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. Platelet Function and Genetic Phenotype Testing Although higher platelet reactivity has been associated with a greater incidence of adverse events in patients undergoing stent implantation, a strategy of adjusting antiplatelet therapy based on routine platelet function testing has not been ben- eficial in reducing ischemic complications.26,443 445 Similarly, a strategy of routine genetic phenotype testing has also not been beneficial and thus is not recommended.26,446 448 A more detailed discussion of these issues and current recommenda- tions about platelet function testing and genetic testing are in 6.3. Risk Reduction Strategies for Secondary Prevention Secondary prevention is a critical aspect of the management of care for the survivor of NSTE-ACS. It has been clearly estab- lished that in this high-risk cohort, subsequent cardiovascular morbidity and mortality can be reduced by a comprehensive approach to favorably modifying patients risk profiles.27 Secondary prevention comprises lifestyle changes, risk fac- tor education, medical therapy, and, where appropriate, revas- cularization. These elements are discussed in Section 6.4. Despite the proven utility of secondary prevention, its imple- mentation remains suboptimal, and enhanced application is a major goal in this patient population. See Online Data Supplement 23 for additional information on risk reduction strategies. 6.3.1. Cardiac Rehabilitation and Physical Activity: Recommendation Class I 1. All eligible patients with NSTE-ACS should be re- ferred to a comprehensive cardiovascular rehabilita- tion program either before hospital discharge or dur- ing the first outpatient visit.449 452 (Level of Evidence: B) The US Public Health Service emphasizes comprehensive car- diac rehabilitation programs,449 and the 2011 secondary pre- vention CPG underscores referral to cardiac rehabilitation for survivors of ACS.27 Since 2007, referral to these programs has been designated a quality performance measure.453 455 Barriers to referral can be obviated by discussion with the patient and referral by the patient s primary care clinician and/or cardio- vascular caregiver. These comprehensive programs provide patient education, enhance regular exercise, monitor risk factors, and address lifestyle modification.456 Aerobic exercise training can generally begin 1 to 2 weeks after discharge in patients treated with PCI or CABG.457 Mild-to-moderate resis- tance training can be considered and started 2 to 4 weeks after Unsupervised exercise may target a heart rate range of 60% to 75% of maximum age-predicted heart rate based on the patient s exercise stress test. Supervised training may target a higher heart rate (70% to 85% of age-predicted Additional restrictions apply when residual isch- emia is present. Daily walking can be encouraged soon after discharge for most patients. Resource publications on exer- cise prescription in cardiovascular patients are available.456,457 Regular physical activity reduces symptoms in patients with cardiovascular disease, enhances functional capacity, improves other risk factors such as insulin resistance and glucose con- trol, and is important in weight control.456 Questionnaires and nomograms for cardiac patients have been developed to guide exercise prescription if an exercise test is unavailable.459 462 See Section 6.4 and Table 10 for more information. 6.3.2. Patient Education: Recommendations Class I 1. Patients should be educated about appropriate cho- lesterol management, BP, smoking cessation, and life- (Level of Evidence: C) 2. Patients who have undergone PCI or CABG derive benefit from risk factor modification and should receive counseling that revascularization does not obviate the need for lifestyle changes.463 (Level of Evidence: C) Results of testing should be discussed with the patient, the patient s family, and/or the patient s advocate in an under- standable manner. Test results should be used to help deter- mine the advisability of coronary angiography, the need for adjustments in the medical regimen, and the specifics for sec- ondary prevention measures. See Section 6.4 and Table 10 for more information on plan of care. 6.3.3. Pneumococcal Pneumonia: Recommendation Class I 1. The pneumococcal vaccine is recommended for patients 65 years of age and older and in high-risk patients with cardiovascular disease.464 466 (Level of Evidence: B) Vaccination with the 23-valent pneumococcal polysaccha- ride vaccine is recommended for all adults 65 years of age. Adults of any age who are at increased risk, including smok- ers and those with asthma, should also be given the vaccine. Immunocompromised adults should receive the 13-valent conjugate vaccine in addition to the 23-valent vaccine.464 466 The influenza vaccine is discussed in Section 6.4. 6.3.4. NSAIDs: Recommendations Class I 1. Before hospital discharge, the patient s need for treat- ment of chronic musculoskeletal discomfort should be assessed, and a stepped-care approach should be used for selection of treatments. Pain treatment be- fore consideration of NSAIDs should begin with ac- etaminophen, nonacetylated salicylates, tramadol, or small doses of narcotics if these medications are not (Level of Evidence: C) Class IIa 1. It is reasonable to use nonselective NSAIDs, such as naproxen, if initial therapy with acetaminophen, nonacetylated salicylates, tramadol, or small doses of narcotics is insufficient.237 (Level of Evidence: C) Class IIb 1. NSAIDs with increasing degrees of relative COX- 2 selectivity may be considered for pain relief only for situations in which intolerable discomfort per- sists despite attempts at stepped-care therapy with acetaminophen, nonacetylated salicylates, tramadol, small doses of narcotics, or nonselective NSAIDs. In all cases, use of the lowest effective doses for the shortest possible time is encouraged.234,235,237,467 (Level of Evidence: C) Class III: Harm 1. NSAIDs with increasing degrees of relative COX- 2 selectivity should not be administered to patients with NSTE-ACS and chronic musculoskeletal dis- comfort when therapy with acetaminophen, nonac- etylated salicylates, tramadol, small doses of narcot- ics, or nonselective NSAIDs provide acceptable pain (Level of Evidence: B) Selective COX-2 inhibitors and other nonselective NSAIDs have been associated with increased cardiovascular risk, and the risk appears to be amplified in patients with established. In a large Danish observa- tional study of patients with first MI (n=58432), the HR and There were dose-related increases in risk of death and non dose-dependent trends for rehospitaliza- tion for MI for all drugs.234,467 An AHA scientific statement on the use of NSAIDs concluded that the risk of cardiovascular events is proportional to COX-2 selectivity and the underly- ing risk in the patient.237 Non-pharmacological approaches were recommended as the first line of treatment, followed by the stepped-care approach to pharmacological therapy, as shown in Figure 4. 6.3.5. Hormone Therapy: Recommendation Class III: Harm 1. Hormone therapy with estrogen plus progestin, or estrogen alone, should not be given as new drugs for secondary prevention of coronary events to post- menopausal women after NSTE-ACS and should Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e381 not be continued in previous users unless the ben- efits outweigh the estimated risks.17,470 472 (Level of Evidence: A) Although prior observational data suggested a protective effect of hormone therapy for coronary events, a randomized trial of hormone therapy for secondary prevention of death and MI (the HERS [Heart and Estrogen/Progestin Replacement] study) failed to demonstrate a beneficial effect.473 There was an excess risk for death and MI early after initiation of hor- mone therapy. The Women s Health Initiative included random- ized primary prevention trials of estrogen plus progestin and Both trials were stopped early owing to an increased risk related to hormone therapy that was believed to outweigh the potential benefits of further study.470 472 It is rec- ommended that post-menopausal women receiving hormone therapy at the time of a cardiovascular event discontinue its use and that hormone therapy should not be initiated for the primary or secondary prevention of coronary events. However, there may be other permissible indications for hormone therapy in postmenopausal women (eg, treatment of perimenopausal symptoms such as flushing or prevention of osteoporosis) if the benefits are believed to outweigh the increased cardiovascular risk. Postmenopausal women who are >1 to 2 years past the ini- tiation of hormone therapy who wish to continue such therapy for another compelling indication should weigh the risks and benefits, recognizing the greater risk of cardiovascular events and breast cancer (combination therapy) or stroke (estrogen).473 6.3.6. Antioxidant Vitamins and Folic Acid: Recommendations Class III: No Benefit 1. Antioxidant vitamin supplements (eg, vitamins E, C, or beta carotene) should not be used for secondary prevention in patients with NSTE-ACS.474,475 (Level of Evidence: A) 2. Folic acid, with or without vitamins B6 and B12, should not be used for secondary prevention in pa- tients with NSTE-ACS.476,477 (Level of Evidence: A) Although there is an association of elevated homocysteine blood levels and CAD, a reduction in homocysteine levels with routine folate supplementation did not reduce the risk of CAD events in 2 trials (the NORVIT [Norwegian Vitamin Trial] and the HOPE [Heart Outcomes Prevention Evaluation] study) that included post MI or high-risk stable patients476 478 and produced poorer outcomes in another study.479 Additionally, in the NORVIT trial, there was a trend toward increased cardio- vascular events (95% CI: 1.00 to 1.50; P=0.05) in the cohort receiving the combination of folic acid, vitamin B6, and vita- min B12; the authors cautioned against using the treatment for Similarly, experience in large clinical trials with antioxidant vitamins has failed to demonstrate ben- efit for primary or secondary prevention.474,475,480 See Online Data Supplement 23 for additional information on antioxidant vitamins and folic acid. 6.4. Plan of Care for Patients With NSTE-ACS: Recommendations Class I 1. Posthospital systems of care designed to prevent hospital readmissions should be used to facilitate the transition to effective, coordinated outpatient care for all patients with NSTE-ACS.481 485 (Level of Evidence: B) 2. An evidence-based plan of care (eg, GDMT) that pro- motes medication adherence, timely follow-up with the healthcare team, appropriate dietary and physi- cal activities, and compliance with interventions for secondary prevention should be provided to patients with NSTE-ACS. (Level of Evidence: C) 3. In addition to detailed instructions for daily exer- cise, patients should be given specific instruction on activities (eg, lifting, climbing stairs, yard work, and household activities) that are permissible and those to avoid. Specific mention should be made of resump- tion of driving, return to work, and sexual activ- (Level of Evidence: B) 4. An annual influenza vaccination is recommended for patients with cardiovascular disease.27,488 (Level of Evidence: C) Education of patients with NSTEMI and their families is criti- cal and often challenging, especially during transitions of care. Failure to understand and comply with a plan of care may account for the high rate of AMI rehospitalization rates in the United States.489,490 An important intervention to promote Figure 4. Stepped-Care Approach to Pharmacological Therapy for Musculoskeletal Symptoms in Patients With Known Cardiovascular Disease or Risk Factors for Ischemic Heart Disease. ASA indicates aspirin; COX-2, cyclooxygenase; GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; and PPI, proton-pump inhibitor. Modified from Jneid et al.8 coordination is to provide patients and caregivers with a com- prehensive plan of care and educational materials during the hospital stay that support compliance with evidence-based thera- The posthospitalization plan of care for patients with NSTE-ACS (Table 10) should address in detail several complex issues, including medication adherence and titration, timely follow-up, dietary interventions, physical and sexual activities, cardiac rehabilitation, compliance with interventions for second- ary prevention, and reassessment of arrhythmic and HF risks. In addition, clinicians should pay close attention to psychoso- cial and socioeconomic issues, including access to care, risk of depression, social isolation, and healthcare disparities.494 496 6.4.1. Systems to Promote Care Coordination There has been improved understanding of the system changes necessary to achieve safer care.497 This includes adoption by all US hospitals of a standardized set of Safe Practices endorsed by the National Quality Forum,498 which over- lap with the National Patient Safety Goals espoused by The Examples of patient safety standards for all patients after AMI include improved communication among clinicians, nurses, and pharmacists; medication recon- ciliation; careful transitions between care settings; and con- sistent documentation. The National Quality Forum has also endorsed a set of patient-centered Preferred Practices for which detail comprehensive specifica- tions that are necessary to achieve successful care coordina- tion for patients and their families. Systems of care designed to support patients with NSTE-ACS, STEMI, and other car- diac diseases can result in significant improvement in patient outcomes. Table 10 provides reference documents for multiple risk-reduction strategies for secondary prevention in the post- hospital phase of NSTE-ACS. These include the 2013 ACC/ AHA CPGs on management of blood cholesterol,18 and the 2014 recommendations for management which were published during the develop- ment of this CPG. To provide the interventions and services listed in Table 10, appropriate resources must be used so that patients with MI have full access to evidence-based therapies and follow-up care. There is a growing emphasis on penalizing hospitals for avoidable hospital readmissions. It is imperative for health systems to work with clinicians, nurses, pharmacists, communities, payers, and public agencies to support the inter- ventions that achieve comprehensive care. Several patient char- acteristics have been predictors of readmission after AMI.502,503 7. Special Patient Groups See Table 11 for summary of recommendations for this section. 7.1. NSTE-ACS in Older Patients: Recommendations Class I 1. Older patients** with NSTE-ACS should be treated with GDMT, an early invasive strategy, and revascu- larization as appropriate.515 519 (Level of Evidence: A) 2. Pharmacotherapy in older patients** with NSTE- ACS should be individualized and dose adjusted by weight and/or CrCl to reduce adverse events caused by age-related changes in pharmacokinetics/dynam- ics, volume of distribution, comorbidities, drug inter- actions, and increased drug sensitivity.515,520 522 (Level of Evidence: A) 3. Management decisions for older patients** with NSTE-ACS should be patient centered, and consider patient preferences/goals, comorbidities, functional (Level of Evidence: B) Class IIa 1. Bivalirudin, rather than a GP IIb/IIIa inhibitor plus UFH, is reasonable in older patients** with NSTE- ACS, both initially and at PCI, given similar efficacy but less bleeding risk.396,526 528 (Level of Evidence: B) 2. It is reasonable to choose CABG over PCI in older patients** with NSTE-ACS who are appropriate can- didates, particularly those with diabetes mellitus or complex 3-vessel CAD (eg, SYNTAX score >22), with or without involvement of the proximal LAD artery, to reduce cardiovascular disease events and readmission and to improve survival.529 534 (Level of Evidence: B) In this CPG, older adults refers to patients 75 years of age.515 Older adults have the highest incidence, prevalence, and adverse outcomes of NSTE-ACS.9,515 517,535,536 Older age is accompanied by comorbidities, polypharmacy, and age- and disease-related physiological changes that adversely impact NSTE-ACS presen- tation, management, and outcome. As older patients are under- represented in clinical trials, the recommendations in this CPG are largely supported by registry data and meta-analyses.516,537 Older patients with NSTE-ACS primarily present with chest pain but frequently have atypical symptoms. ECGs may be less diagnostic than in younger patients.517,538 Older patients with NSTE-ACS derive the same or greater benefit from phar- macological therapies, interventional therapies, and cardiac rehabilitation as younger patients, but older patients receive significantly less GDMT than younger patients, even when adjusted for comorbidities.515 517,535,538,539 In the ACSIS (Acute Coronary Syndrome Israeli Survey) registry, patients >80 years of age referred for early coronary angiography, compared with no angiography, had lower 30-day and 1-year mortality rates.540 Age-related pharmacokinetics and pharmacodynamic changes can alter drug dosing, efficacy, and safety of many NSTE-ACS therapies, as can drug drug interactions CrCl or glomerular filtra- tion rate (GFR) should be estimated initially and throughout care for all older patients with NSTE-ACS, and pharmaceuti- cal agents should be renally and weight dose-adjusted to limit drug toxicity (especially bleeding risk), given the unreliabil- ity of serum creatinine to assess age-related renal dysfunc- (Appendix 4, Table C). Bleeding in older patients with NSTE-ACS is multifactorial, resulting in nar- rower therapeutic windows.541,542,544,546,547 In the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With **Those 75 years of age (see text). Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e383 Early Implementation of the American College of Cardiology/ American Heart Association Guidelines) study, excessive doses of UFH, LMWH, and GP IIb/IIIa inhibitors accounted Aspirin should be maintained at 81 mg per day (after initial stent implantation). Owing to excess bleeding without clinical benefit, the US Food and DrugAdministration lists a Black Box warning that does not recommend adminis- tration of prasugrel to patients with NSTE-ACS who are 75 years of age or weigh <60 kg except in those at very high risk. A metaanalysis of 6 RCTs about the use of GP IIb/IIIa inhibitors in patients with NSTE-ACS reported no significant age-treatment interaction, although older women had signifi- cantly more adverse events.549 Bivalirudin appears safer for older patients with NSTE-ACS PCI than GP IIb/IIIa inhibi- tors plus UFH, with less bleeding and similar efficacy.526,550 AF is more common in older patients with NSTE-ACS, and triple therapy (DAPT and warfarin) entails a marked bleeding In the WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary Stenting) study, it was found that in patients taking oral coagulants who required PCI, use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in thrombotic Nonetheless, practice should not be changed on the basis of this limited study alone. Older patients with NSTE-ACS benefit as much or more than younger patients from an early invasive strategy com- pared with an ischemia-guided strategy.340,341,515,518,519 In a 5-year follow-up meta-analysis of FRISC-II and RITA-3, an early invasive strategy versus an ischemia-guided strategy was associated with a significant reduction in death/MI and MI in patients 75 years of age but not in patients <65 years Although the highest risk reduction in death/MI with an early invasive strategy occurred in those 75 years of age, this strategy was associated with a 3-fold bleeding risk.552 However, despite the overall favorable evidence for an early invasive strategy in older patients, age is the strongest risk fac- tor for this group not undergoing an early invasive strategy.553 PCI has increased in older patients, including the very elderly ( 90 years of age), with success rates similar to younger patients and declining complication rates, including Several large registries report a greater RR reduction in mortality of older patients treated with revascularization versus medical therapy compared with those 65 years of age, despite increased comorbidities.517,540,554 556 Operative mortality rates for CABG in patients 80 years of age with NSTE-ACS range from 5% to 8% (11% for urgent cases) and increase to approximately 13% at 90 years of age. Complications occur more frequently in older patients with Length of stay averages 6 days longer in older patients than in patients <50 years of age, and discharge (to home [52%]) is less frequent than in younger patients.557 In a metaanalysis, off-pump CABG appeared to offer a poten- tially safer and more effective revascularization technique compared with on-pump CABG in older patients with NSTE- Older patients with NSTE-ACS with diabetes mellitus had a greater survival advantage with CABG.529 Evaluation tools can help identify older patients with NSTE-ACS whose risk and comorbidity profile predict mortality within 6 to 12 months and possibly guide a palliative approach.524 See Online Data Supplement 24 for additional information on older patients. 7.2. HF: Recommendations Class I 1. Patients with a history of HF and NSTE-ACS should be treated according to the same risk stratification guidelines and recommendations for patients without (Level of Evidence: B) 2. Selection of a specific revascularization strategy should be based on the degree, severity, and extent of CAD; associated cardiac lesions; the extent of LV dysfunction; and the history of prior revascu- (Level of Evidence: B) In patients with HF and NSTE-ACS, the plan of care should be implemented as in patients without HF using medical therapy and an early invasive approach, because patients with abnormal LV function are at increased risk of mortality and HF itself may be associated with elevated serum troponin in the presence or absence of obstructive CAD. After angiography, risk stratification can be used to select revascu- larization strategies. The effect of surgical revascularization on improving survival has been most clearly demonstrated in patients with both extensive CAD and LV dysfunc- Such patients should undergo testing to iden- tify the severity and extent of ischemia and should in general be referred for coronary angiography. In selected patients with appropriate anatomy, PCI has been used.23,568 In patients who have already undergone CABG or in whom the anatomy is not favorable for CABG, PCI has been performed using CPG- based PCI performance strategies if specific targeted areas that are amenable to PCI can be identified.26 If there is a large amount of ischemic territory and very poor LV function, per- cutaneous ventricular assist devices or, in less severe cases, an IABP can be used for support during the procedure.266,569 573 See Online Data Supplement 25 for additional information on HF. Ventricular arrhythmias are common early after onset of NSTE-ACS, and not all require intervention. The mechanisms for these arrhythmias include continuing ischemia, hemody- namic and electrolyte abnormalities, reentry, and enhanced automaticity. Approximately 5% to 10% of hospitalized patients may develop ventricular tachycardia (VT)/ventricular fibrillation (VF), usually within 48 hours of presentation.574 The incidence of VF in otherwise uncomplicated AMI appears to have decreased within the past few years from >4% to <2%, of which 59% of patients had non Q-wave MI.574 A study of 277 consecutive patients with NSTE-ACS who under- went cardiac catheterization within 48 hours found VT/VF occurring in 7.6% of patients, 60% of which developed within 48 hours after admission.575 Risk factors for VT/VF include HF, hypotension, tachycardia, shock, and low TIMI flow grade. Treatment consists of immediate defibrillation or Table 11. Summary of Recommendations for Special Patient Groups Recommendations COR LOE References NSTE-ACS in older patients Treat older patients ( 75 y of age) with GDMT, early invasive strategy, and revascularization as appropriate I A 515 519 Individualize pharmacotherapy in older patients, with dose adjusted by weight and/or CrCl to reduce adverse events caused by age-related changes in pharmacokinetics/dynamics, volume of distribution, comorbidity, drug interactions, and increased drug sensitivity Undertake patient-centered management for older patients, considering patient preferences/goals, comorbidities, functional and cognitive status, and life expectancy Bivalirudin rather than GP IIb/IIIa inhibitor plus UFH is reasonable for older patients ( 75 y of age), given similar efficacy but less bleeding risk It is reasonable to choose CABG over PCI in older patients, particularly those with DM or multivessel disease, because of the potential for improved survival and reduced CVD events IIa B 529 534 HF Treat patients with a history of HF according to the same risk stratification guidelines and recommendations for patients without HF Select a revascularization strategy based on the extent of CAD, associated cardiac lesions, LV dysfunction, and prior revascularization Cardiogenic shock Recommend early revascularization for cardiogenic shock due to cardiac pump failure I B 560, 588, 589 DM Recommend medical treatment and decisions for testing and revascularization similar to those for patients without DM Post CABG Recommend GDMT antiplatelet and anticoagulant therapy and early invasive strategy because of increased risk with prior CABG Perioperative NSTE-ACS Administer GDMT to perioperative patients with limitations imposed by noncardiac surgery I C 626, 627 Direct management at underlying cause of perioperative NSTE-ACS I C 21, 626 634 CKD Estimate CrCl and adjust doses of renally cleared medications according to pharmacokinetic data Administer adequate hydration to patients undergoing coronary and LV angiography I C N/A Invasive strategy is reasonable in patients with mild (stage 2) and moderate (stage 3) CKD IIa B 649 652 Women Manage women with the same pharmacological therapy as that for men for acute care and secondary prevention, with attention to weight and/or renally calculated doses of antiplatelet and anticoagulant agents to reduce bleeding risk I B 669 673 Early invasive strategy is recommended in women with NSTE-ACS and high-risk features (troponin positive) Myocardial revascularization is reasonable for pregnant women if ischemia-guided strategy is ineffective for management of life-threatening complications IIa C 674 Women with low-risk features (Section 3.3.1) should not undergo early invasive treatment because of lack of benefit and the possibility of harm Anemia, bleeding, and transfusion Evaluate all patients for risk of bleeding I C N/A Recommend that anticoagulant and antiplatelet therapy be weight-based where appropriate and adjusted for CKD to decrease the risk of bleeding There is no benefit of routine blood transfusion in hemodynamically stable patients with hemoglobin levels >8 g/dL III: No Benefit B 699 703 Cocaine and methamphetamine users Manage patients with recent cocaine or methamphetamine use similarly to those without cocaine- or methamphetamine-related NSTE-ACS. The exception is in patients with signs of acute intoxication (eg, euphoria, tachycardia, and hypertension) and beta-blocker use unless patients are receiving coronary vasodilator therapy I C N/A (Continued) Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e385 cardioversion for VF or pulseless sustained VT. Early admin- istration of beta blockers has been associated with reduction in The prophylactic use of lidocaine is not rec- ommended. Although VT/VF is associated with higher 90-day mortality risk, premature ventricular contractions not associ- ated with hemodynamic compromise and accelerated ventric- ular rhythms do not confer higher mortality risks and do not require specific therapy other than maintaining electrolyte bal- ance. NSTE-ACS non-sustained VT occurring >48 hours after admission indicates an increased risk of cardiac and sudden death, especially when associated with accompanying myo- Life-threatening ventricular arrhythmias that occur >48 hours after NSTE-ACS are usually associated with LV dysfunction and signify poor prognosis. RCTs in patients with ACS have shown consistent benefit of implant- able cardioverter-defibrillator therapy for survivors of VT or For other at-risk patients, especially those with significantly reduced LVEF, candidacy for primary prevention of sudden cardiac death with an implantable cardioverter-defi- brillator should be readdressed 40 days after discharge.583 A life vest may be considered in the interim. AF, atrial flutter, and other supraventricular arrhythmias may be triggered by excessive sympathetic stimulation, atrial stress due to volume overload, atrial infarction, pericarditis, electrolyte abnormalities, hypoxia, or pulmonary disease. AF is the most common of these arrhythmias and may develop in >20% of patients. AF is associated with shock, HF, stroke, and Management ofAF requires rate control and adequate anticoagulation according to the 2014 For hemodynamically unstable patients and those with continuing ischemia, treatment should be implemented according to the 2010 advanced cardiac life support CPGs.585 Cocaine and methamphetamine users (cont'd) It is reasonable to use benzodiazepines alone or in combination with NTG to manage hypertension and tachycardia and signs of acute cocaine or methamphetamine intoxication IIa C 741 744 Do not administer beta blockers to patients with recent cocaine or methamphetamine use who have signs of acute intoxication due to risk of potentiating coronary spasm III: Harm C N/A Vasospastic (Prinzmetal) angina Recommend CCBs alone or in combination with nitrates I B 753 758 Recommend HMG-CoA reductase inhibitor, cessation of tobacco use, and atherosclerosis risk factor modification I B 759 763 Recommend coronary angiography (invasive or noninvasive) for episodic chest pain with transient ST-elevation to detect severe CAD I C N/A Provocative testing during invasive coronary angiography* may be considered for suspected vasospastic angina when clinical criteria and noninvasive assessment fail to determine diagnosis IIb B 764 767 ACS with angiographically normal coronary arteries Invasive physiological assessment (coronary flow reserve measurement) may be considered with normal coronary arteries if endothelial dysfunction is suspected Stress (Takotsubo) cardiomyopathy Consider stress-induced cardiomyopathy in patients with apparent ACS and nonobstructive CAD I C N/A Perform ventriculography, echocardiography, or MRI to confirm or exclude diagnosis I B 795 798 Treat with conventional agents (ACE inhibitors, beta blockers, aspirin, and diuretics) if hemodynamically stable I C N/A Administer anticoagulant therapy for LV thrombi I C N/A It is reasonable to administer catecholamines for symptomatic hypotension in the absence of LV outflow tract obstruction IIa C N/A It is reasonable to use IABP for refractory shock IIa C N/A It is reasonable to use beta blockers and alpha-adrenergic agents for LV outflow tract obstruction IIa C N/A Prophylactic anticoagulation may be considered to prevent LV thrombi IIb C N/A *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 but very infrequently. Therefore, provocative tests 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. ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCB, calcium channel blocker; CKD, chronic kidney disease; COR, Class of Recommendation; CrCl, creatinine clearance; CVD, cardiovascular disease; DM, diabetes mellitus; GDMT, guideline-directed medical therapy; GP, glycoprotein; HF, heart failure; IABP, intra-aortic balloon pump; LOE, Level of Evidence; LV, left ventricular; MRI, magnetic resonance imaging; N/A, not available; NSTE-ACS, non ST-elevation acute coronary syndrome; NTG, nitroglycerin; PCI, percutaneous coronary intervention; and UFH, unfractionated heparin. Table 11. Continued Recommendations COR LOE References Sinus bradycardia is especially common with inferior NSTEMI. Symptomatic or hemodynamically significant sinus bradycardia should be treated with atropine and, if not respon- sive, temporary pacing. The incidence of complete heart block is 1.0% to 3.7% in NSTEMI, based on anterior or posterior/ inferior location, respectively.586 Atrioventricular block and bun- dle-branch block develop in approximately 5% of patients.587 High-degree atrioventricular block or bundle-branch block in anterior NSTEMI is more ominous because of a greater extent of myocardial injury and involvement of the conduction system.587 First-degree atrioventricular block does not require treat- ment. High-grade atrioventricular block after inferior NSTEMI usually is transient, with a narrow QRS complex and a junctional escape rhythm that can be managed with an ischemia-guided strategy. Prophylactic placement of a tem- porary pacemaker is recommended for high-grade atrioven- tricular block, new bundle-branch block, or bifascicular block with anterior infarction. Indications for permanent pacing are reviewed in the 2012 device-based therapy CPG.20 7.2.2. Cardiogenic Shock: Recommendation Class I 1. Early revascularization is recommended in suitable patients with cardiogenic shock due to cardiac pump failure after NSTE-ACS.560,588,589 (Level of Evidence: B) AMI is the leading cause of cardiogenic shock. Early revascular- ization is a mainstay in the treatment of cardiogenic shock.560,589 Compared with medical therapy, early revascularization is asso- ciated with improved 6-month mortality560 and 13% absolute mortality reduction at 6 years.588 Urgent revascularization with CABG may be indicated for failed PCI, coronary anatomy not amenable to PCI, and at the time of surgical repair of a mechani- cal defect (eg, septal, papillary muscle, free-wall rupture). Age alone is not a contraindication to urgent revascularization for Mortality after cardiogenic shock has including in older adults,589,590 mortality ranging from approximately 40% with milder forms of to >45% with refractory shock.592 of patients in the IABP-SHOCK (Intra-Aortic Balloon Pump in Cardiogenic Shock) II trial presented with NSTEMI,268 of patients in the TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable Acute Myocardial Infarction PatientsWith Cardiogenic Shock) trial had ST depres- sion on presentation.592 Of the 23% of patients with ACS who had NSTEMI in the GRACE registry, 4.6% of patients experi- enced cardiogenic shock.593 Of the 2992 patients in shock, 57% underwent cardiac catheterization, and in-hospital revasculariza- tion was performed in 47% of this group. In-hospital mortality of all patients with shock was 59%.594 Patients with NSTEMI developed cardiogenic shock later than patients with STEMI, and had higher-risk clinical character- istics, more extensive CAD, and more recurrent ischemia and infarction before developing shock compared with patients with STEMI, and shock developed later in patients with NSTEMI.151 Patients with NSTEMI constituted >17% of those in the SHOCK They were also older and had more comorbidi- ties but had comparable mortality to patients with STEMI. The left circumflex coronary artery was the culprit vessel in 30% of patients with NSTEMI, suggesting the presence of true poste- Dopamine in patients with cardiogenic shock may be associated with increased mortality compared with norepi- The use of percutaneous ventricular assist devices has been hampered by the need for interventional expertise, cost, and lack of supportive evidence.597 IABP has been used for and it may facilitate intervention in patients who are hemodynamically unstable, but it did not reduce mortality or secondary endpoints in 1 RCT of 598 patients with cardiogenic shock complicating AMI.268 Newer devices with higher levels of support have provided better hemodynamic support but without improved clinical outcomes compared with IABP.599,600 See Online Data Supplement 26 for additional information on cardiogenic shock. 7.3. Diabetes Mellitus: Recommendation Class I 1. Medical treatment in the acute phase of NSTE-ACS and decisions to perform stress testing, angiography, and re- vascularization should be similar in patients with and without diabetes mellitus.138,339,601 (Level of Evidence: A) CAD accounts for 75% of deaths in patients with diabetes mel- litus; >30% of patients with NSTE-ACS have diabetes mellitus; and patients with NSTE-ACS and diabetes mellitus have more adverse outcomes (eg, death, MI, readmission withACS, or HF) during follow up.593,602,603 The latter may be related to increased plaque instability and comorbidities, including hypertension, LV hypertrophy, cardiomyopathy, HF, and autonomic dysfunc- Patients with diabetes mellitus and ACS have longer delays from symptom onset to presentation,593,606,607 which may be attributable to their atypical symptoms. There is a U-shaped relationship between glucose levels and mortality in patients with diabetes mellitus and ACS.543 Both hyperglycemia and hypoglycemia have similar adverse effects on in-hospital and 6-month mortality. The urgency to aggressively control blood glucose has been moderated by the results of the NICE-SUGAR (Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regimen) trial.608 In this study of patients admitted to medical and surgical intensive care units, intensive glucose control (target 81 mg/dL to 108 mg/dL) resulted in increased all-cause mortality and hypoglycemia com- pared with moderate glucose control (target <l80 mg/dL). Blood glucose should be maintained at <l80 mg/dL while avoiding hypoglycemia. There is no established role for the administration of glucose-insulin-potassium infusions in NSTE-ACS.609 611 Although patients with diabetes mellitus and NSTE-ACS are at higher risk for in-hospital and longer-term events, they undergo less frequent revascularization procedures. In a mul- tinational study of 6385 patients with ACS, 25% of whom had diabetes mellitus, those with diabetes mellitus had more adverse risk profiles, more atypical presentations, longer treat- ment delays, more HF, and renal insufficiency but underwent less angiography and revascularization.607 In the GRACE and other studies,606 patients with diabetes melli- tus and NSTE-ACS in the United Kingdom603 had higher baseline risk profiles but received effective medical cardiac therapies and revascularization less frequently. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e387 Although there are no RCTs of patients specifically diagnosed with diabetes mellitus andACS, there are ample data on patients with diabetes mellitus treated with PCI or CABG.564,565,613 615 The largest RCT, the FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) trial,616 patients (approximately 30% with recent [interval unspecified] ACS) with 2- or 3-vessel CAD randomized to a DES or CABG. At 5 years, there was a significant decrease in all-cause mortality (P=0.049; MI: P<0.001) associated with CABG. There was no specific analysis of outcomes in patients with recent (interval unspecified) ACS. CABG was also superior to PCI in reducing MACE in other trials564,613 615 (Appendix 4, Table D). The importance of the severity and complexity of CAD was underscoredintheSYNTAXtrial,inwhichthosewithlesssevere and complex CAD had similar outcomes with PCI and CABG compared with those with more severe and complex disease, in which CABG improved outcomes, including survival.355,565 7.3.1. Adjunctive Therapy A meta-analysis (6 trials: 23072 patients without diabetes mel- litus, 6458 patients with diabetes mellitus) of the effect of GP IIb/IIIa platelet receptor inhibitors (abciximab, eptifibatide, and tirofiban) on mortality in NSTEMI revealed that for the entire patient group, a GP IIb/IIIa inhibitor was associated with This benefit was particularly large in the 1279 patients with dia- betes mellitus who underwent PCI (4.0% to 1.2%; P=0.002). 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. 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. 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. 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. 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. 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. 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. 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. 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/). 