CAT 2

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/or cardiogenic shock should undergo immediate angiography within 2 hours of hospital presentation no matter the ECG findings (Class I, LOE A). However, for patients that are hemodynamically and electrically stable without ongoing angina, clinicians must select between an early invasive strategy or an ischemia-guided strategy.

An early invasive strategy is defined as angiography within 72 hours of admission to risk stratify patients based on coronary anatomy. The advantages to an early invasive strategy include rapid evaluation, early revascularizaton, and earlier discharge. An early invasive strategy is indicated for initially stabilized patients with NSTE-ACS without contraindications to angiography and elevated risk of recurrent events (Table 128-6). Multiple studies and meta-analyses suggests that an early invasive strategy is preferred to an ischemia-guided strategy in higher-risk patients with NSTE-ACS as it is associated with lower rates of repeat hospitalization, myocardial infarction, and mortality. In a combined analysis of multiple randomized trials, there was an 11.1% absolute reduction (NNT9) in death and myocardial infarction in the highest risk NSTE-ACS by 5-year follow-up. An early invasive strategy is also associated with less angina and improved quality of life. It should be remembered that these are strategy trials, and not a comparisons of revascularization and medical therapy. Patients undergo revascularization with CABG or PCI revascularization in about 70% of patients randomized to an early invasive strategy and in 40% to 50% of patients randomized to an ischemia-guided strategy.

TABLE 128-6 Intermediate or High Risk Non–ST-Elevation Acute Coronary Syndrome (NSTE-ACS) Criteria

Intermediate or High risk NSTE-ACS is defined by one or more of the following: 1. Recurrent angina/ischemia at rest with low-level activities despite intensive medical

therapy 2. Elevated troponin 3. New/dynamic ST-segment depression 4. Signs/symptoms of heart failure or new/worsening mitral regurgitation 5. High-risk findings from noninvasive testing 6. Hemodynamic instability 7. Sustained ventricular tachycardia (>30 s and/or hemodynamic instability) 8. PCI within 6 mo 9. TIMI risk score ≥3

10. Newly reduced left ventricular function (LVEF < 40%)

In contrast, an ischemia-guided strategy aims to avoid routine angiography unless patients experience refractory or recurrent angina, hemodynamic instability, or objective evidence of severe ischemia. An ischemia-guided strategy is preferred in patients at low risk for recurrent events, especially in troponin negative NSTE-ACS with low TIMI risk scores (≤2) (Table 128-7). Patients undergoing an ischemia-guided strategy should undergo noninvasive testing prior to discharge (Class I, LOE B). The optimal test depends

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on the patient’s baseline ECG, available technologies, and local expertise. Due to low costs and simplicity, the exercise treadmill testing is preferred in patients when the baseline ECG is free of ST changes or LBBB (Class I, LOE C). If there are abnormal ST changes on the baseline ECG, then imaging (Single Photon Emission Computed Tomography or Echocardiogram) can be added to the exercise test (Class I, LOE B). Pharmacologic stress testing with imaging is recommended for patients unable to exercise due to physical limitations (Class I, LOE C).

TABLE 128-7 Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Non–ST- Elevation Acute Coronary Syndrome (NSTE-ACS)

TIMI Risk Score 14-day Risk of Mortality, Recurrent MI, or Severe Ischemia Requiring Revascularization

0-1 4.7% 2 8.3% 3 13.2% 4 19.9% 5 26.2% 6-7 40.9%

TIMI risk score is determined by presence of seven variables on admission and one point given to each of the following: age ≥ 65 y, ≥3 cardiac risk factors, prior CAD defined as stenosis ≥50%, ST deviation on ECG, ≥2 anginal events in 24 h, use of aspirin in prior 7 d, and elevated cardiac troponin.

PRACTICE POINT

NSTE-ACS Low-risk patients with possible ACS do not need admission to the hospital and can be safely monitored in an observation unit. All patients admitted to the hospital should receive the following on admission: aspirin 325 mg followed by 81 mg a day, an oral P2Y12 antagonist (clopidogrel or ticagrelor) loading dose followed by maintenance therapy, and anticoagulation (unfractionated heparin preferred if invasive management possible). Morphine and oxygen should be avoided in most patients. Nitroglycerin should be avoided in patients with right ventricular infarctions, hypotension, and/or recent phosphodiesterase-5 inhibitor use. Upstream glycoprotein IIb/IIIa inhibitors are not indicated in patients with NSTE-ACS when upstream dual antiplatelet therapy (aspirin + oral P2Y12 antagonist) is used. Serial troponin-only testing at 0, 3, and 6 hours can be used to diagnose or rule out myocardial infarction. There is little role for other cardiac biomarkers (CK, CKMB, or myoglobin). Patients with refractory angina or cardiogenic shock should undergo emergent angiography within 2 hours of admission, even if there is no evidence of ST-elevations

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on ECG. Initially stabilized patients at intermediate or high risk should undergo an angiography with intent to perform intervention within 72 hours of admission. Patients at low risk should undergo an ischemia-guided strategy with noninvasive stress testing.

LATE HOSPITAL CARE & HOSPITAL DISCHARGE DUAL ANTIPLATELET THERAPY

All patients with ACS should receive aspirin therapy indefinitely. Regardless if medically managed or revascularized with PCI or surgery, patients should receive low dose 81 mg daily as it appears to be equally efficacious as higher doses but with lower bleeding complications. In addition to aspirin, all patients with ACS should receive a P2Y12 antagonist for 1 year regardless if treated with a bare metal stent or a drug eluting stent or without PCI. There are three options for patients who undergo PCI for ACS: clopidogrel, prasugrel, or ticagrelor. There are two options for patients who are medically managed without PCI: clopidogrel or ticagrelor. There is no consensus to the optimal P2Y12 antagonist in ACS at present.

The benefits of 1 year of dual antiplatelet therapy was established from the CURE trial, where dual antiplatelet therapy (clopidogrel and aspirin) resulted in a 20% reduction (NNT = 48) in cardiovascular death, myocardial infarction, or cerebrovascular accident compared with aspirin alone in 12,562 patients with ACS. This benefit was noted in patients who were managed both conservatively and invasively with PCI. Now that clopidogrel is generic, the low cost makes it an attractive option in ACS.

Prasugrel is a P2Y12 antagonist that is more efficiently metabolized to its active metabolite with greater potency and more rapid onset of action than clopidogrel. In 13,608 patients with ACS in the TRITON TIMI 38 trial, there were lower composite of death, myocardial infarction, and stroke in patients randomized to prasugrel compared to clopidogrel (9.9% vs 12.1%, NNT45, p < 0.001). However, there was significantly more major bleeding with prasugrel (2.4% vs 1.8%, NNH167, p = 0.03). Furthermore, patients over 75 years of age, body weight less than 60 pounds, and a history of stroke or transient ischemic attack had worse outcomes with prasugrel and there is a black box warning to avoid prasugrel in these patients. Despite the warning, up to 18% of patients in real word practice receive received prasugrel with these contraindications. In addition, there is little benefit to prasugrel in patients medically managed for ACS without PCI. In the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, prasugrel failed to reduce cardiac event rates compared to clopidogrel in patients with ACS undergoing medical therapy.

Ticagrelor is a direct acting P2Y12 antagonist that does not require metabolic activation. In 18,624 patients with ACS in the PLATO trial, ticagrelor reduced the composite of death, myocardial infarction, and stroke compared to clopidogrel (9.8% vs 11.7%, NNT53, p = 0.003). This benefit was noted in patients undergoing PCI and those medically managed without PCI. Using the same bleeding definition used in TRITON TIMI 38 (non- CABG TIMI major bleeding), there was again more major bleeding with tiacagrelor compared to clopidogrel (2.8% vs 2.2%, NNH167, p = 0.03). Interestingly, patients randomized in the United States and Canada did not derive a benefit with ticagrelor and trended toward harm. While this finding may be due to chance, interactions with the higher

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aspirin dose may also explain this finding. Therefore, in the United States ticagrelor is approved for use only with the lower aspirin dose (81 mg) with a warning against the use with the higher aspirin dose.

How is one to choose between these three P2Y12 antagonist agents: clopidogrel, prasugrel, and ticagrelor? All three agents have a similar recommendation in the ACCF/AHA guidelines (Class I, LOE B). However, these medications have very different costs, efficacy, and safety considerations. While both ticagrelor and prasugrel were shown to be superior to clopidogrel in large randomized trials, the benefits of these medications over clopidogrel seem to be most pronounced in patients with abnormalities in clopidogrel metabolism. Clopidogrel is a prodrug that requires two-step metabolism into an active metabolite. Patients with abnormalities in the CYP2C19 allele have impaired metabolism, higher on-treatment platelet reactivity, and worse outcomes with clopidogrel. Up to 30% of the US population has abnormalities in this CYP2C19 allele, and clopidogrel carries a warning of reduced efficacy in these patients. In the genetic subgroup analysis of the TRITON TIMI 38 trial, prasugrel and clopidogrel had similar outcomes in patients with normal CYP2C19 alleles. In contrast, the benefit of prasugrel was much greater in patients with abnormal CYP2C19 alleles (NNT16) compared to overall trial (NNT50). A similar trend was noted for ticagrelor in the genetic subgroup analysis of the PLATO trial. Taken together, these trials suggest that the benefits of prasugrel and ticagrelor are most pronounced in patients with abnormal CYP2C19 alleles with clopidogrel. However, for the remaining 65% to 75% of the ACS population, clopidogrel may be as effective, safer, easier to use, and more cost effective. Whether a tailored strategy based on genotype or platelet function testing is safe and effective with improved value is unknown and randomized trials are warranted.

BETA BLOCKERS

Oral β-blockers are recommended within 24 hours of presentation for patients with STEMI (Class I, LOE B) and NSTE-ACS (Class I, LOE A) and should be continued at discharge. β- Blockers decrease heart rate, contractility, blood pressure, and myocardial oxygen consumption. While early β-blockers do not reduce short-term mortality in patients with ACS, they decrease ischemia, reinfarction, and ventricular arrhythmia. Furthermore, β- blockers improve long-term survival in patients with MI complicated by heart failure and ventricular arrhythmia. The long-term duration of routine β-blocker therapy after myocardial infarction without heart failure or hypertension has not been prospectively addressed, but guidelines recommend a 3-year treatment course then reassess the clinical need for the medication. Meta-analysis from the reperfusion era suggests β-blockers can reduce MI (RR 0.72 [95% CI, 0.62-0.83], NNT = 209) and angina (RR 0.80 [95% CI, 0.65- 0.98], NNT = 26) at the expense of increased heart failure (RR 1.1 [95% CI, 1.05-1.16], NNH = 79) and increased cardiogenic shock (RR 1.29 [95% CI, 1.18-1.41], NNH = 90)with no significant impact on mortality. While oral β-blockers are an important part of ACS management, IV β-blockers should usually be avoided as they increase the risk for shock (Class III, LOE B). In addition, oral β-blockers are contraindicated in patients with signs of acute heart failure, evidence of low-output state, increased risk for cardiogenic shock, second- or third-degree heart block, and active asthma. When β-blockers are contraindicated due to asthma exacerbation, then nondihyophyidine calcium channel blockers could be considered as long there are no contraindications (Class I, LOE B).

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RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM INHIBITORS

Angiotensin Converting Enzyme (ACE) inhibitors have been shown to lower mortality in patients with recent myocardial infarction and reduced left ventricular ejection fractions (LVEF) less than 40% (Class I, LOE A). Furthermore, ACE inhibitors should be strongly considered in patients with diabetes mellitus and stable chronic kidney disease (Class I, LOE A). In patients who are intolerant to ACE inhibitors, angiotensin receptor blockers (ARBs) should be considered. While meta-analyses suggest a small (0.48% absolute, NNT = 208) reduction in 30-day mortality with ACE inhibitors in ACS, the clinical significance of this finding is unclear and ACE inhibitor should be used with caution without the above indications given the risk for renal dysfunction and hypotension.

Aldosterone antagonists (eg, eplerenone, spironolactone) are recommended for patients with AMI and LVEF less than or equal to 40% (Class I, LOE B). In the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival) study, demonstrated significantly reduced rates of death from cardiovascular causes or hospitalization for cardiovascular events (relative risk, 0.87; 95% CI, 0.79-0.95; P = 0.002, NNT = 30) in patients with eplerenone initiated within days of admission.

HIGH-INTENSITY STATIN THERAPY

High-intensity statin therapy should be given to all patients with ACS without contraindications (Class I, LOE A). Statins should be started at moderate to high doses as soon as possible on admission and continued indefinitely. The benefits of statin therapy are well known in the primary prevention for high-risk patients and in secondary prevention for patients with CAD. There may also be an early acute benefit in patients with NSTE-ACS. Several studies have demonstrated reduced rates of periprocedural MI with high-dose statin loading before PCI; therefore, a statin is recommended before PCI when possible (Class IIa, LOE A for statin naive).

ANTICOAGULATION USE WITH ANTIPLATELET THERAPY IN ACS

The choice of stent, P2Y12 antagonist, duration of dual antiplatelet therapy, and anticoagulant is important for patients that require anticoagulation after ACS. This includes patients with atrial fibrillation, venous thromboembolism, mechanical heart valves, and left ventricular thrombus. When anticoagulation is warranted, warfarin is the most common anticoagulant agent and clopidogrel and aspirin the most common antiplatelet agents used. Very little data support the safety of the novel anticoagulants and P2Y12 inhibitors in this setting. In addition, patients with a history of gastrointestinal bleeding who require anticoagulation and antiplatelet therapy should also receive proton pump inhibitors (PPIs) (Class I, LOE C). A PPI can also be considered in patients without history of gastrointestinal bleeding when anticoagulation and antiplatelet therapy are warranted (Class IIa, LOE C). While there were early concerns over potential interactions with certain PPIs and clopidogrel metabolism, more recent registry and randomized trials suggest reductions in bleeding complications without increased cardiac events with the combination of PPIs and clopidogrel.

Triple therapy (aspirin, clopidogrel, and warfarin) after PCI is associated with two- to fivefold greater risk of major bleeding compared to dual antiplatelet therapy. Recent studies suggest that aspirin can often be omitted when anticoagulation is warranted after PCI. In the 573 patient randomized WOEST trial, omission of aspirin decreased major

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bleeding complications (44.4% vs 19.4%, NNH [by adding aspirin] 4, p < 0.0001) without any increase in ischemic events. Similar findings were noted in a meta-analysis of 1263 patients from six randomized trials as well as a larger real world registry of 12,165 patients undergoing PCI requiring anticoagulation.

Left ventricular (LV) mural thrombus is found in 3% to 15% of anterior MIs treated with percutaneous coronary revascularization. Pooled studies have noted a fivefold increased risk for systemic embolism with LV thrombus after anterior MI, and anticoagulation therapy decreases this embolic risk. Thus, anticoagulation is recommended for patients with acute MI and asymptomatic LV mural thrombus (Class IIa, LOE C). Anticoagulation after anterior MI without mural thrombus formation is controversial. Currently, the guidelines suggest that anticoagulation therapy may be considered for patients with STEMI and anterior apical akinesis or dyskinesis (IIb, LOE C). However, in a recent retrospective analysis of 460 undergoing PCI for anterior MI without LV thrombus, anticoagulation was actually associated with an increased incidence of stroke (3.1% vs 0.3%, p = 0.02), major bleeding (8.5% vs 1.8%, p < 0.0001), mortality (5.4% vs 1.5%, p = 0.04), length of stay, and readmissions. Furthermore, after propensity matching, anticoagulation was still associated with a fourfold greater incidence of net adverse cardiac events. These findings certainly question the routine use of triple therapy in this population without LV thrombus. Until larger randomized trials are conducted, if anticoagulation is used in this setting, clinicians should probably omit aspirin, add proton pump inhibitors, target lower INR ranges, shorten the anticoagulation course (3 months), and use radial access when possible.

SECONDARY PREVENTION

All patients with ACS should be referred to a comprehensive cardiovascular rehabilitation program (Class I, LOE B). These programs provide patient education, regular exercise, monitor risk factors, and address lifestyle modification. The pneuomococcal vaccine is recommended for patients 65 years and older and high-risk patients with cardiovascular disease (Class I, LOE B). In addition, annual influenza vaccination is recommended for all patients with ACS (Class I, LOE C), and based on randomized controlled trial data has been shown to reduce MACE (NNT = 17) and hospitalization for ACS (NNT = 31). NSAIDs have been associated with increased cardiovascular risk and should largely be avoided in patients with ACS (Class III, LOE B). For patients with chronic musculoskeletal pain, acetaminophen, nonacetylated salicylates, tramadol, or low dose narcotics should be used as required (Class I, LOE C). If NSAIDs are required when these therapies are insufficient, then the nonselective naproxen is preferred over other NSAIDS (Class IIa, LOE C).

PRACTICE POINT

Late Hospital ACS Care and Hospital Discharge All patients with ACS should be discharged with dual antiplatelet therapy.

Options for P2Y12 antagonists include clopidogrel, prasugrel, and ticagrelor after PCI. Options for P2Y12 antagonists include clopidogrel and ticagrelor with medical management without PCI.

All patients with ACS should receive high-intensity statin therapy.

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All patients with MI should receive oral β-blocker therapy for at least 3 years after myocardial infarction and indefinitely for patients with congestive heart failure and/or hypertension. All patients with reduced LVEF ≤ 40% should receive an ACEI or ARB and aldosterone antagonist unless contraindications. When anticoagulation is warranted in patients with PCI for ACS, warfarin is preferred and aspirin can usually be omitted. All patients should be counseled about smoking cessation, diet, and exercise. All patients should be referred to cardiac rehabilitation programs at discharge.

Discharge checklist

Dual antiplatelet therapy High-intensity statin Referral to cardiac rehabilitation Smoking cessation education β-Blocker if myocardial infarction and no contraindications ACE inhibitor (or ARB) if diabetic, chronic renal failure, or LVEF≤40% and no contraindications Aldosterone inhibitor if LVEF≤40% and no contraindications

SUGGESTED READINGS American Heart Association’s Mission: Lifeline:

http://www.heart.org/HEARTORG/HealthcareResearch/MissionLifelineHomePage/Missi on-Lifeline-Home-Page_UCM_305495_SubHomePage.jsp

Amsterdam EA, Wenger NK, Brindis RG, et al. AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228.

Bangalore S, Makani H, Radford M. Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med. 2014;127(10):939-953.

Dewilde WJ, Oirbans T, Verheugh FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomized, controlled trial. Lancet. 2013;381:1107-1115.

Jolly SS, Yusuf S, Cairns J, et al. Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomized, parallel group, multicenter trial. Lancet. 2011;377:1409-1420.

Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med. 2009;361(9):868-877.

McDaniel M, Ross M, Rab ST, et al. A comprehensive acute coronary syndrome algorithm for centers with percutaneous coronary intervention capability. Crit Pathw Cardiol. 2013;12(3):141-149.

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Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003;108(14):1664- 1672.

O’Gara PT, Kushner FG, Ascheim DD, et al. ACCF/AHA guideline for the management of ST- elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140.

Osborne AD, Ali K, Lowery-North D, et al. Ability of triage decision rules for rapid electrocardiogram to identify patients with suspected ST-elevation myocardial infarction. Crit Pathw Cardiology. 2012;11:211-213.

Panju AA, Hemmelgarn BR, Guyatt GH. The rational clinical examination. Is this patient having a myocardial infarction? JAMA. 1998;280(14):1256-1263.

Rab T, Kern KB, Tamis-Holland JE. Interventional Council, American College of Cardiology. Cardiac arrest: atreatment algorithm for emergent invasive cardiac procedures in the resuscitated comatose patient. J Am Coll Cardiol. 2015;66(1):62-73.