Acute cardiac syndromes, investigations and interventions

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Chapter 16 Acute cardiac syndromes, investigations and interventions

Cardiovascular disease (CVD) accounts for 35–40%¹ of deaths in western industrialised society, with coronary artery disease (CAD) being responsible for about half of these. In patients over age 40, acute myocardial infarction (MI) is the cause of approximately 20% of all deaths. Up to 80–90% of these deaths occur outside hospital. Of patients admitted to hospital, mortality is 8–9%,¹ much higher in at-risk groups. Lowering in-hospital mortality from CAD requires us to identify rapidly patients who are at risk and to implement evidence-based treatment regimens.

MYOCARDIAL INFARCTION

MI is necrosis of myocardial cells due to ischaemic injury. Diagnosis is usually made on the basis of clinical suspicion, although tests such as electrocardiography (ECG) and biomarkers, echocardiography or autopsy findings are required to confirm the diagnosis.

Acute MI can occur in association with or result from a number of different pathological and epidemiological mechanisms:²

• a primary coronary artery event such as plaque erosion and/or rupture, fissuring or dissection

• a problem of oxygen supply demand such as coronary spasm, coronary embolism, vasculitis, drug abuse, arrhythmia, anaemia or hypotension

• sudden cardiac death where death precludes determination of causation

• percutaneous coronary intervention (PCI)

• coronary artery bypass grafting (CABG)

Each mechanism may have a different long-term prognosis despite similar biomarker and ECG changes. Such classifications may be clinically important when interpreting the results of clinical trials.²

ACUTE CORONARY SYNDROMES (ACS)

ACS represent the largest group of patients developing MI. They describe the spectrum of patients who present with chest discomfort or other symptoms caused by acute myocardial ischaemia (Figure 16.1). ACS can be further divided into acute MI and unstable angina (USA). Both are invariably caused by recent thrombus formation on pre-existing coronary artery plaque leading to impaired myocardial oxygen supply. In this sense they differ from stable angina, which is usually precipitated by increased myocardial oxygen demand with severe background coronary artery narrowing. Both represent medical emergencies and are one of the most frequent causes of hospital and coronary care unit (CCU) admission.

Figure 16.1 Classification of acute coronary syndromes.

AETIOLOGY AND RISK FACTORS

Atheroma deposits in the walls of coronary arteries provide the substrate for the development of ACS. Major risk factors for the development of coronary artery atheroma are seen in Figure 16.2. Up to 90% of the adult population possess at least one risk factor for the development of atheroma and CAD.

Figure 16.2 Risk factors for the development of atherosclerosis and coronary artery disease (CAD).

Cessation of smoking, lowering plasma cholesterol (diet and medications) and adoption of a more active lifestyle can all help prevent the development of CAD. Treatment of hypertensive patients produces a large and early reduction in stroke incidence (35–40%) and mortality, and a significant fall in MI (20–25%).³ Modification of risk factors is one of the most important means of decreasing the prevalence and mortality from CVD.

PATHOPHYSIOLOGY

Formation of thrombus upon disrupted, fissured or eroded atheromatous plaque is the usual precipitant of an ACS.⁴ Atherosclerotic plaque formation is probably initiated by injury to the vessel wall that may commence even as early as childhood. Highly activated macrophages are attracted to the site of injury and differentiate into tissue macrophages. Macrophages incorporate blood stream lipids into the connective tissue fibres of the plaque, forming a thrombogenic soft lipid core. Plaque development is slow, but is rapidly accelerated in people with risk factors.

‘Vulnerable plaque’ is often rich in lipid and covered by a thin fibrin cap. The cause of plaque rupture or fissuring is unknown but exposes thrombogenic lipid and collagen, which are potent activators of platelets. Development of thrombus upon this eroded plaque results from: (1) platelet adherence and activation; and (2) coagulation pathway activation.

Although many pathways initiate platelet activation, the final common pathway of thrombus formation is via activation of the glycoprotein (GP) IIb/IIIa receptor, the platelet surface membrane receptor for fibrinogen. Activated GP IIb/IIIa receptors cross-link fibrinogen between activated platelets, promoting the formation of platelet thrombi. Platelets aggregate to form ‘white thrombus’; however this thrombus is seldom totally occluding. Activation of coagulation pathways by exposed lipid and fibrin, as well as by the now activated platelets, leads ultimately to thrombin activation and the laying-down of fibrin clot. Red cells are enmeshed in this so-called ‘red thrombus’ complex, which surrounds the ‘white thrombus’. Sudden artery occlusion by thrombus may thus complicate even only moderate-sized plaque; 70% of ACS patients may have a < 50% stenotic lesion and in only 14% is the underlying stenosis > 70% of the lumen diameter (Figure 16.3).

Figure 16.3 (a) Plaque rupture exposes thrombogenic lipid. ‘White thrombus’ is formed by adherent activated platelets. Coronary artery narrowing, distal platelet embolisation or arterial spasm can cause ischaemic myocardial pain and possible myocardial necrosis. This lesion is unstable and may lead to thrombin activation. ‘White thrombus’ is not removed by thrombolytic therapy. (b) Thrombin activation leads to a mesh of fibrin and red blood cells (RBCs) or ‘red thrombus’. Arterial occlusion may result and, in arteries without adequate collateral circulation, myocardial necrosis follows. Complete arterial occlusion is suggested by ST-segment elevation on the electrocardiogram. Prompt reperfusion with thrombolytic therapy or with invasive coronary procedures may prevent extensive myocardial necrosis.

These processes have immediate relevance to treatment:

• Antiplatelet agents prevent platelet adherence and heaping, which limits and even reverses the development of ‘white thrombus’. These agents may target the adenosine diphosphate receptor (e.g. ticlopidine and clopidogrel) or may inhibit cyclooxygenase (e.g. aspirin). Although aspirin has been the major antiplatelet agent and blocks synthesis of thromboxane A₂, it fails to block platelet activation by thrombin, adenosine diphosphate and collagen.

• Fibrinolytic agents lyse ‘red thrombus’ but are not active against ‘white thrombus’.

• Antithrombin agents (e.g. heparins) may limit thrombin activation. Current thrombolytic agents lyse fibrin and red cell thrombus, but paradoxically may increase surface thrombin activation.

Totally occluding thrombus causes myocardial necrosis unless there is good collateral flow or the thrombus is rapidly cleared. Occlusion is often accompanied by ST-segment elevation on the ECG. If thrombus is largely ‘white thrombus’, with minimal or non-occlusive red thrombus, ST-segment elevation is far less likely. Non-occlusive thrombus may be asymptomatic, may cause USA or may cause MI, especially if spasm or distal embolisation of thrombus occurs. Although non-occlusive thrombus is less likely to be associated with early or sudden death, it is indicative of unstable plaque and is strongly associated with reinfarction and death in following months.

Ischaemia results in cellular disruption, loss of function, thinning and softening of the affected myocardium, and subsequently fibrosis and ventricular remodelling.

Infarct size determines:

• left ventricular (LV) systolic function impairment

• stroke volume decrease

• ventricular filling pressure rise (leads to pulmonary congestion and hypotension that may impair coronary perfusion pressures and exacerbate the myocardial ischaemia)

• LV diastolic dysfunction

Initially, infarcted muscle is softened, leading to an increase in ventricular compliance, but as fibrosis takes place compliance is decreased. With time, there is often expansion of the infarcted segment and compensatory hypertrophy of unaffected myocardial cells (i.e. ventricular remodelling). This can commence early after infarction, affecting overall ventricular function and prognosis.

CLINICAL PRESENTATION

The diagnosis of myocardial ischaemia is usually made (suspected) on the basis of clinical history and ECG.²

HISTORY

Patients with myocardial ischaemia can present with chest pain or pressure, syncope, palpitations, dyspnoea or sudden death. Prodromal symptoms of USA occur in the days preceding infarction in 20–60% of patients.

Typically, the pain of acute MI:

• is severe, constant and restrosternal, spreading across the chest

• lasts for more than 20 min and is without a clear precipitant

• may radiate to the throat and jaw, down the ulnar aspect of both arms and to the interscapular area

Sweating, nausea, pallor, dyspnoea and anxiety are common.

The pain of USA may be similar but milder in nature. Features that may suggest it to be ischaemic are:

• waxing and waning characteristics

• reproducibility upon minimal exertion or with emotion

• association with autonomic symptoms

The pain may sometimes be atypical:

• epigastric (leading to possible misdiagnosis)

• confined to the jaw, arms, wrists or interscapular region

• burning or a ‘pressure-like’ sensation

• sharp or stabbing in nature

• reproduced by chest pressure

These features do not necessarily exclude infarction.⁵ Differential diagnosis includes:

• aortic dissection

• pericarditis

Atypical or silent presentations are common: 20–60% of non-fatal infarctions are unrecognised at onset.⁴ This presentation is more common in patients who are elderly, diabetic, have hypertension, who smoke or take non-steroidal anti-inflammatory agents.

The assessment of clinical symptoms alone is insufficient for risk stratification and severity of pain does not usually correlate with the extent of infarction.

PHYSICAL EXAMINATION

Examination of patients with USA is often unremarkable. With more severe infarction and extensive myocardial injury, signs of autonomic activation (pallor, sweating, agitation, clamminess) as well as heart failure and even shock may be apparent. Pericardial friction rubs occur frequently after MI but are usually transient.

LV failure is associated with a higher mortality. Signs include gallop rhythm, tachycardia, tachypnoea and basal crackles. A fourth heart sound is often heard, but a third heart sound usually indicates a large infarction with extensive muscle damage. A systolic murmur may be present and may be transient or persistent. These murmurs can have prognostic significance and usually result from mitral regurgitation, due to either papillary muscle dysfunction or LV dilatation.

Cardiogenic shock, hypotension, oliguria and other features of low cardiac output are associated with particularly poor outcome. Shock may be present without hypotension ⁶ and may develop many hours after onset of symptoms. Right ventricle (RV) infarction results in hypotension and marked elevation of the jugular venous pressure (also seen with major LV dysfunction, usually in association with marked pulmonary venous congestion).

Conditions with similar presentations that do not benefit from thrombolysis are:

• pericarditis (auscultate for pericardial rub)

• aortic dissection (arterial pulses are compared; review chest X-ray if concerned)

It is usual to use the ECG in initial clinical assessments to localise the area of myocardial ischaemia. The pattern of lead involvement may thus assist with localisation of the MI (Figure 16.6).^8,^11,¹² There is a reasonable correlation between the site of infarction as defined by the ECG and the occluded coronary artery and the infarcted region of myocardium (Figure 16.7). However, ECG localisation may differ from angiographic, echocardiographic and autopsy findings, especially where there is collateral circulation or previous CABG. Anterior wall infarctions usually result from occlusion of the LAD; inferior, true posterior and RV infarctions result from occlusion of the RCA or circumflex arteries.

Figure 16.6 Electrocardiogram patterns of myocardial injury. RCA, right coronary artery; LAD, left anterior descending coronary artery; Cx, circumflex coronary artery. *Initial ST-segment depression and T-wave inversion in V₁–V₂, subsequent evolution to tall R-waves in V₁–V₂ and loss of R-wave in V₆. The correlation of electrocardiogram localisation with culprit artery (determined at angiography) and echocardiographic or autopsy localisation is variable.

Figure 16.7 Acute Inferior myocardial infarction (ST-segment elevation in the inferior leads II, III and aVF) with reciprocal ST depression in leads I, aVL, V1 and V2. The addition of right sided (V4R) and posterior leads would help identify the presence of RV and posterior infarction. Reciprocal ST segment depression in leads remote from the site of infarction is a highly sensitive indicator of myocardial infarction. It may be seen in 70% of inferior and 30% of anterior infarctions.

Common ECG patterns of infarction are shown in Figure 16.6. Approximately 40–50% of patients present with anterior infarction and 50% with inferior infarction. Anterior wall infarctions may be extensive or localised (septal, anterior, lateral) whereas inferior infarctions may similarly involve extension to the lateral, posterior or RV myocardium. Of clinical importance:

• 8% of patients with MI will only display ST-elevation in posterior leads V₇–V₈ (true posterior) or in right precordial leads V₃R–V₆R (RV).^4,¹¹

• True posterior infarction involves ‘mirror’ changes in leads V₁ and V₂ and is important to diagnose because the amount of threatened myocardium is similar to that of inferior infarction.

• RV infarction is usually concurrent with inferior wall infarction and very rare in isolation. A V₄R lead (V₄ lead in an equivalent position on the right anterior chest wall) is sensitive and specific for RV infarction.^11,¹²

The resting ECG does not have sufficient predictive value to stratify patients with NSTEACS reliably into those with infarction (NSTEMI) and those without (USA). Up to 18% of patients with MI show no changes on the initial ECG and up to 20% of patients with NSTEACS have normal or minimal CAD.^11,¹² Cardiac biomarkers are necessary to confirm myocardial cellular injury and meet diagnostic criteria for MI.

CARDIAC BIOCHEMICAL MARKERS

• The increasing sensitivity and specificity of cardiac troponins (cTN) has made them the gold standard for the confirmation of myocardial necrosis. Elevated levels should be taken as evidence of myocardial injury and, in the correct setting, as confirmation of MI.^2,⁷

• Troponin measurements have generally replaced creatinine kinase (CK) as the biomarker used to identify the presence of myocardial necrosis.

The typical rise and fall of cardiac markers after infarction are shown in Figure 16.8.

Figure 16.8 Serum biochemical marker changes after acute myocardial infarction. The sensitivity and specificity of cardiac troponins makes them useful for the early diagnosis of MI. Their delayed fall may allow diagnosis where presentation is late. CK or CK-MB are useful if re-infarction with secondary biomarker rise is queried.

Two (cTnT, cTnI) of the three isoforms of the cTn complex are exclusively expressed in cardiac myocytes (specific). Troponin levels allow early and sensitive detection of myocardial necrosis.

TROPONINS

• These are more sensitive indicators than CK and its CK-MB isomer. Up to 20–40% of patients with ACS but normal CK-MB may have elevated cTn levels.

• There is a strong correlation between troponin level, intracoronary thrombus and amount of threatened or ischaemic myocardium.

• Identify patients who will derive benefit from therapies such as low-molecular-weight heparins (LMWHs), glycoprotein inhibitors (GPIs) and early PCI.

The increased sensitivity of troponins compared to CK means that a third of patients previously considered to have USA are now recognised or redefined as having evidence of myocardial necrosis. Troponins also have better specificity than CK, similar to that of its isomer CK-MB. They do not differentiate the cause of the myocardial injury (e.g. ischaemia, myocarditis, trauma), however, and thus clinical context must always be considered.² Troponins are more persistent in the serum (up to 7–10 days) and thus may be useful in diagnosis when presentation is delayed. Whilst CK-MB has traditionally been thought to be a better predictor of reinfarction, a rise in troponin of > 20% some 3–6 hours after onset of suspected reinfarction is also significant.²

Troponins should be checked in all patients with ACS and aggressive therapies should be targeted at patients with elevated levels.⁵

TROPONINS IN CRITICAL ILLNESS

Cardiac-specific troponins are frequently elevated in critical illness, including but not confined to sepsis, pulmonary embolus and renal insufficiency.¹³ It is likely that they are of cardiac origin and are indicative of myocardial injury. Their elevation does correspond with adverse outcomes. Most will not be due to ‘unstable plaque’, however, and the role of standard NSTEMI therapies is uncertain. Clinical context is necessary to decide those likely to have significant underlying CAD that may require acute or subsequent investigation.²

Please also see the latest information at the end of the chapter.

ECHOCARDIOGRAPHY

Two-dimensional transthoracic echocardiography with colour Doppler has good clinical utility as a non-invasive investigation during admission for an ACS. Its primary role is in assessing the degree of regional and global LV dysfunction.

Echocardiography detects regional wall motion abnormalities, which can help confirm or exclude the diagnosis of MI in the small percentage of cases where diagnosis is uncertain (e.g. left bundle branch block (LBBB) or old infarction with atypical presentations). Regional wall motion abnormality and loss of wall thickening with contraction are often present in these cases if due to ischaemia, while their absence suggests that ischaemia is not acute. It is useful for excluding differential diagnoses (e.g. aortic dissection or pericardial effusions), again in a small percentage of patients.²

Echocardiography is subsequently useful to:

• assess infarct size, especially if thrombolysis has interfered with biomarker measurement

• diagnose RV infarction and infarct extension

• assist management by bedside assessment of LV function

• diagnose specific complications, for example, mitral regurgitation, pericardial effusion, mural thrombus and myocardial rupture, including ventricular septal defect

Transoesophageal echocardiography may have an increasing role in the therapy of cardiogenic shock, giving some guide to volume therapy.

Dynamic or graded intravenous (IV) dobutamine stress echocardiography (2–10 days after MI) can assess myocardial viability and distinguish non-viable myocardium from stunned myocardium. Superiority to standard exercise testing has not been proven.

RADIONUCLIDE STUDIES

Radionuclide angiography has little practical role in the emergency-room diagnosis of ACS. Dynamic or functional radionuclide studies (thallium-201 or technetium-99m-sestamibi myocardial perfusion imaging studies) are useful in postinfarction risk stratification and are able to detect ‘threatened myocardium’. They are useful in the later risk assessment of patients who have presented with USA or NSTEMI and where the clinical significance of lesions noted on angiography is uncertain.

STRESS TESTING

Stress testing may be useful in risk stratification and diagnosis of stable angina. Following infarction, the following may be of use:

• submaximal stress testing (to a heart rate of 120 beats/min), predischarge, upon patients with an uncomplicated course

• maximal symptom-limited stress test 3–6 weeks postinfarction

CORONARY ANGIOGRAPHY AND LEFT VENTRICULOGRAPHY

Coronary angiography is the gold standard for the diagnosis (and often treatment) of CAD; however the timing and need for this are determined by clinical risk. In the appropriate clinical setting, coronary angiography will usually identify a ‘culprit artery’ subtending an area of regional wall motion abnormality and additionally may allow definitive treatment of this abnormality. These indications are discussed later.

RISK STRATIFICATION OF ACUTE CORONARY SYNDROME (Figure 16.9)

An immediate goal is to identify patients with STEMI, who will then benefit from reperfusion therapy. This is almost always done on the basis of the presenting ECG.

Figure 16.9 Immediate stratification of acute coronary syndrome (ACS) into those with and without ST-segment elevation identifies patients requiring reperfusion therapy. Early and serial biomarker results in non-ST-segment elevation acute coronary syndrome (NSTEACS) identify patients with unstable angina (normal levels) and those with NSTEMI (elevated levels). Discharge electrocardiogram identifies patients who have sustained Q-wave myocardial infarction (QwMI) and non-Q-wave myocardial infarction (NQwMI). Successful reperfusion therapy may avert or limit the extent of Q-wave development. USA, unstable angina; PCI, percutaneous coronary intervention.

STEMI

STEMI (including new, presumed new LBBB) with persistent pain is the most lethal form of ACS and is usually due to complete occlusion of a coronary artery (> 90% of patients).⁵ It is an indication for reperfusion therapy. Such therapy may be successful and significantly reduce the size of the potential infarction, although some rise in troponin is usually inevitable. Patients who develop ST-segment elevation after admission should also then be stratified to this group.

NSTEACS

Patients have ischaemic chest pain but have ‘non-specific’ ECG changes (normal, ST-segment depression or minimal elevation, T-wave inversion). After serial biomarker testing, these patients will later prove to have either USA pectoris if troponins remain normal or NSTEMI (elevated troponin).

The therapy of NSTEMI aligns more clinically with that of USA than with that of STEMI. These two conditions, both forms of NSTEACS, represent a spectrum of disease and require common treatments directed at platelet inactivation and ‘plaque stabilisation’. The term ‘NSTEACS’ recognises that they are clinically indistinguishable at presentation. The more severe the ischaemia, the higher the need for more aggressive anticoagulation and invasive procedures. Early diagnostic classification using both ECG and troponins allows early risk stratification and evidence-based therapy. Only 35–75% of patients have evidence of coronary thrombus formation and thrombolytic therapy is not beneficial in this group. Indeed, it is associated with worse outcomes.^5,¹⁴

Figure 16.10 displays the incidence of major coronary events over the following 12 months in patients presenting with and without ST-segment elevation. ST-segment depression has lesser early mortality but a similar or higher mortality at 6 months and at 10 years than those presenting with ST-segment elevation.^15,¹⁶ Features that correlate with risk are:

• refractory angina with ischaemic ECG changes

• ischaemia associated with haemodynamic instability or arrhythmia

• recurrent ST-segment change with elevated cTn levels

Figure 16.10 (a) Thirty-day mortality according to British Cardiac Society category. (b) Kaplan–Meier survival area curves for events from admission to 6 months. ACS, acute coronary syndrome.

(Reproduced from Das R, Kilcullen N, Morrell C et al. The British Cardiac Society Working Group definition of myocardial infarction: implications for practice. Heart 2006; 92: 21–6 with permission.)

Q-wave MI (QwMI) or non-Q-wave MI (NqwMI) are older terms used to describe MI. The 10-year mortality of NqwMI (70%) is 10% higher than that of QwMI.¹⁶

IMMEDIATE MANAGEMENT OF ACUTE CORONARY SYNDROMES

PREHOSPITAL CARE

• 50% of deaths from MI occur within the first hour of symptom onset. These deaths are usually due to ventricular fibrillation (VF). Treatment is defibrillation.

Review of trials comparing prehospital to in-hospital thrombolysis suggests a 17% decrease (95% confidence interval, 2–29%) in 30-day mortality.¹⁷

IMMEDIATE HOSPITAL CARE

1 Cardiac monitoring

2 Oxygen via facemask (6–8 l/min)

3 ECG (12-lead) should be taken within 5 min of arrival

4 Aspirin at 160–325 mg should be chewed and swallowed on arrival. IV aspirin can be given if necessary. Clopidogrel can be given if there is aspirin sensitivity or high risk ⁴

5 Sublingual nitroglycerine (GTN) may have beneficial effects. Side-effects include hypotensive reactions and a hypotensive bradycardic response (the Bezold–Jarisch reflex)

6 Venous access is usually established

7 Pain relief should be provided. Pain produces catecholamines which increase ischaemia. GTN, reassurance and small incremental boluses (1–2 mg) of morphine, repeated until pain is relieved, can be given

8 Thrombolytic therapy should be considered for all those patients with ST-segment elevation or presumed new LBBB (STEMI) who have no major contraindication (Figure 16.11) and arrive within clinical timeframes

9 Emergent angioplasty (or rapid transfer to a centre capable of this) should be considered for these patients who have:

• presented to a centre of excellence

• a contraindication to thrombolytic therapy

• cardiogenic shock

• high risk with anticipated moderate response to thrombolytic therapy

10 β-adrenergic blockers (oral) should be commenced in haemodynamically stable patients as soon as possible (usually after thrombolytic therapy has been given ¹⁸ or before PCI)^5,¹⁹

11 Pulmonary oedema if present is treated with upright posture, IV furosemide (40 mg furosemide) IV, GTN or IV nitrates and if severe, with continuous positive airway pressure ventilation

12 Prophylactic antiarrhythmics are not administered

Figure 16.11 Typical indications for reperfusion therapy in acute myocardial infarction.

ACUTE MANAGEMENT OF STEMI (Figure 16.12)

REPERFUSION THERAPY

Prompt initiation of reperfusion therapy (mechanical or pharmacologic) is the ‘gold standard’ for STEMI therapy and is far superior to placebo.

Figure 16.12 Management of ACS with ST-segment Elevation (STEMI). Aspirin, β-blockers and heparin (except if streptokinase used) should be given to all patients without contraindications. Immediate reperfusion with thrombolysis (available in all centres) should be commenced. Immediate PCI is preferred in centres of excellence, where there are contraindications to thrombolysis or where risk favours expedient transfer for such therapy. Glycoprotein IIb/IIIa receptor blockers may reduce complications during PCI.

Reperfusion therapy should be considered for all patients presenting within 12 h of onset of STEMI.^5,²⁰

Indications and contraindications are given in Figures 16.11 and 16.13. Restoration of patency reduces infarct size, preserves LV function, reduces mortality and prolongs survival.

Figure 16.13 Contraindications and cautions for fibrinolytic use in myocardial infarction (advisory following clinical consideration). INR, international normalised ratio; CPR, cardiopulmonary resuscitation; CVA, cerebrovascular accident.

Strategies to achieve reperfusion can include:

1 fibrinolytic (thrombolytic) therapy

2 PCI, e.g. angioplasty with or without stent insertion

3 urgent CABG

Factors that influence treatment choice and outcome are:⁵

• skill and expertise of admitting hospital (availability of PCI)

• time since onset of symptoms

• age and comorbid illness (particularly risk of bleeding and stroke)

• haemodynamic status

• previous PCI or CABG

PERCUTANEOUS TRANSLUMINAL CORONARY INTERVENTION

When delivered in centres of excellence (door to balloon time < 90 min), primary PCI is superior to thrombolytic therapy, with reduced short-term mortality (5.3% versus 7.4%), nonfatal reinfarction (2.5% versus 6.8%) and stroke (1.0 versus 2.0%).

The survival benefit of primary PCI compared with thrombolytic therapy is of the order of 20 lives per 1000 patients treated. These benefits are not uniform and are significantly influenced by its better outcomes in high-risk patients.

Urgent PCI in STEMI should be strongly considered in patients with:

• presentation to cardiological centres of excellence

• contraindications to thrombolysis

• high risk but with predicted small or moderate benefit from thrombolytic therapy (e.g. elderly, diabetic and with presentation beyond 3 h)

• cardiogenic shock even up to 12–36 h after infarction ²¹ (see Chapter 20)

• failed thrombolysis

• previous CABG

Very few patients have contraindications to PCI,¹⁷ although caution is needed in those at risk of contrast-associated renal failure.

THROMBOLYTIC THERAPY

• Thrombolytic therapy (versus placebo) of patients with ST-elevation and/or new LBBB results in a significant mortality reduction (10.9% versus 13.4%; relative risk reduction 19%), a reduction of approximately 20 deaths per 1000 patients treated.^5,¹⁴

• Outcomes are critically dependent upon time from symptom onset to administration of therapy. A goal is ‘door to needle time’ of less than 30 min. Delay is associated with excess mortality.

Thrombolysis within 6 h of symptom onset saves 30 lives per 1000 patients treated; within 7–12 h, the rate is 20 lives per 1000 patients treated, but there is no overall benefit for therapy beyond this time. Up to 40 lives per 1000 could be saved (relative risk reduction 50%) if treatment was given in the first hour.²² Benefit is still present at 20-year follow-up.²³ Largest benefits are seen in anterior infarction (3.7% absolute mortality reduction), less in inferior (0.8% reduction).^5,^14,²⁴

Age has a major impact upon survival following STEMI. Compared with controls thrombolysis reduces mortality at age < 55 years (3.4% versus 4.6%,), age 55–64 years (7.2% versus 8.9%, 18 lives per 1000 patients treated), age 65–75 years (11.1% versus 12.7%, 27 lives per 1000 patients treated) and age > 75 years (24.3% versus 25.3%, 10 lives per 1000). Thus, although the relative reduction in elderly patients is small (4%), the absolute reduction in mortality is still significant.¹⁴

THROMBOLYTIC AGENTS (FIBRINOLYTIC AGENTS)

Commonly licensed thrombolytic agents are streptokinase, tissue plasminogen activator (t-PA), alteplase (rt-PA), reteplase and tenecteplase. These drugs promote the conversion of plasminogen to plasmin, which then lyses fibrin thrombi. The fibrinolytic agents approved for therapy of STEMI differ in a number of ways, including fibrin specificity.

• Streptokinase is a first-generation fibrinolytic drug and is considered non-specific. It converts plasminogen to plasmin with a marked fall in circulating fibrinogen and other factors, resulting in a systemic lytic state. Streptokinase has a prolonged thrombolytic effect and concomitant IV heparin increases bleeding and rate of cerebral haemorrhage.^5,^24,²⁵ It is antigenic (beware previous exposure or recent streptococcal infection) and can result in hypotension and bradycardia, most evident in patients with inferior MI.

• t-PA, a non-antigenic, more fibrin-selective, shorter-acting proteolytic enzyme produced by vascular endothelium, was used as the basis for second-generation fibrinolytic agents (alteplase, recombinant t-PA or rt-PA). By acting more directly at the fibrin surface, and with less degradation of circulating fibrinogen, t-PA is associated with less systemic bleeding. An initial bolus of t-PA with subsequent infusion (accelerated regimen) produces higher patency rates than streptokinase. It has generally been used as the benchmark or control arm in trials.

• Third-generation fibrinolytic agents (reteplase, tenecteplase) are bioengineered products of t-PA with longer half-lives. These agents have gained popularity because they appear to have similar efficacy and side-effect profiles but are simpler to administer.

Major and minor contraindications are shown in Figure 16.13.

SIDE-EFFECTS AND CHOICE OF AGENT

Although newer-generation fibrin-specific agents that are available as a bolus (reteplase/tenecteplase) are generally the fibrinolytics of choice, streptokinase may still be a cost-effective treatment in many.

More efficient (fibrin-specific) thrombolytic agents improved upon the initial results of streptokinase. In Global Utilization of Streptokinase and Tissue Plasminogen Activator to Treat Occluded Arteries (GUSTO-1), accelerated rt-PA regimens were shown to reduce mortality compared to streptokinase (6.3% versus 7.3%, relative rate 14% reduction), but at the price of a small excess of haemorrhagic strokes.^26,²⁷ This represented an extra 10 lives saved per 1000 patients.

The tPA congeners reteplase and tenecteplase have very short initial half-lives, allowing convenient bolus dose administration. Trials of these agents against ‘accelerated rt-PA’ demonstrated equivalence.²⁸ Accordingly these agents have come into frequent use because of their ease of administration. Tenecteplase can be given as a single agent, making it useful for prehospital and emergency hospital use.

Aggressive thrombolysis regimens are associated with lower all-cause mortality rates despite higher rates of cerebral haemorrhage ⁵ that are fatal in 40–60% of cases.²⁵ Of concern with these regimens is that the number of non-fatal strokes (severe disability occurs in 50%) can be problematic in high-risk groups. Accelerated t-PA regimens may result in 5 disabled stroke survivors per 1000 patients treated; streptokinase with subcutaneous heparin may result in 3 per 1000 patients treated.²⁵ Age, recent stroke and hypertension on arrival significantly increase the risk of both lethal and non-lethal stroke. Since these patients were often excluded from trials, specialist input is required on a case-by-case basis to ascertain whether a less aggressive fibrinolytic agent (streptokinase) may be of use.²⁶ Alternatively, strong consideration is given to PCI when thrombolysis is likely to be associated with a high incidence of lethal or non-lethal stroke.

Failure to adjust the dose of fibrinolytic correctly to body weight may be associated with increased mortality and intracerebral haemorrhage.¹⁷

PRIMARY PCI VERSUS THROMBOLYTIC THERAPY

Despite the advantages of PCI over thrombolysis, many patients present to centres that do not offer primary PCI. Given the advantage of PCI over thrombolysis, the possible benefit of transfer to such a centre needs to be considered. Transfer, however, involves an inherent delay and, if this is prolonged, then the advantage of more reliable revascularisation may be rapidly removed by the death of myocardium occurring as a result of the delay.^17,²⁹ Studies of groups of patients suggest that this advantage for groups may be lost if the transfer adds an additional 60–110 min to the process. This may represent an erosion of PCI’s mortality advantage of 0.29–0.40% for every 10-min delay. Well-developed systems need to be in place to minimise transport delays.

The significance of transfer for an individual patient will vary significantly. The incremental effect of delay is most marked in patients who present early. The current results from thrombolytic therapy in patients presenting early (< 3 h) are very good as fresh clots seem more likely to be lysed. However transfer may be advisable in patients at high risk of bleeding or where presentation is late and where, despite thrombolysis, baseline or predicted mortality is high.

INVASIVE STRATEGY (PCI) IS CLEARLY SUPERIOR TO THROMBOLYSIS IF

• There are contraindications to thrombolytic therapy

• There is cardiogenic shock

• Angiography is needed to determine diagnosis and where an occluding lesion is found

FIBRINOLYSIS GENERALLY PREFERRED IF:¹⁷

• Early presentation (3 hours from symptom onset and delay to invasive strategy)

• Invasive strategy is not an option:

• Catheterisation lab occupied or not available

• Vascular access difficulties

• Lack of access to skilled PCI lab

• Delay to invasive strategy:

• Prolonged transport

• (Door-to-balloon) – (door-to-needle) is > 1 hour and specialist centre

• Medical contact-to-balloon or door-to-balloon is > 90 minutes

There is increasing evidence that, in the presence of failed thrombolysis where predicted mortality is high, rescue PCI confers survival benefit.¹⁸ Trials of ‘facilitated PCI’ where pharmacological therapy is routinely followed immediately by PCI are controversial and current evidence favours worse outcomes with this routine approach.^17,¹⁸

ADJUNCTIVE THERAPY USED WITH THROMBOLYSIS AND REPERFUSION (Figure 16.14)

• Improvement in adjunctive or supportive reperfusion therapies has been the major driver of improved outcomes from reperfusion strategies, contributing more than the development of newer antifibrinolytics.

• Compliance with guidelines for administration of these therapies is likely to improve outcomes significantly.

Figure 16.14 Effect of acute (early) interventions upon mortality following acute myocardial infarction. Results are from meta-analyses. Urgent percutaneous coronary intervention (not shown) has not been compared to placebo and offers superior results to thrombolysis for patients who present to centres of excellence. RCT, randomised controlled trial; ACE, angiotensin-converting enzyme.

Adjunctive therapy is necessary after thrombolysis due to the following:

• About 50% of patients fail to obtain or sustain coronary artery patency.

• The underlying artery remains unstable, evidenced by:

• angiographic reocclusion in 30%

• recurrence of ischaemia in 20%

• Current plasminogen activators (thrombolytics) destroy fibrin strands of ‘red thrombus’. They have little effect on underlying exposed thrombin and indeed may be prothrombotic, requiring concomitant antithrombin (e.g. heparin) or anticoagulant therapy.

• Antiplatelet therapies are needed to ‘pacify’ underlying platelet-rich ‘white thrombus’ and plaque.

The major complication of adjunctive therapy is generally an increase in bleeding.

ASPIRIN AND CLOPIDOGREL

All patients undergoing reperfusion therapy for STEMI (PCI or fibrinolysis) should be given aspirin and clopidogrel unless contraindicated.¹⁸

Aspirin is one of the most significant and cost-effective treatments for STEMI. Given acutely in the second International Study of Infarct Survival (ISIS-2) it reduced mortality by 23% and gave a nearly 50% reduction in reinfarction and stroke. Streptokinase also reduced mortality (by 25%), while the combination had an additive effect and reduced mortality by 42%.^24,³⁰ Treatment for a mean duration of 1 month resulted in approximately 25 fewer deaths and 10–15 fewer episodes of non-fatal reinfarction and non-fatal stroke for every 1000 patients treated.³⁰ It does not appear to increase bleeding and benefit is still present after 10 years.

Clopidogrel confers significant additional benefit. Given in conjunction with thrombolytics and aspirin, it reduces the risk of early vessel reocclusion without a significant rise in bleeding.^29,³¹ Patients who undergo PCI and have a stent inserted also benefit if they have received clopidogrel. Benefit is less evident in patients who undergo PCI but do not have a stent placed, and bleeding is problematic.

GLYCOPROTEIN IIB/IIIA INHIBITORS

It is reasonable to use abciximab with primary PCI, but GPIs offer little benefit in patients treated with thrombolytics (full or half-dose).

In theory, GPIs override the platelet activation caused by plasminogen activators, improving patency rates and allowing better reperfusion of small vessels beyond the occluding thrombus. In the setting of PCI, they are proven to be a most important adjunct to the procedure if a stent is placed or lesion dilated. Trials of GPIs in combination with full-dose thrombolytics found increased bleeding. These trials were done with half-dose thrombolytics. Results were again disappointing, with increased bleeding (especially in the elderly) but no survival benefit. In STEMI patients who have not received reperfusion therapy, GPIs do not appear to confer benefit.^29,^31,³²

UNFRACTIONATED HEPARIN (UFH, STANDARD) AND LOW-MOLECULAR-WEIGHT HEPARIN

Antithrombin therapy is generally given in combination with PCI or with fibrin-specific fibrinolytic agents. The net benefit-to-risk ratio of using thrombin inhibitors in MI is not clear, however.

Prior to the use of fibrinolytics and aspirin, a limited number of small trials suggested that UFH reduced mortality (from 13.1% to 9.2%, 20–25% relative rate reduction). With the introduction of fibrinolytics and aspirin, UFH administration was continued. It was usually administered for 24–48 h after the fibrin-specific agents alteplase, reteplase or tenecteplase, reflecting the basis on which the drugs were trialled and licensed. Heparins do not lyse clot, but may decrease rethrombosis.

Despite UFH use, few trials (1239 patients) examined whether it added survival benefit to patients already treated with both thrombolytics and aspirin. At most the effect of UFH seems to be small (perhaps 5 lives saved per 1000 patients treated) and increased bleeding can be problematic.^24,³³

LMWHs are produced by chemical or enzymatic depolymerisation of UFH. Their theoretical advantages include:

• predictable pharmacokinetic profiles and anticoagulant response

• enhanced anti-Xa activity and less affected by platelet factors

• weight-adjusted dosing does not require activated partial thromboplastin time monitoring

• convenient to administer and do not require an IV line, although acquisition costs are higher than for UFH

• lower incidence of thrombocytopenia, skin necrosis, hypersensitivity reactions and catheter-related infections

Comparison of UFH and LMWH has often proven difficult because of large variations in duration of therapy. LMWH is probably superior ^17,³³^–³⁵ to UFH, resulting in lower rates of reinfarction, although the bleeding can be problematic in high-risk patients and caution should be used in this group.¹⁷

Meta-analysis ³⁴ of LMWH versus placebo has suggested that, across the whole ACS spectrum, adjunctive antithrombin therapy with enoxaparin is associated with significantly superior efficacy. Among STEMI³⁴ patients, approximately 21 death or MI events were prevented for every 1000 patients treated with enoxaparin, at the cost of an increase of 4 non-fatal major bleeds.

Despite the increasing use of LMWHs, UFH may still be used where bleeding risk is high or where urgent PCI is anticipated.

The pentasaccharide factor Xa inhibitor fondaparinux has recently demonstrated a moderate reduction in mortality and reinfarction over ‘usual care’ (placebo or UFH). These benefits were seen without an increase in bleeding.³⁶ Like LMWH it has the advantage of ease of administration and absence of need for monitoring but is associated with fewer bleeding complications. Benefits were present in patients at higher risk and not undergoing PCI. End-catheter thrombus was problematic in patients undergoing PCI, suggesting the need for UFH if this therapy is subsequently required. Some benefit was seen in patients who did not receive reperfusion therapy.³⁶

β-BLOCKERS

Haemodynamically stable patients should commence oral β-blockers within 24 h of the onset of symptoms unless contraindicated (pulmonary oedema, asthma, hypotension, bradycardia, advanced atrioventricular block).

Significant benefit from IV β-blockers was seen in the prethrombolysis era, but benefits appear small or absent in the postthrombolysis era.¹⁸ More recent studies have suggested that the use of IV β-blockers is associated with a decrease in reinfarction and VF but with an increase in cardiogenic shock, producing no overall benefit. IV therapy may be useful in patients with hypertension or tachycardia (although it is wise to assess LV function, perhaps with echocardiography). IV β-blockers given to patients receiving PCI produce an early absolute mortality reduction of 1.7%: the benefit is confined to patients not on β-blockers at time of admission.¹⁹

OTHER THERAPIES

Although nitrates may have had a small benefit in prethrombolysis days, there is little evidence of outcome benefit in the postthrombolysis era and indeed complicating hypotension may be harmful. Glucose–insulin–potassium therapies have not been shown to provide benefit under trial conditions.³⁷

COMPLICATIONS OF MYOCARDIAL INFARCTION (Figure 16.15)

ARRHYTHMIAS

Rhythm disturbance occurs in nearly all patients following acute MI and is most likely within the first few hours of onset and during reperfusion. There has been a decline in the incidence of VF from approximately 4.5% of admissions to 1% of admissions with MI. This decrease probably reflects the effect of thrombolytic therapies and better maintenance of electrolytes.

• Correct hypoxia, hypovolaemia or acid–base disturbances.

• Maintain serum potassium in the normal range (4.0–5.0 mmol/l).

• Maintain the serum magnesium level.

Figure 16.15 Mechanical complications of myocardial infarction. CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure; CO, cardiac output; PAC, pulmonary artery catheterisation; RV, right ventricular; RA, right atrial; PA, pulmonary artery.

Prophylactic lidocaine tends to increase mortality and is thus reserved for the treatment of life-threatening ventricular arrhythmias. Prophylactic or routine IV magnesium (< 4 h) was of benefit in the Second Leicester Intravenous Magnesium Intervention Trial (LIMIT II) study but not in the larger ISIS-4 study, and is not of proven benefit.⁵

FAILED THROMBOLYSIS (RESCUE PCI)

A number of patients with STEMI will fail to show resolution of ST-segment elevation with fibrinolysis, suggesting failed reperfusion. Whether this should be treated with further fibrinolysis or PCI, or whether no intervention should be undertaken, has been uncertain. Meta-analysis of a small number of trials suggests that further thrombolysis is not associated with survival or reinfarction benefit and indeed may be harmful. Rescue PCI, compared to conservative management, conferred no survival benefit but was associated with significant reductions in heart failure, requiring 9 patients to be treated to achieve this benefit. Treatment was associated with an increased risk of bleeding and possibly stroke. Consideration for rescue PCI should probably be considered on a case-by-case basis; most benefit is likely to be achieved in shocked or haemodynamically unstable patients.

CARDIAC FAILURE

LV dysfunction with the clinical signs of failure occurs in up to 30–40% of patients. It usually develops when the abnormally contracting segment exceeds 30% of the LV circumference: cardiogenic shock or death results when it exceeds 40%. It is more common in the setting of previous infarction, and is associated with a poor short- and long-term prognosis. With large MI there is progressive thinning of the affected myocardium, with stretching and dilatation of the ventricle, and sometimes frank aneurysm formation.

Angiotensin-converting enzyme (ACE) inhibitors appear to limit dilatation, preserve LV function and improve prognosis. Benefits are maximal in those with poor LV function. ACE inhibitors are thus recommended for all patients with significant LV dysfunction and are usually started early following MI. Captopril has a short half-life and may be started at very small doses in ICU patients (6.25 mg t.d.s.) if the systolic blood pressure is > 100 mmHg (13.3 kPa). Lower starting doses may be considered (e.g. 1–3 mg t.d.s.) in hypotensive but otherwise stable patients. The dose is titrated upwards and a longer-acting agent may be substituted prior to discharge.

RV failure secondary to RV infarction ³⁸ should be distinguished from RV failure secondary to LV failure and should be considered in any patient with inferior MI. It is associated with significantly increased mortality. These patients have a markedly elevated jugular venous pressure with little or no pulmonary congestion. Treatment principles are different to those for LV dysfunction. Patients with RV infarction often respond to volume loading and it is important to maintain RV preload. The latter is guided by clinical response and echocardiography. Pulmonary flotation catheters, seeking to maintain an optimal LV filling pressure at around 16–18 mmHg (2.1–2.4 kPa), are now used less often. Diuretic therapy, afterload reduction and unrecognised hypovolaemia may aggravate hypotension and renal insufficiency in these patients.

CARDIOGENIC SHOCK (SEE Figure 16.15)

Mortality from cardiogenic shock remains very high (55–70%)³⁹ and is the major cause of hospital mortality from STEMI. Patients with cardiogenic shock may have ‘stunned’ myocardium that is capable of improvement with revascularisation and initial intensive medical support. Patients presenting with cardiogenic shock are treated with acute interventional revascularisation (PCI or CABG) in preference to thrombolysis and medical management: the benefits are still present beyond 5 years (survival 32.8% versus 19.6%).²¹

POSTINFARCTION ANGINA AND REINFARCTION

Postinfarction angina unresponsive to medical therapy or with significant ECG changes is an indication for aggressive anti-ischaemic therapy and early PCI. Reinfarction in the 10 days following MI occurs in up to 5–10%; it can be treated with further thrombolysis or angioplasty. Where streptokinase has previously been given, t-PA is preferred because of the possible presence of antibodies that may neutralise activity or cause anaphylaxis.

MITRAL REGURGITATION

Transient mitral valve dysfunction is common after MI. More severe, rupture of a papillary muscle and severe mitral regurgitation occur in about 4% of patients. A decrescendo systolic murmur may be present rather than the typical pansystolic murmur of chronic regurgitation. Posterior leaflet rupture is most common as it receives its blood supply from the dominant coronary artery (usually the RCA), whereas the anterior leaflet has a dual blood supply.

It can complicate even relatively small MI and the diagnosis should be considered if heart failure is disproportionate to the infarct size, even if a murmur cannot be heard. Surgery is usually required; pharmacological and mechanical afterload reduction often provides a bridge.

CARDIAC RUPTURE ²⁰

Rupture of the interventricular septum occurs in about 1–2% of cases of MI, usually in large infarctions (60% of cases). Anterior and inferior infarctions are equally represented.

• It is often heralded by a new long systolic murmur which initially may be soft or absent and the patient may not be haemodynamically compromised. Diagnosis is best confirmed by echocardiography.

• Almost always there is progressive clinical deterioration (untreated mortality of 54% at 1 week and 92% at 1 year). Surgical repair is considered as soon as the diagnosis is made; intra-aortic balloon counterpulsation often provides a bridge to surgery.

Free wall rupture occurs in 1–3% of all hospitalised patients with MI and often occurs very early. Acute rupture of the LV free wall is usually catastrophic, resulting in pulseless electrical activity and death. Subacute rupture (leaking blood is contained by pericardium forming a false aneurysm) is less common and may mimic reinfarction. It requires urgent surgery.

SYSTEMIC EMBOLI

Embolic (ischaemic) stroke occurs in approximately 1% of patients during their hospital admission and in 2% by 12 months.⁴⁰ Most of these cases occur following extensive anterior MI.⁴¹

• 30–40% of anterior Q-wave MIs may be complicated by mural thrombus (echocardiography). Embolisation is most frequent with large or protruding emboli and is uncommon following inferior infarction.

• 5–10% of these may undergo embolisation, usually within the first 10 days.

MANAGEMENT

• The patient is usually put on anticoagulant therapy for ≥ 3 months (initial heparin, then warfarin) if mural thrombus is proven or if extensive anterior regional wall motion abnormality suggests high risk.

• Extensive anterior-wall motion abnormality is best proven by echocardiography. Clinicians should have a high index of suspicion in the presence of large anterior infarction.

• Patients with poor LV function remain at long-term risk of embolic stroke.⁴¹

POST-MI INJURY SYNDROME (DRESSLER’S SYNDROME) AND PERICARDITIS

Pericarditis is a common early complication of extensive anterior and inferior infarction.

• Pericardial rub may be heard in 10–15% of patients with anterior MI, less often with inferior infarction.

• It occurs 24–72 hours after infarction and may mimic ischaemia.

• It is best treated with high-dose aspirin or non-steroidal anti-inflammatory medications.

Dressler’s syndrome is now uncommon (< 1–3%) but is thought to be an immunopathic response to myocardial necrosis. It is characterised by fever, elevated erythrocyte sedimentation rate, a pericardial rub, pleuropericardial pain and arthralgia, and may occur some weeks after MI.

MANAGEMENT OF UNSTABLE ANGINA AND NSTEMI (NSTEACS) (Figure 16.16)

NSTEACS result from the development of non-occluding thrombus upon unstable plaque. Superimposed vasospasm and microembolisation may aggravate myocardial ischaemia. Therapies are directed at ‘white thrombus’ and plaque stabilisation, and at reduction of myocardial oxygen demand.

Figure 16.16 Management of acute coronary syndrome without ST-segment elevation. Aspirin, heparin and beta-blockers are administered to all without contraindications; nitrates are given for symptom control. Patients at intermediary or high risk may have best outcomes following early percutaneous coronary intervention with intravenous glycoprotein IIb/IIIa receptor blockade. Patients who stabilise may be treated medically followed by stress testing to screen for inducible myocardial ischaemia. ASA, acetylsalicylic acid; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; GP, glycoprotein; PCI, percutaneous coronary intervention; LV, left ventricle; ECG, electrocardiogram; MI, myocardial infarction; CABG, coronary artery bypass grafting.

(Modified from Ryan TJ, Antman EM, Brooks NH et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999; 34: 890–911.)

General principles of treatment are:

• immediate relief of ischaemic symptoms

• immediate introduction of antiplatelet therapy, usually in conjunction with an antithrombin agent, to stabilise plaque and prevent complete artery occlusion

• determination of benefits of early invasive versus medical therapy

Thrombolytic agents are generally contraindicated in the treatment of NSTEACS; their routine administration is associated with poorer outcome.^14,⁴²

EARLY INVASIVE VERSUS MEDICAL THERAPY IN NSTEACS

While medical therapy is introduced to all patients, keen observation should be continued for signs of instability which suggest that an invasive approach is appropriate. Prior to the introduction of potent antiplatelet inhibitors as ‘upstream therapy’ and coronary stents, early invasive therapy was associated with minimal benefit or with adverse outcome despite its theoretical attractiveness.⁴³ The development of better adjunctive agents (principally GPI blockers) has led to more recent studies suggesting that early invasive strategies are associated with reduced rates of MI and death.⁴⁴ The benefits of PCI are dependent upon the baseline risk to the patient. Emergent PCI is demonstrated to offer clinical benefit to patients with high-risk features such as elevated troponins, recurrent chest pain and recurrent ECG changes.⁴³

ANTI-ISCHAEMIC AGENTS

1 β-blockers assist symptom control. ß-blockers, administered orally, should be started in the absence of contraindications. Caution is suggested in the early use of IV β-blockers, which should be targeted to specific indications and should be avoided with haemodynamic instability and heart failure.⁴ IV therapy may be warranted for high-risk patients (e.g. with ongoing pain and hypertension) without contraindication to therapy. In these patients, metoprolol at 5 mg IV is commonly given incrementally every 5 min until symptoms are relieved, side-effects are experienced or a dose of 15 mg is reached. Ideally medication is titrated to attain a heart rate of 55–60 beats/min.

2 Nitrates. Sublingual nitroglycerine 300–600 μg is usually given in two doses at least some minutes apart (monitoring blood pressure) to relieve ischaemic pain. Patients with ongoing pain may receive IV nitrates. Evidence of improved outcome is lacking. Hypotension is a contraindication.

3 Calcium channel blockers may provide symptom relief when there are problems with β-blockers and nitrates. They may have a neutral or negative effect on mortality and progression to MI. Nifedipine without concomitant beta-blocker may increase mortality.⁵ As sole agent, only those agents that reduce heart rate should be used (e.g. diltiazem or verapamil).²⁰

ANTIPLATELET THERAPIES

1 Aspirin (acetylsalicylic acid) decreases ‘death or non-fatal MI’ in patients with NSTEACS by approximately 50%.^30,⁴⁵

2 Clopidogrel (in combination with aspirin) was demonstrated in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study to produce a 20% reduction in adverse events (compared to aspirin alone) when commenced early and continued in patients with NSTEMI. Reduction was mainly in MI. Significant early in-hospital benefit was seen.⁴⁶ Clopidogrel is preferred to ticlopidine, its older thienopyridine relative. (Clopidogrel is generally used in conjunction with aspirin in NSTEACS regardless of whether a conservative or invasive approach is planned. Its introduction or continuation should be reviewed if CABG is immediately imminent.^29,³¹)

3 GP IIb/IIIa receptor blockers reduce the 30-day risk of non-fatal MI by 38%^47,⁴⁸ in NSTEMI patients undergoing PCI. Benefit seems to be confined to high-risk patients (elevated troponins) undergoing PCI. Pretreatment with tirofiban may be useful in this group.^29,^31,⁴⁹ They have not been shown to be beneficial in the routine management of ‘medically treated’ patients (GUSTO-IV-ACS).⁵⁰

ANTITHROMBINS AND ANTICOAGULANTS

Heparins significantly reduce the composite of ‘MI or death’ in NSTEACS patients receiving aspirin, although the endpoint of mortality alone has not been significant. The same is true of LMWHs.

Meta-analyses that compared regimens of LMWHs to regimens of UFH found a minimal or less significant reduction in the composite of ‘death, MI and need for urgent revascularisation’ in favour of LMWHs than found when compared in STEMI patients.³³^–³⁵ ⁵¹ However, despite higher acquisition costs, their simplicity, lack of need for monitoring and acceptable safety profile perhaps favour their administration.

Fondaparinux compared to enoxaparin in NSTEACS had similar early efficacy but appeared to do so with fewer bleeding complications. At later follow-up, fondaparinux was associated with lower mortality and cerebrovascular accidents; most of the benefit seemed to accrue from its lesser bleeding rate.⁵² Substitution of fondaparinux for enoxaparin might save 6 lives per 1000 patients treated and might result in 19 less bleeds. There is concern that fondaparinux is not sufficient to prevent stent occlusion and concomitant UFH use is recommended in patients undergoing PCI.

ONGOING AND DISCHARGE CARE OF ACS (SECONDARY PREVENTION) (Figure 16.17)

A number of therapies have been studied in the long-term (secondary) treatment of ACS, both STEMI and NSTEACS:

1 Aspirin (75–160 mg/day) should be continued unless there are strong contraindications. In the first 2 years after MI, aspirin therapy results in an absolute decrease of approximately 36 vascular events (vascular death or non-fatal MI or stroke) for every 1000 patients treated.³⁰

2 Clopidogrel is generally continued throughout the hospital stay in both STEMI ¹⁸ and NSTEMI. In patients who have undergone PCI, continued treatment after discharge is beneficial, although the duration of that treatment is unknown and dependent upon the nature of the stent placed. Given in conjunction with aspirin, clopidogrel is proven to be of benefit when administered long-term to patients at high risk of future cardiovascular events (the CURE study),⁴⁶ although it is associated with an increased risk of bleeding. Clopidogrel is also a useful treatment in patients with aspirin resistance.

3 ß-blockers significantly reduce the incidence of sudden and non-sudden cardiac death in survivors of MI. Benefit is prolonged and is most marked in high-risk patients, for example those with extensive anterior infarction. Given at the time of MI and continued orally, β-blockers have an early and significant effect on mortality, which is apparent at 7 days, although therapy is not appropriate in patients with contraindications.¹⁸ Long-term administration after MI is also associated with survival and reinfarction benefit.^53,⁵⁴

4 ACE inhibitors are recommended in the treatment of all patients recovering from MI.⁵⁵ They significantly reduce mortality in high-risk patients or with symptomatic failure when commenced during recovery from MI. Patients with anterior MI and ejection fraction < 40% maintained on long-term ACE inhibitor therapy may experience a 20% relative reduction in mortality^56,⁵⁷ and a significant reduction in the incidence of LV failure. Benefit is still seen at 4 years posttreatment.⁵⁶ Very early introduction of ACE inhibitors (within 36 h of infarction) may also reduce mortality. In patients intolerant of ACE inhibitors an ACE receptor blocker may be used.⁵⁵

Figure 16.17 Late intervention in acute myocardial infarction.

The aldosterone antagonist eplerenone reduces mortality in asymptomatic patients with low EF post-MI and already receiving β-blockers and ACE inhibitors (see Chapter 20).

5 Lipid-lowering agents. Statins should be commenced in hospital for all patients with ACS. Benefit is maximal in patients with elevated cholesterol and other factors, but benefit is present at all cholesterol levels. Lowering elevated cholesterol concentrations following MI results in a decrease in mortality and reinfarction.⁵⁸ Although data are conflicting, benefit may be evident within 30 days and therapy should be commenced as early as possible. It is thought that statins reduce hypercholesterolaemia and inflammation, stabilising the lipid core, and early introduction may be beneficial.

6 Other anti-ischaemia agents:

• Routine use of calcium channel blockers does not improve outcome and certain agents have been suggested to cause harm. They may be of symptomatic use in patients intolerant of β-blockers or where a concomitant antihypertensive effect is needed.^5,²⁰

• Carvedilol may be of benefit in patients with ACS.

7 Antiarrhythmic therapy is not routinely continued. In the Cardiac Arrhythmia Suppression Trial (CAST), prolonged flecainide therapy was used to suppress ventricular ectopy. Despite doing so, mortality was increased.⁵⁹ Amiodarone in low doses (200 mg/day) may reduce mortality, but results of definitive trials are awaited and it has significant side-effects. It cannot currently be recommended as routine therapy. For patients with actual or who are at high risk of ventricular arrhythmia, consideration may be given to long-term amiodarone or use of an implantable defibrillator.

8 Warfarin given alone or in combination with aspirin is associated with lower rates of a composite of ‘death, reinfarction and thromboembolic stroke’. Concerns about bleeding (especially in the elderly) probably still see its clinical application restricted. Warfarin is useful for patients with proven myocardial thrombus, a large area of regional wall motion abnormality or a generalised thrombotic tendency.⁵

9 Lifestyle advice is most important and all patients should cease smoking and receive advice on exercise and diet. Diabetes should be tightly controlled.

MYOCARDIAL INFARCTION IN THE INTENSIVE CARE UNIT

Myocardial ischaemia is a common problem in the ICU. It also commonly complicates perioperative care of major surgery, with mortality of up to 15–25%. Diagnostic criteria are uncertain but a system has been proposed by Devereaux et al.⁶⁰ There are few randomised controlled trials to guide therapy of postoperative infarction, or infarction complicating the care of the critically ill. Many patients with such presentations were excluded from trials of ACS therapy.

The pathophysiology of postoperative infarction and infarction in ICU patients is probably different to that of ACS.⁶¹ Studies suggest that, in the presence of severe ischaemia, left main disease and triple-vessel disease are common and that ischaemia is secondary to oxygen supply-and-demand problems rather than thrombosis. However, data on this are conflicting.⁶¹ The absence of thrombosis as an underlying pathological mechanism in many suggests that standard aggressive ‘antithrombus’ therapies will have different risk–benefit profiles, and that harm is exacerbated by the often high bleeding risk of these patients.

The patient with significant ST-segment elevation and haemodynamic instability in the ICU presents a difficult problem. Where underlying coronary artery is considered likely, an invasive approach is usually necessary. Thrombolysis is usually precluded by bleeding risk and by uncertainty regarding the causative process. Angiography will allow diagnosis and intervention if necessary; however, the use of adjunctive therapy (short- and intermediate-term) may be associated with significant bleeding. Reversible factors such as hypoxia, severe anaemia, anxiety and tachycardia must all be controlled where possible. Hypotension may limit the ability to administer β-blockers and control tachycardia.

Echocardiography may be useful in confirming regional wall motion abnormality and in confirming the amount of myocardium at risk. Of interest is the Takotsubo syndrome, where anterior ST-segment elevation and apical ballooning on echocardiography, often in association with elevated troponins, may occur in the presence of normal coronary arteries.^9,¹⁰

BLEEDING COMPLICATIONS POSTREPERFUSION THERAPY

The increased use of aggressive fibrinolytic regimens and of adjunctive reperfusion agents has led to troublesome bleeding in some patients. Some knowledge of reversal of these agents is necessary.⁶²

1 GPIIb/IIIa blockers. Abciximab, a chimeric monoclonal antibody, has a short half-life, but antiplatelet activity is still prolonged at 24–48 h. Fortunately transfused platelets are not affected and will assist with bleeding reversal. The newer agents tirofiban and eptifibitide have very short half-lives and antiplatelet action returns to normal 4–8 h after discontinuation. During this period, however, antiplatelet action is profound. It is suggested that administration of fresh frozen plasma (8 units) and platelets (2 units) is likely necessary to reverse antiplatelet action.⁶²

2 Clopidogrel. It is recommended that clopidogrel be ceased at least 5 days before elective CABG, but this is not always possible in emergent surgery or in unstable cases. Major bleeding rates may approach 10% in these cases. Pharmacology suggests that platelet transfusions are necessary to moderate this but dose is unknown.

3 LMWHs. Reversal of LMWHs with protamine is variable and incomplete, even with doses of 100 mg. Protamine may reverse up to 60% of LMWH action. It is suggested that doses of protamine should equal doses of enoxaparin administered on a milligram-per-milligram scale.

4 Fibrinolytic agents. In the setting of life-threatening bleeding, large doses of cryoprecipitate (10–20 units) may be required to replete fibrinogen (target > 1 g/l) and coagulation factors (especially factor VIII). Fresh frozen plasma may supplement factor V and VIII levels. Platelet transfusions at high dose may replace platelets and supplement factor V levels. ε-Aminocaproic acid at a dose of 5 g (0.1 g/kg) over 30–60 min followed by continuous infusion (0.5–1.0 g/h) may assist with bleeding control.⁶²

OUTCOME OF MYOCARDIAL INFARCTION

The in-hospital mortality from acute MI has been steadily decreasing over the past three decades from 15% to 30% in the 1970s to approximately 10% in 1980 and now to around 8–9% in the new millennium.¹ Despite improved mortality, 60% of all deaths occur within the first hour (usually from VF), and usually before reaching a medical facility.¹ Modern management of acute MI has undoubtedly contributed to decreased mortality. Further significant reductions in mortality must come from management strategies within the first hours of the onset of symptoms.

The major in-hospital changes are likely to come from:⁶³

• better hospital organisation to increase access to PCI

• increased use of adjuvant therapies and discharge medications

• increased rates of thrombolysis or PCI in eligible patients

The latter cannot be underestimated. In one study, the in-hospital mortality was 5.7% for those who received thrombolysis but 14.8% for those who were eligible for but did not receive such therapy (9.3% versus 18% in eligible women who did not receive therapy, 10.5% versus 19% in eligible elderly). Up to 24% of eligible patients do not receive reperfusion therapy.⁶³