2 Icahn School of Medicine at Mount Sinai, New York, NY, USA
Background
Definition of disease
Acute coronary syndromes are defined by the presence of symptoms consistent with myocardial ischemia including chest pain and shortness of breath. Types of acute coronary syndrome are further specified by the presence or absence of ECG changes, and/or myocardial biomarkers.
Disease classification
Acute coronary syndromes can be viewed as three different clinical syndromes:
ST elevation myocardial infarction (STEMI).
Non‐ST elevation myocardial infarction (NSTEMI).
Unstable angina (UA).
Incidence/prevalence
Incidence of STEMI: 50 cases per 100 000 patients.
Incidence of NSTEMI: 158 cases per 100 000 patients.
Etiology
Exposure to multiple risk factors as described later result in inflammation within the coronary arteries and formation of lipid‐laden plaques.
Plaques with a thin fibrous cap and large lipid core are prone to rupture, resulting in exposure of prothrombotic factors within the atheroma to blood and subsequent thrombus formation.
Thrombus results in total or partial occlusion of the coronary artery lumen causing ischemia and, if severe enough, infarction.
Pathology/pathogenesis
The pathogenesis of ACS is as simple as a mismatch between myocardial demand and its blood supply causing ischemia and, when severe enough, infarction. For the purpose of this chapter we focus on the formation of the atheromatous plaque, and its rupture, resulting in coronary thrombosis.
Plaque starts as a fatty streak within the intima of blood vessels. At first, circulating LDL molecules aggregate within the intima of the coronary arteries. The oxidation of these LDL molecules results in an inflammatory reaction within the intima. Endothelium is stimulated resulting in the expression of cellular adhesion molecules. Chemoattractants and cytokines are released in the setting of this inflammation, causing circulating monocytes to migrate into the intima and differentiate into macrophages. Macrophages then scavenge oxidized LDLs and transform into foam cells, and subsequently undergo apoptosis. The apoptosis of foam cells results in the formation of a necrotic lipid rich core in some plaques (Figure 16.1).
Several characteristics make a plaque more likely to rupture, including a larger necrotic lipid core, presence of inflammatory cells, and a thin fibrous cap.
Often the culprit lesions of ACS are not flow limiting prior to rupture. These lesions tend not to be heavily calcified, in contrast to the high grade stenotic lesions that are more associated with chronic ischemic coronary disease.
Thrombosis occurs when there is a disruption in the overlying protective endothelium and exposure of blood to the thrombogenic plaque core. This can occur via plaque rupture due to a weak and thinning fibrous cap or from erosion.
If the thrombus is nearly or completely occlusive, the result is mural infarction and thus a STEMI. In the case of a dynamic or incompletely occlusive thrombus, non‐ST elevation acute coronary syndromes (NSTE‐ACS) such as NSTEMI or UA occur (Figure 16.2).
Predictive/risk factors
Risk factor
Odds ratio
Current smoking
2.9
Diabetes
2.4
Hypertension
1.9
Obesity (3rd vs. 1st tertile)
1.6
Psychosocial stress
2.7
Apo B/Apo A1 ratio (5th vs. 1st quintile)
3.3
Prevention
Both primary and secondary prevention in cardiovascular disease is largely a matter of managing the known risk factors stated earlier. Some of the strongest interventions for prevention of cardiovascular disease include smoking cessation, blood pressure control, cholesterol‐lowering medications, weight loss, and good management of diabetes.
Screening
To date there are no tests that are regularly used to screen for cardiovascular disease in asymptomatic patients.
A pooled cohort atherosclerotic cardiovascular disease (ASCVD) risk calculator can be used for patients between 40 and 79 years of age to determine the 10 year risk of cardiovascular disease and stroke. However, this has never been validated in the literature as a screening tool.
Other potential screening tests for cardiovascular disease include high sensitivity C‐reactive protein, coronary calcium score, and ankle‐brachial index. These tests likewise have not been validated by clinical trials as screening tests. They currently hold a class IIB recommendation in the ACC guidelines for assessment of cardiovascular risk as adjunct tests. They may be considered for additional risk stratification if there is still a level of uncertainty regarding starting pharmacologic therapy after using the ASCVD risk calculator.
Primary prevention
Smoking cessation is one of the most effective interventions in primary prevention of cardiovascular disease.
Hypertension is well known to be a significant risk factor for cardiovascular disease and stroke. Recent guidelines recommend keeping blood pressure at <140/90 mmHg in patients aged 30–59 and <150/90 mmHg in patients over 60 years. However, new data from the SPRINT trial suggest that a lower blood pressure goal of <130/80 mmHg in patients with high cardiovascular risk may reduce the risk of major cardiac events even further.
LDL‐lowering therapy with statins has been demonstrated to be effective primary prevention in patients at high risk for cardiovascular disease. Newer data suggest that statins also have a significant impact on primary prevention in patients with lower risk for cardiovascular disease.
Aggressive weight loss interventions have been shown to improve blood pressure and insulin resistance. However to date they have not shown to have a significant effect on cardiovascular events.
Although low dose aspirin has clearly demonstrated a benefit in secondary prevention of cardiovascular disease the picture is less clear in primary prevention. Current USPSTF guidelines recommend low dose aspirin for primary prevention in adults 50–69 years of age with a >10% 10 year ASCVD risk.
Secondary prevention
Similar to primary prevention, much of the evidence in secondary prevention of cardiovascular disease is in managing the main risk factors:
Smoking cessation plays a large role in secondary prevention of cardiovascular disease, and currently holds a class I recommendation in the guidelines.
Blood pressure with a goal of 140/90 mmHg holds a class I recommendation in current guidelines for secondary prevention as well. However, as described, the data from the SPRINT trial may provide evidence for a lower blood pressure goal in the future.
High intensity statin therapy has a class I recommendation for secondary prevention in patients with ACS and no contraindication to statins.
Lifelong antiplatelet therapy with aspirin as well as dual antiplatelet therapy with a P2Y12 inhibitor for up to 12 months has a class I recommendation for secondary prevention in patients with ACS.
Beta blockers are effective in secondary prevention for patients with ACS.
Diagnosis
Differential diagnosis
Differential diagnosis
Features
Aortic dissection
Patient may complain of chest pain radiating to the back. On physical examination the patient may have different blood pressures in different arms. Diastolic murmur can be present in dissection if it resulted in aortic insufficiency. CXR may demonstrate mediastinal widening
Pericarditis
Patient may have a history of a recent viral illness. Pain is typically positional, made worse by lying flat and better by leaning forward. Pericardial friction rub may be appreciated on examination, or muffled heart sounds. ECG typically demonstrates diffuse ST elevation with PR depressions. Echocardiogram may demonstrate pericardial effusion
Pulmonary embolism
Patients typically present with shortness of breath and pleuritic chest pain. They may give a history of recent prolonged immobilization such as recent surgery. They may also have a history of malignancy or family history of blood clots. ECGs most commonly show sinus tachycardia, however they may demonstrate evidence of right ventricular strain such as new right bundle branch block, or rightward axis
Pneumothorax
Patient may give a history of recent chest wall trauma. Patient will likely present with shortness of breath and pleuritic‐type chest pain. Physical examination may demonstrate decreased breath sounds and tracheal deviation. CXR or CT or bedside ultrasound all can establish the diagnosis
Diffuse esophageal spasm
Differentiating features of presentation include dysphagia of solids and liquids. Diagnostic modalities that help to make the diagnosis include endoscopy, barium swallow, and esophageal manometry
Typical presentation
ACS most commonly present with what are referred to as ‘typical’ symptoms. Typical symptoms are described as a pressure or aching in the substernal or left chest areas, classically radiating to one or both arms. The pain can also radiate to the jaw, back, and shoulders. Chest pain in ACS tends to be more diffuse and not well localized, commonly presenting with a crescendo pattern, typically taking several minutes before reaching its highest intensity.
Pain lasting from 10 to 30 minutes is more likely to represent UA, whereas pain lasting more than 30 minutes is more indicative of myocardial infarction or non‐cardiac pain.
Clinical diagnosis
History
When approaching a patient with chest pain there are several aspects of the history to consider. Typical symptoms of ACS occur in the substernal or left chest area, and often radiate to one or both arms as well as the jaw and back. The duration can help distinguish between cardiac and non‐cardiac pain, as pain that lasts for a few seconds or conversely for several days continuously is less likely to represent cardiac chest pain.
Alleviation of pain with rest or nitroglycerine is classically thought to be more indicative of cardiac pain. However, several studies have shown that such factors are limited in their ability to distinguish cardiac from non‐cardiac pain.
Other symptoms associated with ACS can include nausea, vomiting, diaphoresis, and shortness of breath. It is important to consider that as many as one‐third of patients with acute myocardial infarction can present without chest pain. In particular women, older patients, and diabetics are more likely to present without typical symptoms. For this reason, it is critical to assess risk factors for coronary artery disease when taking a history, as this will help to raise or lower your suspicion for ACS.
Physical examination
Physical examination is often unrevealing in patients presenting with ACS.
In the setting of acute myocardial ischemia patients may develop heart failure. Physical exam findings such as rales on respiratory auscultation and elevated jugular venous pulsation may be appreciated in these patients. Other physical exam findings that can occur with ACS include a holosystolic murmur secondary to mitral regurgitation in the setting of papillary muscle dysfunction, S4 gallop, or paradoxical splitting of S2.
However, none of these physical exam findings are sensitive or specific for ACS, and their absence or presence does not rule out or confirm the diagnosis of ACS. Physical examination can be useful to search for other non‐cardiac causes of chest pain.
Useful clinical decision rules and calculators
There are two useful systems to help risk stratify patients with ACS.
TIMI risk scor
The TIMI risk score is calculated on admission through the sum of seven different variables each with a value of 1 point. The variables are age ≥65 years, ≥3 coronary artery disease risk factors, prior coronary stenosis of ≥50%, ST changes on ECG, ≥2 anginal events in the prior 24 hours, use of aspirin in the last 7 days, and elevated cardiac biomarkers. The TIMI risk score can help to risk stratify patients with NSTE‐ACS into lower (<2) and higher (≥2) risk.
Points
All‐cause mortality, new or recurrent MI, or urgent revascularization
0–1
4.7%
2
8.3%
3
13.2%
4
19.9%
5
26.2%
6–7
40.9%
GRACE risk model for risk of death in patients with ACS
Find points for each predictive factor
Killipclass
Points
SBP mmHg
Points
Heart rate
Points
Age
Points
Creatinine(mg/dL)
Points
I
0
≤80
58
<50
0
<30
0
0–0.30
1
II
20
80–99
53
50–69
3
30–39
8
0.40–0.79
4
III
39
100–119
43
70–89
9
40–49
25
0.80–1.19
7
IV
59
120–139
34
90–109
15
50–59
41
1.20–1.59
10
140–159
24
110–149
24
60–69
58
1.60–1.99
13
160–199
10
150–199
38
70–79
75
2.00–3.99
21
≥200
0
≥200
45
80–89
91
≥4.0
28
≥90
100
Other risk factors
Points
Cardiac arrest at admission
39
ST segment deviation
28
Elevated cardiac enzyme levels
14
Add points for all predictive factors
Killip class
SBP
Heart rate
Age
Creatinine
Cardiac arrest
ST segment
Cardiac enzymes
TOTAL POINTS
Look up risk of in‐hospital mortality corresponding to total points
Points
Mortality (%)
Points
Mortality (%)
Points
Mortality (%)
Points
Mortality (%)
≤60
0.2
110
1.1
160
5.4
210
23
70
0.3
120
1.6
170
7.3
220
29
80
0.4
130
2.1
180
9.8
230
36
90
0.6
140
2.9
190
13
240
44
100
0.8
150
3.9
200
18
≥250
≥52
The GRACE risk model uses a score that is based on eight different parameters ranging from 1 to 372. A nomogram can then be used to extrapolate the risk for in‐hospital and post discharge mortality. This risk model is also commonly used to risk stratify patients into low (<109) and high (≥109) risk.
Laboratory diagnosis
List of diagnostic tests
Cardiac troponins (I and T) are sensitive and specific for diagnosis of myocardial infarction. These biomarkers should be ordered on every patient with suspected ACS, and are typically positive within 2–4 hours of symptoms. Current recommendations are that cardiac troponins should be measured at presentation and again 3–6 hours later. If serial troponins are normal but the ECG and clinical picture are consistent with higher risk ACS, additional troponin levels should be checked after 6 hours.
Other myocardial biomarkers such as CK‐MB and myoglobin are no longer considered necessary as they are less sensitive and specific than cardiac troponins.
List of imaging techniques
Electrocardiography (ECG) is critical in the initial evaluation of patients presenting with suspected ACS and should be performed within the first 10 minutes of arrival. ECG is diagnostic of STEMI when there is ST elevation in two contiguous leads of ≥1 mm in all leads other than leads V2‐3. In leads V2‐3 STEMI is ≥2 mm of ST elevation in men ≥40 years and ≥2.5 mm in men <40 years; for women the cutoff is ≥1.5 mm in leads V2‐3. Other ST changes on ECG should also raise suspicion for MI and can be considered STEMI equivalents. Examples include: new left bundle branch block in the appropriate clinical context; ST depressions in V1‐4 can be indicative of a posterior wall MI; and ST depression in multiple leads with ST elevation in aVR may indicate STEMI with a left main or proximal LAD occlusion. Other changes on ECG that may indicate myocardial ischemia include T wave inversions and ST depressions. Deep pathologic Q waves are indicative of an old myocardial infarction. An ECG should be checked every 15–30 minutes within the first hour of presentation and followed serially for evolution.
CXR may be useful in the identification of non‐cardiac causes of chest pain such as pneumothorax. It can also help in the identification of aortic dissection if it demonstrates a widened mediastinum. Chest X‐rays are commonly ordered on most patients presenting with chest pain.
CT angiography of the chest can be useful in ruling out pulmonary embolism and aortic dissection if those two diagnoses are high on the differential. New data suggest that CT of the coronary arteries may be cost effective in diagnosing or ruling out coronary disease in low risk patients with chest pain.
Coronary angiography is the gold standard for diagnosis of coronary artery disease and allow for intervention. This should be done in all patients with STEMI who present within the first 12–24 hours, with evidence of ongoing ischemia, and in the absence of contraindications. Coronary angiography should also be performed in NSTE‐ACS patients who fail ischemic guided therapy as outlined later, or those who are at high risk based on GRACE or TIMI score as outlined earlier.
Non‐invasive cardiac testing can be used in patients with low and intermediate risk NSTE‐ACS to assess for ischemia and for prognostic purposes. Exercise ECG stress testing can be done in those with unstable angina who are asymptomatic and stable for 12–24 hours, or in NSTEMI after 2–5 days. An ECG exercise stress test is useful in patients who can exercise and have a normal resting ECG. In those with an abnormal resting ECG myocardial perfusion imaging (e.g. thallium stress test) can be conducted, and in those who are unable to exercise a pharmacologic stress test with imaging can be performed.
Potential pitfalls/common errors regarding the diagnosis of disease
It is important to consider a broad differential diagnosis when approaching a patient with chest pain. Committing yourself to the diagnosis of ACS without considering other potentially life‐threatening causes of chest pain could result in poor outcomes.
It is not uncommon for patients to present with ‘atypical’ symptoms, particularly women, the elderly, and diabetics. It is critical to closely consider risk factors for ACS in these patients as it can be harder to identify.
Treatment
Treatment rationale
ACS is initially treated medically in the same way whether it is STEMI or NSTE‐ACS.
Standard first line treatment is antiplatelet therapy with non‐enteric coated aspirin at a dose of 162–325 mg and a P2Y12 inhibitor.
Anticoagulation is also indicated in either STE‐ or NSTE‐ACS. The cornerstone of management in STEMI is emergent revascularization.
Current guidelines recommend that patients who present with STEMI, within the first 12–24 hours of symptoms, receive percutaneous coronary intervention (PCI) within 90 minutes of first medical encounter.
In the event that a patient presents with a STEMI to a non‐PCI capable hospital they should be transferred to a PCI capable hospital. In such patients if the anticipated delay from first medical encounter to PCI is >120 minutes they should receive thrombolysis within 30 minutes of first medical contact. They should then be transferred to a PCI capable hospital within 3–24 hours for intervention.
Patients with NSTE‐ACS receive medical therapy as mentioned earlier and are risk stratified using the TIMI or GRACE scoring system. Those who are considered higher risk (TIMI ≥2, or GRACE ≥109) are recommended to undergo early invasive therapy within 24 hours, whereas those who are lower risk are trialed with ischemic‐guided therapy.
In the event that patients who are lower risk fail ischemic‐guided therapy they are also sent for PCI.
Table of treatment
Treatment
Comments
Medical treatment
Antiplatelet drugs
Aspirin 162–325 mg followed by 81 mg daily
Aspirin is the standard first line treatment for all patients with ACS and should be continued indefinitely. In those who cannot tolerate aspirin clopidogrel can be used
P2Y12 inhibitors
Clopidogrel 300–600 mg followed by 75 mg daily
Prasugrel 60 mg followed by 10 mg daily
Ticagrelor 180 mg followed by 90 mg twice daily
Cangrelor: administer IV 30 μg/kg bolus followed by 4 μg/kg/min continuous infusion
A P2Y12 inhibitor should be continued in addition to aspirin for at least 1 year
Clopidogrel has been shown when used with aspirin to be superior to aspirin alone in preventing death and cardiovascular events. Medication should be stopped at least 5 days prior to CABG
Prasugrel has been shown to be an effective P2Y12 inhibitor in combination with aspirin, however with an increased risk of bleeding when compared with clopidogrel. This increased risk was particularly in those patients with prior history of cerebrovascular event, those older than 75 years, and patients with body weight <60 kg. For this reason, prasugrel is contraindicated in these patients. Prasugrel has also been shown to have increased risk of bleeding when given upstream of planned PCI and is thus not indicated for ‘upfront’ therapy
Ticagrelor has been demonstrated to have superior outcomes compared with clopidogrel. Benefit is only seen in patients taking 75–100 mg of aspirin, thus aspirin 81 mg is recommended in these patients. Dyspnea is a common side effect of ticagrelor but rarely limits its use
Cangrelor is the only IV P2Y12 inhibitor that is currently available. It has been shown to have a significant decrease in periprocedural ischemic events when compared with clopidogrel. Cangrelor may play an important role in bridging patients to CABG given its short half‐life
GP IIb/IIIa inhibitors
Eptifibatide IV 180 μg/kg bolus followed by 2 μg/kg/min continuous infusion.
Tirofiban IV loading dose with 25 μg/kg followed by continuous infusion of 0.15 μg/kg/min Abciximab IV loading dose of 0.25 mg/kg followed by 0.125 mg/kg/min (max. of 10 μg/min) continuous infusion for 12 hours
GP IIb/IIIa inhibitors have strong antiplatelet function and were commonly used in the time before P2Y12 inhibitors and dual antiplatelet therapy were standards of care. Current guidelines recommend their use in NSTEMI at the time of PCI in patients who have not been adequately treated with a P2Y12 inhibitor. Their use is also considered reasonable in patients who have been adequately treated with clopidogrel and are being anticoagulated with heparin at the time of PCI. There are not adequate data at this point to support their use in combination with the newer P2Y12 inhibitors
Anticoagulants
Enoxaparin 1 mg/kg subcutaneously every 12 hours
Bivalirudin IV 0.75 mg/kg bolus prior to procedure followed by 1.75 mg/kg/h continuous infusion
Unfractionated heparin (UFH) 60 IU/kg IV (maximum 4000 IU), followed by initial infusion of 12 IU/kg/h (max. 1000 IU/h)
Anticoagulation is standard of care in all patients with definite ACS, in addition to dual antiplatelet therapy
Enoxaparin has been demonstrated to significantly decrease recurrent ischemic events when compared with UFH, however it has a significantly higher bleeding risk. Given that it is renally cleared it should be avoided in patients with significant renal dysfunction (eGFR <30). Recommended duration is throughout the hospitalization or until PCI is done
Bivalirudin is indicated in patients going for PCI with STEMI, or in patients with NSTE‐ACS who are being managed with an early invasive strategy when it can be administered until PCI is performed. It has been demonstrated to be non‐inferior when given alone in comparison with UFH or LMW heparin given with a GP IIb/IIIa inhibitor, however with a lower risk of bleeding. Recent data suggest however that UFH may perform better than bivalirudin with no significant increase in bleeding risk
Fondaparinux administered as 2.5 mg SC daily
UFH has been shown in multiple trials to be an effective anticoagulant for use in ACS. UFH is often the anticoagulant of choice in patients with renal dysfunction as it does not require dose adjustment
Fondaparinux has been demonstrated to be effective in the management of NSTE‐ACS and is typically given for the duration of the hospitalization or until PCI. Of note it is contraindicated in patients with creatinine clearance <30. Furthermore, if the patient undergoes PCI an additional anticoagulant with anti‐IIa activity must be given to prevent catheter thrombosis
Thrombolytics
Alteplase 15 mg, followed by 50 mg over 30 minutes, then 35 mg over 60 minutes
Tenecteplase 40 mg as a single IV push for persons between 70 and 80 kg
Thrombolytics are specifically indicated only for STEMI in the setting of an anticipated delay in primary PCI of over 120 minutes. Use of thrombolytics is specifically contraindicated in the case of NSTE‐ACS
Adjunctive medical therapies
Beta‐blockers
High intensity statins
ACE inhibitor
Angiotensin receptor blockers
Beta‐blockers have been shown to decrease the likelihood of arrhythmias and reinfarction. Current guidelines recommend that beta‐blockers be given within 24 hours to all patients without contraindications such as evidence of cardiogenic shock
High intensity statins are indicated in all patients who present with ACS who do not have a contraindication to receiving treatment
ACE inhibitors are generally recommended to all patients with STEMI with high risk features (previous MI, anterior STEMI, ejection fraction <40%). They should also be given for patients with NSTE‐ACS who have reduced ejection fraction (<40%)
Angiotensin receptor blockers are generally second line treatment and used for patients who are unable to tolerate ACE inhibitors
Procedural management
Percutaneous coronary intervention (PCI)
Early revascularization with PCI is the cornerstone of management in STEMI and high risk NSTE‐ACS. In the case of STEMI, current recommendations are for PCI of the culprit lesion emergently within 90 minutes of presentation to the hospital as described earlier. Current guidelines for NSTE‐ACS are for early PCI (within 24 hours) for patients who are high risk or those who fail ischemic directed therapy
Coronary artery bypass grafting (CABG)
CABG is another option available for revascularization. Although more invasive than PCI it has shown a significant benefit over PCI in patients with multivessel or left main disease, complex coronary anatomy, and comorbidities such as diabetes
Complementary management
Cardiac rehabilitation
Comprehensive cardiovascular rehabilitation programs help to address risk factors for cardiovascular disease, and encourage healthy lifestyle changes, and are generally recommended to all eligible patients
Prevention/management of complications
Bleeding:
All patients should be assessed for bleeding risk. Risk factors include female sex, renal insufficiency, and older age. Anticoagulants and antiplatelet agents should be dosed according to weight when possible and adjusted for renal function to prevent bleeding.
In the case of minor bleeding, treatment with anticoagulation and antiplatelet therapy should not be interrupted. However, with major bleeding, antiplatelet agents and anticoagulants may need to be stopped and reversed if possible.
The recommended transfusion goal is a hemoglobin of 8 g/dL in ACS.
Stroke:
Stroke is a known complication of cardiac catheterization and is difficult to manage in the setting of PCI given the risk for intracranial hemorrhage.
Limited data exist to suggest that thrombolysis is safe in the setting of stroke after PCI. Therefore, it is of critical importance to consider the risks and benefits of thrombolysis carefully before giving it in the setting of a peri‐procedural stroke.
