Acute Coronary Syndrome

Prolonged, severe cardiac chest pain may be due to unstable angina (which comprises recent-onset limiting angina, rapidly worsening or crescendo angina, and angina at rest) or acute myocardial infarction (MI); these are known collectively as the acute coronary syndromes. Although there may be a history of antecedent chronic stable angina, an episode of chest pain at rest is often the first presentation of coronary artery disease.

Diagnosis depends on analysis of the character of the pain and its associated features. Physical examination may reveal signs of important comorbidity, such as peripheral or cerebrovascular disease, autonomic disturbance (pallor or sweating) and complications (arrhythmia or heart failure).

Patients presenting with symptoms consistent with an acute coronary syndrome require urgent evaluation because there is a high risk of avoidable complications, such as sudden death and MI. Signs of haemodynamic compromise (hypotension, pulmonary oedema), ECG changes (ST segment elevation or depression) and biochemical markers of cardiac damage, such as elevated troponin I or T, are powerful indicators of short-term risk. A 12-lead ECG is mandatory and is the most useful method of initial triage. The release of markers such as creatine kinase, troponin and myoglobin is relatively slow but can help guide immediate management and treatment.

If the diagnosis is unclear, patients with a suspected acute coronary syndrome should be observed in hospital. Repeated ECG recordings are valuable, particularly if obtained during an episode of pain. Plasma troponin concentrations should be measured at presentation and, if normal, repeated 6–12 hours after the onset of symptoms or hospital admission. New ECG changes or an elevated plasma troponin concentration confirm the diagnosis of an acute coronary syndrome. 

If the pain has not recurred, troponin concentrations are not elevated and there are no new ECG changes, the patient may be discharged from hospital. At this stage, an exercise test or CT coronary angiogram may help diagnose underlying coronary artery disease.

The acute coronary syndrome in detail - technical

Management of acute coronary syndrome

Essentials

The acute coronary syndrome (ACS) is precipitated by an abrupt change in an atheromatous plaque, resulting in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected vessel. The clinical consequences of plaque rupture can range from an entirely silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, and risk of sudden death.

The choice and timing of management strategy is critically dependent on the extent and severity of myocardial ischaemia, with the spectrum of ACS broken down into three elements: (1) Unstable angina: typical ischaemic symptoms without ST elevation on ECG and without elevated biomarkers of necrosis. (2) Non-ST-elevation myocardial infarction (MI): typical ischaemic symptoms without ST elevation on ECG but with biomarkers of necrosis above the diagnostic threshold. (3) ST-elevation MI: typical ischaemic symptoms with ST elevation on ECG and with biomarkers of necrosis above the diagnostic threshold.

An acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit only in ST segment elevation infarction (or MI with new bundle branch block).

Prompt relief of pain is important, not only for humanitarian reasons, but also because pain is associated with sympathetic activation, vasoconstriction, and increased myocardial work. Effective analgesia is best achieved by the titration of intravenous opioids, with concurrent administration of an antiemetic. High-flow oxygen should be given, especially to those who are breathless or those with any features of heart failure or shock.

The management of prehospital cardiac arrest requires special attention: at least as many lives can be saved by prompt resuscitation and defibrillation as by reperfusion. Patients may also require management of arrhythmic and haemodynamic complications, including heart failure.

Acute coronary syndromes without ST elevation (unstable angina/non-ST elevation MI)

Patients without ST elevation or left bundle branch block can be triaged into low, intermediate, and high-risk categories:

  1. High-risk—patients with typical clinical features of ischaemia and ST-segment depression or transient ST-segment elevation, or with troponin elevation and a high-risk score (Risk calculator downloadable from http://www.outcomes.org/grace or http://www.timi.org/). Patients are also at high risk when ischaemia provokes arrhythmias or haemodynamic compromise.
  2. Intermediate or low risk—patients with clinical features of acute coronary syndrome and nonspecific ECG changes (T wave inversion, T wave flattening, minor conduction abnormalities, etc.).
  3. Low risk or an alternative diagnosis—patients with a normal ECG, normal biomarkers, normal cardiac examination, and normal echo.

Patients at high risk:

  1. High-risk patients with acute ischaemia at initial presentation, or those who develop such features after hospital admission, and especially those with haemodynamic compromise, require emergency assessment for revascularization and potentially benefit from glycoprotein IIb/IIIa inhibition.
  2. Those proceeding to emergency revascularization should receive (a) aspirin; (b) thienopyridine, e.g. clopidogrel; (c) glycoprotein IIb/IIIa inhibition, e.g. abciximab, eptifibatide, and tirofiban; and (d) unfractionated or low molecular weight heparin (LMWH), or a direct thrombin inhibitor, e.g. bivalirudin.
  3. Some patients should receive anti-ischaemic therapy (e.g. nitrates, β-blockers, calcium entry blockers, potassium channel activators, etc.), and some will require antiarrhythmic management or haemodymamic support (e.g. intra-aortic balloon pump to reduce ischaemia and stabilize the patient for revascularization).

Patients developing ST elevation require emergency reperfusion by primary percutaneous coronary intervention (PCI), or—if PCI is not available—by thrombolysis (see below).

Patients at intermediate or low risk—patients with non-ST-elevation ACS and an intermediate risk score require dual antiplatelet therapy (aspirin plus thienopyridine, e.g. clopidogrel) plus anticoagulation (e.g. heparin, LMWH, fondaparinux, or bivalirudin). They are candidates for an early elective revascularization strategy (within c.72 h).

Clinically stable patients with minor or nonspecific ECG abnormalities and a low risk score (including negative repeat troponin) are at very low risk for in-hospital, major cardiac events. Such patients may, nevertheless, have significant underlying coronary artery disease. They require stress testing or perfusion scanning, ideally prior to discharge.

Specific interventions—anti-ischaemic therapies:

  1. nitrates—effective in reducing ischaemia in the in-hospital management of non-ST elevation ACS, but there is no evidence that they improve mortality;
  2. β-blockers—patients with suspected acute coronary syndromes should be initiated on β-blocker therapy unless contraindicated;
  3. dihydropyridine calcium entry blockers—should be employed with β-blockers in acute coronary syndromes to avoid reflex tachycardia. In patients unable to tolerate β-blockers, a heart-rate-slowing calcium antagonist, e.g. diltiazem or verapamil, may be appropriate. Short-acting dihydropyridines should not be used in isolation in ACS.

Antiplatelet therapies:

  1. aspirin 75–325 mg daily—indicated in all patients with acute coronary syndromes unless there is good evidence of aspirin allergy or evidence of active bleeding;
  2. thienopyridine—patients with non-ST-elevation ACS should be given clopidogrel as an initial 300-mg loading dose, followed by continued treatment at a dose of 75 mg daily, in combination with aspirin. Clopidogrel should be given alone to patients with contraindications to aspirin (same regimen). Clopidogrel should be maintained for 12 months, unless the risks of bleeding exceed potential benefits. In patients undergoing PCI, a loading dose of 600 mg of clopidogrel may be used to achieve more rapid inhibition of platelet function. Following PCI, the duration of clopidogrel administration should take account of the type of stent implanted (bare metal or drug-eluting) and the risks of bleeding/thrombosis; Prasugrel is a more potent thienopyridine than clopidogrel (TRITON Study) and has improved outcomes (mainly reduced MI), especially in diabetics. It results in fewer stent thromboses. However there is more bleeding, and it should be avoided in patients with previous intracerebral bleeding or transient ischaemic attack.
  3. GPIIb/IIIa inhibitors—e.g. abciximab, eptifibatide, tirofiban—result in improved outcome in patients requiring urgent percutaneous intervention for non-ST-segment-elevation ACS and in those at intermediate to high risk. Should be administered with oral antiplatelet agents (aspirin and thienopyridines) and anticoagulants (heparin or LMWH).
  4. Ticagrelor, a non thienopyridine P2Y12 platelet antagonist also has improved outcomes compared with clopidogrel (fewer infarctions and fewer deaths and fewer stent thromboses) (PLATO study). Overall rates of bleeding were not increased but non-CABG bleeding was increased. It has been approved by the European Medicines Agency, but has not yet been approved for use in the United States.

Anticoagulation—this is required in addition to antiplatelet therapy. LMWH is better than unfractionated heparin and is most commonly used. In the absence of an urgent/early invasive strategy, fondaparinux (a synthetic pentasaccharide that selectively binds antithrombin and causes inhibition of factor Xa) has the most favourable efficacy/safety profile.

ST-segment-elevation myocardial infarction

Patients with clear-cut evidence of ST-elevation infarction (STEMI) require immediate triage to reperfusion therapy. ‘Fast-track’ systems have been developed to minimize in-hospital delay to reperfusion: these aim to achieve clinical assessment and electrocardiography within 15 min of arrival and rapid transfer for percutaneous coronary intervention or the institution of thrombolytic therapy within 30 min. Audit programmes and continuous training are necessary for centres to achieve this 30-min median ‘door-to-needle’ time.

PCI—Randomized clinical trials of primary PCI vs thrombolysis have shown consistent findings: primary PCI is better, providing more effective restoration of vessel patency, achieving better ventricular function, and improving important clinical outcomes with lower rates of death, re-infarction, stroke, major bleeding, and recurrent ischaemia. Particular gains are seen in haemodynamically compromised patients. In consequence, primary PCI is the preferred therapeutic option in national and international guidelines.

Thrombolysis—prehospital thrombolysis is the next best option if a primary PCI programme is not available, or if transfer times are sufficiently prolonged that reperfusion may not be achieved within 90 min of patient call.

The current reference standard for the comparison of fibrinolytic agents is the accelerated infusion regimen of alteplase (tPA), or—for simplicity—the single-bolus administration of tenecteplase (TNK), which does not require an infusion pump or refrigeration and hence is particularly suited for pre-hospital administration. Internationally, streptokinase remains the most widely used fibrinolytic agent, principally because it is relatively inexpensive.

Antiplatelet agents and anticoagulants:

  1. Aspirin 75–325 mg daily—indicated in all patients with acute coronary syndromes unless there is good evidence of aspirin allergy or evidence of active bleeding.
  2. Thienopyridine—clopidogrel (regimen as described above) should be given to all patients, continuing for at least 1 month in patients managed with fibrinolysis (or as determined by the type of stents implanted).
  3. GP IIb/IIIa inhibitors—e.g. abciximab, eptifibatide, tirofiban—are indicated in patients managed with primary PCI, but not in those managed with fibrinolysis.

Anticoagulants: Patients treated with fibrinolytic therapy should receive LMWH or fondaparinux (a factor Xa inhibitor).

Secondary prevention measures in patients with ACS

Patients require advice and help regarding cessation of smoking (including the avoidance of passive smoking), dietary modification, exercise, rehabilitation, and management of obesity.

The following therapies have been shown to reduce the risk of subsequent cardiovascular events:

  1. antiplatelet therapy—aspirin in a dose of 75 mg/day, clopidogrel 75 mg/day;
  2. β-blockers in those without contraindications;
  3. lipid lowering with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins);
  4. angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB), especially in those with left ventricular dysfunction and heart failure, and benefit is also possible in other patients with vascular disease.

Introduction

The term ‘acute coronary syndrome’ (ACS) describes the clinical manifestations of a heterogeneous spectrum of conditions that share key pathophysiological features: disruption or erosion of coronary atheromatous plaque, changes in vascular tone, and a variable extent of thrombotic occlusion. The clinical presentations are determined by the extent of coronary obstruction, the volume of ischaemic myocardium, and temporal pattern of the atherothrombotic disease process. Acute coronary syndrome occurs in patients with underlying, symptomatic or occult coronary artery disease and flow-limiting or non-flow-limiting atheromatous plaques in the coronary arterial wall.

The ACS is precipitated by an abrupt change in an atheromatous plaque, resulting in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected vessel. For discussion of the mechanisms involved see: Atherosclerosis: Biology and Pathology. The pattern and severity of clinical manifestations are dependent not only upon the degree of obstruction to perfusion, but also on the presence or absence of collateral perfusion, the extent and distribution of fragmented microthrombi, and myocardial oxygen demand in the perfused territory. Thus, the clinical consequences of plaque rupture can range from an entirely silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, and risk of sudden death.

The goals of early management of ACS are to relieve ischaemia (by reducing myocardial oxygen demand, inhibiting thrombotic occlusion, and reducing coronary obstruction), to prevent further thrombotic occlusion, and to prevent or manage complications. The choice and timing of management strategy, including pharmacological treatment and percutaneous or surgical revascularization, is critically dependent on the extent and severity of myocardial ischaemia. Despite sharing key pathophysiological mechanisms across the spectrum of ACS, ST-segment-elevation acute myocardial infarction (STEMI) and non-ST-elevation ACS (unstable angina and non-STEMI) need to be considered separately because an acute reperfusion strategy (primary percutaneous coronary intervention (PCI) or thrombolysis) is of proven benefit in STEMI (or MI with new bundle branch block), but not in the remainder of the syndrome. Thus, although the management of STEMI differs, the remainder of the ACS should be managed as a continuous spectrum, but influenced by risk stratification.

Clinical presentation and presentation of ACS

The ACS may present de novo (as new-onset angina), with typical ischaemic discomfort at rest (rest angina) or on minimal exertion. Alternatively, a previously stable pattern of angina may change, resulting in episodes of typical rest angina or angina provoked by minor exertion (crescendo angina). New-onset exertional angina has not previously been recognized as part of ‘acute coronary symdrome’, but the outcomes are similar (c.7% develop nonfatal MI and 4% die, and a further 19% require revascularization within 15 months) and such patients may fulfill the clinical and ECG/biomarker characteristics of the syndrome (Euroheart survey, GRACE, and CRUSADE registries).

There are three components to the clinical diagnosis of ACS: the symptom description, the ECG, and biomarker evidence of myocyte necrosis. The symptoms must be distinguished from noncardiac pain, and from stable angina. To improve the specificity of diagnosis, clinical trials use a more restricted definition, requiring at least 15 to 20 min of typical ischaemic discomfort or two 5-min episodes at rest. The specificity is further improved when the definition requires objective evidence of ischaemia or evidence of underlying coronary artery disease. ST segment depression on the ECG, especially in association with typical pain, is highly predictive, whereas the less specific ECG abnormalities, including T wave inversion, are less strong predictors. Markers of myocardial damage (troponins or cardiac enzymes) are powerfully predictive, in the presence of a typical clinical syndrome. ST elevation or depression on the ECG and elevated biomarkers of necrosis are markers of higher risk and adverse outcome (Table 1). In the absence of such markers, documented evidence of underlying coronary artery disease (prior infarction or angiographically demonstrated coronary disease) helps to confirm the diagnosis.

In brief, the three components of ACS comprise:

  • unstable angina—typical ischaemic symptoms without ST elevation on ECG and without elevated biomarkers of necrosis
  • non-STEMI—typical ischaemic symptoms without ST elevation on ECG but with biomarkers of necrosis above the diagnostic threshold
  • STEMI—typical ischaemic symptoms with ST elevation on ECG and with biomarkers of necrosis above the diagnostic threshold
Table 1 Prognostic value of admission ECG for early risk stratification in 12 142 patients with an acute coronary syndrome

 

  ST elevation +  ST depression (%) ST elevation (%) ST depression (%) T wave inversion (%) p
Patients 15 28 35 23  
Acute infarction on admission 87 81 47 31 <0.0001
Death  6.8  5.0  5.0 1.8 <0.001
(Re)infarction 6.9  5.1 6.7 4.3 <0.001

Death and reinfarction at 30 days follow-up.

Data from the GUSTO IIb trial.

The definition of MI has recently been revised by a ‘Global Task Force’ of the European Society of Cardiology, the American College of Cardiology, the American Heart association, and others and has identified five subtypes of MI (Bullet list 1).

Bullet list 1 The subtypes of MI

  • Type 1—spontaneous MI related to ischaemia due to a primary coronary event such as plaque fissuring, erosion or rupture, or dissection
  • Type 2—myocardial infarction secondary to ischaemia due either to increased oxygen demand or to decreased supply (e.g. coronary spasm or embolism, anaemia, arrhythmias, hypertension, or hypotension)
  • Type 3—sudden unexpected cardiac death, including cardiac arrest, with symptoms suggestive of myocardial ischemia, accompanied by new ST elevation, or new left bundle branch block, or definite new thrombus by coronary angiography (death before blood samples obtained) or in the lag phase of cardiac biomarkers
  • Type 4—MI associated with PCI
  • Type 5—MI associated with CABG

Outcome of ACS

Trial data and large-scale observational registry studies

Overall, based upon large-scale registries with consistent disease definitions, there are approximately two patients with non-STEMI ACS for each patient with STEMI. Previously, inclusion of patients with chest pain—but without diagnostic features of acute ischaemia—under the term ‘unstable angina’ may have masked the true hazards of the syndrome. Comparisons between studies may be confounded by different disease definitions and varying use of more sensitive markers of myocyte necrosis (troponins), but on the basis of data from randomized trials and prospective registry studies there is no doubt that patients with ACS (with or without persistent ST elevation) are at substantial risk of subsequent cardiac events despite current therapy. About 9 to 11% suffer death or MI in the first 6 months following presentation, and almost half of this risk is within the first 7 days (GUSTO IIb, OASIS Registry, and GRACE Registry). Whereas patients with STEMI are most at risk of death, especially in the first hours of symptom onset, those with non-STEMI ACS are at higher risk after discharge.

Table 2  Mortality in hospital and at 6 months in low-, intermediate-, and high-risk categories in registry populations according to the GRACE (Global Registry of Acute Coronary Events) risk score, which assigns risk on the basis of the following patient characteristics on admission: age, heart rate, systolic blood pressure, serum creatinine, evidence of congestive heart failure, also the presence/absence of cardiac arrest, ST-segment deviation and elevated cardiac enzymes/markers. For calculations, see http://www.outcomes.org/grace

 

Risk category (tertiles) GRACE risk score In-hospital deaths (%)
Low ≤108 <1
Intermediate 109–140 1–3
High >140 >3
Risk category (tertiles) GRACE risk score Post-discharge to 6 months deaths (%)
Low ≤88 <3
Intermediate 89–118 3–8
High >118 >8

From Fox KA, et al. (2006). Prediction of risk of death and mycocardial infarction in the six months after presentation with acute coronary syndrome:prospective multinational observational study (GRACE). BMJ, 333, 1091–4.

The clinical syndrome and outcome

The Braunwald classification categorizes unstable angina according to the mode of onset and time course (Table 3). It was empirically based, but has been validated by prospective studies. Patients with unstable ischaemic pain at rest and those with ST depression have the highest risk of an adverse cardiac event. Similarly, those with unstable angina following acute MI are at an increased risk. Although the classification is useful, many of the patients that present with ACS are in Braunwald class 3B and additional methods of risk characterization are required to optimize management.

Table 3  Classification of unstable angina (Braunwald)

 

Class  
  • A
  • Secondary unstable angina
  • B
  • Primary unstable angina
  • C
  • Postinfarction (<2 weeks) unstable angina
I New-onset, severe or accelerated angina IA IB IC
II Subacute rest angina (<48 h ago) IIA IIB IIC
III Acute rest angina (within 48 h) IIIA IIIB IIIC

From Braunwald E. Circulation 1989, 80, 410–14 (http://circ.ahajournals.org/cgi/reprint/80/2/410)

A diagnostic triage system can be developed for patients with suspected ACS (see below). This is based on ECG changes, biomarker release, and stress or perfusion testing. Patients with evolving STEMI are identified, and those with higher risk separated from those with lower risk. The respective categories of patients require different management strategies.

The ECG and outcome

The 12-lead ECG (performed on admission) provides direct prognostic information (Table 1). The greatest risk of death and subsequent MI is seen in patients with simultaneous ST elevation and depression; the next highest risk is seen in those with transient ST segment elevation or ST segment depression; isolated T wave inversion carries a lower risk. The number of leads demonstrating ST deviation also yields prognostic information: among those with ST deviation in the anterior leads a rate of death or MI of 12.4% was seen at 1 year—higher than seen with similar changes in other locations (TIMI III trial). Patients with a left main and three-vessel coronary artery disease may show a combination of ST-segment elevation and depression.

Ambulatory ST segment recording can identify patients with unstable angina and either silent or symptomatic myocardial ischaemia with an increased risk for major subsequent cardiac events. However, conventional ambulatory monitoring usually requires offline analysis and is not suitable for the prediction of imminent events. Computer-assisted, continuous, multilead, ECG monitoring techniques has become available for real-time ECG and ST segment monitoring. The occurrence and extent of ischaemic territory identified by such continuous recordings can provide additional prognostic information over and above the admission ECG. The information can be combined with biomarkers and, together, they provide additional prognostic information (FRISC study).

Biochemical markers and outcome

Enzymes and biomarkers of necrosis are gradually released into the systemic circulation following complete or transient occlusion of the coronary artery, or fragmentation of a thrombus and embolization. Following total occlusion of the vessel, troponins and creatine kinase (or more specifically CK-MB) are released and are detectable at clearly abnormal levels about 6 to 8 h after the event unless there is extensive collateral perfusion.

The cardiac isoforms of troponin I and troponin T are exclusively expressed in cardiac myocytes and provide specific evidence of myocardial damage. Following infarction, troponins are released from the cytosolic pool and first appear in the circulation in detectable concentrations between 3 and 4 h after the ischaemic event, and reach diagnostic concentrations at 6 to 8 h. Troponin release is evidence of myocardial injury and carries prognostic significance: the greater the troponin release, the greater the risk of subsequent MI and death. However, it is important to recognize that other causes of myocyte necrosis (including myocarditis, pulmonary embolism, and severe heart failure) can give rise to detectable troponin concentrations in the circulation; so the diagnosis of ACS requires the presence of an appropriate clinical syndrome.

When should the cardiac enzymes be measured? The time course of the release of troponins (or enzymes) from myocardium is such that diagnostic concentrations may not be achieved until between 6 and 8 h after an ischaemic event. Thus, a normal value for a patient on arrival does not exclude infarction or unstable angina, but an elevated value is highly predictive of subsequent infarction. Troponins should be measured on arrival and at approximately 8 to 12 h: these provide the highest predictive accuracy. The latest generation of sensitive troponin assays increase diagnostic performance and improve the early diagnosis of myocardial infarction regardless of the time of chest-pain onset. Implementation of a sensitive troponin assay, and lowering the diagnostic threshold for MI, reduces recurrent MI and death in patients with suspected ACS.

Among those with persistently negative troponins and without significant ECG changes, there is a very low risk of subsequent infarction and death (provided that severe underlying coronary artery disease is excluded). Such patients should undergo predischarge stress testing, the best tests being myocardial perfusion scanning or stress echocardiography, but treadmill ECGs on exercise are more widely available.

Markers of inflammation

Inflammatory changes in the vessel wall promote plaque fissuring or erosion, and inflammatory changes also follow episodes of minor myocardial damage. In ACS there is evidence that inflammatory markers (C-reactive protein (CRP), interleukin (IL)-6, and IL-1) are independent predictors of adverse outcome. After the acute phase, continuing inflammation—e.g. with elevated C-reactive protein—occurs in one-half of those whose levels are acutely elevated and identifies a category of patients at increased risk. However, although inflammatory mechanisms are implicated in plaque growth and plaque destabilization, specific anti-inflammatory therapies have not yet been demonstrated to improve outcome, and measurement of CRP or other inflammatory markers is not part of routine clinical practice.

Risk characterization in ACS

The timing and the nature of key management decisions in ACS are dependent upon risk estimation. For example, the choice of reperfusion therapy in ST elevation may be influenced by the presence of comorbidity, bleeding risk, and time delay from symptom onset. Similarly, in non-STEMI ACS, ongoing ischaemia with ST depression or the presence of hypotension or a high risk score may initiate very early re-vascularization. Specific pharmacological (e.g. glycoprotein IIb/IIIa inhibitors) or interventional therapies (PCI) have demonstrated benefit in high- or moderate-risk patients but not in low-risk patients (5-year outcome: RITA 3, FRISC II).

In patients with ACSs, risk can be separated into two components: ‘prior risk’ and ‘acute ischaemic risk’. Prior risk is determined by patient characteristics (age and gender), prior ischaemic heart disease (MI, heart failure, prior angina, etc.), and systemic factors that influence risk (hypertension, diabetes, renal dysfunction, and other life-threatening systemic disorders). These can be considered as the background level of risk that the patients bring with them to the point of presentation. Although several of the individual risk components may not be modifiable, the combined impact of prior risk influences the balance between benefit and risk for each of the therapeutic strategies in ACS. Thus, prior risk ‘sets the baseline’ for risk–benefit decisions.

By contrast, ‘acute ischaemic risk’ is potentially modifiable and determined by the severity of coronary obstruction and the extent of the territory affected. Collateral perfusion, embolization, myocardial oxygen demand, and cytoprotection mechanisms all influence the extent of ischaemia. Patients with similar clinical features may have experienced transient complete occlusion, or severe subtotal occlusion complicated by distal embolization of fragments of a platelet-rich thrombus, and altered vascular tone in the distal territory. Clinical markers of acute ischaemic risk include ECG changes, release of biomarkers of necrosis into the systemic circulation, and mechanical and arrhythmic complications of the ischaemic episode.

Simplistically, prior risk can be regarded as the ‘baggage’ that the patient carries with them, and acute ischaemic risk as an ‘acquired hazard’ arising from the new ischaemic event. The distinction is important because management strategies for prior risk aim to treat heart failure, underlying coronary and systemic disease, and risk factors. The management of acute ischaemic risk aims to reverse the impact of acute coronary obstruction and thrombosis and is the first priority in the management of patients with ACS. Assessment of the extent and impact of underlying coronary artery disease (e.g. with stress testing) and assessment of left ventricular function can take place later in the management of these patients (Bullet list 2).

Bullet list 2 Practical steps to assess risk (in addition to clinical symptoms)

  • 12-lead ECG—obtained directly after first medical contact, repeated after recurrent symptoms
  • Troponin estimation (cTnT or cTnI)—repeated after 6–12 h, if the initial test is negative
  • Apply a risk score (such as GRACE, TIMI—
  • An echocardiogram may be required to rule in/out alternative diagnoses
  • In patients with no recurrence of pain, normal ECG and no troponin elevation, a noninvasive stress test may be required.

Management of ACS without ST elevation (unstable angina/non-STEM)

Anti-ischaemic therapy

Anti-ischaemic therapy can decrease myocardial oxygen consumption by reducing heart rate, lowering blood pressure, or depressing left ventricular contractility, and may also act by inducing vasodilatation. In consequence, anti-ischaemic therapy can limit the progression of occlusion and improve perfusion and improve the supply–demand imbalance. Mechanical revascularization (PCI and coronary bypass surgery) also aims to relieve obstruction and reduce a patient’s susceptibility to ischaemia—these interventions will be considered separately.

Nitrates

Nitrates act by venodilatation and—in higher dose—by arteriolar dilatation, and hence reduce preload and afterload, thereby decreasing oxygen demand. In addition, nitrates can also induce coronary vasodilatation. They are effective in relieving symptoms of ischaemia. In the acute phase of the syndrome, where dose titration is required, they are most conveniently administered intravenously. Once dose titration is no longer required, oral administration is feasible.

Continuous nitrate administration can induce tolerance; so when symptoms are controlled, oral nitrates should be prescribed with appropriate nitrate-free intervals. An alternative is to use drugs with nitrate-like properties but without the same problems of tolerance, such as a potassium channel activator (see below).

Large outcome trials have been conducted with nitrates in acute MI but not in other ACS. However, patients without ST-segment elevation or bundle branch block were randomized within the ISIS-4 trial: their mortality was 5.3% for nitrate treatment and 5.5% for placebo treatment, a nonsignificant difference.

Nitrates are effective in reducing ischaemia in the in-hospital management of non-ST elevation ACS, but there is no evidence that they improve mortality.

β-Blockers

β-Adrenoceptor antagonists reduce heart rate and blood pressure and myocardial contractility and hence decrease myocardial oxygen consumption. They are primarily employed to reduce ischaemia in ACS. Large-scale trials have not been conducted in patients with non-ST elevation ACS. However, in the context of acute MI, β-blockers reduce mortality by approximately 10 to 15% (ISIS-1 study). They may act by reducing ventricular arrhythmias, reinfarction, and myocardial rupture. However, this trial was conducted before the widespread use of reperfusion therapy and the findings may not be relevant to contemporary practice. More recently the large COMMIT/CCS study demonstrated that immediate intravenous (metoprolol 5–15 mg) followed by oral metoprolol 200 mg daily had no effect on mortality, with reductions in recurrent MI and cardiac arrest offset by increased cardiogenic shock. A meta-analysis of five trials involving 4700 patients with threatened MI (treated with intravenous β-blockers followed by oral therapy for c.1 week) resulted in a 13% reduction in the risk of MI. Patients with significantly impaired atrioventricular conduction or asthma or acute left ventricular dysfunction should not receive β-blockers. Although β-blockers may exacerbate acute heart failure, extensive trials have produced strong evidence of a benefit for the gradual introduction of β-blockers in ambulant patients with heart failure.

In the absence of bradycardia or hypotension, patients with suspected ACS should be initiated on β-blocker therapy unless contraindicated.

Calcium entry blockers

These agents inhibit the slow inward current induced by the entry of extracellular calcium through the cell membrane, especially in cardiac and arteriolar smooth muscle. They act by lowering myocardial oxygen demand, reducing arterial pressure, and reducing contractility. Calcium channel blockers can provide symptom relief in patients already receiving nitrates and β-blockers, and may be useful in patients with contraindications to β-blockade. Some agents induce a reflex tachycardia (e.g. nifedipine, nicardipine, amlodipine) and are best administered in combination with a β-adrenoceptor antagonist. By contrast, diltiazem and verapamil are suitable for patients who cannot tolerate a β-blocker because they inhibit conduction through the atrioventricular (AV) node and tend to cause bradycardia. All calcium antagonists reduce myocardial contractility and may aggravate heart failure. Calcium entry blockers have been demonstrated to reduce the frequency of angina in patients with variant angina.

A meta-analysis of calcium entry blockers in ACS indicates a nonsignificant trend towards a higher mortality in treated vs control patients (5.9% vs 5.2%, in 7551 patients). In individual trials, diltiazem has been compared with propranolol, and both agents produced a similar reduction in anginal episodes.

Dihydropyridine calcium-entry blockers should be employed with β-blockers in ACS to avoid reflex tachycardia. In patients unable to tolerate β-blockers, a heart-rate-slowing calcium antagonist may be appropriate. Short-acting dihydropyridines should not be used in isolation in ACSs.

Potassium channel activators

These agents (e.g. nicorandil) have arterial and venous dilating properties, but do not exhibit the tolerance seen with nitrates. They have been shown to be better than placebo in relieving the symptoms of angina. A randomized trial of nicorandil (a combined nitrate-like and potassium channel activator) suggested benefit on a composite clinical endpoint (IONA study), and this drug may be considered as an alternative to nitrate administration.

The following recommendations for anti-ischaemic therapy are based on current clinical and trial evidence:

  • Anti-ischaemic therapy should be administered in conjunction with antithrombotic and interventional therapy (see below), with the overall strategy guided by risk evaluation of the patient (see risk stratification).
  • Patients with suspected ACS should be initiated on nitrate and β-blocker therapy, unless there are contraindications to the use of β-blockers
  • In patients with contraindications to β-blockers, heart rate-slowing calcium antagonists should be employed
  • The combination of a calcium antagonist and β-blocker is superior to either agent alone
  • Angiography and revascularization should be considered in patients with recurrent or persistent ischaemia, or patients with troponin elevation (including non-STEMI). The timing of angiography should be guided by the risk status of the patient.

Antiplatelet therapy

Aspirin

Exposure of the contents of atheromatous plaque to circulating blood triggers platelet activation by several different pathways. Aspirin is a potent and irreversible inhibitor of platelet cyclo-oxygenase, blocking the formation of thromboxane A2 and inhibiting platelet aggregation. Although the effects of aspirin can be overcome in the presence of potent thrombogenic stimuli, nevertheless the benefits of aspirin treatment in unstable angina are clearly defined and substantial. The Antiplatelet Trialists Collaboration demonstrated a reduction of 36% in death or MI with antiplatelet treatment (predominantly aspirin) vs placebo in unstable angina trials. Aspirin treatment significantly reduces subsequent MI, stroke, and vascular death, with the largest reductions seen amongst patients at highest risk. In patients with unstable angina, four key studies have demonstrated that aspirin significantly reduces the risk of cardiac death or nonfatal MI by approximately 50%.

The efficacy of lower-dose aspirin (75 mg/day) therapy has been demonstrated in several studies, including those of Wallentin and colleagues where long-term effects were evaluated in men under 70 years of age with unstable coronary artery disease. After 6 and 12 months of aspirin treatment, the risk of MI or death was reduced by 54% and 48%, respectively (risk ratio 0.52 with 95% confidence intervals 0.37–0.72). The strength of evidence and magnitude of benefit demonstrated with aspirin treatment in non-ST-segment-elevation ACS is such that aspirin is indicated in all patients with ACS, unless there is a clear contraindication. Nevertheless, patients with ACS remain at significant risk despite aspirin therapy. In prospective registry studies of unstable angina/non-STEMI, and in spite of aspirin treatment in more than 80% of patients, the risk of death or MI is approximately 10% at 6 months and the risk of death/MI or refractory angina is approximately 22 to 33% over the same period (OASIS Registry, PRAIS Registry).

Aspirin treatment (75–325 mg daily) is indicated in all patients with ACS unless there is good evidence of aspirin allergy or evidence of active bleeding.

ADP antagonists (thienopyridines)

Ticlopidine and clopidogrel are adenosine diphosphate receptor antagonists, and they block the ADP-induced pathway of platelet activation by inhibiting of the P2Y12 ADP receptor.

Clopidogrel has replaced ticlopidine on account of a superior safety profile and has been tested in a large-scale trial of patients with unstable angina/non-STEMI (n = 12 562, CURE trial). The agent was used on top of existing therapy, and in addition to aspirin. It reduced death, nonfatal MI, and stroke from 11.4 to 9.3% (95% confidence interval 0.72–0.90, p < 0.001). For every 1000 patients treated, there were 28 fewer major cardiovascular complications but six more transfusions. Importantly, benefits were seen across risk groups (diabetics, hypertensives, biomarker elevation or not, revascularization or not). In a substudy (PCI-CURE), clopidogrel also reduced death and MI in those undergoing percutaneous re-vascularization (2.9% clopidogrel vs 4.4% for placebo). Thus, with the combination of clopidogrel and aspirin, there is evidence of early and sustained reductions in the risks of death and MI in patients that present with ACS.

A number of smaller studies have used higher loading doses of clopidogrel (usually 600 mg), and these show more rapid inhibition of platelet aggregation than that achieved with 300 mg. The CURRENT-OASIS 7 trial assessed the effects of double-dose (600 mg loading, 150 mg for one week, then 75 mg daily) versus standard-dose (300 mg loading, then 75 mg daily) clopidogrel in patients with ACS and intended early revascularization. The double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose in patients who underwent PCI.

Long-term clopidogrel administration was tested in the CHARISMA study of 15 603 patients with documented vascular disease or risk factors for vascular disease. Overall, there was no difference in the primary endpoint of cardiovascular death, MI, or stroke. However, in the subgroup of patients with documented cardiovascular disease, the same endpoint was significantly reduced with dual antiplatelet therapy, when compared with aspirin (6.9 vs 7.9%, relative risk 0.88, 95% confidence interval 0.77–0.99). Thus, longer-term treatment with dual antiplatelet therapy should only be considered in those in whom the risk of ischaemic events exceeds the risk of bleeding complications.

Although clopidogrel is the only thienopyridine approved for the medical management of patients with non-ST-elevation ACS, newer P2Y12 inhibitors with more potent receptor affinity and more rapid onset of action are currently under evaluation.

Prasugrel is a more potent thienopyridine with faster onset than clopidogrel. Similar to clopidogrel, prasugrel is a prodrug that requires metabolism by enzymatic hydrolyses in the liver for activation. In moderate–high risk patients with ACS scheduled to undergo PCI, prasugrel (60 mg loading dose, 10 mg maintenance) compared to clopidogrel (300 mg loading dose, 75 mg maintenance), reduced MI and stent thrombosis particularly in diabetic patients, but with an increased risk of major bleeding, including fatal bleeding. Prasugrel should therefore be avoided in patients older than 75 years, with previous intracerebral bleeding or transient ischaemic attack or who weigh less than 60 kg. Prasugrel is approved for use in patients with ACS undergoing PCI.

Ticagrelor is a reversible inhibitor of the platelet P2Y12 receptor and belongs to a new class of antiplatelet agents, the cyclopentyltriazolopyrimidines. It does not require hepatic metabolism to an active form and therefore has a rapid onset with more predictable platelet inhibition. The PLATO study demonstrated that ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) as compared to clopidogrel (300–600 mg loading dose, 75 mg daily thereafter) reduced cardiovascular death, MI, and stent thrombosis without increasing the rate of major bleeding in patients with ACS. This was the first study to demonstrate a mortality benefit with the addition of an antiplatelet agent to aspirin in patients with ACS. Given this was achieved without the excess in major bleeding associated with prasugrel, it is likely that ticagrelor will become the antiplatelet agent of choice. It has been approved by the European Medicines Agency, but has not yet been approved for use in the United States.

Recommendations for thienopyridines are:

  • Patients with non-ST-elevation ACS should be given clopidogrel as an initial 300-mg loading dose, followed by continued treatment at a dose of 75 mg daily in combination with aspirin at a dose of 75–325 mg daily. Clopidogrel should be given alone to patients with contraindications to aspirin (same regimen).
  • Clopidogrel should be maintained for 12 months unless the risks of bleeding exceed potential benefits.
  • In patients undergoing percutaneous coronary intervention, a loading dose of 600  mg of clopidogrel followed by 150 mg for 1 week, should be used to achieve more rapid inhibition of platelet function. Following percutaneous coronary intervention, the duration of clopidogrel administration should take account of the type of stent implanted (bare metal or drug eluting) and the risks of bleeding/thrombosis.
Glycoprotein IIb/IIIa inhibitors

Platelet adhesion is the initial step in haemostasis after disruption of an atheromatous plaque. It is triggered by damage to the vessel wall and exposure of the subendothelium, and is followed by platelet activation and aggregation. Regardless of the agonist, the final common pathway leading to the formation of a platelet aggregate is mediated by the glycoprotein (GP) IIb/IIIa receptor. GPIIb/IIIa receptor antagonists inhibit platelet aggregation irrespective of the agonist, and they prevent binding of fibrinogen to its receptor on the platelet surface.

Three GPIIb/IIIa receptor antagonists have been approved for clinical use: abciximab, eptifibatide, and tirofiban. Abciximab is a chimeric human–murine monoclonal antibody that binds with high affinity to the receptor: it has a long biological half-life of 6 to 12 h, and low levels of receptor occupancy are detected even 2 weeks after treatment. Eptifibatide is a synthetic cyclic heptapeptide with high affinity for the arginine–glycine–aspartic acid ligand-adhesion site of the IIb/IIIa receptor. It inhibits platelet aggregation in a dose-dependent manner and is readily reversible due to competitive binding and a short half-life of approximately 2.5 h. Tirofiban is a nonpeptide tyrosine derivative which also binds to the arginine–glycine–aspartic acid site with high specificity. It inhibits platelet aggregation in a dose- and concentration-dependent manner and is rapidly reversible, with platelet function approaching normal levels in 90% of patients within 4 to 8 h.

Although it is convenient to group glycoprotein IIb/IIIa receptor antagonists together, and undoubtedly there is evidence of a class effect, there are biological and pharmacological differences between the agents.

Trials of GPIIb/IIIa inhibitors

More than 32 000 patients have been randomized in clinical trials involving GPIIb/IIIa inhibitors (16 trials). A highly significant (p < 0.001) benefit is observed for the combined endpoint of death or MI at 48 to 96 h, 30 days, and 6 months. At 30 days the odds ratio is 0.76, or 20 fewer events per 1000 patients treated, and a highly significant benefit is observed for the combined endpoint of death/MI or revascularization at all time points. By contrast, mortality benefits are seen only at 48 to 96 h, with no significant benefit at 30 days or 6 months. A pooled analysis of abciximab trials has revealed a net mortality benefit, but there is no evidence of benefit for abciximab in medically treated patients (GUSTO-4-ACS).

The impact of GPIIb/IIa inhibitors is influenced by the risk status of the patient and whether administered in the context of percutaneous coronary intervention. In a meta-analysis of 29 570 patients, there was a 9% reduction in relative risk overall, but with no significant benefit in those who were medically managed (death and MI at 30 days of 9.3% for IIb/IIIa vs 9.7% placebo, OR 0.95, 95% confidence interval 0.86–1.04). Significant benefit was observed when GP IIb/IIIa inhibitors were maintained during percutaneous coronary intervention (10.5 vs 13.6%, OR 0.74, 95% confidence interval 0.57–0.96). The EARLY-ACS study demonstrated that the use of eptifibatide 12 h or more before coronary angiography was not superior to provisional use after angiography, and early use was associated with more nonfatal bleeding. Similarly, there is no convincing evidence of benefit in low-risk patients, irrespective of interventional strategy.

Indications for treatment with GPIIb/IIIa inhibitors are:

  • Treatment with glycoprotein IIb/IIIa inhibitors results in improved outcome in patients at intermediate to high risk—e.g. those with elevated troponins, ST depression, or diabetes.
  • GPIIb/IIIa inhibitors should be administered with oral antiplatelet agents (aspirin and thienopyridines) and anticoagulants (heparin or low-molecular-weight heparin (LMWH)).
  • Glycoprotein IIb/IIIa inhibitors result in improved outcome in patients requiring urgent percutaneous intervention for non-ST-segment elevation ACS.
  • Bivalirudin may be used as an alternative to GP IIb/IIIa inhibitors plus UFH/LMWH (see below).

Anticoagulants

Unfractionated heparin

Unfractionated heparin is widely used for the treatment of non-ST-elevation ACS, but the evidence on which this is based is less robust than for other widely adopted treatment strategies. In practice, unfractionated heparin is difficult to control because of its unpredictable levels of binding to plasma proteins, and this may be amplified by the acute-phase response. In addition, heparin has reduced effectiveness against platelet-rich and clot-bound thrombin.

Oler and colleagues conducted a meta-analysis of the influence of adding heparin to aspirin in the treatment of patients with unstable angina. Only six randomized trials were available, with 1353 patients included: there were 55 deaths or MIs in the aspirin plus heparin arm and 68 in the aspirin-alone arm, giving a risk reduction of 0.67 and a 95% confidence interval of 0.44 to 1.02. These results do not produce conclusive evidence of benefit from adding heparin to aspirin, but it must be stressed that appropriately powered, larger-scale trials have not been conducted. Nevertheless, clinical practice has adopted unfractionated heparin treatment with aspirin as a pragmatic extrapolation of the available evidence.

Low molecular weight heparin (LMWH)
Trials vs placebo

The FRISC trial tested dalteparin against placebo in aspirin-treated patients with unstable angina/non-STEMI. Some 1506 patients were randomized to receive dalteparin (twice daily for the first 6 days and then once daily at a lower dose for approximately 6 weeks), and the trial showed a highly significant reduction in the frequency of death or new MI at 6 days (1.8% vs 4.8%, with a risk ratio of 0.37). The effects were sustained to 42 days, but were attenuated at 6 months, the differences no longer maintaining significance. Nevertheless, this trial clearly showed the benefit of LMWH over placebo in the presence of aspirin.

Trials vs unfractionated heparin

LMWH possesses enhanced anti-Xa activity in relation to anti-IIa (antithrombin) activity, compared with unfractionated heparin. It also exhibits decreased sensitivity to platelet factor 4 (PF4), has more predictable anticoagulant effect, and lower rates of thrombocytopenia. In view of its enhanced bioavailability, it offers the substantial practical advantage of subcutaneous administration based on a dose per kilogram of body weight and without the need for laboratory monitoring.

Acute-phase treatment (c.2–8 days)

In the FRIC trial, dalteparin was tested against unfractionated heparin in 1400 patients with unstable angina: it had limited power to show a difference, and no significant difference was seen between unfractionated heparin and dalteparin.

The ESSENCE trial was double-blinded and placebo-controlled and tested enoxaparin against unfractionated heparin. The treatments were given for 2 to 8 days (median 2.6 days) and the primary endpoints were death, MI, or recurrent angina. Enoxaparin reduced the primary endpoint from 19.6% to 16.6% at 14 days (odds ratio 0.80 and confidence intervals 0.67–0.98). A similar and significant odds ratio was maintained at 30 days and 1 year. At 1 year, there were 3.7 fewer events/100 patients (p = 0.022). The study was not powered for death/MI alone, but demonstrated corresponding trends for these endpoints.

The TIMI 11b trial was also double-blinded and tested enoxaparin vs unfractionated heparin, but additionally it examined 72 h of treatment vs 43 days of treatment. The results up to 14 days mirrored those seen in the ESSENCE trial: at 14 days the primary outcome occurred was 16.6% (heparin) vs 14.2% (enoxaparin), risk ratio 0.85 (p = 0.03). A combined analysis of ESSENCE and TIMI 11b indicated an absolute reduction of 3.1 per 100 for death/MI/refractory angina, and showed a similar risk ratio of 0.79 (confidence interval 0.65–0.96) for death and MI. Taken together, these findings indicate that short-term treatment with enoxaparin results in about 3 per 100 fewer major cardiac endpoints compared to unfractionated heparin treatment, and this is achieved without additional major bleeding.

Prolonged outpatient treatment

The FRAXIS trial tested fraxaparin, for 6 or 14 days, against unfractionated heparin in 3468 patients; no difference was seen in efficacy, but there was a significant excess of major bleeds with longer-term outpatient treatment. In TIMI 11b, the curves remained separated over the succeeding treatment interval: at 43 days there were 19.6% events (heparin) vs 17.3% (enoxaparin) (p = 0.049), with no evidence of a further separation of the curves. There was 1.4% absolute excess in major bleeds over the chronic phase.

Conclusions from the LMWH studies

There is convincing evidence in aspirin-treated patients (heparin or LMWH is not indicated in the absence of antiplatelet therapy) that LMWH is better than placebo (FRISC trial). The two trials using enoxaparin have provided consistent data in favour of LMWH over unfractionated heparin when administered as an acute regimen. The other trials have produced a similar outcome for the acute phase of treatment and it can be concluded that acute treatment is at least as effective as unfractionated heparin. There is no convincing evidence to support longer-term treatment with LMWH.

Evidence supports the following conclusions regarding the use of heparin:

  • LMWH is superior to placebo in aspirin-treated patients
  • LMWH is at least as effective as unfractionated heparin
  • LMWH can be used in place of unfractionated heparin and has practical advantages over unfractionated heparin

Direct thrombin inhibitors

Direct thrombin inhibitors (e.g. hirudin, bivalirudin) bind directly to thrombin (factor IIa) and inhibit thrombin-induced conversion of fibrinogen to fibrin. They inactivate fibrin-bound thrombin as well as thrombin in the circulation. They do not bind to plasma proteins nor interact with PF4, and hence their anticoagulant effect is predictable.

Hirudin has been tested in large-scale trials (e.g. OASIS-1, OASIS-2, TIMI 9b, GUSTO IIb) against heparin and a combined analysis suggests a 22% relative-risk reduction in cardiovascular death or MI at 72 h, 17% at 7 days, and 10% at 35 days. This combined analysis is significant at 72 h and 7 days but not beyond. Hirudin is licensed for heparin-induced thrombocytopenia but not for ACS.

Bivalirudin was tested in the open-label randomized ACUITY trial in 13 819 patients with moderate- to high-risk non-ST-elevation ACS with a planned invasive strategy. The composite endpoints included death, MI, or unplanned revascularization for ischaemia, major bleeding (noncoronary artery bypass graft (CABG)-related), and net clinical outcome (composite ischaemia or major bleeding). Bivalirudin plus GPIIb/IIIa had similar outcomes (noninferior) to heparin/LMWH plus GPIIb/IIIa and similar rates of bleeding. Bivalirudin alone had similar outcome (noninferior composite) to heparin/low-molecular-weight heparin plus GPIIb/IIIa, but had superior safety (less bleeding). An interaction with the effects of clopidogrel was evident; benefits were seen with clopidogrel but not without.

Oral platelet thrombin receptor antagonists (TRA) are currently under evaluation in a phase III clinical trial programme (TRA 2 degrees P-TIMI 50). SCH 530348 selectively inhibits the cellular actions of thrombin via the protease-activated receptor 1 (PAR-1) on the surface of platelets. Given that the generation of fibrin by thrombin is not affected by PAR-1 inhibition, it is anticipated that this molecule will have potent antithrombotic effects with less bleeding than other novel antiplatelet agents.

Anti-Xa inhibitors

Fondaparinux is a synthetic pentasaccharide that selectively binds antithrombin and causes inhibition of factor Xa. In the OASIS-5 study, 20 078 patients with non-ST-elevation ACS were randomized (double-blind design) to receive 2.5 mg subcutaneous fondaparinux once daily vs subcutaneous enoxaparin 1 mg/kg twice daily for up to 8 days. Fondaparinux was noninferior at 9 days (the primary endpoint), but subsequently those randomized to fondaparinux had reduced mortality and approximately half the rate of major bleeding. In those undergoing PCI, there was an excess of catheter-related thrombi, and administration of this agent requires additional antithrombin therapy (the excess thrombi were not seen when combined with unfractionated heparin and there was no evidence of excess bleeding with this combination). A number of oral factor Xa inhibitors (rivaroxaban, apixaban, and otamixaban) are available and have been assessed in dose-ranging and safety phase II trails of patients with ACS. An efficacy study of apixiban in patients with ACS (APPRAISE 2) was stopped due to excess bleeding, but the ATLAS 2 study of rivaroxaban in addition to dual antiplatelet therapy has completed recruitment and is due to report in 2011.

Anticoagulation for non-ST-elevation ACS:

  • Anticoagulation is required in addition to antiplatelet therapy
  • Anticoagulant options include unfractionated heparin (UFH), LMWH, fondaparinux, and bivalirudin, with choice dependent on the initial strategy (early invasive, or not) and the bleeding risk
  • With an urgent invasive strategy, unfractionated heparin, enoxaparin, or bivalirudin are treatment options
  • In the absence of an urgent/early invasive strategy, fondaparinux has the most favourable efficacy/safety profile

Revascularization

The aim of revascularization in non-ST-elevation ACS is to relieve angina, to alleviate myocardial ischaemia, and to prevent progression to MI or death. The indications for myocardial revascularization are dependent on the risk status of the patients and the presence or absence of evidence of ongoing myocardial ischaemia and/or evidence that the ischaemia has resulted in mechanical or electrical complications. Following angiography, the choice of PCI or coronary artery bypass grafting is dependent on the extent and severity of angiographic stenoses and the comorbidity of the patient. Angiographic analyses from the TIMI-3B and FRISC-2 studies demonstrates that about 30 to 38% of patients with non-ST-elevation ACS have single-vessel disease and 44 to 60% have multivessel disease (>50% diameter stenosis).

Observational studies

Large-scale observational studies have demonstrated wide variations between countries in the use of cardiac catheterization and revascularization for patients with acute ischaemic syndromes and a paradox whereby lower-risk patients are less likely to receive aggressive antithrombotic and interventional treatment than moderate- or higher-risk patients. Similar findings have been observed in the United States of America in the CRUSADE registry. Nevertheless, there is clear evidence over time of increasing use of guideline-indicated therapies (especially class 1 indicated treatments) in non-ST-elevation ACS, including angiography and interventional procedures. Overall, the changing pharmacological and interventional therapies have been associated with striking improvements in outcome, including a halving of new heart failure and a reduced risk of death. Higher rates of revascularization have been associated with an increased frequency of procedural complications, including stroke and major bleeding. Definitive assessment of the impact of revascularization on outcomes requires randomized trials and longer-term follow-up.

Randomized trial data

Several smaller and older trials (including TIMI 3B and VANQWISH) tested the impact of an interventional strategy in ACS. These largely predated modern antithrombotic therapy and modern interventional technology (including PCI and stents). For the sake of completeness, all the randomized trials are included in the overall meta-analysis (see below), but the larger and more recent trials require further description.

The FRISC-II trial compared an invasive strategy with a conservative strategy in patients who were initially stabilized with approximately 6 days of treatment with LMWH. Coronary angiography was performed within the first 7 days and revascularization performed in 71% of those in the invasive arm and 9% of those in the noninvasive arm within 10 days. This was, therefore, the first trial to achieve substantial separations in strategy and to include an appropriately powered population. After 6 months, death or MI occurred in 9.4% of the invasive group compared with 12.1% of the noninvasive group (a risk ratio of 0.78, p = 0.031) and the results remained significant at 1 year, but the mortality and the death or MI outcomes were no longer significant at 5 years. However, the results at 5 years clearly demonstrate that most benefit was seen in higher-risk patients, with no evidence of benefit in low-risk patients. A similar relationship between patient risk status and long-term outcome had been demonstrated in the RITA 3 trial.

The FRISC-II and the RITA 3 trials demonstrated that invasive therapy was associated with an excess early (within 30 days) rate of death or MI due to periprocedure complications. Overall, there was a consistency of benefit (for the efficacy endpoints) across the FRISC-II, TACTICS and RITA-3 trials. RITA 3 demonstrated that most benefit in the first year was in preventing refractory angina, but over 5 years there was a significant benefit in death or MI, and in preventing cardiovascular death, in those randomized to intervention. The more recent ICTUS trial was smaller and had a high rate of intervention in the ‘selective invasive’ arm of the trial, about as high as the intervention arm in RITA 3 and only modestly lower than in the intervention arm of FRISC-II. ICTUS employed a high rate of adjunctive therapies (including GPIIb/IIIa inhibitors), and the trial did not show an overall benefit for intervention. Differences in trial design, in the risk status of the trial populations, and in the definitions of MI in the respective trials must be taken into consideration. Nevertheless, a pooled analysis of all the trials is likely to represent the most reliable interpretation of all of the randomized trial data.

In a meta-analysis of all the trials, published in the European Society of Cardiology Guidelines (Eur Heart J, 2007), there was clear evidence for overall benefit on the outcomes of death or MI at 1 year (9.5% death/MI with intervention, 11.1% conservative strategy; odds ratio 0.84; 95% confidence interval 0.73–0.97). The number needed to treat to prevent one death or MI was 63. However, on the basis of the findings that most benefit was seen in moderate- to higher-risk patients and little or no benefit in lower-risk patients, the European Society of Cardiology Guidelines strongly recommend risk stratification of the patients as the basis for deciding who requires emergency or urgent revascularization, and who does not.

Risk stratification of patients with non-ST-elevation ACS

Risk stratification is required to guide management and therapeutic decisions in patients with non-ST-elevation ACS. Some patients are clearly at high risk at the time of initial presentation, e.g. those with typical ongoing ischaemic pain and ST depression on the ECG. However, for the remainder it may not be possible to identify higher-risk patients on the basis of the clinical features and ECG findings alone. Several studies have demonstrated that simple risk scores can accurately predict short- and longer-term outcome, not only in those with defined characteristics of ACS, but also in patients with suspected cardiac chest pain (GRACE and TIMI risk scores). Using a handheld device, a computer, or a scorecard, risk status can be calculated in less that a minute (risk calculator downloadable from http://www.outcomes.org/grace or http://www.timi.org/). International comparisons have demonstrated superior predictive accuracy for the GRACE score and the European Society of Cardiology 2007 Guidelines for non-ST-elevation ACS recommend this score. The European Society of Cardiology Guidelines also recommend that risk status be re-evaluated, especially if clinical or biochemical features change.

Troponin (cTnT or cTnI) measurement should be performed at presentation (on the basis that those with elevated markers of necrosis on arrival are at increased risk) and repeated after 6 to 12 h if the initial test is negative. Echocardiography may be required to demonstrate the presence or absence of contractile dysfunction or to rule out alternative diagnoses.

There is a substantial late mortality in non-STEMI that is currently under-recognized with 5-year death rates equivalent to patients with STEMI. Although the GRACE risk score was derived and validated for in-hospital and 6-month outcomes, this analysis demonstrates that it has similarly high predictive accuracy for long-term outcomes. The late consequences of presentation with ACS, in terms of death, MI, and stroke, are substantially greater than those seen during the initial in-hospital phase and novel approaches to diminish long-term risk are required. Markers of long-term risk include the following:

  • Increased age, heart rate, blood pressure, or Killip class
  • Previously documented coronary disease, MI, or diabetes
  • ST-segment depression, elevated troponin, or renal dysfunction
  • Impaired left ventricular function, three-vessel or left main disease
  • High risk score
An integrated approach to the patient with non-ST-elevation ACS

Patients with ACS may present to primary care physicians or directly to emergency hospital services. In addition, 15 to 20% of those presenting directly to chest pain clinics have ACS. Among patients presenting with an ACS, approximately 40% have evidence of prior coronary artery disease (e.g. MI, angiographically demonstrated disease, documented angina with a positive stress test).

The evaluation of patients with suspected ACS needs to be considered in a stepwise approach, proceeding from initial assessment and formulation of a working diagnosis (on the basis of clinical evaluation and the results of immediately available diagnostic tests) to confirmation of the diagnosis and stratification of the patients for emergency, urgent, and elective management.

Emergency Department–triage and establishing a working diagnosis

For the patient with chest pain, two issues must be resolved urgently. First, is the chest pain/discomfort thought to be of cardiac origin? This is a clinical judgement and requires prompt and skilled assessment. Secondly, in those with suspected cardiac pain, is there evidence of evolving infarction?

Patients with evolving infarction (ST-segment elevation or bundle branch block and clinical features of infarction) require emergency reperfusion with primary angioplasty, or if unavailable, thrombolysis (see below).

Patients without ST elevation or left bundle branch block can be triaged into low, intermediate, and high-risk categories:

  • High-risk ACS—patients with typical clinical features of ischaemia and ST segment depression or transient ST segment elevation, or with troponin elevation and a high risk score. Patients are also at high risk when ischaemia provokes arrhythmias or haemodynamic compromise.
  • Intermediate or low-risk ACS—patients with clinical features of ACS and nonspecific ECG changes (e.g. T wave inversion, T wave flattening, minor conduction abnormalities).
  • Patients with a normal ECG, normal biomarkers, normal cardiac examination, and normal echo are potentially low-risk ACS or may have an alternative diagnosis.

Management of patients with non-ST-elevation and high-risk status

High-risk patients with acute ischaemia at initial presentation, and especially those with haemodynamic compromise, require emergency assessment for revascularization. Such patients potentially benefit from glycoprotein IIb/IIIa inhibition. Trial evidence also supports an improved outcome with glycoprotein IIb/IIIa inhibition amongst the remainder of patients with troponin positivity or ST-segment depression. Those proceeding to emergency revascularization should receive (1) aspirin, (2) thienopyridine, e.g. clopidogrel, (3) glycoprotein IIb/IIIa inhibition, and (4) unfractionated heparin or LMWH, or bivalirudin. In addition, patients should receive anti-ischaemic therapy (see above) and some patients require antiarrhythmic management or haemodymamic support (e.g. intra-aortic balloon pump to reduce ischaemia and stabilize the patient for revascularization).

Management of patients with non-ST-elevation ACS at intermediate or low risk

Patients without high-risk features on initial presentation require further assessment to guide management. Application of a risk score will reveal that a significant proportion have unsuspected higher risk (approximately one-third based on registry studies). Such patients require monitoring and repeat ECGs (ideally ST segment continuous analysis) and evaluation in a dedicated chest pain, cardiac, or combined assessment unit (while awaiting the results of biomarker and other investigations).

  • Patients who develop high-risk features after initial presentation should be considered for urgent angiography and re-vascularization (within 24–72 h). Such patients also fulfill guideline criteria for GPIIb/IIIa inhibitors and anticoagulant and antiplatelet therapy (as above) and a revascularization strategy. Those developing ST elevation require emergency reperfusion (by primary percutaneous coronary intervention or—if PCI not available—by thrombolysis).
  • Patients with non-ST-elevation ACS and an intermediate risk score require dual antiplatelet therapy (aspirin plus thienopyridine, see above) plus anticoagulation (heparin, LMWH, fondaparinux or bivalirudin, see above). A pooled analysis of randomized trials comparing a routine invasive strategy or selective invasive strategy demonstrated an absolute reduction in recurrent nonfatal MI or cardiovascular death of 11.1% in high-risk patients and a 3.8% in intermediate-risk patients that persisted up to 5 years following revascularization. All patients at intermediate and high risk are candidates for an early elective revascularization strategy (within c.72 h).
  • Clinically stable patients with minor or nonspecific ECG abnormalities and a low risk score (including negative repeat troponin) are at very low risk for in-hospital major cardiac events. Such patients may, nevertheless, have significant underlying coronary artery disease. They require stress testing or perfusion scanning, ideally prior to discharge.

Other considerations

Coronary artery bypass surgery

As demonstrated by the FRISC II study, those with three-vessel or left main coronary artery disease and an ACS can be stabilized in the acute phase with antiplatelet and anticoagulant therapy and can proceed to coronary artery bypass surgery with a low perioperative and postoperative morbidity and mortality in experienced centres (c.2%, 30-day mortality). Based on the findings of the CURE study, bleeding risk is minimized if the thienopyridine (clopidogrel) is stopped for 5 or more days prior to surgery. Patients at high risk for thrombotic events in the presurgery phase may require an intravenous small molecule GP IIb/IIIa inhibitor (to provide more potent but reversible platelet inhibition up until the time of surgery). See Chapter 13.7 for further discussion.

Secondary prevention

All patients with ACS require cardiovascular secondary prevention measures including lifestyle modification (smoking cessation, diet, exercise), oral pharmacological therapy (antiplatelet, cholesterol-lowering, ACE inhibitor/ARB) and the management of established and newly detected comorbidities (e.g. diabetes, hypertension, renal dysfunction, heart failure). These are the same in patients with non-ST-elevation ACS as they are for those with STEMI (see below for details).

ST segment elevation MI (STEM)

Outcome in STEMI is critically determined by the extent and severity of myocardial ischaemia. In addition, the eventual extent of irreversibly injured myocardium is influenced by residual myocardial perfusion (via collaterals or subtotal coronary occlusion), the duration of myocardial ischaemia, and cytoprotective mechanisms including preconditioning. As a result, the clinical consequences of abrupt coronary occlusion can range from an entirely silent episode, to profound ischaemia with major cardiac rhythm disturbances (ventricular fibrillation or asystole), to acute mechanical decompensation with heart failure or cardiogenic shock. The outcome is influenced by the extent to which ischaemia is modified by prompt and effective reperfusion and the presence or absence of significant complications, especially arrhythmias (ventricular tachycardia, ventricular fibrillation, and asystole) and acute heart failure. Prompt and successful reperfusion, e.g. within the first hour of symptom onset, may ‘abort’ or greatly attenuate the eventual extent of MI. Importantly, prompt and effective resuscitation for early ventricular arrhythmias (especially ventricular fibrillation) may have a big impact on survival and freedom from cardiac complications.

The priorities in the management of STEMI are to manage acute life-threatening complications (resuscitation), relieve acute distress, limit the extent of infarction, and treat complications. Beyond the acute phase, attention focuses on secondary prevention and rehabilitation.

Outcome in STEMI

Historically, community-based studies in various populations demonstrated that the case fatality from acute MI, prior to the advent of resuscitation and reperfusion and other modern therapies, was approximately 50% by 1 month after the onset (MONICA studies). About one-half of those deaths were within the first 2 h of symptom onset. However, the risk of death, prior to hospitalization, varies with age: 80% of those above 85 years die before reaching hospital but only 40% of those below 55 years. Before the introduction of cardiac care units in the 1960s, in-patient mortality was in the range of 25 to 30%, and in the 1980s—before the introduction of reperfusion—inpatient mortality averaged about 18%. More recently, the MONICA study from five cities has indicated that the 28-day mortality for patients admitted to hospital with a MI ranged from 13 to 27%, and other studies have provided figures of 10 to 20%.

There is a marked discrepancy between mortality figures from randomized clinical trials and those from observational studies. Publications reporting the outcome for individuals ineligible for inclusion in trials have demonstrated substantially higher death rates than seen in those entered into contemporaneous trials in the same centres. Clinical trials can provide accurate information on what is possible in defined populations (often excluding patients with important comorbidity), and carefully conducted registries can provide an accurate reflection of ‘real-world’ clinical practice. Both approaches are required.

The multinational GRACE registry has demonstrated a decline in in-hospital mortality from 8.4 to 4.6% and new heart failure from 19.5 to 11.0% between 1999 and 2006. The more widespread application of evidence-based pharmacological and reperfusion therapy is closely linked with the improved outcome (with no change in the risk status of patients at presentation), highlighting the importance of ‘closing the gap’ between evidence from guidelines and clinical trials and application in clinical practice. International organizations including the American College of Cardiology and the European Society of Cardiology have stressed this. Special attention needs to be drawn to the more comprehensive provision of acute resuscitation and defibrillation in the community and to the provision of early effective reperfusion.

Prehospital care

The priorities in prehospital care are to establish a prompt diagnosis of suspected acute infarction, to provide effective resuscitation (especially for ventricular fibrillation), and to initiate prehospital thrombolysis if primary PCI is not available. In addition, patients require effective analgesia and the management of acute complications. Where available, telemetry of the ECG can confirm the diagnosis, expedite emergency transfer for primary PCI, and prepare the cardiac team for receiving the patient in the cardiac catheter laboratory. The aim is to provide reperfusion within 90 min of symptom onset. Although this has been demonstrated to be feasible in many centres and various countries, there are major logistic challenges. ‘Door-to-balloon’ times exclude the prehospital phase and, in many instances, ‘door-to-balloon’ times are longer than 90 min, just for this phase of treatment. In rural and other communities with prolonged transfer times to a hospital with PCI facilities, appropriate equipment and training needs to be established to allow prehospital thrombolysis to be administered safely and effectively.

Making a diagnosis of suspected infarction and initiating treatment

A working diagnosis of suspected infarction is based upon typical severe chest discomfort of more than 15 min duration which is unresponsive to glyceryl trinitrate. Characteristically, the pain may radiate to the neck, lower jaw, and arms, and is often accompanied by autonomic features including sweating and pallor. Unless complications are present, physical examination may reveal no significant abnormalities, other than those associated with autonomic disturbance, but signs can include tachycardia or bradycardia, the presence of a third or fourth heart sound, and features of heart failure.

The initial ECG is seldom normal, but may not show the classical features of ST segment elevation or evidence of Q waves (unless prior MI had occurred). Hyperacute T wave changes can be present within minutes of the onset of ischaemia due to coronary occlusion, and this may be followed by the evolution of characteristic ST segment elevation. However, minor or nonspecific ECG abnormalities in conjunction with a characteristic history may signal the early stages of infarction. The working diagnosis relies heavily on the clinical history, and when this suggests MI, repeat ECG within 30 to 60 min (or continuous ST analysis) will frequently reveal the evolution of recognizable ECG changes. It is critically important that infarction that evolves after initial presentation should be detected promptly.

In the prehospital setting, a paramedic or primary care physician may have to rely on the clinical findings to establish the working diagnosis and to initiate immediate treatment. Prompt relief of pain is important, not only for humanitarian reasons, but because pain is associated with sympathetic activation, vasoconstriction, and increased myocardial work. Effective analgesia is best achieved by the titration of intravenous opioids, although some paramedic crews only have access to nonopioid analgesia. Side effects of analgesia include nausea and vomiting, hypotension, and respiratory depression. Antiemetics can be administered concurrently; hypotension and bradycardia will usually respond to atropine and respiratory depression to naloxone. Oxygen should be administered, especially to those who are breathless or those with any features of heart failure or shock (see Chapter 17.1 for information on basic and advanced life support in the management of cardiac arrest or ventricular fibrillation).

The logistics of providing acute care for patients with MI depend upon the locally available facilities. Guidelines recommend an integrated service involving prehospital emergency care (ambulance and paramedic personnel, primary care physicians, etc.) and hospital-based specialists, including cardiologists and emergency care physicians. Within an urban setting, with relatively short transfer times, the shortest delays and the most prompt initiation of reperfusion occurs when the patient seeks an emergency medical ambulance and achieves direct transfer to a hospital with available primary PCI facilities. Studies have shown that once the diagnosis is confirmed (e.g. by telemetry of the ECG) substantial time can be saved by direct transfer of the patient to the catheterization laboratory for PCI rather than transfer via an Emergency Department.

Prehospital thrombolysis

If a primary PCI programme is not available, or if transfer times are sufficiently prolonged that reperfusion may not be achieved within 90 min of patient call, then prehospital thrombolysis is the next best option. The combined analysis of primary PCI vs thrombolysis trials clearly shows superior outcome (deaths, recurrent MI, stroke, etc.) and less bleeding complications (especially intracerebral bleeds) for primary PCI. However, whether primary PCI—with the inherent transfer delays—is superior to very early thrombolysis (administered within the first hour of symptom onset) remains untested in trials of sufficient power.

To date, eight trials have been conducted comparing prehospital with in-hospital administration of thrombolytic therapy. Depending upon the clinical setting, between 30 and 130 min are saved by prehospital thrombolysis (fibrinolytic drug plus aspirin). Overall, for the complete study population of 6607 patients, the 30-day mortality was 10.7% for those receiving in-hospital administration of thrombolysis, and 9.1% for those where it was administered prior to hospital admission. This amounts to a 17% relative reduction in early mortality with a p value of 0.02 (1.6% absolute reduction). Complication rates were similar for community-treated and hospital-initiated thrombolysis, although ventricular fibrillation occurred more frequently with community administration and necessitated well-trained staff and the availability of defibrillators. The greatest benefit is seen when prehospital treatment is applied in remote settings where transport delays are more than 1 h. Several studies have indicated that about 20 patients with chest pain require evaluation for each patient found to be eligible for thrombolytic therapy in the community. Nevertheless, with appropriate training and facilities, prehospital care can provide a gain of approximately 20 lives per 1000 treated amongst eligible patients.

Prehospital cardiac arrest

The management of prehospital cardiac arrest requires special attention. At least as many lives can be saved by prompt resuscitation and defibrillation as by reperfusion. For these reasons, emergency assessment of the patient with suspected infarction necessitates that the clinician or paramedic has access to a defibrillator and the skills to manage cardiac arrest promptly and effectively. The provision of basic or advanced life-support training to paramedic ambulance crews, together with semiautomatic defibrillators, has resulted in a substantial increase in the number of patients surviving out-of-hospital cardiac arrest. Before the institution of such programmes, successful resuscitations were opportunistic and often relied on the availability of a bystander with medical or nursing training. Nationwide figures indicate that resuscitation now achieves survival in 7 to 10% of those patients found with cardiac arrest and in whom the initial rhythm is thought to be ventricular fibrillation. With effective integrated programmes, higher success rates have been achieved: for instance, in the south-eastern region of Scotland, about 14% survive to reach hospital alive, and in Seattle, with a well-established community training and resuscitation programme, the figure exceeds 20%. About one-half of those reaching hospital alive survive to be discharged home.

Emergency Department triage and management

Ideally, in those with typical clinical features and ST elevation on the ECG, a working diagnosis has been made in the prehospital setting (by paramedics with ECG telemetry or by a primary care physician) and early management initiated prior to hospital arrival. Where facilities are available, the patient should be transferred directly to the catheterization laboratory (with the team alerted while the patient is in transit), or if the decision is made for thrombolysis, then this is administered before arrival in hospital.

In-hospital evaluation is required in the remainder, where the symptoms are unclear, the ECG not diagnostic, or where significant comorbidity is present (e.g. bleeding risks). The priority immediately after arrival at the hospital is to identify those patients with ST elevation infarction for prompt reperfusion therapy. Triage is usually performed in the Emergency Department, or, in some institutions, patients with a high probability of infarction gain direct access to a cardiac care assessment area. An integrated strategy involving the paramedic or ambulance system, the emergency physicians, and the cardiologists is required. ‘Fast track’ systems have been developed to minimize in-hospital delay to reperfusion: these are facilitated by specifically trained medical and nursing staff, with the aim of ensuring clinical assessment and ECG within 15 min of arrival and rapid transfer for PCI or the institution of thrombolytic therapy within 30 min. Audit programmes and continuous training are necessary for centres to achieve this 30-min median ‘door-to-needle’ time.

Definite vs suspected infarction

Rapid triage systems allow the identification of patients with clearly defined clinical and ECG features of infarction, i.e. characteristic symptoms of infarction which persist at rest and are not relieved by glyceryl trinitrate, in the presence of at least 1-mm ST segment elevation in two or more contiguous leads, or the development of bundle branch block. Clinical trials have employed ECG criteria of a 1-mm ST elevation for limb leads and 2 mm for chest leads, a definition that improves specificity, but is associated with reduced sensitivity.

Amongst those without diagnostic ECG changes, a working diagnosis of suspected MI or non-ST-elevation ACS can be established. Such patients require repeat clinical and ECG assessments or continuous ST analysis to detect those with evolving infarction and separate them from those with unstable angina or non-ST-elevation infarction.

The rationale for minimizing delays to reperfusion

Experimental and clinical data demonstrate that the duration of ischaemia prior to reperfusion is a critical determinant of the eventual extent of myocardial damage. These data are supported by the improved outcome seen with prehospital vs in-hospital thrombolysis, also observational data from large clinical trials in which survival gain diminishes with each additional hour of ischaemia. The Fibrinolytic Trials Overview suggests about 1.6 additional deaths per hour of delay per 1000 treated, and a more recent meta-analysis suggests that early time delay is especially important.

The relationship between the duration of ischaemia and the extent of infarction is nonlinear: the greatest potential for salvage occurs when reperfusion is initiated within 60 min of the onset of infarction. Under such circumstances, a proportion of patients (5–7%) will have the infarction aborted and will not develop Q waves or significant enzyme elevation despite characteristic ST elevation on the initial ECG. Minimizing the time delay is, therefore, critical in salvaging myocardium. Based on data from individual trials, and from the Fibrinolytic Trials Overview, most benefit occurs within the first 3 h of the onset of infarction, and highly significant benefits still occur at up to 6 h. Statistically significant gains are still present at 12 h, but beyond 12 h the benefits are marginal. However, some patients present with a stuttering pattern and in the presence of persistent or intermittent ST segment elevation and continuing symptoms of ischaemia, reperfusion beyond 12 h may salvage significant ischaemic myocardium.

Differential diagnosis

Critically, thrombolytic therapy or angiography for anticipated primary angioplasty will be of no benefit to those who do not have MI and may convey significant hazards. Such patients suffer the dual hazards of thrombolysis or angiography in the acute phase of their illness and the delay in initiating appropriate treatment. Furthermore, those treated inappropriately with thrombolysis will experience the bleeding hazards of the drug (a net increase in intracerebral haemorrhage of c.0.5%) and the disrupted coagulation system will render other emergency surgery (e.g. for perforated peptic ulceration) more hazardous. Alternative cardiac diagnoses include non-ST-segment-elevation ACS, myocarditis, pericarditis, and aortic dissection. Noncardiac diagnoses include gastrointestinal pain of oesophageal, peptic, or biliary origin; pancreatitis; pulmonary embolism; and respiratory and musculoskeletal disorders.

Aortic dissection presents a particular problem when it extends proximally to the origin of the right coronary artery and produces inferior infarction. CT, MRI, or transoesophageal echocardiography may be required to establish the diagnosis.

Transthoracic echocardiography can be valuable when infarction is suspected, but characteristic ECG features are absent: normal left ventricular function excludes significant infarction, and conversely a regional contraction abnormality helps to confirm the diagnosis of ischaemia or possible infarction. However, in those with prior myocardial damage, the differentiation of new from old mechanical dysfunction is complex and requires specialist assistance.

Cardiac enzymes are helpful when abnormal, but most patients present within 3 h of the onset of symptoms and insufficient time has elapsed to produce a diagnostic release of biomarkers of necrosis (troponins, creatine kinase (CK), or CK-MB). Patients with suspected infarction but normal ECGs require further clinical ECG and biomarker estimations 4 to 6 h after the suspected event.

Among elderly and very elderly patients (>90 years of age), the presentation of infarction is often atypical. They may not experience a typical pattern of symptoms and concomitant multisystem disorders may obscure the diagnosis. MI must be considered in the differential diagnosis of abrupt collapse, haemodynamic disturbance of sudden onset, or severe nonspecific symptoms in elderly patients.

Continuing management in the Cardiac Department

Administration of analgesia, management of rhythm and haemodynamic compromise, and initiation of antithrombotic therapy (heparin, LMWH, aspirin, clopidogrel, GPIIb/IIIa inhibitors, etc.) should have been initiated shortly after the diagnosis of ST-elevation MI is made (in the Emergency Department or Cardiac Assessment Area or prehospital). The first priority is for emergency reperfusion (primary PCI, or if unavailable thrombolysis). Patients may require management of heart failure and arrhythmias and pain relief while in transit to reperfusion therapy, but every effort should be made to avoid delays to reperfusion.

Percutaneous coronary intervention

Primary PCI

Primary angioplasty is defined as PCI without concomitant fibrinolytic therapy. It requires prompt availability of a highly skilled interventional cardiology team with substantial experience of the procedure.

See also: Percutaneous coronary intervention

Randomized clinical trials of primary PCI vs thrombolysis have shown consistent findings: primary PCI has superior outcomes. In experienced centres it is more effective in restoring patency, achieves better ventricular function, and improves important clinical outcomes, with lower rates of death, reinfarction, stroke, major bleeding, and recurrent ischaemia (Table 4). Particular gains are seen in haemodynamically compromised patients and those with cardiogenic shock. In consequence, primary PCI is the preferred therapeutic option in national and international guidelines (SIGN, European Society of Cardiology PCI Guidelines, American College of Cardiology, and American Heart Association).

Table 4  Advantages of primary percutaneous coronary intervention over thrombolysis

 

Clinical indices Event rate (%) Absolute risk (%) Relative risk (%) NNT
Thrombolysis PCI
Short-term mortality (4–6 weeks) 8 5 3 36 33
Long-term mortality (6–18 months) 8 5 3 38 33
Stroke 2 <1 2 64 50
Re-infarction 8 3 5 59 20
Recurrent ischaemia 18 7 11 59  9
Death or nonfatal reinfarction 12 7 5 44 20
Need for CABG 13 8 5 36 20

Data from Hartwell D et al. Clinical Effectiveness and Cost-Effectiveness of Immediate Angioplasty for Acute Myocardial Infarction: Systematic Review and Economic Evaluation. Health Technology Assess 2005; 9(17)

Patients are transferred as an emergency to the cardiac catheterization laboratory and angiography undertaken (radial artery or femoral artery access) to establish coronary anatomy and the nature of the vessel occlusion. A flexible guide wire is then passed across the occluded lesion and balloon angioplasty (usually accompanied by stent implantation) performed (‘primary PCI’), thereby restoring patency to the previously occluded coronary artery.

Adjunctive GPIIb/IIIa inhibitors are indicated for primary PCI. Meta-analysis of 11 trials and 27 115 patients has demonstrated reduced short-term (30 day) and long-term (6–12 months) mortality (absolute relative risk, 1 and 1.8% respectively; relative relative risk 29%), as well as a reduction in 30-day reinfarction (absolute relative risk 0.9%) with the use of abciximab in primary PCI.

  • Primary percutaneous coronary angioplasty (PCI) is the treatment of choice in patients with STEMI.
  • Primary PCI requires a highly experienced interventional team with 24-h availability and an integrated approach to management to achieve reperfusion with the minimum of delay—ideally within 90 min of symptom onset.
  • GP IIb/IIIa inhibitors are indicated for patients receiving primary PCI.
  • Where primary PCI is unavailable, the patient should undergo prompt thrombolytic therapy, provided no contraindications are present.
  • The limit in treating all potentially eligible patients with reperfusion therapy has not been reached. Internationally, at least one-third of all MIs (without a major bleeding risk) receive neither thrombolysis nor primary PCI.
Rescue PCI

Thrombolytic therapy may fail to achieve effective reperfusion in 30% or more of those in whom it is administered for STEMI. Patients experience continuing symptoms of ischaemia and failure of resolution of ST elevation on the ECG (<50% resolution of the ST elevation within 1 h of administration). Rescue PCI is more effective than repeat thrombolysis or conservative treatment in improving outcome (REACT trial). Thus, in centres where primary PCI is not available, logistics need to be established for prompt transfer for rescue percutaneous coronary intervention of patients in whom thrombolysis does not result in signs of reperfusion.

Facilitated PCI

The combination of full-dose or reduced-dose fibrinolysis followed by emergency PCI has been tested in large-scale trials and shown worse outcomes and greater bleeding risks (ASSENT 4 Trial). Hence, planned emergency PCI after thrombolysis is not recommended. although later PCI—after the impact of thrombolysis has resolved—may be of benefit (GRACIA 2 Study). The latter approach should be considered as part of the strategy to deal with residual stenoses after PCI (prior to hospital discharge), rather than as ‘facilitated’ PCI.

Thrombolytic treatment

Thrombolytic treatment refers to the combination of antiplatelet therapy (aspirin and clopidogrel) with fibrinolytic treatment. The fibrinolytic agent, directly or indirectly, converts plasminogen to plasmin and plasmin lyses fibrin in the clot. Cross-linked fibrin is more resistant to fibrinolytic drugs than a newly formed fibrin clot.

The combination of aspirin and a fibrinolytic agent has undergone extensive clinical testing in trials involving more than 100 000 patients. Additional trials have been conducted comparing one fibrinolytic agent with another. For patients presenting within 6 h of symptom onset, and with ST elevation or bundle branch block, approximately 30 deaths are prevented per 1000 patients treated. For those presenting between 7 and 12 h, approximately 20 deaths are prevented per 1000 patients treated, and beyond 12 h the benefits are inconclusive. Thrombolysis is a very cost-effective treatment for acute MI. A sustained benefit on survival has been demonstrated 14 years after thrombolysis.

The ISIS-2 trial demonstrated that the benefits of aspirin treatment were additional to those of fibrinolytic treatment, each achieving about 25 lives saved per 1000 patients treated (for the whole of the study population). Thus, in combination, about 50 lives are saved per 1000 patients treated, but the benefits are larger than this among those presenting within 3 h of infarction with ST segment elevation or bundle branch block.

Overall, the largest absolute benefit is seen in patients at highest risk, although the proportional benefit may be similar for all. High-risk patients include those over 65 years of age, those with a systolic blood pressure below 100 mmHg, and those with anterior infarction or more extensive ischaemia (see primary angioplasty below). The absolute benefit in lives saved per 1000 treated is 11 ± 3 for those under 55 years of age; 18 ± 4 for those between 55 and 64; 27 ± 5 for those 65 to 74; and 10 ± 13 for those over 75. However, for ST depression there is a net hazard of 14 lives lost per 1000 treated, and for those with a normal ECG 7 lives lost per 1000 treated (Fibrinolytic Trials Overview). Thus, evidence supports thrombolysis treatment only for those patients with ST elevation or bundle branch block.

Hazards of thrombolysis

Thrombolytic therapy is associated with a significant excess of haemorrhagic complications, including cerebral haemorrhage. Overall, about 2 nonfatal strokes occur per 1000 patients treated, and of these half are moderately or severely disabling. An additional 2 strokes per 1000 patients are fatal, and the net impact on mortality includes such patients. The risk of stroke increases with age, especially for those over 75 years of age, and for those with systolic hypertension. There is also an excess of noncerebral bleeds of about 7 per 1000 treated. Bleeding occurs at arterial and venous puncture sites, hence blood sampling or cannulation of vessels should be limited to sites where external compression can achieve haemostasis.

Streptokinase and other streptokinase-containing agents can produce hypotension and, rarely, allergic reactions. Routine administration of hydrocortisone is not indicated. When hypotension occurs, it can be managed by interrupting the streptokinase infusion, lying the patient flat or head down, and by the administration of atropine or intravascular volume expansion.

Comparison of thrombolytic agents

The most widely used thrombolytic agents are streptokinase, alteplase (tissue plasminogen activator, tPA), tenecteplase (TNK), and reteplase (rPA). The GISSI International Trial and ISIS-3 international trial both failed to find a difference in outcome between streptokinase and tPA. However, the GUSTO trial (Global Utilization of Streptokinase and Tissue plasminogen active for Occluded coronary arteries) employed an accelerated administration of alteplase over 90 min and intravenous heparin adjusted using the activated partial thromboplastin time, finding 10 fewer deaths per 1000 patients treated with alteplase compared with the streptokinase group. Meta-analysis confirms the superiority of clot-specific agents (e.g. alteplase, tenecteplase) over streptokinase.

The current reference standard for the comparison of fibrinolytic agents is the accelerated infusion regimen of alteplase (tPA), or for simplicity the single-bolus administration of tenecteplase (TNK). Tenecteplase does not require an infusion pump nor refrigeration and hence is particularly suited for prehospital administration, but internationally streptokinase remains the most widely used fibrinolytic agent, principally because it is relatively inexpensive.

Which combinations of treatments are effective?

Combination of fibrinolytic therapy or primary PCI with glycoprotein IIb/IIIa inhibitors

Despite the benefits in STEMI of antiplatelet therapy with aspirin, and with aspirin plus clopidogrel, large-scale randomized trials (ASSENT-3 and GUSTO V) have not shown significant overall benefit from use of GPIIb/IIIa inhibitors in combination with fibrinolysis in this condition. By contrast, there is evidence to support the use of GPIIb/IIIa inhibitors with primary PCI.

Combination of fibrinolytic therapy or primary PCI with clopidogrel

Clopidogrel is indicated for primary and elective PCI after MI in order to reduce thrombotic risks. Guidelines suggest that higher loading doses of clopidogrel can be used to minimize delays to effective antiplatelet therapy (e.g. 600-mg loading dose). A 600-mg loading dose of clopidogrel followed by 150 mg for 1 week is recommended for patients with ACS who undergo PCI (CURRENT-OASIS 7 trial) as double-dose clopidogrel was associated with fewer cardiovascular and stent thrombosis events compared to the standard dose. Prasugrel, as compared to standard-dose clopidogrel (300 mg loading, 75 mg maintenance), was associated with a reduction in nonfatal MI and stent thrombosis in patients with ACI (TRITON-TIMI 38). However, this reduction in ischaemic events was associated with an increase in TIMI major bleeding after CABG surgery and it remains uncertain whether prasugrel is superior to the higher-dose clopidogrel regimen.

In patients treated with thrombolysis, there is clear evidence that the addition of clopidogrel provides further benefit, although with significant increases in bleeding risk. This has been tested in a trial of coronary patency (CLARITY) and in a very large-outcome trial (COMMIT). Thus, there is clear evidence—at least for about 1 month of treatment—for improved outcomes by adding clopidogrel to fibrinolytic therapy plus aspirin.

Combination of fibrinolytic therapy with unfractionated or LMWH or fondaparinux

The combination of LMWH with fibrinolytic therapy for STEMI was tested in a very large double-blind randomized trial (n = 20 506 patients) of enoxaparin vs unfractionated heparin. Death or recurrent MI occurred in 12% of patients with unfractionated heparin and 9.9% with enoxaparin, with the major benefit being reduced reinfarction. There was an increase in major bleeding (2.1% vs 1.4%), but not in intracranial bleeding. Hence enoxaparin has clear advantages, including subcutaneous administration without laboratory monitoring, over unfractionated heparin in ST-elevation myocardial intervention.

Fondaparinux (a factor Xa inhibitor) has been tested against placebo in patients with STEMI in whom the investigator had not planned to give a form of heparin (e.g. streptokinase administration or no fibrinolysis). There was clear advantage for the fondaparinux (OASIS 6 trial), with no increase in bleeding but improved survival and improved reinfarction. Thus, in these groups of patients fondaparinux has clear benefits and no disadvantages. In a second stratum of the same study, fondaparinux was tested against heparin/LMWH (in these patients, the investigator had planned to give a form of heparin). Similar efficacy and lower bleeding was seen with fondaparinux. The only limitations were in patients proceeding to primary or other PCI, where fondaparinux was associated with an increase in the rate of catheter-related thrombotic events. However, it appears that these events may be avoided by supplementary unfractionated heparin (exact amount to be defined). Thus fondaparinux may offer an attractive anticoagulant option, especially in patients without a planned PCI.

Coronary artery bypass surgery (CABG)

In the acute phase of MI, the role of CABG is limited to those patients with acute mechanical complications, such as ventricular septal defect or mitral regurgitation due to papillary muscle rupture. Unless such mechanical complications are present, the hazards of acute bypass surgery are significantly increased compared to delayed revascularization in a stabilized patient. The Danish DANAMI study investigated the role of revascularization in those with ischaemia during the recovery phase of MI. It suggested that, following infarction, individuals with symptomatic or electrocardiographic ischaemia on stress testing experience significant long-term benefit from surgical revascularization.

Further in-hospital management

The period of hospitalization for reperfused and uncomplicated patients following STEMI has progressively shortened, and is now in the range of 3 to 5 days. Thus there are time pressures to initiate lifestyle modifications, drug therapy for secondary prevention, and rehabilitation measures. It is essential to initiate these management steps before hospital discharge to minimize the risk that they are not carried out afterwards.

The main aims of further in-hospital management are the identification and treatment of acute complications of infarction, identification of patients at increased risk for subsequent cardiac events, and initiation of secondary prevention and rehabilitation.

Major complications may be apparent at the time of presentation and haemodynamic, arrhythmic, or ischaemic complications may be evident shortly thereafter. Nevertheless, in the period beyond the first 12 to 24 h, it is appropriate to focus attention on the points listed above.

Identification and treatment of complications of infarction

Failure of reperfusion

Electrocardiographic markers of failed thrombolysis reperfusion are the persistence of ST segment elevation together with clinical and haemodynamic features of continuing ischaemia. Continuous computed ST analysis allows the most accurate definition of ECG changes, but an approximation can be obtained with repeated 12-lead ECGs and measurement of ST segment elevation. In those with successful reperfusion, ST segments decrease to less than 50% of peak elevation within 60 min.

In addition, some patients exhibit reperfusion arrhythmias (ventricular tachycardia, idioventricular rhythm, and—rarely—ventricular fibrillation). Such arrhythmias are more common in the presence of marked ischaemia and prompt reperfusion within 60 to 90 min of occlusion.

Rescue angioplasty is the appropriate management for failed reperfusion, and consists of mechanical recanalization of the occluded vessel with percutaneous intervention, including stent implantation. This strategy achieves an ‘open artery’, and randomized trial data (REACT Trial) shows superior outcome compared with repeat thrombolysis or conservative management.

Cardiogenic shock

In cardiogenic shock, mechanical contractile abnormalities of the left ventricle or acute haemodynamic complications (papillary muscle rupture or ventricular septal defect) lead to reduced blood pressure and impaired tissue perfusion. Clinically, the condition is recognized by a systolic blood pressure of less 90 mmHg together with impaired tissue flow, as reflected by oliguria, impaired cerebral function, and peripheral vasoconstriction. Between 5 and 20% of those patients admitted to hospital with acute MI demonstrate cardiogenic shock, although the frequency has been reduced by thrombolytic therapy and primary PCI. The mortality rate when cardiogenic shock complicates an acute coronary event is in excess of 70%, if acute revascularization is not possible.

Time delay is critically important in the management of cardiogenic shock: mortality rises progressively if more than 2 h have elapsed since its onset. Treatment aims to improve the recovery of acutely ischaemic myocardium (mechanical and surgical revascularization) and to support the circulation with a combination of inotropes, vasodilators, and loop diuretics. Evidence suggests that the most important treatment may be to reopen the infarct-related artery. In addition, the SHOCK trial has demonstrated that aggressive treatment with intra-aortic balloon pumping (IABP) followed by surgical revascularization may also significantly reduce mortality.

In addition to achieving reperfusion, management of the patient with cardiogenic shock after MI may require inotropic support in addition to intra-aortic baloon pumping. Dopamine is commonly used, initially at a low ‘renal dose’ (1–5 µg/kg per min) that activates dopaminergic receptors (but also has an effect on the circulation), but if necessary at higher doses of 5 to 20 µg/kg per min that have positive inotropic and chronotropic effects. In doses above 20 µg/kg per min, there is activation of α-adrenoceptors with undesirable peripheral vasoconstriction and a decline in renal perfusion. Dobutamine acts mainly as a β1-adrenoceptor agonist and is used in the range of 2 to 40 µg/kg per min. Phosphodiesterase inhibitors have both inotropic and vasodilator effects and, although they have produced favourable haemodynamic responses, the studies conducted have not shown an improvement in outcome.

The management of pulmonary oedema consists of opiates (to relieve distress and to reduce vascular resistance), oxygen, vasodilators, and diuretics. If it is severe, patients may require positive end-expiratory ventilation or even full mechanical ventilation. Vasodilators (including nitrates, salbutamol, and sodium nitroprusside) reduce venous and pulmonary arterial pressure, but tachycardia may be a limiting feature and their use is limited in those who are profoundly hypotensive. Loop diuretics are employed in bolus intravenous doses or by infusion.

In all instances, decisions to proceed to mechanical external support of the circulation or mechanical ventilation need to take account of the extent to which the cardiac dysfunction may be reversible, the presence of comorbidity, and the wishes of the patient and their family.

Left ventricular dysfunction and heart failure

Large-scale trials of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been conducted in patients with left ventricular dysfunction and those with clinical and radiological features of heart failure. Clear evidence demonstrates improved short- and long-term outcome with ACE inhibitors/ARBs in patients with heart failure and those with asymptomatic left ventricular dysfunction.

Caution must be exercised with the introduction of ACE inhibitors in patients with intravascular volume depletion, when they can cause hypotension, and in patients with low arterial pressure or renal impairment. ACE inhibition should commence with a very small dose (e.g. 6.25 mg of captopril), with dosages increased progressively in conjunction with clinical monitoring. They can provoke deterioration in renal function in patients with renal artery stenosis and in those with significant pre-existing renal impairment, hence it is important to check serum electrolytes and creatinine during early treatment and follow-up.

Arrhythmias

A wide variety of arrhythmias can be seen in the context of acute MI and its treatment. The most serious, including ventricular fibrillation, ventricular tachycardia, and heart block, can lead to cardiac arrest. However, routine administration of antiarrhythmic agents is not indicated. They are almost invariably negatively inotropic, and they may also be pro-arrhythmic in the context of acute coronary ischaemia. An overview of randomized trials into the use of prophylactic lignocaine (lidocaine) showed that it increased mortality. Ventricular fibrillation should be treated with direct current (DC) cardioversion, and recurrent ventricular arrhythmias require antiarrhythmics (e.g. amiodarone). Importantly, attention should be paid to electrolyte imbalance and the correction of reversible ischaemia or other factors provoking arrhythmias. 

Heart block of any degree can occur after acute MI. It is more common with inferior than anterior infarction because the right coronary artery supplies the atrioventricular node, and also because vagal reflexes are more likely from this area. It is often transient, and does not necessarily imply a large infarct, except when it occurs with anterior infarction, in which case the prognosis is grave. Temporary transvenous pacing is justified when bradycardia compromises the circulation, but is not advocated ‘prophylactically’.

Ventricular septal defect, papillary muscle rupture, and myocardial rupture

Rupture of the interventricular septum occurs in up to 3% of acute infarctions and is responsible for about 5% of deaths due to MI. Rupture in the apical area may complicate anterior infarction and in the basal inferior area may complicate inferior infarction. Clinically, the condition is associated with the development of a new pansystolic murmur and clinical features of a left-to-right shunt with increased pulmonary congestion. The findings are confirmed on echocardiography or cardiac catheterization. Surgery should be undertaken as soon as possible: the outlook for those who are not operated upon is very bleak, with few surviving. However, some patients with small shunts survive the acute phase, in which case they may suffer the later consequences of the shunt.

Papillary muscle rupture occurs as a result of acute ischaemic damage due to obstruction of either the left anterior descending or circumflex coronary arteries. It causes the abrupt onset of severe mitral regurgitation and accounts for 5% of deaths after acute MI. The complication generally occurs within the first week after infarction, and may be recognized as the abrupt onset of acute pulmonary oedema. It is often accompanied by a new systolic murmur, but when the left atrial pressure rises acutely the murmur may be insignificant. The findings are confirmed with echocardiography. The management is acute surgical repair with or without revascularization.

In the patient who deteriorates haemodynamically after MI—with hypotension, pulmonary oedema, or both—it is important to consider the possibility of a ventricular septal defect or acute mitral regurgitation. However, it can be impossible to distinguish between the two on clinical grounds. Both classically produce a new pansystolic murmur, and although differences between the murmurs have been described, these are not robust enough to discriminate with certainty in the individual case. Acute mitral regurgitation is best diagnosed by echocardiography, but transthoracic echocardiography may be unable to detect a ventricular septal defect in a reliable manner. Transoesophageal echocardiography is better, as is the use of a contrast-enhanced technique. If this is unavailable, an alternative approach is to pass a flow-directed pulmonary catheter and take blood samples from the pulmonary artery, right ventricle, and right atrium. A step-up in oxygen tension between the right atrium and the pulmonary artery indicates the presence of a left-to-right shunt and confirms the diagnosis of a ventricular septal defect.

Myocardial rupture may follow acute infarction, usually involving the free wall of the left ventricle. It is responsible for approximately 10% of all deaths in acute MI. Half of the ruptures occur within the first week, and 90% within 2 weeks. The location of rupture is usually within the infarcted area, but may be at the junction with adjacent normal myocardium. In most cases, death is immediate and due to electromechanical dissociation. The patient is unresponsive to resuscitation measures but, rarely—with subacute rupture—patients can be supported until surgical repair is performed. The diagnosis is made on clinical and echocardiographic criteria with assessment for possible cardiac tamponade. In some patients, partial rupture of the free wall can result in the late development of a false aneurysm.

Left ventricular thrombus

A left ventricular thrombus can be detected using echocardiography in up to 40% of patients with acute anterior MI. The thrombus is usually located at the apex in association with a dyskinetic or aneurysmal section of myocardium with impaired contractile function. The thrombus may be large, and is associated with risks of embolization (in 15–20% of cases). Anticoagulation with heparin followed by warfarin is advised in patients with extensive infarction and those in whom apical aneurysms or mural thrombi are detected. Both, thrombolysis and surgical repair, have been successfully conducted. However, there is no clear evidence that either strategy is superior (provided there is no evidence of embolization).

Pericarditis

Pericarditis may complicate an extensive MI, and may be manifest clinically as a pericardial friction rub accompanied by pleuritic chest pain. A small pericardial effusion may be detected using echocardiography. Dressler’s syndrome is a rare late complication and is associated with pericarditis between 2 weeks and 3 months after acute infarction. It has an autoimmune basis, often accompanied by pleural and pericardial effusions. It is managed with salicylates or nonsteroidal anti-inflammatory agents. The frequency of both pericarditis and Dressler’s syndrome is reduced with acute reperfusion.

An integrated approach to the management of STEMI

Pre-hospital management

In a patient with suspected acute infarction, the priorities are to establish whether typical clinical features and ST elevation (or left bundle branch block) are present, and if so to initiate reperfusion with the absolute minimum of delay. Where possible, the diagnosis is confirmed and the transfer of the patient arranged by telemetry of the ECG. The phrase ‘time is muscle’ has been coined for acute STEMI. Acute resuscitation may be required for cardiac arrest or major arrhythmic complications, especially ventricular fibrillation. Additional priorities are to provide analgesia and oxygen. Prehospital thrombolysis may be given by appropriately trained paramedic crews, when transfer times to a PCI hospital are such that more than 90 min will lapse from diagnosis to PCI.

In-hospital management
Initial triage and management

Initial assessment involves the identification of those with clear-cut evidence of STEMI (based on clinical and diagnostic ECG criteria). Such patients require immediate triage to reperfusion therapy (primary PCI, or if unavailable thrombolysis with a fibrinolytic agent plus an antiplatelet agents). In transit to primary PCI or while preparing pharmacological reperfusion, patients may require further analgesia and management of arrhythmic and haemodynamic complications, including heart failure.

Patients in whom the diagnosis of MI is suspected, but the ECG criteria are not diagnostic, should be managed in an intensive care setting (in the Emergency Department or Cardiac Care Unit with repeat ECG evaluation at 30-min intervals (or ST segment analysis). Cardiac biomarkers (troponins) may be elevated at presentation, if sufficient time has lapsed from onset of ischaemia (4–6 h), or they may become elevated following arrival (repeat measurement at 8–12 h). Such patients may be divided into those with evidence of non-STEMI (ECG and troponin elevation) and those with unstable angina (T wave inversion, ST segment depression, or transient ST segment elevation, without elevated cardiac troponins). Among those with minor or nonspecific ECG changes and no enzyme elevation, re-evaluation should take place for alternative diagnoses, and stress testing performed subsequently to detect underlying coronary artery disease. A key component of initial evaluation of those without ST elevation or left bundle branch block involves risk stratification (see above). Echocardiography may be valuable to detect signs of ischaemia/infarction or to demonstrate normal contractile function in those with an alternative diagnosis.

Later in-hospital management

During this phase the management of complications, initiation of secondary prevention, and early cardiac rehabilitation should take place. In high-risk patients (those with recurrent acute ischaemia or those with failure of ST segment resolution and continuing pain), emergency PCI or surgical revascularization can be performed in appropriately equipped centres.

Regular clinical and electrocardiographic assessments are required during the recovery phase to detect acute mechanical and arrhythmic complications, and to identify impaired contractile function in patients who will benefit from ACE inhibitor/ARB treatment. This treatment is indicated in those with overt heart failure in the acute phase and also indicated for secondary prevention in patients with established vascular disease (HOPE trial). Thus, ACE inhibitors or ARBs are indicated for those with vascular disease, irrespective of whether there is evidence of overt heart failure or impaired left ventricular function in acute phase. Patients also require lipid-lowering therapy: robust evidence demonstrates that all patients with MI or non-ST-elevation ACS will benefit (MRC/BHF Heart Protection Study). There is evidence to support management of diabetes with glucose and insulin during the in-hospital and early posthospital phase.

All patients will benefit from smoking cessation, the management of hypertension (systolic pressure to less than 140 mmHg), and dietary and lifestyle modification (including exercise) (SIGN Guideline 2007). After STEMI, patients benefit from participation in a rehabilitation programme, with improved quality of life, symptom relief, and return to an active lifestyle or occupation.

Secondary prevention measures in those with STEMI or non-STEMI ACS

Following an ACS, patients require dietary and lifestyle advice including the support necessary to discontinue smoking (including nicotine replacement therapy) (SIGN Guideline 2007). Lipids should be measured within the first 24 h of admission, with evidence supporting the use of lipid-lowering therapy. Individuals with documented coronary artery disease, and especially those with left ventricular contractile dysfunction or heart failure, have reduced long-term risks of death and MI if maintained on an ACE inhibitor or ARB. In addition, patients may require antianginal therapy if revasculariztion is incomplete and all should receive long-term, low-dose aspirin. Clopidogrel should be given for at least 1 month in STEMI (the limits of the evidence) and a year for non-ST-elevation ACS (or as determined by the type of stents implanted).

Nonpharmacological interventions

Evidence supports the following nonpharmacological interventions in secondary prevention: cessation of smoking (including the avoidance of passive smoking); dietary modification; exercise; rehabilitation; and management of obesity.

Pharmacological interventions

Trial evidence supports therapeutic interventions to modify the following conditions: hyperlipidaemia; left ventricular dysfunction and heart failure; diabetes mellitus; and hypertension.

Reduction of cardiovascular risk

Evidence (summarized in Tables 5 and 6) supports the following therapies to reduce the risk of subsequent cardiovascular events: antiplatelet therapy (aspirin in a dose of 75 mg/day, clopidogrel 75 mg day); β-blockers in those without contraindications; lipid-lowering with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins); ACE inhibitor or ARB especially in those with left ventricular dysfunction and heart failure, and benefit is also possible in other patients with vascular disease (Table 6).

Table 5  Estimated benefits of long-term secondary prophylactic treatment/intervention after MI

 

Treatment/intervention   Problems prevented per 1000 patient-years of treatment
All post-MI patients (unless specific contraindications exist)
Aspirin (meta-analysis) 7 vascular deaths
9 nonfatal reinfarctions
3 nonfatal strokes
Oral β-blocker 21 deaths
21 re-infarctions
Statin (hyperlipidaemia, post-MI) 7 deaths
11 re-vascularizations
12 nonfatal MIs
3 strokes
4 congestive heart failure
13 angina
Statin (average cholesterol, post-MI, CARE) 2 deaths
9 re-vascularizations
4 nonfatal MIs
2 strokes
4 unstable angina
Smoking cessation (observational studies) 15 deaths
46 re-infarctions
Post-MI patients with LVD or heart failure (additional treatment unless specific contraindications exist)
ACE inhibitor (left ventricular ejection fraction ≤ 40%) 12 deaths
9 MIs
10 congestive heart failure (requiring hospital admission)
ACE inhibitor (heart failure) 45 deaths
26 congestive heart failure (severe)

LVD, left ventricular dysfunction.

Sivers F Evidence-based strategies for secondary prevention of coronary heart disease, 2nd edn. A&M Publishing, Guildford, Surrey. - now owned by Wiley.

Table 6  Comparison of the treatment benefits from interventions to prevent cardiovascular events

 

Problems/therapy Events prevented NNT*
Severe hypertension (DBP 115–129 mmHg) Death or stroke or MI 3
Coronary artery bypass surgery for left main stem stenosis Death 6
Aspirin for transient ischaemic attack Death or stroke 6
Statin for hyperlipidaemia, post-MI/angina (4S) Death or nonfatal MI or CABG/PTCA or cerebrovascular event 6
Warfarin for atrial fibrillation Stroke 7
ACE inhibitor for LV dysfunction post-MI CV death or hospitalization for CHF 10
Statin for average cholesterol post-MI (CARE trial) or stroke Death or nonfatal MI or CABG/PTCA 11
Aspirin post-MI CV death or stroke or MI 12
Statin for average/elevated cholesterol, post-MI/unstable angina (LIPID trial) Death or nonfatal MI or CABG/PTCA or stroke 15
Beta-blocker post-MI Death 20
ACE inhibitor for LV dysfunction CV death or hospitalization for CHF 21
ACE inhibitor for vascular disease (HOPE) Deaths 50
  MI 42
  Stroke 67
Statin for hypercholesterolaemia in primary prevention Death or nonfatal MI or CABG/PTCA or stroke 26
Mild hypertension (DBP 90–109 mmHg) Death or stroke or MI 141

ACE, angiotensin converting enzyme; CABG, coronary artery bypass grafting; CARE, Cholesterol and Recurrent Events Trial; CHF, congestive heart failure; CV, cardiovascular; DBP, diastolic blood pressure; HOPE, Heart Outcomes Prevention Evaluation Trial; LIPID, Long-term Intervention with Pravastatin in Ischaemic Disease Trial; LV, left ventricle; MI, mycocardial infarction; NNT, estimated number of patients that need to be treated for 5 years to prevent one event; PTCA, percutaneous transluminal coronary angioplasty.

Sivers F Evidence-based strategies for secondary prevention of coronary heart disease, 2nd edn. A&M Publishing, Guildford, Surrey.

Anticoagulants

These are indicated in those with high risks of embolism due to left ventricular or atrial thrombus. There is evidence to support the use of anticoagulants in post-MI patients but no definitive evidence that such treatment is superior to aspirin therapy. Current trials are evaluating the role or oral antithrombins and oral anti-Xa inhibitors following ACS.

Hormone replacement therapy (HRT)

HRT is not indicated for risk reduction after ACS. When used to relieve menopausal symptoms, HRT is associated with a small, but increased, risk of thrombotic events.

Calcium channel blockers

An overview of data from 19 000 patients, based on all randomized trials of acute infarction and unstable angina, suggests that the available calcium channel blockers are unlikely to reduce the rate of subsequent infarct development, infarct size, or subsequent infarction. They may, however, have indications for the relief of angina (especially heart-rate-lowering calcium antagonists).

Antiarrhythmic agents

A review of the effects of antiarrhythmic agents (with the exception of β-blockers) does not demonstrate a beneficial impact on mortality. Many have significant proarrhythmic complications and negative inotropic effects.

Read more:

Atherosclerosis biology and pathology

Further reading

 
 
Sivers F (1999). Evidence-based strategies for secondary prevention of coronary heart disease, 2nd edition. A&M Publishing, Guildford.
 
Stone GW, et al. (2006). for the ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med, 355, 2203–16.
 
Tunstall-Pedoe H, et al. (1996). Sex differences in myocardial infarction and coronary deaths in the Scottish MONICA population of Glasgow 1985–1991. Circulation, 93, 1981–92.
 
Van de Werf F, et al. (2005). Access to catheterization facilities in patients admitted with acute coronary syndrome: multinational registry study. BMJ, 330, 441.
 
Wallentin L, et al. (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 361, 1045–57.
 
Wiviott SD, et al. (2007). Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med, 357, 2001–15. 
 
Yusuf S, et al. (1985). B-blockade during and after mycocardial infarction: an overview of the randomized trials. Progr Cardiovasc Dis, 27, 335–71.
 
Yusuf S, et al. (1998). Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or mycocardial infarction without initial ST elevation. Lancet, 352, 507–14.
 
Yusuf S, et al. (2001). Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med, 345, 494–502.
 
Yusuf S, et al. (2004). Effect of potentially modifiable risk factors associated with mycocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet, 364, 937–52.
 
Yusuf S, et al. (2006). Effects of Fondaparinux, a factor Xa inhibitor, on mortality and reinfarction in patients with acute mycocardial infarction presenting with ST-segment elevation. Organization to Assess Strategies for Ischemic Syndromes (OASIS)-6 Investigators. JAMA, 295, 1519–30.
 
Yusuf S, et al. (2006). Efficacy and safety of fondaparinux compared to enoxaparin in 20,078 patients with acute coronary syndromes without ST segment elevation. The OASIS (Organization to Assess Strategies in Acute Ischemic Syndromes)-5 Investigators. N Engl J Med, 354, 1464–76.