Arman Qamar and Benjamin M. Scirica
Case Presentation
A 65 year-old man with history of hypertension, hypercholesterolemia and diabetes mellitus pre- sented with two hours of severe substernal chest pain radiating to left arm in addition to diapho- resis and nausea. At the time of presentation to the emergency department, his electrocardio- gram showed inferior and posterior ST-segment elevations (Fig. 12.1) and serum troponin T was 0.30 ng/mL (reference range <0.01 ng/mL). He was treated with aspirin, intravenous nitroglyc- erin, ticareglor, metoprolol, atorvastatin, and heparin.
Question What approach should guide this patient’s further management?
Answer All patients with acute coronary syn- drome with ST-segment elevation myocardial infarction (STEMI) should undergo emergent reperfusion therapy with primary percutaneous coronary intervention (PCI) or fibrinolysis.
This patient underwent emergent invasive cor- onary angiography, which revealed a discrete 90 % lesion in the proximal right coronary artery.
He was treated by primary PCI with drug-eluting stent placement. The patient had an uneventful hospital course and was discharged on aspirin, ticagrelor, metoprolol, atorvastatin and lisinopril.
Principles of Management Diagnosis
Acute coronary syndrome (ACS) refers to spec- trum of conditions associated with acute myocar- dial ischemia and/or infarction that are most frequently due to sudden decrease in coronary blood flow from an atherothrombotic obstruction.
The first step in the management of patients with ACS is prompt recognition, as beneficial effects of therapy are greater when started soon after pre- sentation, and steadily decline in the hours that follow the first signs of myocardial injury. The most common symptom that prompts the diag- nostic evaluation of ACS is chest discomfort.
Classification of patients presenting with ACS is based on electrocardiogram. Patients with persis- tent ST-segment elevation are deemed as having ST-segment elevation ACS (STE-ACS) due to the presumed acute complete coronary occlusion and are candidates for immediate reperfusion therapy with either primary angioplasty or fibrinolysis.
Absence of ST-segment elevation in a patient with ACS suggests non-ST segment elevation ACS (NSTE-ACS) (Fig. 12.2), which is further classi- fied on the basis of biomarkers of myocardial
A. Qamar • B.M. Scirica (*)
Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
e-mail: [email protected]
12
necrosis. In an appropriate clinical setting, if the biomarkers are elevated the patient is classified as having a non-ST segment elevation MI (NSTEMI), otherwise, without elevated biomarkers; the patient should be diagnosed with unstable angina (UA) (Fig. 12.3). The primary diagnostic bio- markers of ACS are Troponin T and Troponin I.
With contemporary troponin assays, CK-MB and myoglobin are less useful for diagnosis of ACS. However, patients with end-stage-renal dis- ease and no clinical evidence of ACS could have chronically elevated troponins. With conventional assays, this is more common with cardiac tropo- nin T than cardiac troponin I. In the diagnosis of ACS, cardiac troponin values must manifest an acute pattern consistent with the ischemic symp- toms and electrocardiographic changes.
ECG abnormalities and elevated biomarkers in isolation are insufficient to make the diagnosis of ACS, and must be interpreted in an appropriate clinical context. MI must be discriminated from other acute and chronic causes of myocardial injury, such as pulmonary embolism, severe sep- sis, and end-stage renal disease, which occur commonly in the intensive care setting. Moreover, MI may be further classified into those caused by acute atherothrombotic coronary events (Type 1 MI) and those caused by supply–demand mis- match, as is seen in instances of myocardial injury with necrosis where a condition other than
CAD contributes to an imbalance between oxy- gen demand and supply, e.g., coronary endothe- lial dysfunction, coronary artery spasm, coronary embolism, tachy-/bradyarrhythmias, anemia, respiratory failure, hypotension, and hyperten- sion with or without left ventricular hypertrophy (Type 2 MI). We typically reserve the term acute coronary syndrome for patients with acute ath- erothrombosis (Type 1 MI).
Once the diagnosis of STEMI, NSTEMI or unstable angina is made, the acute management of the patient involves achievement of several goals followed by initiation of therapy that may improve the long-term prognosis.
Initial Assessment and Early Risk Stratification
Clinical assessment of a patient with ACS should begin as soon as the patient arrives in the emer- gency department and continues in hospital wards or the intensive care units. Initial assess- ment includes evaluation for hemodynamic sta- bility and early risk stratification. A 12-lead ECG should be obtained in all patients with suspected ACS within 10 min after first medical contact and immediately read by an experienced physician.
Early risk stratification in patients with ACS is critical to identify those at higher risk of adverse
Fig. 12.1 EKG demonstrating inferior and posterior ST-segment elevations in a patient with STEMI
a
b
Fig. 12.2 EKG demonstrating diffuse T wave inversion (a) and ST depression in patients with NSTE-ACS (b)
Fig. 12.3 Acute coronary syndromes
cardiac events and may benefit from a more aggressive therapeutic approach [1–4]. Analyses from several large clinical trials have established a number of predictors of adverse outcomes among patients with STEMI, NSTEMI and unstable angina. However, with need for emer- gent reperfusion therapy through primary angio- plasty or fibrinolysis in patients with STEMI, their clinical utility in early therapeutic decision- making is less relevant to STEMI patients. Some of the early predictors of poor outcome from STEMI include age, tachycardia, low blood pres- sure, Killip class (Table 12.1), time to reperfu- sion, diabetes mellitus, anterior infarct location, smoking status, renal function and elevated bio- marker. Examples of validated risk score include the TIMI risk score for STEMI [5] and NSTEMI/
UA [6] and the GRACE Risk Score [7].
Initial Medical Therapy
Patients with STEMI, NSTEMI and unstable angina are treated with similar medical regimens, with the exception of fibrinolysis, which should be limited to STEMI patients. The timing of ini- tiation of medication may vary between STEMI and NSTEMI/UA.
Anti-ischemic Therapy
Oxygen Supplemental oxygen should be admin- istered to patients with ACS with arterial oxygen saturation less than 90 %, respiratory distress, cyanosis or other higher risk features of hypox- emia. The value of supplemental oxygen therapy in ACS patients without hypoxia is unclear, as several studies have suggested that supplemental
oxygen in normoxic patients with ACS may increase myocardial injury and mortality [8, 9].
Nitrates Patients with continuing chest pain should be initially treated with sublingual nitro- glycerin (0.3–0.4 mg) every 5 min for up to three doses. If ischemic pain persists, intravenous nitroglycerin should be considered if not contra- indicated. Nitrates should not be administered to patients with severe aortic stenosis, or patients who received a phosphodiesterase-5 inhibitor, and should be cautiously used in patients with suspected right ventricular infarction due to their dependence on pre-load [10].
Morphine In patients with ACS, it is reasonable to administer intravenous morphine for analgesia if the patient has continued chest pain despite maximally tolerated anti-ischemic medications.
NSAIDS (except aspirin) in patients with ACS are associated with increased risk of major adverse cardiac events; therefore, its use in ACS patients is not recommended [11].
Beta-Adrenergic Blockers In patients with ACS beta-blockers decrease myocardial isch- emia and frequency of ventricular arrhythmias and increase long term survival [12]. Oral beta- blocker therapy should be initiated within the first 24 h in patients who do not have signs of HF, evidence of low-output state, increased risk for cardiogenic shock (>70 years of age, systolic blood pressure <120 mmHg, heart rate >110 bpm or heart rate <60 bpm) or other contraindications to beta-blockade (e.g., PR interval >0.24 s, sec- ond- or third-degree heart block without a cardiac pacemaker, active asthma, or documented reac- tive airway disease). Beta-blockers should be titrated to decrease the heart rate to less than 70/
min while maintaining a systolic blood pressure above 120 mmHg. A non-dihydropyridine cal- cium channel blocker (CCB) (e.g., verapamil or diltiazem) should be considered in patients in whom beta-blockers are contraindicated.
Statin therapy High-intensity statin (atorvas- tatin 80 mg or rosuvastatin 40 mg) should be started or continued in all patients with ACS
Table 12.1 Killip classification of acute myocardial infarction
Class I No evidence of heart failure
Class II Findings consistent with mild to moderate heart failure (S3 gallop, lung rales less than one-half way up the posterior lung fields or jugular venous distension) Class III Overt pulmonary edema
Class IV Cardiogenic shock
without contraindication. Statins in ACS reduces cardiac deaths, recurrent MI, need for repeat revascularization, and stroke [13].
Anti-thrombotic Therapy
All patients with ACS, in the absence of contra- indications, should receive aspirin, a second antiplatelet agent, and an anticoagulant. The AHA/ACC guidelines for anti-thrombotic med- ical management of NSTE-ACS is provided in Fig. 12.4.
Antiplatelet Therapy
In the absence of an absolute contraindication, antiplatelet therapy with aspirin and a P2Y12 inhibitor is indicated in all patients with ACS.
Aspirin Uncoated aspirin (325 mg) should be administered to all patients with ACS without contraindications as early as possible on pre- sentation, and a maintenance dose of aspirin (81–162 mg daily) should be continued indefinitely.
Fig. 12.4 AHA/ACC recommendations for initial anti-thrombotic therapy in NSTE-ACS (From Amsterdam et al. [2].
Reprinted with permission from Elsevier Limited)
P2Y12 receptor inhibitors P2Y12 receptor inhibitors are administered to patients with ACS according to the type of presentation and how they are treated:
Glycoprotein IIb/IIIa Inhibitors In patients with very high risk features including, mark- edly elevated troponin, recurrent ischemic dis- comfort, dynamic ECG changes, or hemodynamic instability not treated with a P2Y12 inhibitor, a IIb/IIIa inhibitor (abcix- imab, eptifibatide or tirofiban) may be consid- ered at the time of PCI.
Anticoagulation In patients with ACS, antico- agulation is recommended for all patients, in addi- tion to antiplatelet therapy irrespective of initial treatment strategy. Anticoagulation is continued for 48 h or until PCI is performed. Anticoagulation options include:
• STEMI patients
– Primary PCI - In patients with STEMI treated with primary PCI, a loading dose of a P2Y12 receptor inhibitor should be given as early as possible (clopidogrel [600 mg fol- lowed by 75 mg/day], ticagrelor [180 mg followed by 90 mg BID], or prasugrel [60 mg followed by 10 mg/
day]). Ticagrelor as compared with clopidogrel significantly reduces rate of death from vascular causes, MI, or stroke [14].
– Fibrinolysis - In patients with STEMI treated with fibrinolysis, clopidogrel [300 mg loading dose for age < =75 year old or 75 mg for
>75 year old, followed by 75 mg/
day] should be administered at the time of presentation.
• NSTEMI/UA patients
– PCI - In patients with NSTEMI/UA undergoing PCI with stenting should receive a loading dose of a P2Y12 inhibitor at the time of the procedure (clopidogrel [600 mg followed by 75 mg/day], ticagrelor [180 mg fol- lowed by 90 mg BID], or prasugrel [60 mg followed by 10 mg/day]).
Ticagrelor and Prasugrel, as com- pared with clopidogrel, significantly reduce rate of death from vascular causes, MI, or stroke [14, 15].
– Other NSTEMI/UA patients - In patients with NSTEMI/UA treated with either an early invasive approach or an ischemia driven approach should receive either clopidogrel (600 mg followed by 75 mg/day) or ticagrelor (180 mg followed by 90 mg BID), or prasugrel (60 mg followed
by 10 mg/day). Ticagrelor as com- pared with clopidogrel significantly reduces rate of death from vascular causes, MI, or stroke [14].
• In addition to aspirin, a P2Y12 inhibitor should be administered for at least 12 months to all patients with ACS [16].
• Unfractionated heparin (UFH) (initial loading dose of 60 IU/kg (maximum 4,000 IU) with initial infusion of 12 IU/kg per hour (maximum 1,000 IU/h) adjusted per activated partial thromboplastin time),
• Low-molecular weight heparin (LMWH) (1 mg/kg subcutaneous (SC) every 12 h (reduce dose to 1 mg/kg SC once daily in patients with creatinine clearance [CrCl]
<30 mL/min)). LMWH has been shown to be superior to UFH in STEMI patients treated with fibrinolysis.
• Bivalirudin (0.10 mg/kg loading dose followed by 0.25 mg/kg per hour [only in patients managed with an early inva- sive strategy]), or
• Fondaparinux (2.5 mg SC daily [only in NSTEMI/UA; additional heparin needed if patients received PCI]).
Early Reperfusion and Revascularization STEMI
In patients with STEMI, rapid restoration of myocardial blood flow reduces mortality [17].
Current guidelines recommend primary PCI within 90 min or less for STEMI patients with symptom onset within 12 h, who arrive at PCI- capable hospital or 120 min or less for those who initially present to a non-PCI capable hospital and are then transferred to a PCI-capable hospital [1, 4]. Figure 12.5 provides a flow diagram for revascularization decisions in STEMI patient.
Fibrinolytic therapy, unless contraindicated should be initiated in patients with STEMI who cannot receive primary PCI within 120 min of first medical contact (Table 12.2). Decisions whether to transfer a patient for PCI vs. immedi- ate administration of a fibrinolytic should take into account (1) the risk of complications of the
STEMI; (2) the risks associated with fibrinolytic;
(3) the timing of presentation relative to symp- tom onset; and (4) the anticipated transfer time for primary PCI. In general, fibrinolysis may be preferred in early presenting patients, particu- larly when accompanied by a large myocardial territory at risk, and the time to PCI is anticipated to be longer than 90–120 min. Primary PCI should be favored in late presenters, those with shock, and when the diagnosis of STEMI is in doubt, or contraindications to fibrinolysis exist.
NSTE-ACS
In patients with NSTE-ACS who have refractory angina, hemodynamic or electrical instability an immediate invasive coronary angiography should be performed with intent to perform revasculariza- tion if appropriate based on coronary anatomy.
Furthermore, NSTE- ACS patients who have an elevated risk of adverse cardiac events should be treated with an early invasive strategy (coronary
STEMI patient who is a candidate for reperfusion
Initially seen at a PCI-capable
hospital
Initially seen at a non–PCI-capable
hospital+
Send to cath lab for primary PCI
Diagnostic angiogram
Medical
therapy only PCI CABG
Urgent transfer for PCI for patients with evidence of failed reperfusion
or reocclusion Transfer for
primary PCI DIDO time £30 min
Administer fibrinolytic agent within 30 min of
arrival when anticipated FMC- device >120 min FMC-device
time as soon as possible and
£120 min
Transfer for angiography and revascularization within 3–24 h for other patients as
part of an invasive strategy+ (Class lla, LOE: B)
(Class l, LOE: B)
(Class l, LOE: B)
(Class lla, LOE: B) FMC-device time
£90 min (Class I, LOE: A)
Fig. 12.5 AHA/ACC recommendations for reperfusion therapy choice in STEMI (From O’Gara et al. [1]. Reprinted with permission from Elsevier Limited)
angiography with intent to perform revasculariza- tion within 24 h of admission) [18]. However, a delayed invasive strategy (coronary angiography with intent to perform revascularization within 25–72 h of admission) is reasonable for NSTE-ACS patients at low risk of adverse clinical events.
Fibrinolytic therapy should not be used for reperfu- sion in patients with NSTE-ACS [19].
Evidence Contour
Several aspects of management in a patient with ACS remain without consensus. Recent trials have attempted to settle uncertainty behind many approaches involved in the care of patients with ACS.
Routine Early PCI After Successful Thrombolysis in STEMI
Many patients with STEMI present to hospitals that are not PCI-capable and cannot undergo PCI within the timelines suggested in current guidelines,
instead, they are treated with fibrinloysis as the ini- tial reperfusion therapy. Initial studies showed no clinical benefit with routine early PCI after success- ful fibrinolysis [20]. However, one study showed a strategy of immediate transfer to a PCI-capable hos- pital within 6 h after successful fibrinolysis for PCI to be associated with lower incidence of primary composite endpoint of death, recurrent MI, heart failure or cardiogenic shock compared to standard therapy alone with delayed coronary angiography or rescue PCI when indicated [21]. A strategy of routine transfer and angiography at 3–24 h is rea- sonable in patients who have undergone initial reperfusion therapy with a fibrinolytic.
Culprit Only vs Complete Revascularization in STEMI
STEMI patients with obstructive non-culprit lesions are at increased risk of major adverse car- diac events. However, past guidelines recommend revascularization of culprit lesions only unless complicated by cardiogenic shock. Results from observational and small randomized controlled
Table 12.2 Fibrinolytic regimens for STEMI
Fibrinolytic agent Dose Fibrin specificitya Antigenic
Patency rate (90-min TIMI 2 or 3 flow)
Fibrin-specific
Tenecteplase (TNK-tPA) Single IV weight- based bolusb
++++ No 85 %
Reteplase (rPA) 10 U + 10-U IV boluses given 30 min apart
++ No 84 %
Alteplase (tPA) 90-min weight- based
infusionc ++ No 73–84 %
Non-fibrin-specific
Streptokinased 1.5 million units IV given over 30–60 min
No Yese 60–68 %
From O’Gara et al. [1]. Reprinted with permission from Elsevier Limited
IV indicates intravenous, rPA reteplase plasminogen activator, TIMI thrombolysis in myocardial infarction, TNK-tPA tenecteplase tissue-type plasminogen activator, tPA tissue-type plasminogen activator
aStrength of fibrin specificity; “++++” is more strong, “++” is less strong
b30 mg for weight <60 kg; 35 mg for 60–69 kg; 40 mg for 70–79 kg; 45 mg for 80–89 kg; and 50 mg for ≥90 kg
cBolus 15 mg, infusion 0.75 mg/kg for 30 min (maximum 50 mg), then 0.5 mg/kg (maximum 35 mg) over the next 60 min; total dose not to exceed 100 mg
dStreptokinase is no longer marketed in the United States but is available in other countries
eStreptokinase is highly antigenic and absolutely contraindicated within 6 months of previous exposure because of the potential for serious allergic reaction
trials (RCTs), though suggest potential benefit with complete revascularization in STEMI patients with obstructive non-culprit lesions. Such a strategy may be reasonable in selected patients who have residual critical disease after primary PCI. Data from ongoing large RCTs will help to define any role and timing of routine PCI of non- culprit stenoses in patients with STEMI [22].
Manual Thrombectomy During Primary PCI in STEMI
Based on prior studies, past practice guidelines [1]
recommended routine manual thrombectomy to prevent distal embolization, improve coronary per- fusion and reduce adverse events. Subsequent stud- ies, however, found that a strategy of routine manual thrombectomy compared with PCI not only did not reduce cardiovascular deaths, recur- rent MI, cardiogenic shock or heart failure but led to possibly increased rates of stroke [23]. Therefore, routine manual thrombectomy is not recommended for all patients undergoing primary PCI.
Ezetimibe in Acute Coronary Syndromes
Ezetimibe, a nonstatin drug that decreases intes- tinal absorption of cholesterol was found to reduce adverse cardiac events when added to simvastatin in a larger trial of patients with ACS [24]. This is a first trial showing a net benefit with addition of a nonstatin LDL-C lowering agent to statin therapy and suggests a promising role of other novel interventions including recently improved PCSK9 inhibitors in lowering LDL-C and improving cardiovascular outcomes.
Optimal Duration of Dual Antiplatelet Therapy (DAPT)
Large proportions of patients with ACS are treated with invasive strategy and undergo PCI with drug-eluting stents (DES). Current practice guidelines recommend DAPT with aspirin and a
P2Y12 inhibitor for 12 months in patients treated with a DES. Two recent randomized trials have demonstrated that dual antiplatelet therapy beyond 12 months, compared with aspirin alone, reduced risk of stent thrombosis and major car- diac events, in particular in those patients with prior ACS [25, 26].
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