Chapter 21 Marini Acute Coronary Syndromes

21

CHAPTER

Acute Coronary Syndromes

• Key Points 1. In ischemic heart disease, survival and ventricular function are maximized by rapidly reestablishing sufficient myocardial blood flow to prevent myo­ cardial necrosis. Percutaneous coronary interven­ tion is the reperfusion modality of choice, but if there are substantial delays in transfer to the cath suite, then fibrinolytic therapy should be used in lytic-eligible patients. The door-to-balloon time should be less than 90 minutes. 2. Reducing myocardial oxygen consumption by limit­ ing heart rate (avoidance of exercise and judicious use of β -blockade), reducing afterload (controlling hypertension and normalizing ventricular filling pressures), and alleviating excessive catecholamine stimulation are important steps to optimize myocar­ dial supply and demand. 3. Myocardial oxygen supply can be quickly and sim­ ply boosted with nitrates, restoring normal oxy­ gen saturation and optimization of hemoglobin concentration. 4. Most patients should receive agents to interrupt the clotting cascade, as well as oxygen (when needed), pain relievers, and β -blockers in those without signs of ventricular insufficiency. All suitable candidates should be considered for immediate interventional procedures (angioplasty/stent) or for antithrombotic therapy. The presence of ST segment elevation and the duration of chest pain prior to arrival have a direct bearing on the value of thrombolytics and interventional catheterization. 5. After stabilization has been achieved, an angiotensin-converting enzyme inhibitor and high-dose statin

NON–ST ELEVATION ACUTE CORONARY SYNDROMES: UNSTABLE ANGINA AND NON–ST ELEVATION MYOCARDIAL INFARCTION Definitions and Pathophysiology of Acute Coronary Syndrome Unstable angina (UA) and non–ST segment eleva- tion myocardial infarction (NSTEMI) are now grouped under the heading of non–ST elevation acute coronary syndromes (NSTE-ACSs). Because they share a common underlying pathophysiology, the management of these two conditions is quite similar. UA is synonymous with the terms pre- infarction angina , crescendo angina , intermediate coronary syndrome , and acute coronary insufficiency. NSTEMI implies non–Q wave myocardial injury. The main difference between UA and NSTEMI is that biomarkers of myocardial necrosis are elevated in the latter (e.g., creatine kinase–myocardial band [CK–MB], troponin-I, troponin T). Myocardial ischemia results from an imbalance between oxygen supply and demand. Anginal chest pain is the clinical expression of this imbalance. Because the left ventricle (LV) comprises most of the cardiac muscle mass and faces the greater after- load, it is at higher risk for ischemia. Myocardial oxygen delivery may be limited by (1) coronary ath- erosclerosis, (2) plaque rupture with thrombosis, (3) coronary artery spasm, (4) anemia, (5) hypoxemia, (6) limited diastolic filling time (tachycardia), and (7) hypotension. Four major factors increase cardiac oxygen demand: (1) tachycardia and/or increased systemic

should be considered to minimize the risk of lasting ventricular dysfunction.

436

437

CHAPTER 21 • Acute Coronary Syndromes

metabolic demands for cardiac output, (2) height- ened LV afterload causing increased transmural wall tension (e.g., hypertension, LV cavity dilation, aortic stenosis), (3) increased LV mass (hypertrophy), and (4) increased contractility. Despite the predisposi- tion of the LV to ischemia, conditions that cause hypertrophy, dilation, or increased afterloading of the right ventricle (RV) also can put its muscle mass at risk. For example, pulmonary embolism may pre- cipitate RV ischemia—a phenomenon that is most common in patients with underlying right coronary artery (RCA) narrowing or cor pulmonale . Instability of a coronary atherosclerotic plaque is the key to the pathophysiology of ACS and infarc- tion. Degree of coronary narrowing plays a second- ary role. Histologic studies of coronary vessels have shown that atherosclerotic plaques are intimomedial in location. In general, there are two types of coro- nary plaques: (1) stable plaque with small lipid core and thick fibrous cap and (2) unstable plaque with large lipid core and thin cap. The former generally causes stable angina pectoris if it causes significant obstruction of the vessel (>50% to 70% of the ves- sel lumen diameter). Soft, lipid-laden plaques with thin caps are more prone to rupture, promote local clotting, and provoke ACS. Many of these plaques do not cause significant obstruction of the lumen of coronary vessels before the onset of the ACS. Hence, the patient may not have experienced any cardiac symptoms prior to the onset of ACS even with exercise, and stress tests may be negative. Acute instability and rupture of one or more coronary plaques with superimposed thrombosis are central to the pathophysiology of ACS. This clot, composed of platelets and thrombin, not only produces a fixed vessel occlusion but also stimu- lates reversible vasoconstriction. The resulting sudden coronary artery occlusion, which may be total or subtotal, causes acute myocardial ischemia or infarction. UA represents a high-risk transition period during which most patients undergo accel- erated myocardial ischemia. If unchecked, this transition culminates in acute myocardial infarc- tion (AMI) or sudden cardiac death (SCD) in up to 15% of patients within just a few weeks. Coronary angiography in many of these patients demonstrates complex coronary plaque lesions with varying degrees of superimposed thrombosis. Intravascular ultrasonic examination of coronary vessels (IVUS) is another useful tool that has helped shed consid- erable light, not only on the pathophysiology but

also on the management of coronary artery disease (CAD), particularly in the setting of ACS. The key role of platelets in the pathophysiology of ACS has undergone considerable review in the past decades. Platelet activation and aggregation encourage formation and propagation of a platelet- rich or “white” clot over a ruptured atherosclerotic plaque in patients with UA and NSTEMI. This contrasts with the fibrin-rich or “red” clot seen in the coronaries of patients with STEMI. The current recommendations on the use of antithrombin and antiplatelet therapies in NSTEMI and that of fibri- nolytic therapy in patients with STEMI derive not only from the pathophysiology of these conditions but also from the results of informative clinical trials performed within the last two decades. The term UA denotes new pain or a departure from a previous anginal pattern. UA occurs at rest or with less provocation than stable angina. Pain lasting longer than 15 minutes also suggests UA. Angina occurring in the early post-MI period or within weeks of an interventional coronary pro- cedure also is best termed “unstable.” Commonly, the pain is described as a “tightness,” “heaviness,” or “squeezing” in the substernal region. UA may awaken patients from sleep or present as pain at a new site such as the jaw or arm. Elderly, female, and diabetic patients are more likely to experience atypical symptoms, pain intensity, and distribution. Although the classical description is one of heavy central chest pressure radiating to the jaw and left arm, it is rational to raise suspicion of UA or evolv- ing MI in patients reporting acute pain from “nose to navel.” Autonomic manifestations (nausea, vom- iting, tachycardia, or sweating) also favor “instabil- ity.” Blood pressure frequently rises before the onset of pain, even in resting patients. Rising blood pres- sure boosts afterload, increasing wall tension and myocardial O 2 consumption. Less commonly, the abrupt onset of dyspnea and congestive heart failure (CHF) may be the only manifestation of UA. Diagnosis History and Physical Examination

Data Profile Electrocardiographic Changes

Electrocardiographic patterns are invaluable in deter- mining the presence of coronary occlusion and in

438

SECTION II • Medical and Surgical Crises

guiding the nature and urgency of therapeutic inter- vention. During episodes of ischemic chest pain, elec- trocardiogram (ECG) features may include (1) ST segment elevation or depression, (2) T wave flattening or inversion, (3) premature ventricular contractions (PVCs), or (4) conduction disturbances, including bundle-branch block (Fig. 21-1). Q waves often but not invariably indicate completed infarction. ST seg- ment elevation strongly correlates with fresh coronary occlusion (STEMI), whereas ST depression in asso- ciation with or without T wave inversion indicates ischemia without acute coronary luminal occlusion (non-STEMI or NSTEMI). Perhaps only 20% to 25% of ACS syndromes are STEMIs. Reversible ST depression or T wave inversion is detectable in most affected patients if continu- ous ECG monitoring is used, a finding that may not emerge during a single 12-lead ECG. Even with intensive monitoring, ECG findings are absent in up to 15% of symptomatic patients with UA. Therefore, a normal ECG does not exclude a diagnosis of UA or MI. Conversely, it has been estimated that up to 70% of all ECG-documented episodes of ischemia are clinically silent. Cardiac Enzyme Markers Elevated total CK (including the CK–MB fraction) and cardiac troponins (I and T) are markers of myo- cardial necrosis and indicate an MI, even in the absence of convincing ST segment–T wave changes. Troponins (I/T) are more sensitive and specific in making the diagnosis of an AMI than is CK-MB. Their rise may be delayed 1 to 3 hours after onset, so that their absence at a very early stage does not exclude an ongoing AMI. Once present, elevations are often detected for 10 days or longer, especially in patients with renal insufficiency. Troponin eleva- tion in NSTE-ACS correlates with adverse progno- sis. These are also patients who are likely to benefit from aggressive antiplatelet regimens and from early coronary angiography and revascularization. Highly sensitive C-reactive protein (hs-CRP) levels are also

increased in patients with ACS. ACS patients with the highest levels of hs-CRP and troponins have the worst prognosis. Prognostic Factors Patients with UA have a lower short-term mortality rate (2% to 3% at 30 days) compared to those with acute NSTEMI (5% to 7% at 30 days). The in-hos- pital or short-term mortality of patients with STEMI is higher compared with those with NSTEMI (6% to 9% vs. 5% to 7% at 30 days). However, the long- term mortality in NSTEMI (10% to 12%) is similar to or greater than that associated with STEMI (9% to 11%), likely because of their greater incidence of multivessel CAD. Thrombolysis in Myocardial Infarction Risk Score Several risk variables have been identified in patients with NSTE-ACS. A value of 1 has been assigned to each risk variable, and the total score has been shown to bear a linear relationship with risk of adverse events (death, MI, recurrent isch- emia, and need for urgent revascularization) in the short term. The variables are (1) age greater than or equal to 65 years, (2) prior coronary stenosis greater than or equal to 50%, (3) presence of greater than or equal to three coronary risk factors, (4) ST segment deviation on admission ECG, (5) elevated cardiac biomarkers, (6) greater than or equal to two anginal episodes in the last 24 hours, and (7) prior use of aspirin (marker for vascular disease). The adverse event rate is 4% to 5% for thrombolysis in myocardial infarction (TIMI) risk score of 0 to 1 but approaches 40% for those with score of 6 to 7. Elevated levels of hs-CRP indicate a worse prognosis in each TIMI scoring category. Management of NSTE-ACS Patients with NSTE-ACS should be monitored closely and should receive aggressive antithrombotic,

FIGURE 21-1. Electrocardiographic evolution of AMI. SEMI, subendocar­ dial (nontransmural) MI.

439

CHAPTER 21 • Acute Coronary Syndromes

Reducing Myocardial Oxygen Consumption The principal measures to decrease myocardial oxy- gen consumption are to limit heart rate and after- load. These goals are immediately accomplished by curtailing physical activity with bed rest. Exercise stress tests are contraindicated in unstable patients because frank infarction may ensue. Arrhythmias like atrial fibrillation (AF) and sinus tachycardia should be controlled, both to reduce O 2 consump- tion and to optimize diastolic filling time, thereby maximizing the sufficiency of coronary perfusion. Controlling hypertension and CHF decreases myo- cardial wall tension and therefore facilitates per- fusion (see Chapter 22). Situations that increase heart rate (anxiety, use of short-acting nifedipine) or both heart rate and total body oxygen consump- tion (e.g., thyrotoxicosis, alcohol withdrawal, stimu- lant drug intoxication, anxiety, agitation, infections, etc.) should be promptly recognized and corrected. β -Blockers effectively reduce myocardial oxygen consumption by decreasing heart rate and cardiac contractility and improve O 2 supply by lengthening diastolic filling time. β -Blocking drugs are particu- larly useful in reducing oxygen consumption in the tachycardic and hypertensive patient with UA and

antiplatelet, and antianginal treatments (Fig. 21-2). Most patients with UA can be stabilized with appro- priate medical therapy. Although the immediate urgency of STEMI-ACS is attenuated, coronary angiography and revascularization procedures have become increasingly popular in the treatment of these patients over the course of the last decades. Emergent coronary angiography and revasculariza- tion procedures are uncommon for NSTE-ACS patients, but most are advised to undergo coronary angiography and possible revascularization within a few days of admission to the hospital. Coronary revascularization procedures include either percu- taneous coronary interventions (PCIs) (PTCA and stenting) (Fig. 21-3) or coronary artery bypass graft (CABG) surgery. Essentially, only patients with con- traindications for invasive cardiac procedures are treated by noninvasive medical management alone. Thrombolytics are not advisable in most (nonoc- clusive) NSTE-ACS because “red thrombus” is not present and because thrombolytics have proco- agulant properties. Apart from considerations relat- ing to coronary patency, the two basic principles in the treatment of UA are to reduce myocardial O 2 demand and improve O 2 supply.

Chest Pain

Targeted H&P 12 Lead ECG O 2 , Morphine, ASA, TNG

Low-Mod Risk Pain Relieved Quickly Negative Troponin

Mod-High Risk Prolonged Pain, Dynamic ST Pos. Troponin, Prior PCI or CABG

Enoxaparin or Heparin Eptifibatide / Tirofiban (Clopidogrel if No CABG Planned)

R/O AMI With ECG & Serial Troponins

Consider Cath in 1–2 Days

Stress Imaging Study

Early Cath / PCI or CABG

Mod-Large Reversible Defect

No Reversible Ischemia or Small Region Only

Continue Med Rx

NSTEMI Algorithm

FIGURE 21-2. Non–ST elevation MI (NSTEMI) management algorithm. ECG, electrocardiogram.

440

SECTION II • Medical and Surgical Crises

FIGURE 21-3. Steps in balloon angioplasty with intracoronary stent deployment.

ACS but are contraindicated in acute heart failure, coronary artery spasm, or severe bronchospasm. Selective β -blocking agents such as carvedilol may be used cautiously in patients with modestly impaired ejection fractions and tachycardia, but, in general, should be withheld until stability is achieved. Increasing Myocardial Oxygen Supply The most important treatments under this category are the strategies for myocardial revascularization, which include percutaneous coronary angioplasty, coronary stenting, and coronary artery bypass sur- gery (dealt with later in this chapter). Myocardial oxygen supply can also be increased simply by boosting hemoglobin saturation or elevating hemo- globin concentration to levels higher than 9 g/dL, in severely anemic patients. Pharmacotherapy is also necessary to optimize myocardial perfusion. Nitroglycerin (NTG) is used commonly and may be administered sublingually, orally, transcutaneously, or intravenously. (For unstable patients, the intravenous route is most eas- ily regulated and reliable.) In addition to dilating coronary vessels, NTG also decreases wall tension of the LV by reducing preload and, to a lesser extent, afterload. Acting through these mechanisms, NTG also reduces the risks of life-threatening arrhythmias in acute ischemia. Nitrates are effective both for classical and variant angina because of their direct coronary vasodilating properties. NTG is titrated to relieve chest pain or to reduce blood pressure by 10% to 20%. Usually, intravenous doses of 0.7 to 2.0 μ g/kg/min suffice. Intravenous NTG usually

is begun at 5 to 15 μ g/min and titrated upward as necessary in increments of 5 μ g/min every 5 minutes up to a maximum dose of 200 μ g/min. Headache is a common side effect but usually responds to simple oral analgesics. When the dose is excessive or the patient is dehydrated, hypo- tension and reflex tachycardia result from NTG- induced vasodilation. These adverse effects usually can be offset by volume expansion or α -agonist therapy. Because ethanol is used as a vehicle for NTG infusions, violent adverse reactions may occur in those rare patients taking Antabuse. Obviously, use of high doses of NTG for prolonged periods may also produce alcohol intoxication. Within 48 to 72 hours of initiating NTG therapy, tolerance is often observed, necessitating higher infusion rates. Seldom seen problems induced by NTG therapy include increased intraocular and intracranial (IC) pressures and methemoglobinemia. Coronary spasm, a major contributor to myocar- dial ischemia provoked by the irritating products of plaque rupture, may be ameliorated by nitrates or calcium channel blockers. Blockers of slow calcium channels (e.g., nifedipine, nicardipine, and amlo- dipine) can be rapidly effective in reversing coro- nary spasm. In UA, these drugs should be viewed as adjuncts to nitrate, β -blocker, and antithrombotic therapy. Because calcium antagonists have vasodi- lating, negative inotropic, and positive chronotropic actions, they may not always be well tolerated. If coronary vasodilating effects predominate, myo- cardial oxygen supply–demand balances benefits. Conversely, if systemic vasodilation, hypotension, and reflex tachycardia predominate, myocardial

441

CHAPTER 21 • Acute Coronary Syndromes

Clopidogrel, Ticlopidine, and Prasugrel These agents, which are used in conjunction with aspirin for dual antiplatelet therapy, belong to the thienopyridine class. They prevent platelet aggrega- tion by noncompetitive inhibition of the adenosine diphosphate (ADP) binding to the type 2 puriner- gic (P2Y 12 ) receptor, thereby inhibiting the activa- tion of the glycoprotein IIb/IIIa receptor complex. Because ticlopidine requires 3 to 6 days of therapy for full antiplatelet effect and carries small but noteworthy risks of neutropenia (2.5%) and throm- botic thrombocytopenic purpura–hemolytic uremia syndrome (TTP–HUS), it has been replaced by safer and effective ADP receptor agents, such as clopidogrel. Clopidogrel has been extensively studied in patients with ACS and in those who have received intracoronary stents. The life-threatening adverse effects seen with ticlopidine are far fewer with clopidogrel. In the CURE trial, clopidogrel use in ACS was found to significantly reduce risk of car- diovascular events (mostly reinfarctions) compared to aspirin alone. The usefulness of clopidogrel as an agent in reducing risk of cardiovascular events in patients who have received coronary stents has been clearly demonstrated in the PCI-CURE and CREDO trials. Clopidogrel is usually given as an oral bolus of 300 mg, followed thereafter at a dose of 75 mg once daily. The antiplatelet effects of clopidogrel are seen within hours. Significant blood levels may be achieved sooner with a larger bolus dose of the medication (600 or 1,200 mg). Along with ASA (81 mg once daily), it is given for a month after the implantation of bare-metal coronary stents and for at least 3 to 6 months after insertion of drug-eluting coronary stents. In patients with ACS, clopidogrel can be continued for 9 to 12 months. In some individuals at high risk for future cardiovas- cular events, clopidogrel with low-dose aspirin may be continued indefinitely if there are no contraindi- cations and if cost is not an issue. There is a slight but significant increase in risk of bleeding with combination of clopidogrel and aspirin (3% to 5% risk of major bleeding), particularly in the elderly population. Prasugrel and ticagrelor are recently introduced oral thienopyridine ADP receptor antagonists avail- able for patients with ACS. They are both more powerful antiplatelet agents than clopidogrel and achieve platelet-inhibiting effects more quickly.

oxygen demand can outstrip supply and ischemia can worsen. Therefore, caution must be exercised to avoid hypotension or excessive tachycardia when using calcium channel antagonists. Antiplatelet Therapy Aspirin Most patients with NSTE-ACS have an ulcerated atherosclerotic plaque covered by a subocclusive accumulation of platelets, thrombin, and red blood cells. Typically, these patients have platelet-rich or “white clot.” Therefore, aggressive antiplatelet therapies are indicated in stabilizing them. Aspirin (162 to 325 mg daily) should be initiated immedi- ately for all patients with ACS unless compelling contraindications exist. Cyclooxygenase-1 (COX- 1)-mediated platelet aggregation is inhibited within 15 minutes when non–enteric-coated tab- lets are chewed and swallowed. Aspirin reduces synthesis of both thromboxane A2 (TXA-2) and prostacyclin. TXA-2 is a powerful promoter of platelet aggregation. Prostacyclin, on the other hand, promotes vasodilation and inhibits platelet aggregation. Low-dose aspirin preferentially inhib- its TXA-2 synthesis, and endothelial prostacyclin synthesis is inhibited by high-dose aspirin. In the VA cooperative study, Canadian multicenter trial, and RISC trial, aspirin was found to reduce the risk of death and AMI by approximately 50% in patients with NSTE-ACS. In a large meta-analy- sis by the Antithrombotic Trialist’s Collaboration, aspirin reduced risk of death, MI, and stroke by about 46%. The benefits of aspirin may persist for years with continued therapy. The risk of recurrent events is reduced by at least 25%. The risk of coro- nary reocclusion after PCIs is reduced by about 50% with use of aspirin. At the low doses (75 to 150 mg) needed for platelet inhibition, few hem- orrhagic or gastrointestinal side effects occur. At a lower dose, aspirin caused 2.5% major bleeds with 1% requiring transfusions. Aspirin resistance is seen in about 5% to 10% of patients, and these individuals are at increased risk for cardiovascular events. Although inhibition of platelet aggregation may complicate subsequent coronary artery sur- gery, aspirin-related clotting defects are reversible with platelet transfusions. Dipyridamole does not enhance the protective effect of aspirin in coro- nary ischemia, but clopidogrel and ticlopidine do complement the anti-ischemic effect of aspirin.

442

SECTION II • Medical and Surgical Crises

Ticagrelor is a relatively reversible agent, whereas the effects of both clopidogrel and prasugrel linger for days. Although potency is an advantage of pra- sugrel, it comes at the cost of higher incidence of bleeding complications. Although their ultimate place is as yet undetermined, these newer agents reduce the incidence of stent thrombosis and have been trial-determined to reduce the likelihood of recurrent ischemic events. They may be a good option for those who present with stent thrombosis with clopidogrel, in those with multiple drug-elut- ing stents, and in those at less risk of bleeding (like the younger patient population). Glycoprotein 2b/3a Receptor Inhibitors Gp2b/3a receptor inhibitor agents are the most powerful intravenous form of antiplatelet agents available. The Gp2b/3a receptor binds to fibrino- gen, which actually forms the molecular link that bridges adjacent platelets in the process of plate- let aggregation. By binding to the Gp2b/3a recep- tors, these agents inhibit binding of fibrinogen to this receptor and thus inhibit platelet aggregation. Although the use of these agents in ACS manage- ment had surged in prior years, their use presently is more restricted, as precatheterization treatment with dual antiplatelet therapies has become more common and bivalirudin now displaces heparin as an antithrombotic in the catheterization labora- tory. There are two broad classes of these agents: (1) large-molecule agents like abciximab (ReoPro) and (2) small-molecule agents (peptide-like eptifi- batide [Integrilin] and non–peptide-like tirofiban [Aggrastat]). Because abciximab molecules bind irreversibly to the Gp2b/3a receptor and produce permanent noncompetitive platelet inhibition, the clinical effects of the medication can last for 7 to 10 days. Severe uncontrolled bleeding associated with abciximab should be addressed by stopping the medication and transfusing platelets. The small- molecule agents bind reversibly to the Gp2b/3a receptor to produce competitive platelet inhibition. The antiplatelet effects usually reverse within 4 to 6 hours of stopping the medication. Platelet trans- fusions should not be given for bleeding provoked by small-molecule Gp2b/3a receptor antagonists, as transfusion inhibits new platelet formation. The risk of major bleeding with Gp2b/3a recep- tor antagonists is 2.5% to 4.0%. Most of the bleed- ing experienced from these agents is from vascular

access sites after PCI. Severe thrombocytopenia with counts less than 50,000/mm 3 occurs in 0.5% to 1.5% of patients who receive abciximab. Because thrombocytopenia can develop within hours of initiating an abciximab infusion, it is prudent to check platelet counts within 4 hours of starting the infusion and again at the end of the infusion. Severe thrombocytopenia is rare with small-mol- ecule agents (tirofiban and eptifibatide). There is also a small chance (0.5% to 1.0%) of develop- ing serious pulmonary hemorrhage with abciximab therapy. This potentially fatal condition is rarely if ever encountered with the small molecular weight Gp2b/3a receptor antagonists. Catheterization lab- oratory practices currently favor the use of bivali- rudin (a direct thrombin inhibitor [DTI]) over the customary heparin plus GP2b/3a inhibitor strategy during the procedure and immediate postprocedure phases. Although of equivalent efficacy to the lat- ter combination, bivalirudin has been demonstrated in large clinical trials to be associated with lower bleeding risk. High cost may be a factor that limits its use in some environments. Adequate doses of intravenous heparin given urgently along with oral aspirin reduce mortality and morbidity in patients with ACS by immedi- ately interrupting the process of clotting on the coronary endothelium. The combination of hepa- rin and aspirin is superior to aspirin alone in pre- venting the early complications of UA. Superiority of the combination probably results from the dif- ferent mechanisms of the two treatments: heparin inhibits soluble clotting factors and thrombin- mediated platelet aggregation, whereas aspirin inhibits COX-mediated platelet aggregation. Even though the addition of heparin to aspirin raises the bleeding incidence slightly, the risk–benefit ratio almost always favors combination therapy. The goal of heparin therapy is to rapidly achieve and maintain a partial thromboplastin time (PTT) of 1.5 to 2.0 times the patient’s baseline or labo- ratory control value. This goal is best achieved using an intravenous bolus (60 units/kg, with a maximum dose of 4,000 units), followed by a con- tinuous intravenous heparin infusion at a rate of 12 units/kg/h (maximum 1,000 units/h). The hep- arin infusion should be continued until coronary Antithrombotic Therapy Unfractionated Heparin

443

CHAPTER 21 • Acute Coronary Syndromes

revascularization. Today, most of the ACS patients receive an intravenous infusion of a Gp2b/3a recep- tor antagonist for 12 to 24 hours after PCI. They are also typically on aspirin and clopidogrel long term after PCI. In patients who are candidates for coronary bypass surgery, heparin and aspirin should be continued until surgery. In patients who are not candidates for coronary angiography and revascu- larization, heparin should be continued for 3 to 5 days. There is a risk of rebound angina when the heparin infusion is stopped. Thereafter, long-term use of aspirin alone can result in a 50% reduction in the incidence of angina recurrence. Unfractionated heparin (UFH) is a heterog- enous mixture of polysaccharides with molecular weights ranging from 3,000 to 30,000. There are several disadvantages with UFH. The antithrombin binding sites of heparin can be bound by a number of other plasma proteins, by platelet factor 4, and also by endothelial cells, thereby diminishing its therapeutic effect. Furthermore, heparin does not bind to clot-bound thrombin and to factor Xa bound to platelets inside a clot. Thus, there is the possibil- ity of clot propagation while the patient is receiving heparin. Heparin-induced thrombocytopenia (HIT) is another serious adverse effect. Perhaps surpris- ingly, in this ACS setting, the currently available low molecular weight alternatives may be more effective in selective categories but have not been shown to offer dramatic risk–benefit advantages across the entire “at-risk” population. Low Molecular Weight Heparins These are homogenous glycosaminoglycans with molecular weight ranging from 4,000 to 6,000. Low molecular weight heparins (LMWH) have greater anti–factor Xa activity and less anti–factor IIa activ- ity as compared to UFH. They act mainly by pre- venting thrombin generation and have lesser effect on a PTT as compared to UFH. Assays measuring anti–factor Xa activity are now in widespread use. Enoxaparin is the most popular of all LMWH that has been shown to be efficacious in patients with NSTE-ACS, as in acute pulmonary embolism and deep venous thrombosis. Enoxaparin has been reported in clinical trials to hold a modest advantage over UFH in reducing cardiovascular events, with risk of death, recurrent ischemia, and MI. Benefit appears more pronounced in patients with high- risk features like troponin elevation and those with higher TIMI risk scores.

In patients with ACS who have creatinine clear- ance greater than 30 mL/min, enoxaparin is used in the dosage of 1 mg/kg subcutaneously twice daily. There is little need to monitor the clotting param- eters because the therapeutic effect is quite con- sistent and predictable. The anticoagulant effect with enoxaparin is consistent because of very little binding to plasma proteins, endothelial cells, and macrophages. When thought advisable, as in mas- sively obese patients, anti–factor Xa activity can be monitored. Enoxaparin’s risk of thrombocytopenia is quite low. Major bleeding is also uncommon, but the risk may be higher in the elderly and those with renal failure. In patients requiring CABG, the drug should be stopped 12 to 24 hours prior to the operation. In patients undergoing cardiac catheter- ization and PCI, there is always a concern for bleed- ing because of concomitant use of UFH, Gp2b/3a receptor antagonists, and clopidogrel. The follow- ing rule of thumb can be used for heparin dosing in patients needing PCI: within 8 hours of having received a dose of enoxaparin, no additional UFH is needed for PCI; between 8 and 12 hours, use UFH at dose of 25 to 50 units/kg; and if greater than 12 hours after receiving enoxaparin, use 50 to 70 units/kg of UFH. Despite its proven efficacy, only a minority of patients in North America and 50% of patients in Europe receive LMWH for ACS. Direct Thrombin Inhibitors The direct thrombin inhibitor (DTI) agents avail- able are hirudin, lepirudin (recombinant hirudin), argatroban, and bivalirudin. These agents are sub- stantially more expensive than UFH and enoxa- parin. They are powerful anticoagulants and their anticoagulation effect is consistent and predictable. DTIs do not depend on antithrombin III for their activity. They bind to thrombin (factor IIa) and thus inhibit coagulation process. Because thrombin is also a powerful platelet activator, DTIs also inhibit platelet activation. In a large meta-analysis, DTIs were shown to reduce rates of recurrent ischemia and infarctions as compared to heparin in patients with NSTE-ACS, but their use was associated with increased incidence of major bleeding requiring blood transfusions. DTIs are currently only recom- mended for ongoing use in those with HIT. However, the use of bivalirudin in the setting of coronary intervention has dramatically increased, ever since the REPLACE-2 trial showed significantly reduced procedure-associated bleeding rates compared with

444

SECTION II • Medical and Surgical Crises

heparin and Gp2b/3a receptor antagonists. This drug, though expensive, has become popular with interventional cardiologists. Fibrinolytic Therapy There is no proven benefit of fibrinolytic therapy in NSTE-ACS. This is probably because a completely occlusive coronary thrombus is present in fewer than 50% of patients, because platelet-rich thrombi, which predominate in coronary vessels of patients with NSTE-ACS, are resistant to dissolution with fibrinolytic therapy and because fibrinolytics pro- mote platelet aggregation. Fibrinolytic agents have not been demonstrated to be effective in reduc- ing the risk of MI or death in NSTE-ACS and in fact may be deleterious. This is in stark contrast to STEMI-ACS, where the effectiveness of fibrino- lytic therapy has been proven. Therefore, fibrino- lytics are contraindicated in NSTE-ACS, except in unusually high-risk and unstable patients as a tem- porizing measure during transport to a center where PCI is available. Invasive Strategy of Coronary Angiography and Percutaneous Coronary Intervention Several recent studies have demonstrated ben- efit with an early invasive strategy in patients with NSTE-ACS as compared to conservative treat- ment strategy. In the early invasive strategy, patients undergo coronary angiography and revascularization within 12 to 48 hours of presentation to the hospi- tal with ACS. In the conservative strategy, patients undergo coronary angiography only for significant recurrent ischemia or ischemia demonstrated by stress testing. The early invasive strategy results in lower short-, intermediate-, and long-term major cardiac event rates (death, MI, recurrent ischemia, and revascularization rates) and shorter lengths of stay in the hospital. This is particularly true in patients with high-risk characteristics like elevated serum cardiac biomarkers (like troponins), ongoing chest discomfort, and dynamic ST–T changes on ECG. In intermediate-risk patients, a conservative strategy may be as good as an early invasive strat- egy. In low-risk patients, a conservative strategy is preferred. It has been shown that use of aggressive medi- cal regimens including “upstream” use of Gp2b/3a receptor antagonist (e.g., tirofiban or eptifibatide) for 12 to 24 hours before PCI reduces the risk of MI or death after PCI by at least 30% to 40%.

The majority of patients with NSTE-ACS will be candidates for PCI after coronary angiography (70% to 80%). Compared to balloon angioplasty, coronary stenting appears to substantially reduce recurrent ischemia and infarction. Restenosis in 3 to 6 months is a major limitation with bare-metal stents and occurs because of an intimal hyperplasia reaction to the vessel wall injury. Widespread use of drug-eluting stents has reduced long-term restenosis and repeat revascularization rates by 50% to 70%. However, with current stents, these patients must remain on long- term clopidogrel and aspirin therapy. Emergent cardiac catheterization and revascu- larization in NSTE-ACS are needed less commonly. The indications include pulmonary edema, hypoten- sion, and malignant ischemic ventricular arrhyth- mias. Most of the other high-risk patients can be stabilized with medical management for 12 to 48 hours before angiography and revascularization. Coronary Bypass Graft Surgery Versus Stenting The mortality risk with urgent CABG in NSTE-ACS patients is around 4% to 5%. The other complica- tions of bypass surgery include stroke and cognitive abnormalities. This is mainly due to cross-clamping of the aorta and the use of cardiopulmonary bypass. These risks should be borne in mind, especially while operating on elderly patients. The complica- tions and recovery times have improved over the course of the two decades because of refinement in surgical techniques and postoperative care. The advent of left internal mammary artery (LIMA) graft- ing to the left anterior descending (LAD) artery was a major advance in bypass surgery since the 1980s. The use of off-pump bypass surgery may reduce the risk of stroke in elderly patients. The usual length of stay in the hospital is 5 to 7 days, but it may take up to 2 to 3 months for the patients to recover back to their usual pre-event baseline. Only 20% to 30% of NSTE-ACS patients need urgent CABG. The classical indications for CABG include (1) significant left main coronary stenosis, (2) multivessel CAD with left ventricular ejection fraction (LVEF) less than 40%, (3) CAD with sig- nificant valvular disease (aortic stenosis and mitral insufficiency), (4) diabetes mellitus with multi- vessel CAD, (5) coronary anatomy unsuitable for PCI, and (6) failed PCI. It is preferable to stabilize these patients with medical management prior to CABG. Sometimes, an intra-aortic balloon pump (IABP) may be needed for prior stabilization in

445

CHAPTER 21 • Acute Coronary Syndromes

patients with hypotension, CHF, and LV dysfunc- tion. However, with the ever-expanding capabilities of interventional cardiology, many of the patients who previously would have been offered bypass sur- gery are now receiving DES. The debate of which is better (bypass surgery or stenting) in patients with complex coronary disease (multivessel CAD, total occlusions, left main CAD, etc.) continues. The SYNTAX trial has compared the use of DES (paclitaxel-eluting) to CABG surgery in patients with over 1,800 patients with complex CAD who were randomized to either bypass surgery or multivessel stenting. The combined endpoint of death, repeat revascularization, stroke, and MI at 1 year favored bypass surgery. The differences were driven mainly by higher repeat revascularization rates in the stent arm of the trial. The risk of death or MI was no dif- ferent in the two arms. The risk of stroke was more than three times higher in the surgical group. This trial, although providing some clear insights, has by no means put to rest the raging debate. The recom- mendation therefore is to individualize therapy after taking into considerations the following factors: (1) coronary anatomy, (2) LV function, (3) comorbid conditions, (4) age of the patient, and (5) patient’s wishes. Intra-aortic Balloon Pump An IABP may occasionally prove needed for hemody- namic stabilization while awaiting PTCA or CABG, particularly for patients with LV dysfunction, CHF, hypotension, or acute mechanical defects (e.g., mitral regurgitation [MR] or ventricular septal defect [VSD]). Balloon inflation during diastole augments coronary perfusion and deflation during systole decreases LV afterload. Unless a rapidly correct- able mechanical defect is present, IABP does not improve outcomes. Risk Factor Modification For the patient who has been stabilized medically or following revascularization procedures, risk fac- tor modification is essential in preventing recur- rent ischemia, infarction, and sudden death from progression of CAD. Smoking cessation, control of diabetes mellitus and hypertension, correction of abnormal lipid patterns, and weight reduction are critical elements in risk factor modification. Most should remain on aspirin, β -blockers, high- dose statins, and angiotensin-converting enzyme inhibitors (ACEI). Establishing a regular program

of exercise is pivotal in achieving these goals and improving activity tolerance. Patients with good exercise capacity are known to have fewer cardio- vascular events and seem to tolerate them better. ACUTE CORONARY SYNDROMES: ST ELEVATION MYOCARDIAL INFARCTION (ACS-STEMI) Mechanisms STEMI results from plaque rupture and formation of superimposed thrombus. The thrombus that causes complete occlusion of a major coronary artery is usually rich in fibrin and red blood cells (red clot). This is in contrast to the thrombus seen with NSTE- ACS, which is characterized by formation of a plate- let-rich thrombus (white clot). Following complete coronary occlusion, a wave of myocardial necrosis spreads from the endocardium to the epicardium. The process of infarction is usually completed in 24 hours, and it is called a “full-thickness” or com- pleted infarction. Q waves are typically seen in the ECG with a completed or full-thickness infarction, but their presence does not always indicate a final- ized pathogenic process. If angiography is performed promptly, a fresh occlusive coronary thrombus may be demonstrated in most cases (approx. 90%). Nonthrombotic spasm of the coronary arteries in an area of atherosclerosis is responsible for a small fraction of AMIs. Rarely, coronary flow may be inter- rupted by embolism in patients with endocarditis, prosthetic valves, or rheumatic valvular disease. Only 5% to 10% of patients sustaining an MI have anatomically normal coronary arteries. (Although spontaneous thrombolysis of clot is suspected, the mechanism of infarction in these cases usually remains unknown.) Cocaine is responsible for an alarming number of MIs. Because cocaine enhances platelet aggregation, causes vasoconstriction, and increases heart rate through catecholamine-medi- ated mechanisms, it can produce infarction even in patients with normal coronary arteries.

Diagnosis History

1. Classical Presentation: The typical presen- tation is one characterized by the abrupt onset of left-sided or retrosternal chest, neck, and jaw

446

SECTION II • Medical and Surgical Crises

discomfort, which has been described as burn- ing, squeezing, or pressure-like sensation lasting for more than 30 minutes. The discomfort may radiate to the arms, neck, back, or jaw. It must be emphasized that the pain description may be highly atypical (burning, stabbing, sharp) or may be localized only to the arm, neck, or epi- gastrium. Autonomic symptoms (nausea, vom- iting, sweating) are more common than in UA, especially when the MI is inferior. Up to 20% of MIs are painless (more likely in diabetics and the elderly). Young age, paucity of classic risk factors, and atypical chest pain character are more com- mon in patients with cocaine-induced infarction. 2. Atypical Presentation: Symptoms may mimic gastroesophageal reflux, cholecystitis, or an acute abdomen. Acute onset of shortness of breath, heart failure, dizziness, syncope, and weakness are occasionally encountered as atyp- ical manifestations of an AMI. 3. SilentMI: Clinically silent infarcts are detected incidentally on an ECG, echocardiogram, or nuclear scan. Silent MI is usually experienced by diabetics with autonomic dysfunction. Physical Examination Blood pressure and pulse rate usually are mildly increased. (Tachycardia is more common in anterior or lateral MI than in inferior or posterior MIs, in which bradycardia is more likely.) Fever may accom- pany uncomplicated MI but rarely exceeds 101°F or persists beyond 1 week. An S4 gallop is very common, whereas an S3 suggests congestive fail- ure, especially if accompanied by pulmonary rales. A paradoxically split S2 indicates increased LV ejection time or left bundle-branch block (LBBB). A systolic murmur should raise the suspicion of acute papillary muscle dysfunction, especially if the patient has presented late (typically, a few days after onset of symptoms). A pericardial friction rub com- monly appears in the first 48 hours after a transmu- ral MI and may be easily confused with a murmur. Although also possible in a classic MI, findings of a hyperadrenergic state (mydriasis, agitation, hyper- tension, diaphoresis, and/or tachycardia) should raise suspicion of cocaine-induced infarction. Electrocardiogram 1. ST Segment Deflection: ST elevation greater than or equal to 1 mm in two or more contigu- ous leads is highly suggestive of STEMI. ST

elevation has high localizing value (Table 21-1). The typical ST elevation seen with STEMI has an outward convexity. The ST segment eleva- tions usually return to baseline with myocardial reperfusion and can be used to monitor rep- erfusion therapies. The differential diagnosis includes hyperkalemia, acute central nervous system (CNS) injury, acute myocarditis, acute pericarditis, left ventricular hypertrophy, api- cal cardiomyopathy, Wolff–Parkinson–White syndrome, early repolarization abnormalities, and LV aneurysm. Some of these may mimic an AMI and hence have been termed “pseudo- infarct” patterns. 2. Evolution of ECG Changes: A series of repolarization changes are seen on ECG after complete coronary artery occlusion. The first transient abnormalities seen are the hypera- cute T waves (tall, peaked, and symmetrical T waves). Hyperacute T waves are usually gone by the time of initial presentation for emer- gency care. This is followed by convex, upward ST elevation, which is a sign of transmural myocardial ischemic injury. The number of leads showing the abnormality has a bearing on the size of the infarction and prognosis. T wave inversions are seen with persistent transmural ischemia. By this time, the ST elevations have begun to subside. Q waves are a sign of com- pletion of the infarction and may take hours to days to develop. Persistent ST elevation beyond 3 to 4 weeks is a sign of an LV aneurysm. 3. Posterior MI: This manifests as ST depres- sion (>2 mm) in leads V 1 to V 3 . It is usually seen in conjunction with an inferior wall MI, Table 21-1.  Anatomic Patterns of Myocardial Injury Location of Injury Affected Leads Inferior II, III, F Anterior/septal V 2 –V 4 Anterolateral V 3 –V 6 Lateral I, AVL, occasionally V 6 Apical II, III, F, V 5 , V 6 Posterior a V 1 and V 2 and V 3 R, V 4 R a ST segment depression with R waves; T wave is inverted initially and then becomes upright.

447

CHAPTER 21 • Acute Coronary Syndromes

but can present on its own as a true posterior infarction. This may occur with either left cir- cumflex or distal RCA occlusion. 4. RV Infarcts: In about 30% of inferior wall infarctions, RV infarcts manifest on ECG as ST depressions in V 1 and V 2 and ≥ 1 mm ST ele- vations in right-sided chest leads, particularly V 3 R and V 4 R. Pure RV infarcts resulting from occlusion of RV marginal branch vessels may sometimes mimic an anterior MI by causing ST elevations in leads V 1 and V 2 . 5. New LBBB: New LBBB is typically seen with large MIs and carries an in-hospital mortality rate of 20% to 25%. There is a substantial ben- efit from reperfusion therapy (21% reduction in mortality at 7 weeks, which translates into 49 lives saved per 1,000 patients treated). How- ever, an MI may be missed in a significant num- ber of individuals with new complete LBBB, and therefore, they are less likely to get reper- fusion therapies than STEMI patients. Criteria for diagnosis of MI in the presence of LBBB are based on ST segment concordance or discord- ance: (1) greater than or equal to 1 mm con- cordant elevation, (2) greater than or equal to 5 mm discordant elevation, and (3) greater than 1 mm ST segment depressions in leads V 1 to V 3 . Presence of one or more of these criteria makes a diagnosis of AMI more likely with LBBB. 6. Normal ECG: ECG may be normal in high lateral wall infarctions, as this area may be elec- trocardiographically “silent.” Cardiac Enzymes Creatine Kinase Although now of secondary prominence to tropo- nins, traditional creatine kinase measurements con- tinue to be diagnostically helpful. Total CK and MB fractions begin to rise by 4 to 8 hours of onset of an MI, reach a peak by 18 to 24 hours, and return back to baseline by 48 to 72 hours. CK peaks earlier in non–Q wave infarctions and in patients who have received thrombolytic therapy to abort an acute infarction. The rapid washout of CK associated with thrombolysis may produce peak enzyme levels as early as 30 minutes after reperfusion. Peak CK activity correlates with the extent of muscle loss. Levels are checked every 8 hours, and three negative CK–MB levels help rule out an AMI. CK– MB levels greater than 3% of total CK levels are used to make a diagnosis of an AMI. The sensitivity

and specificity of CK–MB in the diagnosis of an AMI are lower than that of troponin. Thus, one may have a small infarct with normal CK–MB but slightly elevated troponins. Total CK may be mildly elevated by trivial skeletal muscle injury (e.g., severe exercise or intramuscular injection). Even though CK–MB is relatively specific for cardiac muscle, it may be released during massive skeletal or smooth muscle damage (e.g., rhabdomyolysis, polymyositis, small bowel surgery). Cardiac Troponins There are two types of cardiac troponin assays avail- able (T and I). Both are cardiac-specific regulatory proteins; troponin-I is in more widespread use. Highly sensitive and specific in making a diagnosis of AMI, their levels elevate within 6 to 8 hours of onset of an AMI, peak by 3 to 5 days, and gener- ally last for 7 to 12 days. Renal insufficiency slows their clearance. Thus, they aid in making a diagnosis of a remote MI. They are also helpful in making a diagnosis of an MI in certain situations like rhabdo- myolysis, polymyositis, and renal failure where the CK–MB levels may be elevated. Although sensitive, the serum aspartate amino- transferase is not sufficiently specific for diagnosis. Similarly, total lactic dehydrogenase (LDH) rises in most cases of MI but has a low specificity. Levels of the LDH-2 isoenzyme normally exceed those of the LDH-1 isoenzyme. Reversal of the ratio suggests MI. LDH begins to rise 12 to 24 hours after coro- nary occlusion, peaking at 2 to 4 days and resolving in 7 to 10 days. Because LDH rises later than cre- atine phosphokinase (CPK), it may be used to diag- nose infarction in patients presenting more than 24 hours after onset of symptoms. Accumulating expe- rience with troponin-I suggests it to be a sensitive and specific serum marker of myocardial damage. Echocardiography Although echocardiography cannot be considered a definitive test for ischemia, it is a helpful adjunc- tive technique. Echocardiography offers informa- tion that can help make a diagnosis of ischemia or infarction. A focal wall motion abnormality seen on the echocardiogram in the proper clinical setting can help make the diagnosis of acute ischemia or infarction, especially when the ECG is not help- ful. Echocardiography can also help in providing an explanation for hypotension or congestive symptoms in patients with an AMI (e.g., LV or RV dysfunction,