Acute Coronary Syndrome

AUTHORS: George H. Nasr, MD and Pranav M. Patel, MD, FACC, FAHA, FSCAI

Acute coronary syndrome (ACS) represents a spectrum of clinical disorders that results from a sudden and unpredictable decrease of blood flow to the myocardium. ACS is a life-threatening disorder that incurs high, and in some cases immediate, mortality. This syndrome is usually due to interaction of vulnerable atherosclerotic plaque in the coronary arteries with that of activated clotting factors and platelets in the systemic circulation. In the modern era, management of ACS involves highly protocolized and systematic care of both procedural and medical therapies guided toward restoring blood flow to the heart. The spectrum of ACS is predominated by two important subtypes: ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). The third category of ACS is called unstable angina (UA) and falls within the NSTEMI subtype. The type of ACS dictates the timing of reperfusion, with STEMI being the most severe and always emergent. In this spectrum, UA and NSTEMI are represented by an abnormal ECG without the presence of ST-segment elevation in the appropriate clinical setting (i.e., chest discomfort). NSTEMI is additionally characterized by positive cardiac biomarkers. STEMI is characterized by ST-segment elevation on ECG in the appropriate clinical setting.¹ With the advent and widespread use of the high-sensitivity troponin, the diagnosis of UA has changed to NSTEMI in almost all patients formerly diagnosed with UA. This is in part due to patients previously diagnosed with UA having abnormally elevated high-sensitivity troponin levels.² Thus ACS should be thought of as a continuous spectrum as UA will often progress to a myocardial infarction (MI) if left untreated (Table 1). Because of this continuum, the 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines have grouped UA and NSTEMI into a single category called non-ST-elevation ACS (NSTE-ACS).³

TABLE 1 Acute Coronary Syndromes

Spectrum of Acute Coronary Syndrome
	Unstable Angina	NSTEMI	STEMI
Chest discomfort	1	1	1
Cardiac biomarkers	2	1	1
ECG changes	TWI and/or ST depression	TWI and/or ST depression	ST elevation or presumed new left bundle branch block
Pathophysiology	Partial/transient thrombotic occlusion	Partial/transient thrombotic occlusion	Complete thrombotic occlusion

ECG, Electrocardiogram; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment myocardial infarction; TWI, T-wave inversion.

Synonyms

ACS

NSTEMI

STEMI

Acute MI

ICD-10CM CODES
I20.0		Unstable angina
I21.0-I21.3		ST elevation (STEMI)
I21.4		Non-ST elevation (NSTEMI) myocardial infarction
I24.9		Acute ischemic heart disease, unspecified

Epidemiology & Demographics

Incidence

In the U.S., cardiovascular disease accounts for approximately 640,000 deaths each year. The estimated annual incidence of heart attacks in the U.S. is 600,000 new attacks and 200,000 recurrent attacks.⁴ Approximately 70% of MIs are listed as NSTEMI, with the remainder being listed as STEMI. Patients presenting with NSTE-ACS have worse long-term prognosis than patients presenting with STEMI. This is due to the higher comorbidity profile of patients presenting with NSTE-ACS (i.e., significantly older population, higher burden of comorbidities, and frequent history of coronary artery disease [CAD]). The underlying etiology, atherosclerotic CAD, remains the number one cause of mortality.⁴

Predominant Sex and Age

In the U.S., the median age at ACS presentation is 68 yr old (interquartile range 56 to 79), and the male:female ratio is approximately 3:2. In a 2005 to 2011 study sponsored by National Heart, Lung, and Blood Institute, the average age-adjusted first MI or fatal coronary heart disease rates per 1000 population in patients age 35 to 84 yr of age were 3.7 for white men, 5.9 for black men, 2.1 for white women, and 4.0 for black women.⁴ As noted in this study, heart disease affects African Americans disproportionately. Heart disease is also the leading cause of death in women, surpassing all forms of cancer.⁴

Risk Factors

Hypertension, diabetes mellitus, dyslipidemia, tobacco use, and family history of premature CAD (CAD in a male first-degree relative younger than 55 yr or a female younger than 65 yr of age) are all associated risk factors for CAD. There are also female-specific risk factors for CAD, including disorders of pregnancy and early onset of menopause. Refer to the topic “Angina Pectoris” for an extensive list of risk factors. Presence of these risk factors cause damage to the vascular endothelium and progression of atherosclerotic coronary artery plaques.

Physical Findings & Clinical Presentation

Symptoms often, but not always, include chest discomfort described as a pressure that may radiate to the shoulders, neck, jaw, or back. Typical angina is substernal in location, brought on by emotional or physical stress, and relieved with rest and/or nitroglycerin. The pain and discomfort associated with an ACS event is often diffuse rather than localized and often associated with diaphoresis.
Women, diabetics, the elderly (>75 yr old), and postoperative patients often have an atypical presentation for ACS.
UA has three typical presentations:
1. Rest angina: Angina occurring at rest and usually prolonged for longer than 20 min.
2. New-onset angina: New-onset angina of at least Canadian Cardiovascular Society (CCS) class III symptoms (Table 2).
3. Progressive angina: Previously diagnosed angina that has become distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by ≥1 CCS class to at least CCS class III severity).
“Anginal equivalents” may include dyspnea, nausea, vomiting, and fatigue.
ECG for NSTE-ACS may reveal transient ST-segment elevation, ST-segment depression, and/or new T-wave inversion. ECG for definition of STEMI will reveal ≥1-mm ST-segment elevation at the J-point in two contiguous leads other than leads V₂-V₃ in which cut-points are ≥2-mm in men ≥40 yr, ≥2.5-mm in men <40 yr, or ≥1.5-mm in women regardless of age.¹
Physical examination findings alone are insufficient for the diagnosis of ACS. The physical examination may provide clues as to alternative diagnoses, such as aortic dissection (differences in pulse and blood pressure between the arms, murmur of aortic regurgitation), aortic stenosis, pericarditis (friction rub), cardiac tamponade (pulsus paradoxus), and pneumothorax (absent breath sounds). In ACS, it is important to assess the patient’s hemodynamic stability, as signs of heart failure may be present. These signs include elevated jugular venous pressure (JVP), presence of an S3 gallop, rales, and to a lesser extent, peripheral edema. The degree of heart failure with MI can be represented by the Killip classification, with the greater the Killip classification, the greater the mortality noted ⁵:
1. Killip Class 1 is no heart failure.
2. Killip Class 2 includes individuals with rales, elevated JVP, and S3 on examination.
3. Killip Class 3 includes individuals with frank pulmonary edema.
4. Killip Class 4 describes individuals in cardiogenic shock or hypotension with evidence of vasoconstriction noted.

TABLE 2 Grading of Angina Pectoris According to CCS Classification

Class		Description of Stage
I		“Ordinary physical activity does not cause angina,” such as walking or climbing stairs. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation.
II		“Slight limitation of ordinary activity.” Angina occurs on walking or climbing stairs rapidly; walking uphill; walking or stair climbing after meals; in cold, in wind, or under emotional stress; or only during the few hours after awakening. Angina occurs on walking 0.2 blocks on the level and climbing 0.1 flight of ordinary stairs at a normal pace and under normal conditions.
III		“Marked limitations of ordinary physical activity.” Angina occurs on walking 1-2 blocks on the level and climbing one flight of stairs under normal conditions and at a normal pace.
IV		“Inability to carry on any physical activity without discomfort-anginal symptoms may be present at rest.”

Adapted with permission from Campeau L: Grading of angina pectoris (letter), Circulation 54:522-523, 1976. © 1976, American Heart Association, Inc.From Braunwald E et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina), J Am Coll Cardiol 36:970-1062, 2000.

Etiology

The hallmark of ACS is vulnerable atherosclerotic plaque, which typically has a thin fibrous cap and a large lipid core. This vulnerable plaque can spontaneously rupture, which leads to platelet activation and aggregation and a systemic inflammatory cascade, leading to thrombus formation. STEMI typically results from complete thrombotic occlusion of a coronary artery, whereas NSTE-ACS often has partial occlusion. Angiographically, it is often the intermediate coronary artery lesions (30% to 50% diameter vessel stenosis) that lead to subtotal or total vessel occlusion in two thirds of STEMI cases.

PEARLS AND CONSIDERATIONS

The overall goal for patients with ACS is to relieve myocardial ischemia and to prevent recurrent cardiovascular events. This is achieved by targeting both vulnerable coronary plaque and activated clotting factors and platelets in the blood. Revascularization, whether it is chemical (i.e., thrombolysis) or mechanical (i.e., percutaneous coronary intervention [PCI]), is needed to prevent further events and improve flow within the coronary artery lumen. In the modern era, PCI has improved outcomes for patients presenting with ACS.⁸ For patients with STEMI, time from onset of ischemia to revascularization guides the reperfusion strategy. STEMI patients presenting to a hospital with PCI capability should be treated with primary PCI within 90 min of first medical contact (Figs. 3 and 4). At non-PCI-capable hospitals where the first medical contact to PCI is more than 120 min, thrombolytic therapy should be given to eligible patients within the first 12 h after symptom onset; thrombolytics should not be administered 24 h after initial diagnosis of STEMI (Table 3).⁸ In patients who receive thrombolytic agents, coronary angiography can be done at a receiving hospital as soon as possible but not within the first 2 to 3 h after administration of a fibrinolytic agent. Thrombolytic agents come in two forms, fibrin specific (alteplase, reteplase, tenecteplase, staphylokinase) and nonfibrin specific (streptokinase, anistreplase, urokinase). Absolute contraindications to thrombolytic therapy include the following: History of intracranial hemorrhage, known structural cerebral vascular lesion, known intracranial neoplasm, ischemic stroke within 3 mo, suspected aortic dissection, active bleeding, head trauma within 3 mo, or intracranial surgery within 2 mo. Relative contraindications include ischemic stroke more than 3 mo prior, dementia, major surgery within 3 wk, current oral anticoagulant therapy, and traumatic or prolonged CPR.⁹ Antithrombotic therapy is needed to reduce thrombus burden, prevent further thrombosis, and improve coronary artery flow.

TABLE 3 Reperfusion Strategies

Anticipated time from FMC to PCI	>120 min	<120 min
	and	or
Symptom duration?	<12 h	<24 h
	and	or
Thrombolytic eligible?	YES	NO
Reperfusion strategy	Thrombolytics and transfer	Primary PCI

FMC, First medical contact; PCI, percutaneous coronary intervention.

Figure 4 Right Coronary Artery after Successful Percutaneous Coronary Artery Stenting During ST-Elevation Myocardial Infarction

Figure 3 Right Coronary Artery Totally Occluded Proximally During ST-Elevation Myocardial Infarction

Nonpharmacologic Therapy

STEMI is a medical emergency and requires immediate reperfusion therapy; the best outcomes are seen with cardiac catheterization and primary PCI. Guidelines call for a goal door-to-balloon time of ≤90 min.⁹
Patients with NSTE-ACS should be risk stratified in conjunction with the cardiology consult service. Risk scores such as the TIMI and GRACE scores can be used to decide between an early invasive strategy and an ischemia-guided strategy. Overall, an early invasive strategy is associated with better outcomes in patients with higher risk (i.e., TIMI score >3 or GRACE >140) and involves cardiac catheterization followed by revascularization with PCI or coronary artery bypass grafting (CABG) within 4 to 24 h of presentation. An ischemia-guided strategy involves aggressive medical management and revascularization only if ischemia recurs or is documented on noninvasive testing.³ This should be reserved only for selected patients with low-risk scores (TIMI score 0 to 2). The early invasive strategy can be further stratified by timing:
1. Immediate (within 2 h): Patients with refractory or recurrent angina despite optimal initial treatment, signs or symptoms of heart failure, new or worsening mitral regurgitation, hemodynamic instability, sustained ventricular tachycardia or ventricular fibrillation
2. Early (within 24 h): No characteristics from the immediate category but new ST-segment depression, a GRACE risk score >140 or temporal change in troponin
3. Delayed invasive (25 to 72 h): None of the immediate or early characteristics but renal insufficiency, LV ejection fraction (EF) of <40%, early post-infarct angina, history of PCI within the past 6 mo, prior CABG, GRACE risk score of 109 to 140, or TIMI score of ≥2
Continuous ECG monitoring is recommended for all ACS patients. Supplemental oxygen should be administered to patients with arterial oxygen saturation of <90%, respiratory distress, or other high-risk features of hypoxemia. Finger pulse oximetry should be used to assess arterial oxygen saturation.⁸

Acute General Treatment

Table 4 is a summary of recommendations for standard medical therapy in the early hospital care phase of management of patients with NSTE-ACS.³
Antithrombotic therapy (Table 5) is critical in treating the underlying pathophysiology of ACS. This consists of administering antiplatelet and anticoagulant agents (Table 6).
Antiplatelet agents (Table 7) inhibit platelet activation and aggregation. Aspirin is an irreversible cyclooxygenase inhibitor that blocks platelet aggregation and should be administered to all ACS patients without contraindications.
All patients with ACS should receive full-dose nonenteric-coated chewable aspirin of 162 to 325 mg to establish a high blood level for its antiplatelet effects to occur. Thereafter, daily dose of 81 mg should be continued indefinitely.³
Clopidogrel is a thienopyridine agent that inhibits platelet activation and aggregation. It should be administered in all ACS patients, with the timing dependent on the clinical scenario and management strategy. It requires a loading dose of 300 to 600 mg followed by 75 mg/day. It should be discontinued at least 5 days before CABG to avoid excessive bleeding related to surgery. If a patient is unable to take aspirin in the setting of hypersensitivity or major gastrointestinal intolerance, a loading dose of clopidogrel followed by daily maintenance should be started.³
Other antiplatelet agents that can be substituted instead of clopidogrel include prasugrel and ticagrelor. Ticagrelor has a half-life of 12 h with a more rapid onset and more consistent onset of action. In the PLATO trial, there was a reduction in death from vascular causes, MI, and stroke in patients with NSTE-ACS with ticagrelor over clopidogrel without an increase in the rate of overall major bleeding.¹⁰ This benefit is limited to patients taking aspirin 75 to 100 mg/day. Prasugrel is not recommended as the initial antiplatelet agent in patients with NSTE-ACS. Multiple studies have demonstrated an increase in bleeding in patients taking prasugrel; in particular, those who are >75 yr old, with low body weight (<60 kg), or with a history of cerebrovascular events.¹¹ Cangrelor is an IV ADP-P2Y12 receptor antagonist that may be used initially as a load in the emergency department before an invasive strategy, given its initial action and quick platelet recovery time. As a rule, all ACS patients should have two antiplatelet agents initiated and should be continued up to 12 mo regardless of treatment strategy.³
GP IIb/IIIa inhibitors (Table 8) may be considered as an intravenous antiplatelet therapy in addition to aspirin for medium- or high-risk patients with NSTE-ACS in whom an invasive strategy is planned (Class IIb). Eptifibatide and tirofiban are preferred agents over abciximab for NSTE-ACS patients; however, for STEMI patients undergoing primary PCI, IV abciximab has the same Class IIa indication as tirofiban and ptifibatide.⁹
Anticoagulant agents should be administered to all ACS patients, irrespective of initial treatment strategy. Options include either unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH; enoxaparin), or factor Xa inhibitors such as fondaparinux, or direct thrombin inhibitors such as bivalirudin (Table 9).⁹
For STEMI, fondaparinux can be used for anticoagulation. It has been shown to decrease bleeding complications as compared with either UFH or LMWH. However, it should not be used as the sole anticoagulant in PCI because of the risk of catheter thrombosis.⁹
Bivalirudin is a reversible direct thrombin inhibitor and may be considered as an alternative to UFH and GP IIb/IIIa inhibitors in patients with STEMI who are undergoing primary PCI. When bivalirudin was compared to UFH plus a glycoprotein IIb/IIIa inhibitor in patients with STEMI and PCI, less bleeding and a short- and long-term reduction in cardiac events and overall mortality was observed. With bivalirudin, there is no risk of heparin-induced thrombocytopenia, less bleeding is observed, and the anticoagulant effect can be monitored during intervention by the activated clotting time. Similar results were reported in the use of bivalirudin alone in patients with UA/NSTEMI in the ACUITY trial when compared to enoxaparin/UFH with GP IIb/IIIa arms.¹²
Beta-blocker therapy reduces ischemia by decreasing myocardial oxygen demand and has a proven long-term mortality benefit. Oral therapy should be initiated within 24 hours of onset of ACS unless signs or symptoms of heart failure and shock are present or bradycardia precludes its use. Oral administration, titrated to a heart rate of 50 to 60 beats/min, is preferred.⁹ Intravenous beta-blockers can be administered to STEMI patients who are hypertensive or have ongoing ischemia; they should be avoided if the patients have any of the following:
1. Signs of heart failure
2. Evidence of a low output state
3. Increased risk for cardiogenic shock
4. Other relative contraindications to beta-blockade (PR interval >0.24 sec, second- or third-degree heart block, active asthma, or reactive airway disease)
Nitroglycerin is a vasodilator that should be administered to relieve chest discomfort in all ACS patients. It can be administered sublingually at first, up to 3 doses, followed by intravenous administration if symptoms persist. In the setting of an inferior STEMI, it is necessary to rule out a right ventricular (RV) infarct with a right-sided ECG before the administration of nitroglycerin.⁹ This is because RV infarcts are preload dependent and nitroglycerin decreases preload through venodilation, which leads to hypotension in this setting. This can be corrected by discontinuing nitroglycerin and starting bolus intravenous fluids. Nitrates should not be administered in patients who recently received a phosphodiesterase inhibitor. Of note, nitroglycerin provides no mortality benefit in ACS patients.
Oxygen should be administered to patients with signs of acute heart failure, cardiogenic shock, or an arterial oxyhemoglobin saturation of <90%. The 2014 ACC/AHA guidelines report no demonstrated benefit for routine use of supplemental oxygen in normoxic patients with NSTE-ACS; rather, emerging data suggest that routine use of oxygen can lead to adverse effects such as increased coronary vascular resistance, reduced coronary blood flow, and increased mortality rate.³
Morphine can be used intravenously in patients with NSTE-ACS if there is continued ischemic chest pain despite treatment with maximally tolerated antiischemic medications (Class IIb).⁷
Calcium channel blockers (nondihydropyridine) may be used in patients with persisting or recurrent symptoms, despite treatment with beta-blockers and nitroglycerin. They work by having negative inotropic and chronotropic effects and causing coronary vasodilation. They are especially useful when beta-blockers are contraindicated and in patients with coronary artery spasm. Calcium channel blockers should not be used in cases of severe LV dysfunction, pulmonary edema, increased risk for cardiogenic shock or advanced heart blocks.⁹
Patients routinely taking NSAIDs (except for aspirin), both nonselective as well as COX-2-selective agents, before ACS should discontinue those agents at the time of presentation because of the increased risks of mortality, reinfarction, hypertension, heart failure, myocardial rupture, along with overall cardiovascular and bleeding events. However, there is evolving evidence for the role of colchicine to reduce recurrent event risk in the acute post-MI period, with the COLCOT trial showing a reduction in death from cardiovascular causes, resuscitated cardiac arrest, recurrent MI, stroke or urgent hospitalization for angina leading to coronary revascularization.¹³ No guidelines have been published that reflect the results of this trial.
ACE inhibitors may be added and should be used within 24 h of onset of ACS in all patients with depressed LV function (EF <40%) and those with a history of hypertension, diabetes mellitus, or stable chronic kidney disease. Angiotensin receptor blockers (ARBs) should be used in patients who are ACE inhibitor intolerant.³
Table 10 summarizes indications and cautions for adjunctive medical therapies for patients with STEMI.
Refer to topic “Cocaine Overdose” for treatment of cocaine-related ACS.

TABLE 10 Indications and Cautions for Adjunctive Medical Therapies for Patients With ST-Elevation Myocardial Infarction

Therapy	Indications	Cautions
Beta-adrenergic receptor-blocking agents	Oral: All patients without contraindication IV: Patients with refractory hypertension or ongoing ischemia without contraindication	Signs of congestive heart failure Low-output state Increased risk for cardiogenic shock Prolonged first-degree or high-grade atrioventricular block Reactive airways disease
Angiotensin-converting enzyme (ACE) inhibitors	Anterior myocardial infarction and LVEF ≤0.40 or congestive heart failure All patients without contraindication	Hypotension Renal failure Hyperkalemia
Angiotensin receptor-blocking agents (ARBs)	Intolerant of ACE inhibitors	Hypotension Renal failure Hyperkalemia
Statins	All patients without contraindications	With drugs metabolized via CYP3A4, fibrates Monitor for myopathy, hepatotoxicity Adjust dose for lipid targets
Nitroglycerin	Ongoing chest pain Hypertension and congestive heart failure	Suspected right ventricular infarction SBP <90 (or 30 mm Hg below baseline) Recent use of a type 5 PDE inhibitor
Oxygen	Clinically significant hypoxemia (SpO₂ <90) Congestive heart failure Dyspnea	Chronic obstructive pulmonary disease and CO₂ retention
Morphine	Pain Anxiety Pulmonary edema	Lethargic or moribund patient Hypotension Bradycardia Known hypersensitivity

IV, Intravenous; LVEF, left ventricular ejection fraction; PDE, phosphodiesterase; SBP, systolic blood pressure.

From Zipes DP: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

TABLE 9 Pharmacologic Characteristics of Parenteral Anticoagulants Commonly Used in the Management of Patients With Acute Coronary Syndrome

	Unfractionated Heparin	Enoxaparin	Bivalirudin	Fondaparinux
Route of administration	IV	SC (first dose IV ^a)	IV	SC (first dose IV ^a)
Frequency of dosing	Continuous IV infusion	Twice daily; once daily if CrCl <30 ml/min	Continuous IV infusion	Once-daily injection
Clearance	Primarily nonrenal	Renal	Renal, proteolytic cleavage	Renal
Use in ACS patients with moderate renal impairment	Yes	Yes (dose reduction)	Yes (dose reduction)	Yes ^b
Use in ACS patients undergoing dialysis	Yes	No experience	Yes (dose reduction)	No experience ^c
Routine laboratory monitoring	Yes	No	No ^d	No
Dose	Adjust dose according to the results of the aPTT	Fixed weight adjusted	Fixed weight adjusted	Fixed
Accumulation in renal failure	No	Yes	Yes	Yes
Nonanticoagulant side effects	Allergy, HIT	HIT (rare)	-	-
Nonbleeding contraindications	Allergy, immune HIT	Allergy, immune HIT	Allergy	Allergy
Antidote	Protamine sulfate	Protamine sulfate partially reverses	No	No

ACS, Acute coronary syndromes; aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; HIT, heparin-induced thrombocytopenia; IV, intravenous; SC, subcutaneous.

^aThe first dose of enoxaparin was given by the intravenous route in the TIMI-11B (Thrombolysis In Myocardial Infarction 11B) and EXTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment, Thrombolysis in Myocardial Infarction 25) studies. The first dose of fondaparinux was given by the intravenous route in the OASIS-6 (Optimal Antiplatelet Strategy for Interventions 6) trial.

^bAcute coronary syndrome patients with creatinine up to 265 μmol/L were eligible for inclusion in the OASIS-5 and -6 trials (equivalent to an estimated creatinine clearance of 15-20 ml/min in a 70-kg patient who is 70 yr of age).

^cFondaparinux is contraindicated in patients with venous thromboembolism who have severe renal impairment.

^dMonitoring and dose adjustment required in patients with creatinine clearance below 30 ml/min.

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 8 Pharmacologic Characteristics of Intravenous Antiplatelet Drugs Used in the Management of Acute Coronary Syndrome

Characteristic	Gp Iib/Iiia Inhibitors			ADP RECEPTOR ANTAGONISTS
Characteristic	Abciximab	Eptifibatide	Tirofiban	Cangrelor
Class	Fab fragment	Nonpeptide	Cyclic heptapeptide	Nonthienopyridine
Onset	Rapid	Rapid	Rapid	Rapid
Drug half-life	10-30 min	2 h	2.5 h	3-6 min
Reversibility of platelet inhibition	Slow	Rapid	Rapid	Rapid
Excretion	Unknown	40%-70% renal	50% renal	Dephosphorylation

ADP,Adenosine diphosphate; GP, glycoprotein.

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 7 Pharmacologic Characteristics of Oral Antiplatelet Drugs Commonly Used in the Management of Acute Coronary Syndrome

Characteristic	Aspirin	ADP Receptor Antagonists
Characteristic	Aspirin	Clopidogrel	Prasugrel	Ticagrelor
Class	COX inhibitor	Thienopyridine (second generation)	Thienopyridine (third generation)	Cyclopentyl triazolopyrimidine
Target	COX-1	P2Y12	P2Y12	P2Y12
Dose	162- to 325-mg loading dose; 75-325 mg/day maintenance dose	300- to 600-mg loading dose; 75 mg/day maintenance dose	60-mg loading dose; 10 mg/day maintenance dose	180-mg loading dose; 90 mg bid maintenance dose
Prodrug	No	Yes	Yes	No
Time to effect ^a	<1 h	4-6 h ^b	<1 h	<1 h
Drug half-life	20 min	Min	Min	12 hr
Reversible	No	No	No	Yes

ADP, Adenosine diphosphate; bid, twice daily; COX, cyclooxygenase.

^aAfter loading dose.

^bIncreased antithrombotic benefit was seen after the first hour in patients enrolled in the COMMIT trial who did not receive a loading dose, but maximum effect is not seen until after 4-6 h.

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 5 Summary of Recommendations for Antithrombotic Therapy

Recommendations	Dosing, Special Considerations	COR	LOE
Aspirin
Nonenteric-coated aspirin to all patients promptly after presentation	162-325 mg	I	A
Aspirin maintenance dose continued indefinitely	81-325 mg/day ∗	I	A
P2Y12 Inhibitors
Clopidogrel loading dose followed by daily maintenance dose in patients unable to take aspirin	75 mg	I	B
P2Y12 inhibitor, in addition to aspirin, for up to 12 mo for patients treated initially with either an early invasive or initial ischemia-guided strategy:		I	B
Clopidogrel	300- or 600-mg loading dose, then 75 mg/day
Ticagrelor	180-mg loading dose, then 90 mg twice daily
P2Y12 inhibitor therapy (clopidogrel, prasugrel, or ticagrelor) continued for at least 12 mo in post-PCI patients treated with coronary stents	N/A	I	B
Ticagrelor in preference to clopidogrel for patients treated with an early invasive or ischemia-guided strategy	N/A	IIa	B
Glycoprotein (GP) IIb/IIIa Inhibitors
GP IIb/IIIa inhibitor in patients treated with an early invasive strategy and DAPT with intermediate/high-risk features (e.g., positive troponin)	Preferred options are eptifibatide or tirofiban	IIb	B
Parenteral Anticoagulant and Fibrinolytic Therapy
SC enoxaparin for duration of hospitalization or until PCI is performed	1 mg/kg SC every 12 h (reduce dose to 1 mg/kg/day SC in patients with CrCl <30 ml/min) Initial 30-mg IV loading dose in select patients	I	A
Bivalirudin until diagnostic angiography or PCI is performed in patients with early invasive strategy only	Loading dose 0.10 mg/kg, followed by 0.25 mg/kg/h Only provisional use of GP IIb/IIIa inhibitor in patients also treated with DAPT	I	B
SC fondaparinux for the duration of hospitalization or until PCI is performed	2.5 mg/day SC	I	B
Administer additional anticoagulant with antiIIa activity if PCI is performed while patient is on fondaparinux	N/A	I	B
IV UFH for 48 hr or until PCI is performed	Initial loading dose 60 IU/kg (max 4000 IU) with initial infusion 12 IU/kg/h (max 1000 IU/h) Adjusted to therapeutic APTT range	I	B
IV fibrinolytic treatment not recommended in patients with NSTE-ACS	N/A	III: Harm	A

APTT, Activated partial thromboplastin time; COR, class of recommendation; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; IV, intravenous; LOE, level of evidence; max, maximum; N/A, not available; NSTE-ACS, non-ST-elevation acute coronary syndromes; PCI, percutaneous coronary intervention; SC, subcutaneous; UFH, unfractionated heparin.

^∗The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg/day.

Modified from Amsterdam EA et al: 2014 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 64:e139-228, 2014, in Zipes DP: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

TABLE 6 2014 Guideline Recommendations for Antithrombotic Agents in Patients With Non-ST-Elevation Acute Coronary Syndrome

Antiplatelet Therapy
Nonenteric-coated, chewable aspirin (162-325 mg) should be given to all patients without contraindications on presentation, and a maintenance dose of aspirin (81-325 mg/day) continued indefinitely. In patients who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance, a loading dose of clopidogrel (300 or 600 mg) followed by a daily maintenance dose of 75 mg should be substituted. Either clopidogrel or ticagrelor can be used initially with either an early invasive or ischemic guided strategy (COR I, LOE: B). Ticagrelor may be preferred over clopidogrel as the initial treatment (COR IIa, LOE: B). In patients treated with ticagrelor, the preferred aspirin maintenance dose is 81 mg/day. Use prasugrel only in patients receiving coronary stents (COR I, LOE: B). The use of glycoprotein IIb/IIIa receptor inhibitors is reserved mainly to the time of PCI in high-risk patients who were not adequately pretreated with P2Y12 inhibitors (COR I, LOE: A) or in those patients who were adequately pretreated with P2Y12 inhibitors but have a high-risk profile (COR IIa, LOE: B). Clopidogrel and ticagrelor should be discontinued at least 5 days (COR I, LOE: B) and prasugrel at least 7 days (COR I, LOE: C) before major surgery.
Anticoagulant Therapy
Enoxaparin is recommended at presentation (COR I, LOE: A); other options include unfractionated heparin (UFH) (COR I, B) and fondaparinux (COR I, LOE: B). If an early invasive strategy is planned, bivalirudin (COR I, LOE: B) is also an option. If fondaparinux is used initially, add UFH or bivalirudin just before or during PCI to prevent catheter-related thrombosis (COR I, LOE: B). Bivalirudin is preferred over UFH plus GP IIb/IIIa inhibitor in patients undergoing PCI who are at high risk of bleeding (COR IIa, LOE: B). It is reasonable to use enoxaparin during PCI if it was used as the initial anticoagulant (COR IIb, LOE: B).

COR, Class of recommendation; LOE, level of evidence; PCI, percutaneous coronary intervention.

Modified from Eisen A, Giugliano RP: Antiplatelet and anticoagulation treatment in patients with non-ST-segment elevation acute coronary syndrome: comparison of the updated North American and European guidelines, Cardiol Rev 24:170-176, 2016; and Amsterdam EA et al: 2014 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 64: e139-228, 2014, in Zipes DP: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

TABLE 4 Summary of Recommendations for Standard Medical Therapy in the Early Hospital Care Phase of Management of Patients With Non-ST-Elevation Acute Coronary Syndrome (NSTE-ACS)

Recommendations	COR	LOE
Oxygen
Administer supplemental oxygen only with oxygen saturation <90%, respiratory distress, or other high-risk features for hypoxemia.	I	C
Nitrates
Administer sublingual NTG every 5 min ×3 for continuing ischemic pain and then assess need for IV NTG.	I	C
Administer IV NTG for persistent ischemia, HF, or hypertension.	I	B
Nitrates are contraindicated with recent use of a phosphodiesterase inhibitor.	III: Harm	B
Analgesic Therapy
IV morphine sulfate may be reasonable for continued ischemic chest pain despite maximally tolerated antiischemic medications.	IIb	B
NSAIDs (except aspirin) should not be initiated and should be discontinued during hospitalization for NSTE-ACS because of the increased risk of MACE associated with their use.	III: Harm	B
Beta-Adrenergic Blockers
Initiate oral beta blockers within the first 24 h in the absence of HF, low-output state, risk for cardiogenic shock, or other contraindications to beta blockade.	I	A
Use of sustained-release metoprolol succinate, carvedilol, or bisoprolol is recommended for beta-blocker therapy with concomitant NSTE-ACS, stabilized HF, and reduced systolic function.	I	C
Reevaluate to determine subsequent eligibility in patients with initial contraindications to beta blockers.	I	C
It is reasonable to continue beta-blocker therapy in patients with normal LV function with NSTE-ACS.	IIa	C
IV beta blockers are potentially harmful when risk factors for shock are present.	III: Harm	B
Calcium Channel Blockers (CCBs)
Administer initial therapy with nondihydropyridine CCBs with recurrent ischemia and contraindications to beta blockers in the absence of LV dysfunction, increased risk for cardiogenic shock, PR interval >0.24 sec, or second- or third-degree atrioventricular block without a cardiac pacemaker.	I	B
Administer oral nondihydropyridine calcium antagonists with recurrent ischemia after use of beta blocker and nitrates in the absence of contraindications.	I	C
CCBs are recommended for ischemic symptoms when beta blockers are not successful, are contraindicated, or cause unacceptable side effects.∗	I	C
Long-acting CCBs and nitrates are recommended for patients with coronary artery spasm.	I	C
Immediate-release nifedipine is contraindicated in the absence of a beta-blocker.	III: Harm	B
Cholesterol Management
Initiate or continue high-intensity statin therapy in patients with no contraindications.	I	A
Obtain a fasting lipid profile, preferably within 24 h.	IIa	C

COR, Class of recommendation; HF, heart failure; IV, intravenous; LOE, level of evidence; LV, left ventricular; MACE, major adverse cardiovascular events; N/A, not available; NSAIDs, nonsteroidal antiinflammatory drugs; NTG, nitroglycerin.

^∗Short-acting dihydropyridine calcium channel antagonists should be avoided.

From Amsterdam EA et al: 2014 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 64:e139-228, 2014 in Zipes DP: Braunwald’s heart disease: a textbook of cardiovascular medicine, ed 11, Philadelphia, 2019, Elsevier.

Chronic Rx

Post-ACS medical therapy involves aspirin, statin, beta-blocker, and a second antiplatelet agent such as clopidogrel, ticagrelor, or prasugrel.
In patients already on an oral anticoagulant for another diagnosis such as atrial fibrillation, the duration of triple therapy should be minimized. Strategies aimed at minimizing the risk of bleeding in patients treated with triple therapy (dual antiplatelet therapy and an oral anticoagulant) are summarized in Table 11. The WOEST trial showed that using clopidogrel along with an oral anticoagulant but without aspirin resulted in a significant reduction in bleeding complications compared with those patients on a triple therapy of oral anticoagulant, aspirin, and clopidogrel.¹⁴ It is a class IIB recommendation in those patients with atrial fibrillation and a CHADS-VASC score of ≥2 after coronary revascularization to consider using clopidogrel concurrently with oral anticoagulant (Table 12) but without aspirin. Similarly, the AUGUSTUS trial in 2019 demonstrated that triple therapy (aspirin, P2Y12 inhibitor, direct oral anticoagulants [DOAC], or warfarin) was associated with substantial increases in bleeding without improved thrombotic protection compared with P2Y12 inhibitor and oral anticoagulation alone.¹⁵
Lipid lowering with high-intensity statins has been shown to reduce death, MI, and cardiac events at 16 wk when administered early (within 24 to 96 h after ACS). Additional data demonstrated the benefit of early high-intensity statin therapy with low density lipoprotein (LDL) targets <70 mg/dl in ACS.³
ACE inhibitors may be added to treat hypertension and should be used in all patients with depressed LV function (EF <40%) or pulmonary vascular congestion. ARBs should be used in patients who are ACE inhibitor intolerant.³
An aldosterone blocker should be used in post-MI patients without significant renal dysfunction (creatinine >2.5 mg/dl in men or creatinine >2.0 mg/dl in women) or hyperkalemia (K >5.0 mEq/L) who have an EF of <40% and are already on therapeutic doses of an ACE inhibitor and a beta-blocker.³
Cardiac rehabilitation and a monitored exercise program should be recommended at the time of discharge.³
Aggressive risk factor management, including smoking cessation, weight loss, diet and exercise, diabetes control, and so on, for secondary prevention of future events is crucial.³

TABLE 11 Strategies Aimed at Minimizing the Risk of Bleeding in Patients Treated With Triple Therapy (Dual Antiplatelet Therapy and an Oral Anticoagulant)

Proposed Approach		Rationale
Aspirin maintenance dose ≤100 mg/day		Higher aspirin maintenance doses increase bleeding, and there is no evidence that they improve efficacy.
PPI with a preference for agents that interfere less with CYP 2C19 (e.g., pantoprazole)		Much of the excess bleeding is from the GI tract. The use of acid-suppressive agents that interfere less with CYP 2C19 minimizes the potential for a negative interaction with clopidogrel.
Preference for a nonvitamin K antagonist oral anticoagulant		Dabigatran 110 mg twice daily and apixaban 2.5 or 5.0 mg twice daily are associated with lower rates of bleeding than warfarin.
For warfarin, use a target INR of 2-2.5		Some evidence that a restricted target INR range reduces the risk of bleeding.
Manage warfarin in a specialized anticoagulation clinic		Compared with usual care, specialist clinics achieve a higher TTR of the INR.
Minimize duration of triple therapy		The risk of bleeding is highest during the first 30 days but remains elevated with long-term treatment.
Avoid NSAIDs		NSAIDs are a common cause of upper GI bleeding.
Avoid prasugrel and ticagrelor		Prasugrel and ticagrelor cannot be recommended because they are more potent than clopidogrel and cause more bleeding.

CYP, Cytochrome P-450; GI, gastrointestinal; INR, international normalized ratio; NSAID, nonsteroidal antiinflammatory drug; PPI, proton pump inhibitor; TTR, time in therapeutic range.

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

TABLE 12 Pharmacologic Characteristics of Warfarin and New Oral Anticoagulants Evaluated in Phase III Trials for the Long-Term Management of Acute Coronary Syndrome

Characteristic	Warfarin	Rivaroxaban	Apixaban
Target	VKORC1	Factor Xa	Factor Xa
Prodrug	No	No	No
Bioavailability (%)	100	80	60
Dosing	Variable, once daily	Fixed, 2.5 or 5 mg twice daily ^a	Fixed, 5 mg twice daily (2.5 mg twice daily in selected patients)
Half-life	Mean: 40 h (range: 20-60 h)	7-11 h	12 h
Renal clearance (%)	Nil	66 ^b	25
Routine coagulation monitoring	Yes (INR)	No	No
Drug interactions	Multiple	Potent inhibitors of CYP3A4 and P-gp ^c	Potent inhibitors of CYP3A4 and P-gp ^c
Antidote	Yes (vitamin K, PCC, FFP)	Yes (Andexanet alfa)	Yes (Andexanet alfa)
Approved for ACS management	Yes	Yes, in Europe	No

ACS, Acute coronary syndromes; CYP3A4, cytochrome P-450 3A4; FFP, fresh frozen plasma; fXa, activated factor X; INR, international normalized ratio; PCC, prothrombin complex concentrates; P-gp, P-glycoprotein; VKORC1, C1 subunit of vitamin K epoxide reductase. Strategies Aimed at Minimizing the Risk of Bleeding in Patients Treated With Triple Therapy (Dual Antiplatelet Therapy and an Oral Anticoagulant).

^aA once-daily regimen was tested in atrial fibrillation.

^bHalf of renally cleared rivaroxaban is cleared as unchanged drug and half as inactive metabolites.

^cPotent inhibitors of both CYP3A4 and P-glycoprotein include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Potent inhibitors of CYP3A4 include azole antifungals, macrolide antibiotics (e.g., clarithromycin), and protease inhibitors (e.g., atazanavir).

From Hoffman R et al: Hematology: basic principles and practice, ed 7, Philadelphia, 2018, Elsevier.

Referral

All ACS patients should be cared for in conjunction with the cardiology consult service.
When appropriate, referral to a cardiac surgeon may be necessary for CABG and comprehensive heart team approach.
At the time of discharge, patients should be referred for cardiac rehabilitation.

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