg, 2000 5000 U) to achieve ACT of 250 300 s for HemoTec, 300 350 s for Hemochron No IV GPI planned: 70 100 U/kg loading dose to achieve target ACT of 250 300 s for HemoTec, 300 350 s for Hemochron *Drugs presented in order of the COR and then the LOE as noted in the Preamble. When more than 1 drug exists within the same LOE, and there are no comparative data, then the drugs are listed alphabetically. ACT indicates activated clotting time; COR, Class of Recommendation; GPI, glycoprotein IIb/IIIa inhibitor; IV, intravenous; LOE, Level of Evidence; N/A, not applicable; PCI, percutaneous coronary intervention; SC, subcutaneous; and UFH, unfractionated heparin. Modified from Levine et al.26 studies of ticagrelor did not translate to a lower risk of bleed- ing or lessen the need for transfusion compared with clopido- grel when CABG was performed early (ie, <5 days) after drug See Online Data Supplements 21 and 22 for more informa- tion on myocardial revascularization. 6. Late Hospital Care, Hospital Discharge, And Posthospital Discharge Care 6.1. General Principles (Cardioprotective Therapy and Symptom Management) The goals of therapy after NSTE-ACS are to restore the patient to normal activities to the extent possible and to use the acute event to re-evaluate the plan of care, particularly lifestyle and risk factor modification. Aggressive risk factor modifications that can prolong survival should be the main goal of long-term management of patients with stable CAD. Patients presenting with NSTE-ACS represent a high-risk cohort in whom sec- ondary cardiovascular disease prevention is likely to be par- ticularly effective (Table 10). Clinicians have an opportunity to provide evidence-based care to this high-risk cohort and to aggressively treat the underlying atherosclerotic process through lifestyle modification and effective pharmacological In most cases, the inpatient anti-ischemic medi- cal regimen should be continued after discharge, and the anti- platelet/anticoagulant medications should be changed to an outpatient regimen. The goals for continued medical therapy after discharge relate to potential prognostic benefits (primar- ily shown for antiplatelet agents, beta blockers, statins, and inhibitors of the renin-angiotensin aldosterone system, espe- cially for LVEF <0.40).Added benefits are control of ischemic symptoms (nitrates, beta blockers, CCBs, and ranolazine) and treatment of major risk factors such as smoking, hypertension, dyslipidemia, physical inactivity, obesity, and diabetes mel- Selection of a medical regimen should be individual- ized to each patient on the basis of in-hospital findings, risk factors for CAD, drug tolerability, and recent procedural inter- ventions. The mnemonic ABCDE (Aspirin, Antianginals, and ACE Inhibitors; Beta Blockers and BP; Cholesterol and Cigarettes; Diet and Diabetes Mellitus; Education and Exercise) is useful in guiding treatment.428 6.2. Medical Regimen and Use of Medications at Discharge: Recommendations Class I 1. Medications required in the hospital to control isch- emia should be continued after hospital discharge in patients with NSTE-ACS who do not undergo coro- nary revascularization, patients with incomplete or unsuccessful revascularization, and patients with re- current symptoms after revascularization. Titration of the doses may be required.427,428 (Level of Evidence: C) 2. All patients who are post NSTE-ACS should be giv- en sublingual or spray nitroglycerin with verbal and written instructions for its use.429 (Level of Evidence: C) 3. Before hospital discharge, patients with NSTE-ACS should be informed about symptoms of worsening myocardial ischemia and MI and should be given verbal and written instructions about how and when to seek emergency care for such symptoms.429 (Level of Evidence: C) 4. Before hospital discharge, patients who are post NSTE-ACS and/or designated responsible caregiv- ers should be provided with easily understood and culturally sensitive verbal and written instructions about medication type, purpose, dose, frequency, side effects, and duration of use.429 (Level of Evidence: C) 5. For patients who are post NSTE-ACS and have ini- tial angina lasting more than 1 minute, nitroglycerin (1 dose sublingual or spray) is recommended if an- gina does not subside within 3 to 5 minutes; call 9-1-1 immediately to access emergency medical services.429 (Level of Evidence: C) 6. If the pattern or severity of angina changes, suggest- ing worsening myocardial ischemia (eg, pain is more frequent or severe or is precipitated by less effort or occurs at rest), patients should contact their clinician without delay to assess the need for additional treat- ment or testing.429 (Level of Evidence: C) 7. Before discharge, patients should be educated about modification of cardiovascular risk factors.428 (Level of Evidence: C) 6.2.1. Late Hospital and Posthospital Oral Antiplatelet Therapy: Recommendations Class I 1. Aspirin should be continued indefinitely. The mainte- nance dose should be 81 mg daily in patients treated with ticagrelor and 81 mg to 325 mg daily in all other (Level of Evidence: A) 2. In addition to aspirin, a P2Y12 inhibitor (either clopi- dogrel or ticagrelor) should be continued for up to 12 months in all patients with NSTE-ACS without contraindications who are treated with an ischemia- guided strategy. Options include: Clopidogrel: 75 mg daily289,296 (Level of Evidence: B) or Ticagrelor : 90 mg twice daily293,294 (Level of Evidence: B) 3. In patients receiving a stent (bare-metal stent or DES) during PCI for NSTE-ACS, P2Y12 inhibitor therapy should be given for at least 12 months.330 Options include: Clopidogrel: 75 mg daily296,331 (Level of Evidence: B) or Prasugrel#: 10 mg daily302 (Level of Evidence: B) or Ticagrelor : 90 mg twice daily293 (Level of Evi dence: B) Class IIa 1. It is reasonable to use an aspirin maintenance dose of 81 mg per day in preference to higher maintenance The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.290 #Patients should receive a loading dose of prasugrel, provided they were not pretreated with another P2Y12 receptor inhibitor. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e377 Table 10. Plan of Care for Patients With NSTE-ACS Plan of Care Resources/References Medications Antithrombotic therapies Sections 6.2.1 and 6.2.2 Beta blockers Section 4.1.2.3 ACE inhibitors/ARBs/aldosterone antagonists Section 4.2 CCBs Section 4.1.2.4 Statins 2013 Blood cholesterol CPG18 Discontinuation of antithrombotic therapies for elective surgical and medical procedures with increased risk of bleeding 2014 SIHD focused update10 2012 Management of AMI in patients with persistent STEMI CPG19 2011 Secondary prevention CPG27 2007 Science Advisory on the prevention of premature discontinuation of DAPT in patients with coronary artery stents504 Inappropriate use of analgesics (NSAIDs) 2010 Expert consensus document on PPIs and thienopyridines430 Use of PPIs 2011 PCI CPG26 Risk factor modification/lifestyle interventions and physical activity/cardiac rehabilitation Smoking cessation Tobacco cessation toolkit505 Diet nutrition 2013 Lifestyle CPG15 Physical activity 2013 Lifestyle CPG15 2011 Secondary prevention CPG27 Cardiorespiratory fitness (MET capacity) 2011 Secondary prevention CPG27 2010 Performance measures on cardiac rehabilitation454 2012 Scientific statement on sexual activity and cardiovascular disease231 Management of comorbidities Overweight/obesity 2013 Obesity CPG16 2011 Secondary prevention CPG27 Statins 2013 Lifestyle CPG15 2013 Blood cholesterol CPG18 Hypertension 2014 Report on high BP501 2013 Science advisory on high BP control506 Diabetes mellitus 2013 Position statement on standards of medical care in diabetes507 HF 2013 HF CPG14 Arrhythmia/Arrhythmia risk 2012 Focused update incorporated into the 2008 DBT CPG20 Psychosocial factors Sexual activity 2012 Scientific statement on sexual activity and cardiovascular disease231 2013 Consensus document on sexual counseling for individuals with cardiovascular disease and their partners508 Gender-Specific issues 2007 Cardiovascular disease prevention in women CPG475 Depression, stress, and anxiety 2008 Science advisory on depression and coronary heart disease509 Alcohol use 2011 Secondary prevention CPG27 Culturally sensitive issues 2009 Consensus report on a comprehensive framework and preferred practices for measuring and reporting cultural competency510 Return to work schedule Clinician follow-up Cardiologist 2011 Secondary prevention CPG27 2013 Hospital to Home Quality Initiative511 Primary care clinician Advanced practice nurse/physician assistant Pharmacists 2013 Discharge counseling for patients with HF or MI512 Other relevant medical specialists Electronic personal health records Influenza vaccination 2005 Recommendations for prevention and control of influenza37 (Continued) doses in patients with NSTE-ACS treated either inva- sively or with coronary stent implantation.26,331,368,385 388 (Level of Evidence: B) 2. It is reasonable to use ticagrelor in preference to clop- idogrel for maintenance P2Y12 treatment in patients with NSTE-ACS who undergo an early invasive or (Level of Evidence: B) 3. It is reasonable to choose prasugrel over clopidogrel for maintenance P2Y12 treatment in patients with NSTE-ACS who undergo PCI who are not at high risk for bleeding complications.302,303 (Level of Evidence: B) 4. If the risk of morbidity from bleeding outweighs the anticipated benefit of a recommended duration of inhibitor therapy after stent implantation, ear- lier discontinuation (eg, <12 months) of P2Y12 inhibi- tor therapy is reasonable.330 (Level of Evidence: C) Class IIb 1. Continuation of DAPT beyond 12 months may be considered in patients undergoing stent implanta- tion. (Level of Evidence: C) 6.2.2. Combined Oral Anticoagulant Therapy and Antiplatelet Therapy in Patients With NSTE-ACS Class I 1. The duration of triple antithrombotic therapy with a vitamin K antagonist, aspirin, and a P2Y12 recep- tor inhibitor in patients with NSTE-ACS should be minimized to the extent possible to limit the risk of bleeding. (Level of Evidence: C) 2. Proton pump inhibitors should be prescribed in pa- tients with NSTE-ACS with a history of gastroin- testinal bleeding who require triple antithrombotic therapy with a vitamin K antagonist, aspirin, and a (Level of Evidence: C) Class IIa 1. Proton pump inhibitor use is reasonable in patients with NSTE-ACS without a known history of gastro- intestinal bleeding who require triple antithrombotic therapy with a vitamin K antagonist, aspirin, and a (Level of Evidence: C) Class IIb 1. Targeting oral anticoagulant therapy to a lower in- ternational normalized ratio (INR) (eg, 2.0 to 2.5) may be reasonable in patients with NSTE-ACS man- aged with aspirin and a P2Y12 inhibitor. (Level of Evidence: C) The combination of oral antiplatelet therapy and oral anti- coagulant therapy significantly increases the risk of bleed- ing. This risk varies widely, but on average, the addition of a single antiplatelet agent increased the risk of bleeding from a range of 2% to 3% to a range of 4% to 6%, whereas the addi- tion of DAPT to oral anticoagulant therapy ( triple therapy ) increased the risk of bleeding from a range of 4% to 6% to a range of 10% to 14%.432 435 This risk was also related to the duration of triple therapy. In patients with NSTE-ACS in whom there are indica- tions for triple therapy, the benefit of such therapy in terms of prevention of stent thrombosis, thromboembolic events, and recurrent MI must be weighed against the risk of bleeding complications. Similarly, DAPT, in addition to anticoagulant Patient/family education Plan of care for AMI 2010 CPG for cardiopulmonary resuscitation and emergency cardiovascular care part 9: postcardiac arrest care31 Recognizing symptoms of MI Activating EMS, signs and symptoms for urgent vs. emergency evaluations CPR training for family members Risk assessment and prognosis Advanced directives Social networks/social isolation Socioeconomic factors Access to health insurance coverage Access to clinicians Effective communication and care coordination513 Disability Cardiovascular disability: updating Social Security listings514 Social services Community services ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; CPG, clinical practice guideline; CPR, cardiopulmonary resuscitation; DAPT, dual antiplatelet therapy; DBT, device-based therapy; ECC, emergency cardiovascular care; EMS, emergency medical services; HF, heart failure; MET, metabolic equivalent; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory drug; NSTE-ACS, non T-elevation acute coronary syndromes; PCI, percutaneous coronary intervention; PPI, protein pump inhibitor; SIHD, stable ischemic heart disease; and STEMI, ST-elevation myocardial infarction. Table 10. Continued Plan of Care Resources/References Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e379 therapy, requires consideration of the increased risk of bleed- ing. It is essential that therapeutic decision making in this crit- ical area include discussion with the patient about the options, advantages, and limitations of available approaches. Recommendations about the management of patients treated with triple therapy have been published in ACC/AHA CPGs and by other organizations.17,26,430,433,436 Although some organi- zations have recommended a target INR of 2.0 to 2.5 in patients with atrial fibrillation (AF) who require triple therapy,437 others continue to recommend a target INR of 2.0 to 3.0.12,436 The HAS- BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/ Alcohol Concomitantly) score has relevance in these delibera- No prospective study to date has demonstrated that a target INR of 2.0 to 2.5 reduces bleeding complications. Whenever possible, shorter durations of triple therapy are favored in preference to longer durations of triple therapy. In patients with NSTE-ACS who require oral anticoagulation for AF, mechanical heart valve, deep venous thrombosis, or other conditions, a bare-metal stent may offer the advantages of lower bleeding risk over a DES because of the potentially shorter dura- tion of triple antithrombotic therapy. The WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) trial is the first published study to address the question of optimal antiplate- let therapy in patients taking oral anticoagulant medication.440 WOEST was a randomized, open-label trial of 563 patients (approximately 25% of whom had NSTE-ACS) receiving oral anticoagulant therapy and undergoing coronary stenting. Patients randomized to single antiplatelet treatment with clopidogrel had significantly fewer bleeding complications and no increase in thrombotic events compared with those randomized to DAPT with aspirin and clopidogrel. Larger clinical trials are needed to compare double versus triple therapy in the setting of coronary stenting and NSTE-ACS. One such study that has been initiated is PIONEERAF-PCI (an Open-Label, Randomized, Controlled, Multicenter Study Exploring two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects With Atrial Fibrillation who Undergo Percutaneous Coronary Intervention). Although there are some data on therapy with aspirin, clop- idogrel, and warfarin, there is sparse information on the use of inhibitors (prasugrel, ticagrelor), direct thrombin inhibitor (dabigatran), or factor-Xa inhibitors (rivaroxaban, apixaban) in patients receiving triple therapy. Prasugrel302 produce a greater degree of platelet inhibi- tion than clopidogrel and are associated with greater rates of These are important potential disadvan- tages in patients requiring triple therapy, a group in which the inherent risks of bleeding are significantly increased. (Overall bleeding risk was not increased with ticagrelor, although there was increased bleeding in certain subgroups on this drug).412 Because there are no well-established therapies to reverse the anticoagulant effects of the newer oral antiplatelet agents, caution is required when considering the use of these agents in patients who require triple therapy and are at significantly increased risk of bleeding. This admonition is especially important in elderly patients, a group in which bleeding risk is inherently increased (Section 7.1). Proton pump inhibitors decrease the risk of gastrointesti- nal bleeding in patients treated with DAPT431 and are used in patients treated with DAPT who have a history of gastrointes- tinal bleeding and those at increased risk of bleeding, which is associated with oral anticoagulation therapy even if there is no history of gastrointestinal bleeding.430 On the basis of these results, proton pump inhibitors are also used in patients receiving triple antithrombotic therapy who have a history of gastrointestinal bleeding. Although the clinical evidence that omeprazole and esomeprazole diminish the antiplate- let efficacy of clopidogrel is weak,430 the US Food and Drug Administration has issued a warning to avoid concomitant use of these 2 proton pump inhibitors with clopidogrel.442 6.2.3. 