The ACUITY trial in ACS (13819 patients, 3852 with diabe- tes mellitus) reported that 30-day adverse clinical outcomes (death, MI, or unplanned revascularization) or major bleeding were increased in patients with diabetes mellitus (12.9% ver- Bivalirudin plus a GP IIb/IIIa inhibitor resulted in increased similar rates of the composite ischemia compared with heparin plus a GP IIb/IIIa inhibitor. Bivalirudin alone was associated with a similar increased rate of composite ischemia but less major bleeding (3.7% versus 7.1%; P<0.001). Several studies evaluated the benefit of oral antiplatelet ther- apy duringACS in patients with diabetes mellitus. In TRITON- TIMI 38, patients with diabetes mellitus had a greater reduction in ischemic events without an observed increase in TIMI major bleeding with prasugrel compared with clopidogrel.618 In PLATO, ticagrelor compared with clopidogrel reduced isch- emic events irrespective of diabetic status and glycemic con- trol, without an increase in major bleeding.619 See Online Data Supplement 27 for additional information on diabetes mellitus. 7.4. Post CABG: Recommendation Class I 1. Patients with prior CABG and NSTE-ACS should receive antiplatelet and anticoagulant therapy ac- cording to GDMT and should be strongly considered for early invasive strategy because of their increased (Level of Evidence: B) Although CABG reduces morbidity and mortality in selected patients with complex CAD, they remain at risk for develop- ment of disease progression of ungrafted native vessels or significant atherothrombotic disease in saphenous vein grafts and subsequent ACS. These patients constitute a higher-risk groupbecausetheyhavealreadyundergoneCABG,typicallyfor more extensive CAD, and they have more comorbidities.620 624 In the PURSUIT trial, 12%1,134 of the patients had prior CABG and more adverse follow-up outcomes, including increased mortality, but had a benefit with eptifibatide similar to those without prior CABG.622 Patients with prior CABG are less likely to undergo early catheterization after NSTEMI.


These patients constitute a higher-risk groupbecausetheyhavealreadyundergoneCABG,typicallyfor more extensive CAD, and they have more comorbidities.620 624 In the PURSUIT trial, 12%1,134 of the patients had prior CABG and more adverse follow-up outcomes, including increased mortality, but had a benefit with eptifibatide similar to those without prior CABG.622 Patients with prior CABG are less likely to undergo early catheterization after NSTEMI. In the Get With The Guidelines study of patients with NSTEMI, 18.5% had prior CABG and a lower likelihood of early inva- sive evaluation but had higher rates of guideline-recommended clopidogrel and bivalirudin therapy and lower rates of GP IIb/ IIIa and anticoagulant therapy.625 In patients with prior CABG who develop NSTE-ACS that is related to an ungrafted native coronary vessel, treatment should follow GDMT.26 Because patients with prior CABG presenting with ACS are a high-risk group with increased comorbid characteris- tics and high-risk anatomy, a strategy of early angiography should be implemented (unless clinically contraindicated), and these patients should receive optimal antiplatelet and anticoagulant therapy. See Online Data Supplement 28 for additional information on post-CABG. 7.5. Perioperative NSTE-ACS Related to Noncardiac Surgery: Recommendations Class I 1. Patients who develop NSTE-ACS following noncar- diac surgery should receive GDMT as recommended for patients in the general population but with the modifications imposed by the specific noncardiac surgical procedure and the severity of the NSTE- (Level of Evidence: C) 2.


Patients who develop NSTE-ACS following noncar- diac surgery should receive GDMT as recommended for patients in the general population but with the modifications imposed by the specific noncardiac surgical procedure and the severity of the NSTE- (Level of Evidence: C) 2. In patients who develop NSTE-ACS after noncardiac surgery, management should be directed at the un- (Level of Evidence: C) Patients with NSTE-ACS following noncardiac surgery should be managed according to the guidelines for patients in the gen- eral population, with risk stratification and guideline-based phar- macological and invasive management directed at the etiology (eg, hypertension, tachycardia, HF, hypotension, sepsis, and ane- mia) with modifications based on the severity of NSTE-ACS and the limitations imposed by the noncardiac surgical procedure. The definition of ACS has a substantial effect on reported Some patients may not be able to give a history of ischemic symptoms because of the noncardiac sur- gery. The criteria in the 2012 Third Universal Definition of MI should be applied.21 In patients at risk of ACS following non- cardiac surgery, routine monitoring of troponins and ECGs may be performed. As the sensitivity of troponin assays improves, the frequency of identifying perioperative MI will increase. In the POISE (Perioperative Ischemic Study Evaluation) trial,645 of 8351 patients randomized to extended-release metoprolol versus placebo, 5.7% of patients in the control group had a perioperative MI typically occurring within 48 hours and often not associated with ischemic symptoms. ACS in the setting of noncardiac surgery is associated with increased mortality.


ACS in the setting of noncardiac surgery is associated with increased mortality. Several risk scores have been developed to determine the probability of mortality.646 648 A meta-analysis of the prognostic value of troponin and CK-MB after noncar- diac surgery that included 14 studies enrolling 3318 patients demonstrated that elevated troponin after surgery was an independent predictor of mortality both in the hospital and at Markedly elevated troponins are associ- ated with increased mortality compared with minimal troponin elevation, even though the latter still indicates a postoperative In patients with UA in whom the risks of bleed- ing with antiplatelet therapy outweigh the benefits, GDMT with beta blockers, nitrates, and ACE inhibitors should be optimized to achieve symptom control. In patients with a rela- tive or absolute contraindication to antiplatelet or anticoagu- lant therapy, coronary angiography may be helpful to identify anatomy requiring revascularization after recovery from the noncardiac surgery. 7.6. CKD: Recommendations Class I 1. CrCl should be estimated in patients with NSTE- ACS, and doses of renally cleared medications should be adjusted according to the pharmacokinetic data for specific medications.649,650 (Level of Evidence: B) 2. Patients undergoing coronary and LV angiogra- phy should receive adequate hydration. (Level of Evidence: C) Class IIa 1. An invasive strategy is reasonable in patients with mild (stage 2) and moderate (stage 3) CKD.649 652 (Level of Evidence: B) CKD is a major risk factor for poor outcomes in patients with Patients with impaired renal function have additional adverse baseline characteristics, including older age, a history of prior HF, and peripheral arterial disease. It is prudent to omit LV angiography in patients with CKD and assess LV function with echocardiography.


It is prudent to omit LV angiography in patients with CKD and assess LV function with echocardiography. In an analysis from 3 ACS trial databases of 19304 patients with NSTEMI, 42% (8152 patients) had abnormal renal func- tion on the basis of serum creatinine and calculated CrCl; total mortality and mortality/MI were increased at 30 days and 180 days. CrCl was independently associated with mortality (HR: 0.81) and the risk of mortality/MI (HR: 0.93).656 The VALIANT (Valsartan in Acute Myocardial Infarction) trial included 14527 high-risk patients with AMI with LV dysfunc- tion or HF and a serum creatinine level 1.5 mg/dL.658,659 The Modification of Diet in Renal Disease equation was used, and patients were analyzed based on their estimated GFR. There was an increasing adjusted HR for both death and the compos- ite endpoint of cardiovascular death, reinfarction, HF, stroke, or resuscitation after cardiac arrest with decreasing estimated GFR. For death, with a GFR <45.0 mL per minute/1.73 m2 , the adjusted HR was 1.70 compared with patients with a GFR in whom the adjusted HR was 1.14. There are insufficient data on the benefit-to-risk ratio of an invasive strategy in patients with NSTE-ACS and advanced CKD (stages 4 and 5).652 There is also less evidence-based medical therapy and revasculariza- tion data in patients with CKD because of the risk for con- trast-induced nephropathy, increased need for dialysis, and increased mortality. Multiple studies have evaluated radio- graphic agents, including ionic versus nonionic media and isosmolar or low-osmolar agents. The strength and consistency of relationships between spe- cific isosmolar or low-osmolar agents and contrast-induced nephropathy or renal failure are insufficient for selection of low-osmolar and isosmolar media.


The strength and consistency of relationships between spe- cific isosmolar or low-osmolar agents and contrast-induced nephropathy or renal failure are insufficient for selection of low-osmolar and isosmolar media. Limitation of the risk of contrast-induced nephropathy is based on reduced contrast and adequate hydration.661 A recent meta-analysis of 5 RCTs evaluated 1453 patients with NSTE-ACS and CKD, all with GFR <60 mL per min- Patients were analyzed according to baseline renal function: stage 3a, 3b, and 4 to 5. An invasive strategy was associated with a nonsignificant reduction in all-cause mortality and the composite of death or nonfatal MI. An early invasive strategy in patients with CKD and ACS reduced rehospitalization and resulted in a trend toward lower mortal- ity and nonfatal reinfarction. The increased risk of mortality associated with mild, moderate, and severe CKD is evident across studies, and risks are increased as the gradient of renal See Online Data Supplement 29 for additional information on CKD. 7.6.1. Antiplatelet Therapy Patients with CKD with ACS are at increased risk for isch- emic complications, including stent thrombosis and post PCI ischemic events.663 They are also predisposed to higher bleeding complications, which, in addition to the lack of clinical trial data, result in their undertreatment with anti- platelet therapy. Patients with advanced CKD exhibit high residual platelet reactivity despite treatment with clopi- dogrel independent of the presence of diabetes mellitus.664 Hyporesponsiveness to thienopyridines is associated with increased adverse cardiovascular outcomes, including car- and higher dosing regimens of clopidogrel do not appear to further suppress adenosine diphosphate-induced platelet aggregation.664,666 Although prasugrel may be more efficient than doubling the dose of clopidogrel in achieving adequate platelet inhi- no clinical studies have demonstrated its efficacy in patients with CKD with ACS.


Patients with advanced CKD exhibit high residual platelet reactivity despite treatment with clopi- dogrel independent of the presence of diabetes mellitus.664 Hyporesponsiveness to thienopyridines is associated with increased adverse cardiovascular outcomes, including car- and higher dosing regimens of clopidogrel do not appear to further suppress adenosine diphosphate-induced platelet aggregation.664,666 Although prasugrel may be more efficient than doubling the dose of clopidogrel in achieving adequate platelet inhi- no clinical studies have demonstrated its efficacy in patients with CKD with ACS. Ticagrelor, however, was studied in a prespecified analysis from the PLATO trial.668 In patients with an estimated GFR <60 mL per minute (nearly 21% of patients in PLATO with available central laboratory serum creatinine levels), ticagrelor significantly reduced the primary cardiovascular endpoint (17.3% versus 22.0%; HR: 0.77; 95% CI: 0.65 to 0.90) compared with clopido- Notably, this was associated with a 4% absolute risk reduction in all-cause mortality favoring ticagrelor and with no differences in major bleeding, fatal bleeding, and non CABG-related major bleeding events, demonstrating its util- ity in patients with renal insufficiency. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e389 7.7. Women: Recommendations Class I 1. Women with NSTE-ACS should be managed with the same pharmacological therapy as that for men for acute care and for secondary prevention, with atten- tion to weight and/or renally calculated doses of anti- platelet and anticoagulant agents to reduce bleeding (Level of Evidence: B) 2. Women with NSTE-ACS and high-risk features (eg, troponin positive) should undergo an early invasive (Level of Evidence: A) Class IIa 1. Myocardial revascularization is reasonable in preg- nant women with NSTE-ACS if an ischemia-guided strategy is ineffective for management of life- (Level of Evidence: C) Class III: No Benefit 1.


Myocardial revascularization is reasonable in preg- nant women with NSTE-ACS if an ischemia-guided strategy is ineffective for management of life- (Level of Evidence: C) Class III: No Benefit 1. Women with NSTE-ACS and low-risk features (see Section 3.3.1) should not undergo early invasive treatment because of the lack of benefit141,345,346 and the possibility of harm.141 (Level of Evidence: B) Women of all ages have higher rates of in-hospital and long- term complications of NSTE-ACS than men, including bleed- ing, HF, cardiogenic shock, acute renal failure, recurrent MI, stroke, and readmissions.670,675,676 Women present later after symptom onset of NSTE-ACS and have higher rates of inappropriate discharges from the Women more commonly report atypical symp- toms than men.675,679 Women presenting with chest pain are more likely than men to have either a noncardiac cause or cardiac causes other than obstructive epicardial coronary dis- Women with NSTE-ACS with no apparent obstructive epicardial disease have a 2% risk of death or MI within 30 days and require secondary prevention and symp- Women derive the same treatment benefit as men from aspi- rin, clopidogrel, anticoagulants, beta blockers, ACE inhibi- tors, and statins.385,670 672,675,676,683,684 Despite worse outcomes, women with NSTE-ACS are underprescribed guideline- directed pharmacological therapy, both during the acute ill- ness and at discharge.538,685,686 The basis for pharmacotherapy for women with NSTE-ACS with abnormal biomarkers and/ or functional tests, but without significant obstructive epicar- dial disease, remains unclear (Section 7.13). In addition to risk factor modification, some studies support the benefit of imipramine, ranolazine, beta blockers, and/or ACE inhibitors to reduce adverse outcomes.687 Women with NSTE-ACS incur a higher rate of bleeding complications672,673 (Section 7.8) and renal failure.


In addition to risk factor modification, some studies support the benefit of imipramine, ranolazine, beta blockers, and/or ACE inhibitors to reduce adverse outcomes.687 Women with NSTE-ACS incur a higher rate of bleeding complications672,673 (Section 7.8) and renal failure. A risk score has been developed to attempt to reduce the bleeding risk in women with NSTE-ACS.688 The decision for an early invasive versus an ischemia-guided strategy in women with NSTE-ACS is based on a meta-analysis366 and post hoc gender analyses of clinical trials, including FRISC II, RITA-3, and TACTICS-TIMI 18.344,346,689 The Agency for Healthcare Research and Quality analysis of an early invasive versus ischemia-guided strategy345 provides further evidence that an early invasive strategy should be reserved for women with positive troponins, as shown in TACTICS-TIMI 18.346 Such women had a significant reduction of death and MI at 1 year with an early invasive versus ischemia-guided strategy. Women with NSTE-ACS and no elevation in troponin who underwent an early invasive strategy had a nonsignificant increase in events, as did women with a low-risk TIMI score (OR: 1.59 for early invasive versus ischemia-guided strategy), prompting the Class III recommendation in this CPG. The NCDR-ACTION registry reported increased com- plication rates of myocardial revascularization in women (https://www.ncdr.com/webncdr/action/). Women also have higher rates of contrast-induced nephropathy and vascular Despite having fewer high-risk angio- graphic lesions, a higher percentage of normal LV function, and up to 25% angiographically normal coronary arteries, women with NSTE-ACS have a paradoxically higher rate of persistent angina, reinfarction, functional decline, and depression after PCI.141,675,677,680,682 and a of DES for NSTE-ACS reported no gender differences in short- and long-term (up to 5 years) outcome, including target vessel revascularization, MACE, cardiac death, or MI. However, women were older and had more comorbidities than men at enrollment.


However, women were older and had more comorbidities than men at enrollment. Women with NSTE-ACS referred for CABG are older with more comorbidities, which is reflected by higher periproce- dural mortality, HF, bleeding, MI, and renal failure.686,695,696 Women required more periprocedural IABP, vasopressors, mechanical ventilation, dialysis, and blood products and had longer stays in the intensive care unit and hospital, higher rates of wound infection, depression, and longer recovery.549,677 An Agency for Healthcare Research and Quality metaanal- ysis of 10 RCTs through December 2011 reported no efficacy or safety difference between PCI and CABG for NSTE-ACS in men or women in 30-day or 1-year MACE (death/MI/stroke). At 2 years, the procedural success remained equal in women but favored CABG in men (P=0.002).345,564 The Agency for Healthcare Research and Quality reported similar outcomes in women with diabetes mellitus with PCI and CABG for NSTE-ACS at 7 years, but men with diabetes mellitus had fewer events with CABG. A prespecified gender analysis of the FREEDOM trial favored CABG over PCI for women with diabetes mellitus, although the difference was not as signifi- cant as it was for men.616 Consistent with the European Society of Cardiology recom- mendations, myocardial revascularization should be reserved for pregnant women with NSTE-ACS and very serious com- plications unresponsive to medical therapy.674 See Online Data Supplement 30 for more information on women. 7.8. Anemia, Bleeding, and Transfusion: Recommendations Class I 1. All patients with NSTE-ACS should be evaluated for the risk of bleeding. (Level of Evidence: C) 2. Anticoagulant and antiplatelet therapy should be weight-based where appropriate and should be ad- justed when necessary for CKD to decrease the risk of bleeding in patients with NSTE-ACS.522,697,698 (Level of Evidence: B) Class III: No Benefit 1.


Anticoagulant and antiplatelet therapy should be weight-based where appropriate and should be ad- justed when necessary for CKD to decrease the risk of bleeding in patients with NSTE-ACS.522,697,698 (Level of Evidence: B) Class III: No Benefit 1. A strategy of routine blood transfusion in hemody- namically stable patients with NSTE-ACS and hemo- globin levels greater than 8 g/dL is not recommend- (Level of Evidence: B) Anemia in patients with ACS is associated with an increased risk for Holter monitor detected recurrent ischemia and for MACE, with greater anemia correlating with greater risk.704 708 In 1 large analysisofmultiplestudies,theriskofadverseoutcomewashigher in patients with NSTE-ACS with hemoglobin levels <11 g/dL.704 The potentially detrimental effects of severe anemia include decreased myocardial oxygen delivery and increased MVO2 related to maintenance of a higher cardiac output.704,709,710 Patients with anemia are less likely to be treated with aspirin, and patients with ACS and anemia are likely to have more bleeding complica- tions with PCI.711 This has been correlated with increased short- term risk of MACE outcomes, including mortality; long-term risk The ACUITY study suggests that the risk of mortality associated with bleeding is at least as great as that associated with procedure-related or spontaneous MI.718 Major bleeding is a coprimary endpoint in many trials and is a consideration when assessing the net clinical ben- efit of a new drug. A universal definition of bleeding has been proposed to assist clinicians.547,719 721 The incidence of major bleeding in patients with ACS varies widely (0.4% to owing to differing definitions of major bleeding, patient populations, anticoagulation regimens, and PCI or CABG.


A universal definition of bleeding has been proposed to assist clinicians.547,719 721 The incidence of major bleeding in patients with ACS varies widely (0.4% to owing to differing definitions of major bleeding, patient populations, anticoagulation regimens, and PCI or CABG. Factors in patients with ACS related to an increased bleeding risk include older age, female sex, lower body weight, history of prior bleeding and/or invasive procedures, anemia, use of GP IIb/IIIa inhibitors or thrombolytics, and Non weight-based dosing of anticoagu- lants and dosing of antithrombin and antiplatelet medications that are not adjusted for CKD are associated with an increased risk of bleeding.522,697,698 Bleeding is related to adverse out- comes because it may be a marker of underlying disease, such as occult malignancy; leads to cessation of antithrombin and antiplatelet therapy; may prompt transfusion, which itself may have adverse effects; can cause hypotension; and, if intracra- nial, can be fatal.724 Proton pump inhibitors decrease the risk of upper GI bleeding, including in patients treated with DAPT. Proton pump inhibitors are used in patients with a history of prior GI bleeding who require DAPT and are an option in patients at increased risk of GI bleeding.26,430 Evaluation of the risk of bleeding includes a focused his- tory of bleeding symptoms, identification of predisposing comorbidities, evaluation of laboratory data, and calculation of a bleeding risk score.688,716,725 Approximately 15% of all patients with NSTE-ACS and 3% to 12% of those not under- going CABG receive blood transfusion.702 Rates vary widely and are closer to the lower figure but increase in association with factors such as coronary intervention, anticoagulant/ antithrombotic therapy, older age, female sex, anemia, renal insufficiency, and frailty.


Proton pump inhibitors are used in patients with a history of prior GI bleeding who require DAPT and are an option in patients at increased risk of GI bleeding.26,430 Evaluation of the risk of bleeding includes a focused his- tory of bleeding symptoms, identification of predisposing comorbidities, evaluation of laboratory data, and calculation of a bleeding risk score.688,716,725 Approximately 15% of all patients with NSTE-ACS and 3% to 12% of those not under- going CABG receive blood transfusion.702 Rates vary widely and are closer to the lower figure but increase in association with factors such as coronary intervention, anticoagulant/ antithrombotic therapy, older age, female sex, anemia, renal insufficiency, and frailty. Tissue oxygenation does not change or may actually decrease with transfusion.722 Blood transfu- sion in patients with ACS is associated with an increased risk of adverse outcome, including death.702 704 A restrictive trans- fusion strategy leads to an outcome that is at least as good, if not better, than a liberal transfusion strategy.699,700 An analysis of a large ACS registry found no benefit from blood transfu- sion in patients with a nadir hematocrit >24%.702 In a meta- analysis of 10 studies of patients with AMI, transfusion versus no transfusion was associated with an increase in all-cause A restric- tive approach to transfusion generally consists of no routine transfusion for a hemoglobin level >7 g/dL to 8 g/dL.699,700,727 A restrictive approach to blood transfusion is advocated by the American Association of Blood Banks700 and the European Society of Cardiology.727 On the basis of data available at the time of publication, a strategy of routine liberal blood transfu- sion in hemodynamically stable patients with NSTE-ACS and mild to moderate anemia is not recommended. See Online Data Supplement 31 for more information on anemia, bleeding, and transfusion.


See Online Data Supplement 31 for more information on anemia, bleeding, and transfusion. The incidence of thrombocytopenia in patients with ACS var- ies from 1% to 13%. In 1 large prospective registry, one third of patients treated with prolonged heparin therapy developed some degree of thrombocytopenia.728 Independent risk fac- tors for the development of thrombocytopenia include lower baseline platelet count, older age, ACS, cardiac or vascular surgery, intravenous UFH or both UFH and LMWH, duration of heparin therapy, and low body mass index.728 730 The risk of thrombocytopenia is increased in patients treated with abcix- imab and, to a lesser degree, with eptifibatide or tirofiban.731 734 Thrombocytopenia on presentation or related to antithrom- botic therapy is associated with significantly increased risk of thrombotic events, MI, major bleeding, and in-hospital mor- tality in patients with and without ACS.728 731,735 739 The OR for development of these endpoints with thrombocytopenia (com- pared to without thrombocytopenia) is 2 to 8. Data from the CATCH (Complications After Thrombocytopenia Caused by as a threshold, below which there is a linear augmentation in probability of bleeding.740 Results from CATCH highlighted that thrombocytopenia and heparin-induced thrombocytope- nia are often not diagnosed.728 Thrombocytopenia is gener- ally a contraindication for GP IIb/IIIa inhibitor therapy; direct thrombin inhibitors are often considered in preference to UFH or LMWH in patients with thrombocytopenia. See Online Data Supplements 31 and 32 for additional information on anemia, bleeding, and transfusion. 7.10. Cocaine and Methamphetamine Users: Recommendations Class I 1. Patients with NSTE-ACS and a recent history of cocaine or methamphetamine use should be treated Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e391 in the same manner as patients without cocaine- or methamphetamine-related NSTE-ACS.


Patients with NSTE-ACS and a recent history of cocaine or methamphetamine use should be treated Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e391 in the same manner as patients without cocaine- or methamphetamine-related NSTE-ACS. The only ex- ception is in patients with signs of acute intoxication (eg, euphoria, tachycardia, and/or hypertension) and beta-blocker use, unless patients are receiving coro- nary vasodilator therapy. (Level of Evidence: C) Class IIa 1. Benzodiazepines alone or in combination with nitro- glycerin are reasonable for management of hyperten- sion and tachycardia in patients with NSTE-ACS and signs of acute cocaine or methamphetamine intoxica- (Level of Evidence: C) Class III: Harm 1. Beta blockers should not be administered to patients with ACS with a recent history of cocaine or metham- phetamine use who demonstrate signs of acute intoxi- cation due to the risk of potentiating coronary spasm. (Level of Evidence: C) Cocaine exerts multiple effects on the cardiovascular system, which may precipitate ACS.48,744,745 Acute cocaine exposure results in increased BP, heart rate, endothelial dysfunction, and platelet aggregation, all of which may precipitate ACS. Cocaine s direct vasoconstrictor effect can produce coronary vasospasm. Long-term use of cocaine results in progressive myocyte damage and accelerated atherosclerosis.48,744,745 ACS in patients with a history of cocaine use should be treated in the same manner as patients without cocaine use.744 The exception is in patients with ACS in the presence of acute cocaine intoxication.


Long-term use of cocaine results in progressive myocyte damage and accelerated atherosclerosis.48,744,745 ACS in patients with a history of cocaine use should be treated in the same manner as patients without cocaine use.744 The exception is in patients with ACS in the presence of acute cocaine intoxication. Because cocaine stimulates both alpha- and beta-adrenergic receptors, administration of intravenous beta blockers may result in unopposed alpha stimulation with worsening coronary spasm.48,132,744 746 Evidence suggests it is safe to administer intravenous beta blockers in patients with chest pain and recent cocaine ingestion, although information is lacking about the effects of beta-blocker administration dur- ing the acute stages of cocaine intoxication.747,748 Intravenous beta blockers should be avoided in patients with NSTE-ACS with signs of acute cocaine intoxication (euphoria, tachycar- dia, and/or hypertension). In these patients, benzodiazepines alone or in combination with nitroglycerin have been useful for management of hypertension and tachycardia owing to their effects on the central and peripheral manifestations of acute cocaine intoxication.741 744 Methamphetamine abuse is becoming increasingly com- mon in the United States owing to the ease of manufactur- ing and the lower cost of methamphetamines compared with Methamphetamines may be ingested orally, inhaled, or used intravenously. Methamphetamine affects the central nervous system by simultaneously stimulating the release and blocking the reuptake of dopamine and norepi- Like cocaine, methamphetamine exerts multiple effects on the cardiovascular system, all of which may pre- The acute effects of methamphetamine are euphoria, tachycardia, hypertension, and arrhythmias. MI may result from coronary spasm or plaque rupture in the presence of enhanced platelet aggregation. Long-term use of methamphetamine has been associated with myocardi- tis, necrotizing vasculitis, pulmonary hypertension, and car- Because methamphetamine and cocaine have similar pathophysiological effects, treatment of patients with ACS associated with methamphetamine and cocaine use should theoretically be similar.


Long-term use of methamphetamine has been associated with myocardi- tis, necrotizing vasculitis, pulmonary hypertension, and car- Because methamphetamine and cocaine have similar pathophysiological effects, treatment of patients with ACS associated with methamphetamine and cocaine use should theoretically be similar. See Online Data Supplement 33 for additional information about cocaine and methamphetamine users. 7.11. Vasospastic (Prinzmetal) Angina: Recommendations Class I or in combination with long- are useful to treat and reduce the frequency of vasospastic angina. (Level of Evidence: B) 2. Treatment with HMG-CoA reductase inhibi- cessation of tobacco use,761,762 and addition- al atherosclerosis risk factor modification762,763 are useful in patients with vasospastic angina. (Level of Evidence: B) 3. Coronary angiography (invasive or noninvasive) is recommended in patients with episodic chest pain ac- companied by transient ST-elevation to rule out se- vere obstructive CAD. (Level of Evidence: C) Class IIb 1. Provocative testing during invasive coronary angiog- raphy may be considered in patients with suspect- ed vasospastic angina when clinical criteria and non- invasive testing fail to establish the diagnosis.764 767 (Level of Evidence: B) Vasospastic (Prinzmetal) angina chest pain typically occurs without provocation, is associated with ST-elevation, and usu- ally resolves spontaneously or with rapid-acting nitroglycerin. Vasospastic angina may also be precipitated by emotional stress, hyperventilation, exercise, or the cold. It results from coronary vasomotor dysfunction leading to focal spasm,768 which may occasionally be multifocal within a single vessel and rarely involves >1 vessel. Vasospastic angina occurs with normal coronary arteries, nonobstructive CAD, and obstruc- tive CAD, but prognosis is least favorable with the latter. ST-elevation indicates transmural ischemia and corresponds to the distribution of the involved artery.769 A circadian varia- tion is often present; most attacks occur in the early morn- The most prominent coronary risk factor is smoking.


ST-elevation indicates transmural ischemia and corresponds to the distribution of the involved artery.769 A circadian varia- tion is often present; most attacks occur in the early morn- The most prominent coronary risk factor is smoking. Most episodes resolve without complications, but arrhyth- mias, syncope, MI, and sudden death can occur.772 Provocative testing during invasive coronary angiography (eg, using ergonovine, acetylcholine, methylergonovine) is relatively safe, especially when performed in a controlled manner by experienced operators. However, sustained spasm, serious arrhythmias, and even death can also occur very infrequently. Therefore, provocative testing should be avoided in patients with significant left main disease, advanced 3-vessel disease, presence of high-grade obstructive lesions, significant valvular stenosis, significant LV systolic dysfunction, and advanced HF. Nonpharmacological provocative tests, such as cold pressor and hyperventilation, have been used diagnostically; potent vasoconstrictors (eg, acetylcholine) may be useful when non- invasive assessment is uninformative.764 767 Smoking, which exacerbates coronary vasospasm, should be proscribed, and CCBs are first-line therapies642 ; long-acting nitrates are also effective when combined with CCBs.755,758 Statins improve endothelium-dependent vasodilation and can be useful in vaso- Magnesium supplementation and alpha- receptor blockers may be effective and can be added.755,758 7.12. ACS With Angiographically Normal Coronary Arteries: Recommendation Class IIb 1.


ACS With Angiographically Normal Coronary Arteries: Recommendation Class IIb 1. If coronary angiography reveals normal coronary arteries and endothelial dysfunction is suspected, invasive physiological assessment such as coronary flow reserve measurement may be considered.629,773 776 (Level of Evidence: B) ACS associated with angiographically normal or nonob- structive (<50% stenosis) coronary arteries (also referred to as syndrome X) may be related to coronary endothelial ; plaque rupture that may be evident only with ; coronary vasospasm779 ; and coro- nary artery dissection.780 Myocarditis may present with elec- trocardiographic and biomarker findings similar to ACS and can be distinguished by magnetic resonance imaging.781 783 Intracoronary ultrasound and/or optical coherence tomog- raphy to assess the extent of atherosclerosis and exclude obstructive lesions may be considered in patients with possi- ble ACS and angiographically normal coronary arteries.778 If ECGs during chest pain are not available and coronary spasm cannot be ruled out, coronary angiography and provocative testing with acetylcholine, adenosine, or methacholine and 24-hour ambulatory ECG may be undertaken after a period of stabilization. Endothelial dysfunction is more common in women than in men,679,777,784 786 and chest pain is typical In the absence of a culprit coronary lesion, prognosis of coronary endothelial dysfunction and/or occult plaque rupture is favorable.765,787 Risk factor reduction and medical therapy with nitrates, beta blockers, and CCBs alone or in combination are consid- ered for endothelial dysfunction.788 790 High doses of arginine have also been given.791 Imipramine or aminophylline have been used in patients with endothelial dysfunction for contin- ued pain despite optimal medical therapy. In postmenopausal women, estrogen reverses acetylcholine-induced coronary arterial vasoconstriction, presumably by improving endothe- lium-dependent coronary vasomotion, and reduces frequency of chest pain.792 However, estrogen is not recommended because of its demonstrated increase in cardiovascular and Spontaneous coronary artery dissection affects a young, predominantly female population.


In postmenopausal women, estrogen reverses acetylcholine-induced coronary arterial vasoconstriction, presumably by improving endothe- lium-dependent coronary vasomotion, and reduces frequency of chest pain.792 However, estrogen is not recommended because of its demonstrated increase in cardiovascular and Spontaneous coronary artery dissection affects a young, predominantly female population. Treatment of spontaneous coronary artery dissection with CABG or stenting is described to improve outcome,794 but high rates of stenting complica- tions are reported.780 7.13. Stress (Takotsubo) Cardiomyopathy: Recommendations Class I 1. Stress (Takotsubo) cardiomyopathy should be con- sidered in patients who present with apparent ACS and nonobstructive CAD at angiography. (Level of Evidence: C) 2. Imaging with ventriculography, echocardiography, or magnetic resonance imaging should be performed to confirm or exclude the diagnosis of stress (Takotsubo) (Level of Evidence: B) 3. Patients should be treated with conventional agents (ACE inhibitors, beta blockers, aspirin, and diuret- ics) as otherwise indicated if hemodynamically sta- ble. (Level of Evidence: C) 4. Anticoagulation should be administered in patients who develop LV thrombi. (Level of Evidence: C) Class IIa 1. It is reasonable to use catecholamines for patients with symptomatic hypotension if outflow tract ob- struction is not present. (Level of Evidence: C) 2. The use of IABP is reasonable for patients with re- fractory shock. (Level of Evidence: C) 3. It is reasonable to use beta blockers and alpha- adrenergic agents in patients with outflow tract obstruction. (Level of Evidence: C) Class IIb 1. Prophylactic anticoagulation may be considered to inhibit the development of LV thrombi.


Prophylactic anticoagulation may be considered to inhibit the development of LV thrombi. (Level of Evidence: C) Stress (Takotsubo) cardiomyopathy (also referred to as tran- sient LV apical ballooning or Takotsubo cardiomyopathy) mimics NSTE or STEMI.799 803 There is no obstructive CAD, and the distribution of electrocardiographic changes and LV wall motion abnormalities usually includes >1 coronary artery Cardiac troponin elevations are usually modest.798 The majority of cases occur in postmenopausal women, and presentation is typically precipitated by emotional or physi- cal stress. Imaging by echocardiography, ventriculography,696 or magnetic resonance imaging699 demonstrates characteristic hypokinesis or dyskinesis of the LV apex with basilar increased contractility. Variants include hypokinesis of the mid or base of the left ventricle,795 and right ventricular involvement is com- In the vast majority of patients, electrocardiographic and LV wall motion abnormalities normalize within 1 to 4 weeks, and recurrences are uncommon.805 The pathogenesis has been attributed to excess catecholamine release,803 coro- nary spasm, or small coronary vessel hypoperfusion.806 Care is predominantly supportive and includes beta block- ers, vasodilators, and catecholamines. The latter 2 interven- tions must be used cautiously, because they may induce outflow tract obstruction.800 If shock is present, IABP can be used. Prophylactic anticoagulation should be considered to prevent or treat LV thrombus.798 Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e393 Obesity is associated with conditions such as dyslipidemia, diabetes mellitus, hypertension, arrhythmias, and HF that adversely affect ACS outcomes. In the MADIT (Multicenter Automatic Defibrillator Implantation)-II trial, there was an inverse relation between body mass index and both all-cause mortality and sudden cardiac death in patients with LV dys- function after MI.807 In the SYNERGY trial of 9837 patients with NSTEMI, mortality was lower in morbidly obese patients, consistent with the obesity paradox.


In the MADIT (Multicenter Automatic Defibrillator Implantation)-II trial, there was an inverse relation between body mass index and both all-cause mortality and sudden cardiac death in patients with LV dys- function after MI.807 In the SYNERGY trial of 9837 patients with NSTEMI, mortality was lower in morbidly obese patients, consistent with the obesity paradox. 808 The obe- sity paradox has not been clarified and is under continuing investigation. Standard approaches to weight reduction in obese patients are usually unsuccessful in producing large decreases in weight. A weight reduction study of obese and morbidly obese patients following AMI resulted in weight loss of only 0.5% in obese patients and 3.5% in morbidly obese patients after 1 year.809 Two drugs, controlled-release are available for weight reduction but have not been studied in patients fol- lowing NSTE-ACS. Bariatric surgery has been successful in reducing cardiovascular risk factors, including diabetes mel- litus, hypertension, and dyslipidemia but has not been evalu- ated in post ACS patients.812 The 2013 obesity CPG provides comprehensive strategies for weight reduction.16 7.15. Patients Taking Antineoplastic/ Immunosuppressive Therapy Antineoplastic or immunosuppressive therapy may contrib- ute to the development of NSTE-ACS. For example, anti- neoplastic agents such as gemcitabine, sorafenib sunitinib, and 5-fluorouracil have been associated with coronary artery spasm or stenosis.813,814 Trastuzumab and possibly other anti- cancer drugs may alter biomarker levels.815 Antineoplastic agents can induce changes in the arterial wall,813 and modula- tors of inflammation may promote atherogenesis.816 In patients receiving these agents, it is prudent to communicate with the prescribing clinician about the necessity of their continuation during NSTE-ACS and future resumption. 8. Quality of Care and Outcomes for ACS Use of Performance Measures and Registries 8.1. Use of Performance Measures and Registries: Recommendation Class IIa 1.


Use of Performance Measures and Registries: Recommendation Class IIa 1. Participation in a standardized quality-of-care data registry designed to track and measure outcomes, complications, and performance measures can be beneficial in improving the quality of NSTE-ACS (Level of Evidence: B) The development of national systems for ACS is crucial and includes the participation of key stakeholders to evaluate care using standardized performance and quality-improvement measures for ACS.819,821 Standardized quality-of-care data reg- istries include the NCDR Registry Get With the Guidelines, the Get With the Guidelines quality-improvement program, the Acute Myocardial Infarction Core Measure Set, and performance measures required by The Joint Commission and the Centers for Medicare and Medicaid Services.817,823 825 The AHA has promoted its Mission: Lifeline initiative to encourage cooperation among prehospital emergency medi- cal services personnel and cardiac care professionals.817 The evaluation of ACS care delivery across traditional boundar- ies can identify problems with systems and enable application of modern quality-improvement methods.818,820,822 On a local level, registries as part of the Chronic Care Model were asso- ciated with improved outcomes in chronic diseases, including 9. Summary and Evidence Gaps Despite landmark advances in the care of patients with NSTE- ACS since the publication of the 2007 UA/NSTEMI CPG,212 many emerging diagnostic and therapeutic strategies have posed new challenges. There is general acceptance of an early invasive strategy for patients with NSTE-ACS in whom sig- nificant coronary vascular obstruction has been precisely quantified. Low-risk patients with NSTE-ACS are documented to benefit substantially from GDMT, but this is often subopti- mally used. Advances in noninvasive testing have the potential to identify patients with NSTE-ACS who are at intermediate risk and are candidates for invasive versus medical therapy. Newer, more potent antiplatelet agents in addition to antico- agulant therapy are indicated irrespective of initial treatment strategy.


Newer, more potent antiplatelet agents in addition to antico- agulant therapy are indicated irrespective of initial treatment strategy. Evidence-based decisions will require compara- tive-effectiveness studies of available and novel agents. The paradox of newer and more potent antithrombotic and anti- coagulant drugs that reduce major adverse cardiac outcomes but increase bleeding risk occurs with greater frequency in patients with AF. Patients with AF who develop NSTE-ACS and receive a coronary stent are the population at risk from triple anticoagulant/antiplatelet therapy. This regimen has been reported to be safely modified by elimination of aspirin, a finding that requires confirmation. Among the most rapidly evolving areas in NSTE-ACS diagnosis is the use of cardiac troponin, the preferred bio- marker of myocardial necrosis. Although a truly high-sensi- tivity cardiac troponin is not available in the United States at the time this CPG was prepared, the sensitivity of contempo- rary assays continues to increase. This change is accompa- nied by higher rates of elevated cardiac troponin unrelated to coronary plaque rupture. The diagnostic quandary posed by these findings necessitates investigation to elucidate the opti- mal utility of this advanced biomarker. A promising approach to improve the diagnostic accuracy for detecting myocardial necrosis is measurement of absolute cardiac troponin change, which may be more accurate than the traditional analysis of relative alterations. Special populations are addressed in this CPG, the most numerous of which are older persons and women. More than half of the mortality in NSTE-ACS occurs in older patients, and this high-risk cohort will increase as our population ages. An unmet need is to more clearly distinguish which older patients are candidates for an ischemia-guided strategy compared with an early invasive management strategy.An appreciable number of patients with NSTE-ACS have angiographically normal or nonobstructive CAD, a group in which women predominate.


An unmet need is to more clearly distinguish which older patients are candidates for an ischemia-guided strategy compared with an early invasive management strategy.An appreciable number of patients with NSTE-ACS have angiographically normal or nonobstructive CAD, a group in which women predominate. Their prognosis is not benign, and the multiple mechanisms of ACS postulated for these patients remain largely speculative. Clinical advances are predicated on clarification of the patho- physiology of this challenging syndrome. A fundamental aspect of all CPGs is that these carefully developed, evidence-based documents cannot encompass all clinical circumstances, nor can they replace the judgment of individual physicians in management of each patient. The sci- ence of medicine is rooted in evidence, and the art of medicine is based on the application of this evidence to the individual patient. This CPG has adhered to these principles for optimal management of patients with NSTE-ACS. Presidents and Staff American College of Cardiology Patrick O Gara, MD, FACC, President Shalom Jacobovitz, Chief Executive Officer William J. Oetgen, MD, MBA, FACC, Executive Vice President, Science, Education, and Quality Amelia Scholtz, PhD, Publications Manager, Clinical Policy and Pathways American College of Cardiology/American Heart Association Lisa Bradfield, CAE, Director, Science and Clinical Policy Emily Cottrell, MA, Quality Assurance Specialist, Science and Clinical Policy Alexa Papaila, Specialist, Science and Clinical Policy American Heart Association Elliot Antman, 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 Marco Di Buono, PhD, Vice President, Science, Research, and Professional Education, Office of Science Operations Jody Hundley, Production Manager, Scientific Publications, Office of Science Operations References 1. Committee on Standards for Developing Trustworthy Clinical Practice Guidelines; Institute of Medicine. Clinical Practice Guidelines We Can Trust.


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