ACUTE VIOLATION OF CIRCULATORY ACTIVITY

ACUTE VIOLATION OF CIRCULATORY ACTIVITY

 

 

Diagnosis and treatment

 

Introduction

 Acute circulatory insufficiency

 Anatomy and physiology

Life is provided through a variety of mechanisms, however all of

them depend on proper circulation. Circulation itself consists of 2

parts: work of heart (pump of the body) and vessels, through which

blood is pumped to the most remote organs and tissues. During every

systolic contraction heart pumps 70_80 ml of blood (so called stroke

volume). So if the heart rate is 70 beats per minute, heart pumps

nearly 5 liters of blood, what makes more than 7 tones per day.

From the left ventricle blood gets to the arterial system of the

systemic circuit. Arteries contain 15% of the whole circulating blood

volume; they carry blood from the heart to their distal departments –

arterioles (vessels of resistance). Arterioles themselves are defining

blood distribution: in condition of constriction (spasm) they make

blood supply of the capillaries impossible (ischemia appears). On the

contrary, in condition of dilatation they provide maximal

oxygenation. When arterioles are blocked due to the spasm blood is

flowing through the arterio_venous anastomoses directly to the

venous system.

Distribution of blood in the vascular bed (% of CBV).

a. heart cavity 3%

b. arteries 15%

c. capillaries 12%

d. venous system 70%

Among the natural vasoconstrictors (agents, which cause

constriction of the blood vessel) are epinephrine, norepinephrine,

serotonin, angiotensin II. Stress enhances the secretion of

cathecholamines, their blood concentration increases and arterioles

constrict. Spasm of the arterioles is the basis of blood flow

centralization: peripheral flow is disregarded in order to provide brain

with the oxygenated blood as long as possible. To the group of

vasodilatators (agents, which provide dilatation of the vessels) belong

“acid” metabolites (lactate, pyruvate, adenylic acid, inosinic acid),

_

bradykinin, acetylcholine, different medicines (neuroleptics, β_

adrenergic antagonists, peripheral vasodilatators, ganglionic blocking

agents, etc.), some exogenous poisons. All of them cause blood flow

decentralization: opening of arterioles and distribution of the blood

from central vessels to the capillary bed.

Capillaries are the interweaving network of the smallest body

vessels with the general length of 90_100 thousands kilometers.

However simultaneously work only 20_25% of them. They provide

metabolic exchange bringing oxygen and nutrients to the tissues and

take back wastes of metabolism. Periodically, every 30_40 seconds

one of them get closed and others open (vasomotion effect).

Capillaries contain 12% of the whole circulating blood volume, but

different pathological conditions can increase this amount even 3

and more times.

“Used” blood from the capillaries flows to the venous system.

Veins are the blood reservoir, which contains 70% of the total

circulating blood volume. Unlike arteries they are capable of volume

control and thus they influence the amount of blood, which returns

to the heart.

The most important haemodynamic index of venous system is

central venous pressure. CVP represents the pressure which blood

causes to the walls of cava veins and right atrium. This parameter is

an integral index of circulating blood volume, systemic vascular

resistance and pump function of the heart. It can be measured with a

special device called “phlebotonometer” (pic. 4.9) or with a usual

infusion set and a ruler. Normally CVP measured from the sternum

point is 0_14 cm H2O and from midaxillary line _ 8_15 cm H2O.

Fig. Angiografia of patient with MI

Central venous pressure decreases (sometimes even to negative)

in case of:

– blood loss

– excessive water loss (dehydration)

– distributive shock (decrease of peripheral resistance due to

venous and arterial dilatation)

In those conditions decreases volume of blood returning to the

heart and thus suffers cardiac output. In case of negative CVP cardiac

arrest is highly probable.

_

Central venous pressure increases in case of:

– heart failure (insufficiency of left or right ventricle)

– hypervolemia (excessive blood infusion, improper infusion

therapy)

– obstructions to blood flow (pulmonary embolism, cardiac

tamponade, etc.)

When CVP over 15_16 cm H2O is combined with left ventricle

insufficiency the risk of pulmonary edema is very high.

Blood pressure is an integral index of arterial part of systemic

haemodynamics. Talking about blood pressure we may refer to

systolic, diastolic, pulse and mean arterial pressure. Systolic (Psyst)

and diastolic (P diast) pressures are measured with the manometer

(method with the usage of phonendoscope was invented by M.

Korotkoff). Pulse pressure (PP) is a difference between systolic and

diastolic blood pressure.

Mean arterial pressure (MAP) is calculated according to the

formula:

MAP= P dias + 1/3 PP mm Hg

MAP defines the level of pressure necessary for the metabolic

exchange in the tissues. Its measurement allows the evaluation of

tissue perfusion level.

Blood pressure depends on different factors, but the most

important are cardiac output and vascular resistance (mostly

arterioles). This dependence is direct, thus you can increase blood

pressure using:

– infusion of vasoconstrictors – solutions of epinephrine,

phenylephrine (mesaton), etc. (they will increase the vascular

resistance);

– infusion of hydroxyethyl starch solutions or saline (they will

increase circulating blood volume)

– infusion of cardiac glycosides or other medicine which stimulate

Myocardium

     Fig. Chest pain

General volume of blood in the body of a healthy adult is nearly

7% from the body weight: 70 ml per kilogram for male and 65 ml per

kilogram of body weight for female. Of course circulating blood

volume is lower, because part of blood is out of metabolic processes

_

as a reserve. CBV can be measured with the infusion of coloring

substance to the blood flow (Evans blue, polyglucin) and later

evaluation of its dissolution degree.

Therefore measurement of CVP, BP, cardiac output and

circulating blood volume allow to evaluate condition of circulation

system of the patients and to provide adequate correction.

4.2. Acute heart failure; shock and collapse

Acute cardiovascular failure is a state of cardiac and vascular

inability to provide adequate supply of tissue metabolic needs with

oxygenated blood and nutrients. This, earlier or later, causes cellular

death.

The reasons of the failure vary greatly: mechanic injuries, blood

loss, burns, dehydration, exogenous and endogenous intoxications,

immediate hypersensitivity reaction, ischemic heart disease, neural

and humoral regulation disorders of vascular tone.

Acute cardiac failure is a disorder of heart pumping action. It

develops due to primary heart problems or secondary, under the

influence of extracardiac factors such as infection or intoxication.

There are two types of heart failure: left_sided and right_sided.

Left_sided heart failure is an inability of left ventricle to pump

blood from the pulmonary circuit to the systemic circuit. The most

common reasons of it are myocardial infarction, mitral insufficiency,

left AV valve stenosis, aortic valve stenosis, aortal insufficiency,

hypertonic disease, coronary sclerosis, acute pneumonia.

Coronary circulation is possible only during the diastole and in

those conditions every violation of coronary passability decreases

cardiac output. This way during the systole part of the blood is not

injected into aorta, but stays in the left ventricle. Diastolic pressure in

the left ventricle increases and blood is literally forced to stagnate in

the left atrium. At the same time right ventricle functions normally

and continues to pump usual amounts of blood to the pulmonary circuit.

Thus hydrostatic pressure in the vessels of pulmonary circulation

increases, fluid part of the blood moves first to the lung tissue and

then, through alveolar_capillary membrane, to the alveolar lumen.

Clinically pulmonary edema begins with dyspnea (during

physical activity or rest). Later attacks of dyspnea are connected

with persistent cough with white or pink blood_tinged phlegm. During

the attack patient tries to sit as in this position breathing is easier.

This condition is called “heart asthma”. When hydrostatic pressure

is over 150_200 mm Hg, fluid part of blood moves to the alveolar

lumen causing development of pulmonary edema.

Pulmonary edema is divided into interstitial and alveolar edema.

Interstitial edema is a condition during which serous part of

stagnated in the pulmonary circuit blood infiltrates the lung tissue,

including peribronchial and perivascular spaces.

During alveolar edema not only the plasma, but also blood

components (red and white blood cells, platelets) get out from the

vessels. During the respiratory act blood mixes with the air creating

large amount of “foam”, which violates gas exchange. This way, in

addition to circulatory hypoxia, hypoxic hypoxia appears.

Condition of the patient gets worth quickly. Sitting position is

optimal, but not as helping as previously. Respiratory rate is nearly

30_35 breathes per minute, but attacks of breathlessness are constant.

Skin is pale with acrocyanosis. Hypoxia of central nervous system

usually causes psychomotor agitation. Respiratory acts are noisy;

during cough pink blood_tinged phlegm is released. Auscultation

allows you to hear different wet rales, sometimes it’s even possible to

hear them standing aside the patient without phonendoscope.

Pulmonary edema can be also divided according to the blood

pressure level: the one with elevated pressure is caused by a

hypertonic disease, aorta valve insufficiency or disorders of cerebral

perfusion; another one is caused by total myocardial infarction, acute

inflammation of myocardial muscle, terminal valve defects, severe

pneumonia and is characterized with normal or low blood pressure.

Immediate aid

– make sure patient is sitting with his legs down (orthopnea)

– provide oxygenation through nasal catheter (before placing

oil it with glycerin, insert it to the depth of 10_12 cm – distance from

the wing of the nose to auricle) or face mask. Do not use Vaseline,

because it can burn in atmosphere with high concentration of oxygen.

However if catheter is not deep enough patient will suffer from

an unpleasant “burning” feeling, because oxygen flow will dry mucosa

layer of the nasal cavity; also in this situation concentration of oxygen

will be lower than expected.

– put venous tourniquets on the limbs in order to reduce amount

of blood returning to heart: venous bed of limbs can reserve up to 1,7

liters of blood;

– constantly control heart and kidney activity (ECG, SaO2 , and

blood pressure are checked automatically trough the monitor; to

control diuresis you should insert Foley catheter;

– catheterize central vein, because amount of infusions should

be based on central venous pressure;

– use medical “defoamers” if they are available (ethyl alcohol or

antiphomsylan solution) combined with oxygen inhalation;

– medical treatment: 1% morphine solution (decreases

intravascular pressure of pulmonary circuit, inhibits respiration

center in medulla oblongata preventing dyspnea progress, sedates

patient);

– solutions of diuretics are used to decrease the circulating blood

volume ( 6_12 ml of 1% furosemid solution, solution of ethacrynic

acid), however be careful with them in case of low blood pressure;

diuretic effect will last up to 3 hours after i/v infusion, the expected

diuresis is 2_3 liters;

– if blood pressure allows you can try to use nitroglycerin to

reduce intravascular pressure of pulmonary circuit (1 or 2 tablets

with 10 minutes interval);

– cardiac glycosides for improvement of the heart action (0,025%

digoxin solution, 0,05% strophanthin solution, 0,06% corglicon solution);

– in case of high pressure (over 150 mm Hg) use ganglionic

blocking agents (1 ml of 5% pentamin solution diluted in 150 ml of

saline, give i/v slowly; diluted with saline 250 mg of trimethaphan

solution), because they reduce pressure in pulmonary circuit and lower

the amount of blood getting to right half of the heart, however be

careful with the dosage and monitor blood pressure level carefully;

– never use osmotic diuretics in case of pulmonary edema – they

will increase blood volume and thus heart load!!!;

– when everything listed above failed and patient is worsening

with every second you should intubate him and start artificial

ventilation with positive end expiratory pressure (begin with 4_6 cm

H2O).

Right_sided heart failure is an inability of right ventricle to

pump blood from systemic circuit to the pulmonary circuit due to its

weakness or an obstruction to the blood flow.

It occurs in case of pulmonary embolism, right ventricle

infarction, excessive infusion therapy (especially including citrated

blood) in patients with heart insufficiency, lung diseases (bronchial

asthma, emphysema, pneumosclerosis) which cause increase of right

ventricular load.

Patients have acrocyanosis, tachycardia, dyspnea, pronounced

neck veins, ankle swelling, enlarged liver, ascytis. Central venous

pressure is highly increased (up to 20_25 cm H2O), however

pulmonary edema does not appear.

Intensive treatment is mostly pathogenetic:

– limit the infusions (give only life_necessary solutions, check

the water balance of the patient and reduce drinking water if

necessary);

– in case of citrated blood transfusions use 5_10 ml of 10% calcium

gluconate solution per every 500 ml of blood to prevent

hypocalcaemia;

– in case of bronchial spasm use bronchial spasmolytics;

– to remove excessive fluid from the body use diuretics

(furosemide solution for example);

– metabolic acidosis is corrected with 4% solution of sodium

bicarbonate (i/v slowly with acid_base state control);

– in case of pulmonary embolism anticoagulants are used –

fraxiparine 0,6 mg subcutaneously; heparin solution – 5000 IU every

4 hours; fibrinolytic drugs (streptokinase, fibrinolysin, urokinase, etc.)

Shock is a pathological state which can be described as a tissue

hypoxia caused by hypoperfusion. Pathogenetic basis of shock

depends on its reason (trauma, toxins, thermal injury) and at the

same time on reactivity of the organism (level of defense mechanisms

mobilization).

Stimulation of sympathetic nervous system – production of

catecholamines and other vasoactive substances by hypothalamus

and adrenal glands is the universal response of the body to the stress.

Those mediators interact with the receptors of peripheral vessels

causing their constriction and at the same time they dilatate the

vascular bed of life_important organs. This is so called “centralization

of the flow”: rational decrease of blood flow in less important tissues

(skin, organs of abdominal cavity, kidneys) in case of aggressive

external influence for the protection of life itself (brain, heart, lungs).

However influence of shock agents (pain, hypovolemia, destroyed

cells, toxic metabolites), extended microcirculation violations (vascular

spasm, microthrombosis and sludge) and caused by them tissue ischemia

lead to hypoxic affection and cellular death of the internal organs. Further

it can bring multiple organ dysfunction syndrome.

Collapse is a vascular failure. It occurs when body is not able to

provide blood flow according to the new level of its needs (either

because reaction is not fast enough or because sympathetic activation

fails).Vascular bed volume and circulating blood volume are

disproportional: too much blood gets to the microcirculation

vascular reserve and the amount, which returns to the heart is not

enough for the systemic needs (so called “decentralization” of the

blood flow). Cardiac output and blood pressure decrease, that causes

hypoperfusion of the central nervous system and thus

unconsciousness and life_threatening complications.

Collapse definition is a bit nominal, because if such reaction

extends in time the state of shock develops. Shock itself can equally

run as a vascular failure or as a sudden clinical death.

 

New acute coronary syndromes terminology and implications for diagnosis

The terminology used to describe ACS continues to evolve, with the emergence of the term “non-ST-segment-elevation acute coronary syndrome” (NSTEACS). This reflects a shift away from establishing a definitive diagnosis at presentation, and towards a more clinically appropriate strategy of forming a rapid working diagnosis with its implications for initial clinical decision making.

At presentation, the initial diagnostic nomenclature focuses on risk stratification to direct treatment strategies. Establishing a definitive diagnosis often requires time, particularly for evidence of myocardial necrosis to emerge, and has important implications pertaining to prognosis, diagnostic coding, and social issues such as insurance and licensure. 

 

1 Defining acute coronary syndromes over time: presentation to final diagnosis

 

ECG = electrocardiogram.

 

Initial working diagnosis

 

The initial working diagnosis is based on the clinical presentation and the initial electrocardiogram (ECG) findings and, in particular, the presence or absence of ST-segment elevation. As the vast majority of patients who present with initial ST-segment elevation develop biochemical evidence of myonecrosis, the term “ST-segment-elevation myocardial infarction” (STEMI) is often used from the outset in these patients.

ACS without ST-segment elevation on the presenting ECG represent a broad spectrum of risk, but are collectively referred to as NSTEACS. This grouping is useful because emergency reperfusion therapy is not indicated (unless ST-segment elevation develops later), and further investigation is required to classify the patient’s risk and determine the most suitable treatment (see sections on Investigations and Management of patients with STEMI for further details).

 

Final diagnosis

 

The final diagnostic attribution (ie, clinical label) has important and persisting implications for the patient, both prognostically and socially. Current international criteria for the diagnosis of myocardial infarction have a strong emphasis on biomarkers, specifically troponin, given its high sensitivity and, in particular, specificity for myonecrosis.5 The diagnostic criteria for acute, evolving or recent myocardial infarction are defined as:

 

Typical rise in the serum level of troponin or a more rapid rise in the serum level of the MB isoenzyme of creatine kinase (CK-MB) with at least one of the following:

 

Ischaemic symptoms;

Development of pathological Q waves on the ECG;

ECG changes indicative of ischaemia (ST-segment elevation or depression); and

Coronary artery intervention (eg, coronary angioplasty or coronary bypass surgery);

or

Pathological findings of an acute myocardial infarction.

 

This definition requires a temporal appreciation of the cardiac markers, and therefore differentiation between non-ST-segment-elevation myocardial infarction and unstable angina (without evidence of myonecrosis) must be delayed.

Acute management of chest pain

Getting to hospital

 

Chest discomfort at rest or for a prolonged period (more than 10 minutes, not relieved by sublingual nitrates), recurrent chest discomfort, or discomfort associated with syncope or acute heart failure are considered medical emergencies. Other presentations of ACS may include back, neck, arm or epigastric pain, chest tightness, dyspnoea, diaphoresis, nausea and vomiting. Very atypical pain, including sharp and pleuritic pain, is more common in women, people with diabetes and older people.3,7,8

People experiencing such symptoms should seek help promptly and activate emergency medical services to enable transport to the nearest appropriate health care facility for urgent assessment (grade D recommendation). Ideally, transport should be by ambulance. However, where ambulance response times are long, alternatives may need to be considered. Patients should be strongly discouraged from driving themselves because of the risk to other road users.

The most important initial requirement is access to a defibrillator to avoid early cardiac death from reversible arrhythmias. All Australian ambulances now carry defibrillators, and there is promise in further exploring public access defibrillation opportunities. In the case of cardiac arrest occurring in a setting where a defibrillator is not immediately available, cardiopulmonary resuscitation should be commenced immediately.

 

Actions in transit

Aspirin (300 mg) should be given unless already taken or contraindicated (grade A recommendation), and should preferably be given early (eg, by emergency or ambulance personnel) (grade D recommendation). Oxygen should also be given (grade D recommendation).

Glyceryl trinitrate and intravenous morphine should be given as required (grade D recommendation).

Where appropriate, a 12-lead ECG should be taken en route and transmitted to a medical facility (grade B recommendation).

Receiving medical facilities should be given warning of incoming patients in whom there is a high suspicion of ACS, particularly STEMI, or those whose condition is unstable (grade B recommendation).

Where formal protocols are in place, prehospital treatment should be given, including fibrinolysis in appropriate cases (grade A recommendation). See section on management of patients with STEMI for further discussion of prehospital fibrinolysis.

 

On arrival

All patients presenting with suspected ACS should be subject to ongoing surveillance and have an ECG completed within 5 minutes of arrival at the medical facility (grade A recommendation). The ECG should be assessed promptly by an appropriately qualified person (grade D recommendation).

Oxygen and pain control should be given as required (grade D recommendation).

 

People experiencing symptoms of ACS should seek help promptly and activate emergency medical services.

The most important initial requirement is access to a defibrillator to avoid early cardiac death from reversible arrhythmias.

Aspirin should be given early (eg, by emergency or ambulance personnel) unless already taken or contraindicated.

Oxygen should be given, as well as glyceryl trinitrate and intravenous morphine as required.

As a minimum, receiving medical facilities should be given warning of incoming patients in whom there is a high suspicion of ACS, particularly STEMI, or whose condition is unstable.

Where appropriate, a 12-lead ECG should be taken en route and transmitted to a medical facility.

Where formal protocols are in place, prehospital treatment (including fibrinolysis in appropriate cases) should be facilitated.

 

Patients presenting with a suspected ACS should undergo immediate electrocardiography. Further investigations may be necessary, but should not delay treatment.

While other serious diagnoses can present similarly to ACS (eg, pulmonary embolism, aortic dissection, pericarditis), once these have been excluded and ACS is considered the most likely diagnosis further delay in treatment is unnecessary and inappropriate.

Investigations and invasive vascular access techniques should not delay reperfusion therapy if indicated on the basis of ST-segment elevation on the ECG.

Patients whose condition is unstable should have early consultation with a cardiologist.

Cardiac biomarkers are becoming increasingly important to the diagnosis of myocardial infarction. See Box 2 for recommendations and rationale regarding their measurement.

 

Electrocardiography

Electrocardiography is necessary to detect ischaemic changes or arrhythmias. It should be noted that the initial ECG has a low sensitivity for ACS, and a normal ECG does not rule out ACS. However, the ECG is the sole test required to select patients for emergency reperfusion (fibrinolytic therapy or direct PCI). Patients with STEMI who present within 12 hours of the onset of ischaemic symptoms should have a reperfusion strategy implemented promptly (grade A recommendation) — see the section on management of patients with STEMI for recommendations.

 

Accurate ECG interpretation in a patient with chest pain is critical. Basically, there can be three types of problems – ischemia is a relative lack of blood supply (not yet an infarct), injury is acute damage occurring right now, and finally, infarct is an area of dead myocardium. It is important to realize that certain leads represent certain areas of the left ventricle; by noting which leads are involved, you can localize the process. The prognosis often varies depending on which area of the left ventricle is involved (i.e. anterior wall myocardial infarct generally has a worse prognosis than an inferior wall infarct).

 

Video: MI site and coronary thrombosis

 

 

Figure: Ischemia: Note symmetric T wave inversions in leads I, V2-V5.

 

 

Figure: Injury: 

Note ST

 segment elevation in leads V2-V3 (anteroseptal/anterior wall).

 

 

Figure 36: Infarct: Note Q waves in leads II, III, and aVF (inferior wall).

 

 

For the posterior wall, remember that vectors representing depolarization of the anterior and posterior portion of the left ventricle are in opposite directions. So, a posterior process shows up as opposite of an anterior process in V1. Instead of a Q wave and ST elevation, you get an R wave and ST depression in V1.

 

Figure: Posterior wall infarct. Notice tall R wave in V1. Posterior wall infarcts are often associated with inferior wall infarcts (Q waves in II, III and aVF).

 

Two other caveats: One is that normally the R wave gets larger as you go to V1 to V6. If there is no R wave “progression” from V1 to V6 this can also mean infarct. The second caveat is that, with a left bundle branch block, you cannot evaluate “infarct” on that ECG. In a patient with chest pain and left bundle branch block, you must rely on cardiac enzymes (blood tests) and the history.

 

Blood tests

 

Measurements should include:

Serum troponin I or T levels (or CK-MB if troponin is not available).

Full blood count.

Serum creatinine and electrolyte levels, particularly potassium concentration, as hypokalaemia is associated with an increased risk of arrhythmias, especially ventricular fibrillation10 (grade B recommendation). Knowledge of kidney function (expressed as estimated glomerular filtration rate) is strongly encouraged (grade B recommendation) given the association between renal impairment and adverse outcomes (evidence level III).11

Serum creatine kinase (CK) level.

Serum lipid levels (fasting levels of total cholesterol, low-density-lipoprotein cholesterol, high-density-lipoprotein cholesterol and triglycerides) within 24 hours.

Blood glucose level.

Chest x-ray

A chest x-ray is useful for assessing cardiac size, evidence of heart failure and other abnormalities (grade D recommendation), but should not delay reperfusion treatment where indicated.

 

Further investigations

 

Patients without ST-segment elevation on the initial ECG should be further observed and investigated to promptly identify patients suitable for an emergency reperfusion strategy (based on ECG changes) and/or determine the best management protocol for NSTEACS based on risk stratification (see section on Management of patients with NSTEACS).

The ECG is the sole test required to select patients for emergency reperfusion (fibrinolytic therapy or direct PCI).

Patients with STEMI who present within 12 hours of the onset of ischaemic symptoms should have a reperfusion strategy implemented promptly.

Patients with a suspected ACS without ST-segment elevation on the ECG should undergo further observation and investigation to rule out other diagnoses, enable risk stratification and determine the most appropriate treatment strategy.

Patients with a normal ECG and cardiac biomarker levels after an appropriate period of observation should, where practicable, undergo provocative testing (eg, stress test) before discharge.

 

2 Recommendations and rationale for measuring cardiac biomarker levels

 

Management of patients with ST-segment-elevation myocardial infarction

 

STEMI is defined as presentation with clinical symptoms consistent with an acute coronary syndrome with ECG features including any of:

 

§                     Persistent ST-segment elevation of ≥ 1 mm in two contiguous limb leads;

§                     ST-segment elevation of ≥ 2 mm in two contiguous chest leads; or

§                     New left bundle branch block (LBBB) pattern.6 (Note that LBBB is presumed new unless there is evidence otherwise; echocardiography may be useful to detect regional wall contraction abnormalities.)

 

Patients with STEMI usually have a completely occluded coronary artery with thrombus at the site of a ruptured plaque. Restoring coronary patency as promptly as possible is a key determinant of short-term and long-term outcomes (level I evidence).14–18

Patients with STEMI who present within 12 hours of the onset of ischaemic symptoms should have a reperfusion strategy implemented promptly (grade A recommendation).

 

Reperfusion therapy

 

Reperfusion may be obtained with fibrinolytic therapy or PCI. A combination of fibrinolysis and PCI may also be used (facilitated or rescue PCI). Coronary artery bypass graft (CABG) surgery may occasionally be more appropriate — particularly in patients who have suitable anatomy and are not candidates for fibrinolysis or PCI. CABG surgery may also be considered in patients with cardiogenic shock19 or in association with mechanical repair.12

 

Antiplatelet therapy

 

Aspirin (300 mg) should be given to all patients with STEMI unless contraindicated and, in the absence of significant side effects, low-dose therapy should be continued in the long term (grade A recommendation).16,20

There is evidence that clopidogrel (300–600 mg loading dose) should be prescribed in addition to aspirin for patients undergoing PCI with a stent.21–23 In patients selected for fibrinolytic therapy, clopidogrel (300 mg) should be given in addition to aspirin, unless contraindicated (grade B recommendation).24 Note, however, that if it is thought that the patient is likely to require CABG acutely, clopidogrel should be withheld.

Clopidogrel (75 mg daily) should be continued for at least a month after fibrinolytic therapy, and for up to 12 months after stent implantation, depending on the type of stent and circumstances of implantation (level II evidence; grade B recommendation).25

 

Antithrombin therapy

With PCI: Antithrombin therapy should be used in conjunction with PCI (grade A recommendation). The dose of unfractionated heparin therapy will depend on concomitant use of glycoprotein (GP) IIb/IIIa inhibitors. The aim should be to obtain an activated clotting time (ACT) between 200 and 300 seconds if using GP IIb/IIIa inhibitors, or between 300 and 350 seconds if these drugs are not used (grade B recommendation). It may be advisable to give a bolus of heparin while the patient is in transit to the catheterisation laboratory (grade D recommendation).

The role of enoxaparin in acute STEMI in conjunction with PCI remains to be determined, but it appears to be safe and effective at a dose of 0.75 mg/kg (grade D recommendation).

With fibrinolysis: Antithrombin therapy should be used with fibrin-specific fibrinolytic agents (grade A recommendation).26,27

Unfractionated heparin should be given as an initial bolus dose of 60 units per kilogram of body weight (with a maximum dose of 4000 units) followed by an initial infusion of 12 units per kilogram per hour (maximum units 1000 per hour), adjusted to attain the activated partial thromboplastin time (APTT) at 1.5 to 2 times control (about 50–70 seconds; grade B recommendation).12

Enoxaparin may be used in conjunction with fibrin-specific fibrinolytic agents in patients under the age of 75 years, provided they do not have significant renal dysfunction. An intravenous bolus dose of 30 mg followed by a 1 mg/kg subcutaneous injection every 12 hours in combination with tenecteplase is the most comprehensively studied therapy.12 Care should be taken in patients who are aged over 75 years, or who have renal dysfunction, as dose adjustment is required.12

The use of antithrombin therapy in conjunction with streptokinase therapy is optional.28

Glycoprotein IIb/IIIa inhibitors

It is reasonable to use abciximab with primary PCI, although there are conflicting data (grade B recommendation). It appears the earlier it is used, the greater the advantage.29 When used in patients with STEMI undergoing primary PCI, the timing of administration of abciximab is a matter of clinical judgement.30,31

Full-dose GP IIb/IIIa inhibitors should be avoided with fibrinolytic therapy (grade B recommendation) as there is evidence of excessive bleeding (including intracranial haemorrhage) with this combination.32 It is unclear how early full-dose GP IIb/IIIa inhibitors can be safely given after fibrinolysis, but it is probably at least 4 hours after administration of fibrin-specific fibrinolytic agents and 24 hours after administration of streptokinase.32

The combination of GP IIb/IIIa inhibitors with reduced doses of fibrinolytic therapy is not recommended. There is no significant advantage over full-dose fibrinolytic therapy alone, and the risk of bleeding is increased, particularly in the elderly.32 This combination has been used for facilitated PCI.32

 

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

§                     Antithrombin therapy should be given in combination with PCI or fibrinolytic therapy with fibrin-specific fibrinolytic agents, but its use in conjunction with streptokinase is optional.

§                     It is reasonable to use abciximab with primary PCI, but GP IIb/IIIa inhibitors should generally be avoided with full or reduced doses of fibrinolytic therapy.

 

3 Summary of adjuvant therapy associated with reperfusion

Medication	Primary percutaneous coronary intervention	Fibrin-specific fibrinolytic
Aspirin	Yes	Yes
Clopidogrel	Yes (unless the need for acute CABG is likely)	Yes (unless the need for acute CABG is likely)
Heparin	Unfractionated heparin (ACT 200–300 s if using glycoprotein IIb/IIIa inhibitors, 300–350 s if not) or Enoxaparin*	Unfractionated heparin (APTT 1.5–2 times control [approx 50–70 s]) or Enoxaparin*
Glycoprotein IIb/IIIa inhibitors	Abciximab optional	No
CABG = coronary artery bypass graft. ACT = activated clotting time. APTT = activated partial thromboplastin time. * Care should be taken in patients aged over 75 years, or those who have significant renal dysfunction — dose adjustment is required.

 

Choice of reperfusion therapy

 

§                     Choice of reperfusion strategy depends on a number of factors, with time delay (both to presentation and potential PCI or fibrinolytic therapy) playing a major role in determining best management.

§                     In general, PCI is the treatment of choice, provided it can be performed promptly by a qualified interventional cardiologist in an appropriate facility.

§                     In general, the maximum acceptable delay from presentation to balloon inflation is:

·                                             60 minutes if a patient presents within 1 hour of symptom onset; and

·                                             90 minutes if a patient presents later.

Note: for patients who present late (3–12 hours after symptom onset) to a facility without PCI capability, it is appropriate to consider transfer for primary PCI if balloon inflation can be achieved within 2 hours (including transport time).

§                     All PCI facilities should be able to perform angioplasty within 90 minutes of patient presentation.

§                     Fibrinolysis should be considered early if PCI is not readily available, particularly in rural and remote areas.

§                     When there are major delays to hospitalisation (more than 30 minutes), prehospital fibrinolysis should be considered.

§                     Reperfusion is not routinely recommended in patients who present more than 12 hours after symptom onset and who are asymptomatic and haemodynamically stable.

 

4 Hospital management of ST-segment-elevation myocardial infarction*

Assuming no contraindications to fibrinolytic therapy — see Box 5. † Time delay refers to time from first medical contact to balloon. ‡ Patients with ongoing symptoms or instability should be transferred for PCI.
Note: Reperfusion after 12 hours is indicated for cardiogenic shock, ongoing pain or haemodynamic instability (see text).

 

5 Contraindications and cautions for fibrinolysis use in ST-segment-elevation myocardial infarction*

 

Absolute contraindications         

Risk of bleeding

§                     Active bleeding or bleeding diathesis (excluding menses)

§                     Significant closed head or facial trauma within 3 months

§                     Suspected aortic dissection (including new neurological symptoms)50

Risk of intracranial haemorrhage

§                     Any prior intracranial haemorrhage

§                     Ischaemic stroke within 3 months

§                     Known structural cerebral vascular lesion (eg, arteriovenous malformation)

§                     Known malignant intracranial neoplasm (primary or metastatic)

Relative contraindications

Risk of bleeding

§                     Current use of anticoagulants: the higher the international normalised ratio (INR), the higher the risk of bleeding

§                     Non-compressible vascular punctures

§                     Recent major surgery (< 3 weeks)

§                     Traumatic or prolonged (> 10 minutes) cardiopulmonary resuscitation

§                     Recent (within 4 weeks) internal bleeding (eg, gastrointestinal or urinary tract haemorrhage)

§                     Active peptic ulcer

Risk of intracranial haemorrhage

§                     History of chronic, severe, poorly controlled hypertension

§                     Severe uncontrolled hypertension on presentation (> 180 mmHg systolic or > 110 mmHg diastolic)

§                     Ischaemic stroke more than 3 months ago, dementia, or known intracranial abnormality not covered in contraindications

Other

§                     Pregnancy

 

 

6 Prehospital management of ST-segment-elevation myocardial infarction (STEMI)

Choice of fibrinolytic agent

 

There are four fibrinolytic agents currently available in Australia; streptokinase and the tissue fibrin-specific fibrinolytic agents alteplase, reteplase and tenecteplase. The properties of these agents are summarised in Box 7.

Fibrin-specific fibrinolytic agents have been shown to reduce mortality compared with streptokinase in patients with STEMI who present within 6 hours of symptom onset (level I evidence).55 Fibrin-specific fibrinolytic agents also lack the significant acute side effects of hypotension and allergy caused by streptokinase (level I evidence). Streptokinase may be associated with a lower incidence of intracranial haemorrhage, particularly in older people (level I evidence), but the overall mortality is still lower with the use of fibrin-specific fibrinolytic agents (level II evidence).56 Tenecteplase is associated with a lower rate of bleeding than alteplase (level II evidence).57

Second-generation fibrin-specific fibrinolytic agents can be given as either single or double bolus injections, which makes them significantly easier to use than streptokinase.

In combination therapy, PCI combined with fibrin-specific fibrinolytic agents appears to have greater efficacy and results in fewer complications than PCI combined with streptokinase (level III evidence, grade B recommendation).58

Streptokinase should not be given to patients with previous exposure (more than 5 days ago) to the drug (grade B recommendation). There is also evidence that streptokinase may be less effective in Aboriginal and Torres Strait Islander peoples because of the high levels of skin infection (and thus streptococcal antibodies), particularly in remote populations.45,59 It is therefore an inappropriate choice of agent in these populations (level III evidence, grade B recommendation). Making second-generation fibrin-specific fibrinolytic agents the standard choice is likely to decrease inequalities of care between Indigenous and non-Indigenous populations, in addition to providing superior reperfusion.

Therefore, second-generation fibrin-specific fibrinolytic agents which are available as a bolus (ie, reteplase, tenecteplase) are the fibrinolytics of choice (grade A recommendation). These agents should be available at all centres where fibrinolysis may be required (grade D recommendation).

 

§                     Second-generation fibrin-specific fibrinolytic agents that are available as a bolus (ie, reteplase, tenecteplase) are the fibrinolytics of choice.

§                     These agents should be available at all centres where fibrinolysis may be required.

§                     Streptokinase is a particularly inappropriate choice for Aboriginal and Torres Strait Islander patients or patients with previous exposure to the drug.

§                    

7 Fibrinolytic agents — prescribing information and properties

Details	Tenecteplase (TNK)	Reteplase (r-PA)	Alteplase (rt-PA)	Streptokinase
Dose (also see product information)	Up to 10 000 international units (50 mg) on basis of body weight: < 60 kg — 6000 units 60–70 kg — 7000 units 70–80 kg — 8000 units 80–90 kg — 9000 units > 90 kg — 10 000 units	10 units Ч 2, 30 minutes apart (give each bolus slowly over no more than 2 minutes)	For patients > 65 kg: 15 mg bolus; then 50 mg over 30  minutes and 35 mg over the next 60 minutes For patients ≤ 65 kg: 15 mg bolus; then 0.75 mg/kg over 30 minutes and 0.5 mg/kg over the next 60 minutes.	1.5 million international units over 30–60 minutes
Bolus administration	Yes	Yes	No	No
Antigenic12	No	No	No	Yes
Systemic fibrinogen depletion12	Minimal	Moderate	Mild	Marked
Lives saved per 1000 patients treated (approximate number at 30 days)	3553	3554	3555	2514

 

 

 

§                     Patients who have had STEMI should be considered for early transfer to a tertiary cardiac centre with PCI facilities and links to cardiac surgical facilities.

§                     If early transfer is not possible, all patients should be transferred or referred as soon as is practicable for assessment of the need for revascularisation through PCI or CABG.

 

Management of patients with non-ST-segment-elevation acute coronary syndromes. Risk stratification

 

The initial objective of evaluation is to define the likelihood of an ACS as the cause of a patient’s presentation. Most patients will present with prolonged or recurrent central chest discomfort but others, particularly the elderly, people with diabetes and women, may present with atypical symptoms. These include neck, jaw, back or epigastric discomfort or dyspnoea, diaphoresis, nausea and vomiting. Age is an important risk factor, and the presence (or absence) of coronary risk factors adds little to the accuracy of the diagnosis in middle-aged or elderly patients, but is more useful in making a diagnosis in younger patients. A history of physical or emotional stress before symptom onset increases the likelihood of an ACS. Most patients with NSTEACS are normal on physical examination. An abnormal ECG, particularly dynamic ST-segment deviation (≥ 0.5 mm) or new T-wave inversion (≥ 2 mm) will confirm the diagnosis, but the ECG may be normal or show minor changes in up to 50% of cases.

The second objective of evaluation is to determine the risk of short-term adverse outcomes, which will direct the management strategy. Box 8 provides a paradigm for the risk stratification of patients presenting with suspected NSTEACS, and a simplified risk assessment algorithm is shown in Box 9. Most patients admitted to hospital with possible NSTEACS will have intermediate-risk or high-risk features (Box 8), and these patients are best managed with a structured clinical pathway (see Investigationssection). Patients with clinical features consistent with NSTEACS and high-risk features are best managed with aggressive medical and invasive therapy (detailed later). Patients with diabetes or chronic kidney disease with typical symptoms of ACS would be considered to be at high risk, but those with atypical symptoms and normal ECGs and cardiac biomarker levels may initially be considered at intermediate risk until a diagnosis is made. Patients with low-risk unstable angina may be managed with upgraded medical therapy and outpatient cardiac referral.

 

8 Features associated with high-risk, intermediate-risk and low-risk non-ST-segment-elevation acute coronary syndromes (NSTEACS)

High-risk features

Presentation with clinical features consistent with acute coronary syndromes (ACS) and any of the following high-risk features:

§                     Repetitive or prolonged (> 10 minutes) ongoing chest pain or discomfort;

§                     Elevated level of at least one cardiac biomarker (troponin or creatine kinase-MB isoenzyme);

§                     Persistent or dynamic electrocardiographic changes of ST-segment depression ≥ 0.5 mm or new T-wave inversion ≥ 2 mm;

§                     Transient ST-segment elevation (≥ 0.5 mm) in more than two contiguous leads;

§                     Haemodynamic compromise — systolic blood pressure < 90 mmHg, cool peripheries, diaphoresis, Killip Class > I, and/or new-onset mitral regurgitation;

§                     Sustained ventricular tachycardia;

§                     Syncope;

§                     Left ventricular systolic dysfunction (left ventricular ejection fraction < 0.40);

§                     Prior percutaneous coronary intervention within 6 months or prior coronary artery bypass surgery;

§                     Presence of known diabetes (with typical symptoms of ACS); or

§                     Chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute) (with typical symptoms of ACS).

Intermediate-risk features

Presentation with clinical features consistent with ACS and any of the following intermediate risk features AND NOT meeting the criteria for high-risk ACS:

§                     Chest pain or discomfort within the past 48 hours that occurred at rest, or was repetitive or prolonged (but currently resolved);

§                     Age > 65 years;

§                     Known coronary heart disease — prior myocardial infarction with left ventricular ejection fraction ≥ 0.40, or known coronary lesion more than 50% stenosed;

§                     No high-risk changes on electrocardiography (see above);

§                     Two or more of the following risk factors: known hypertension, family history, active smoking or hyperlipidaemia;

§                     Presence of known diabetes (with atypical symptoms of ACS);

§                     Chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute) (with atypical symptoms of ACS); or

§                     Prior aspirin use.

Low-risk features

Presentation with clinical features consistent with an acute coronary syndrome without intermediate-risk or high-risk features. This includes onset of anginal symptoms within the last month, or worsening in severity or frequency of angina, or lowering of anginal threshold.

 

 

 

Treatment of NSTEACS

 

Aspirin is recommended (unless contraindicated) in all low-risk, intermediate-risk and high-risk patients (grade A recommendation).

High-risk patients should be treated with aggressive medical management (level I evidence, grade A recommendation) (see below) and arrangements should be made for coronary angiography and revascularisation (level I evidence, grade A recommendation), except in those with severe comorbidities, including general frailty (grade A recommendation). Age alone should not be a barrier to aggressive therapy.

Patients at intermediate risk should be observed by staff trained in cardiac care practice and should undergo an accelerated diagnostic evaluation and further risk stratification (level III evidence, grade B recommendation). Accurate assessment can be improved by the use of structured forms for admission and continuing evaluation.79–82 During the evaluation process, intermediate-risk patients are observed as described in the Investigations section, with frequent electrocardiography (with or without continuous ST-segment monitoring), repeat troponin testing and provocative testing if a repeat troponin assay is negative.

Low-risk patients may be discharged on upgraded medical therapy after an appropriate period of observation and assessment (see Investigations section). These patients (including those manifesting anginal symptoms for the first time within the previous month or with a change in the tempo of their angina) are considered unstable, as some will have atherothrombotic disease with a definite risk of progression to myocardial infarction. These patients should be treated with β-blockers and aspirin, and cardiac assessment should be obtained urgently.

Treatment of patients with NSTEACS on the basis of risk is summarised in Box 10.

 

10 Treatment strategies for patients with non-ST-segment-elevation acute coronary syndromes (NSTEACS), based on risk stratification

 

Medical management of high-risk patients

 

Antiplatelet therapy: Early treatment should be initiated with aspirin83–86 (grade A recommendation) and clopidogrel (300 mg loading dose and 75 mg daily)87 (grade B recommendation), with the following considerations:

§                     Clopidogrel should be avoided in patients likely to require emergency coronary bypass surgery (those with severe widespread ST-segment depression or haemodynamic instability);

§                     If possible, clopidogrel should be discontinued 5 days before coronary bypass surgery;

§                     Clopidogrel should be given (preferably more than 6 hours) before planned percutaneous coronary intervention (level I evidence, grade A recommendation),21,22 but may be omitted if coronary angiography is planned immediately;

§                     If relevant, warfarin therapy should be discontinued and heparin given along with the recommended antiplatelet therapy (grade D recommendation).

Antithrombin therapy: Unfractionated heparin or subcutaneous enoxaparin should be given until angiography or for 48–72 hours (level I evidence, grade A recommendation).88–90 The enoxaparin dose must be reduced in patients with impaired renal function.

GP IIb/IIIa inhibitors: Intravenous tirofiban or eptifibatide is particularly recommended in high-risk patients in whom an invasive strategy is planned (level I evidence, grade A recommendation). Administration should commence as soon as a high-risk feature is identified.91,92 Intravenous tirofiban or eptifibatide are also recommended if patients continue to have ischaemia while receiving enoxaparin or unfractionated heparin (level III evidence, grade B recommendation).

Concomitant tirofiban is particularly beneficial and recommended in patients with diabetes (level I evidence, grade A recommendation).

Other: A β-blocker should be given unless contraindicated (level I evidence, grade A recommendation).93 Intravenous glyceryl trinitrate can be given for refractory pain (grade D recommendation).

In patients with diabetes, good glycaemic control should be targeted in hospital and after discharge. This may require considering an insulin-based regimen in hospital and for 3 or more months after discharge in selected patients (grade B recommendation).94

Early medical management of NSTEACS is summarised in Box 11.

 

Early coronary angiography (within 48 hours) and revascularisation is recommended in patients with NSTEACS and high-risk features (grade A recommendation), except in patients with severe comorbidities. In addition to the features listed in Box 8, pain or ischaemia refractory to medical therapy and high-risk features on early exercise testing can also identify patients suitable for early invasive therapy.

A risk score devised by the TIMI (Thrombolysis In Myocardial Infarction) study group95 has been validated as a valuable measure of early risk in NSTEACS.66,91,96 It uses a seven-point score derived from:

§                     age greater than or equal to 65 years;

§                     more than three coronary risk factors;

§                     prior angiographic coronary obstruction;

§                     ST-segment deviation;

§                     more than two angina events within 24 hours;

§                     use of aspirin within 7 days; and

§                        elevated levels of cardiac biomarkers.

§                       

§                        Fig. ECG with MI

Additional risk stratification on the basis of a TIMI risk score of greater than three for deciding which patients might be transferred for early invasive management may be considered where funding is constrained, but it must be remembered that 14-day cardiac event rates are still considerable, even for those with low scores (see Box 12). Appropriate patients should be transferred for angiography within 48 hours, and aggressive medical therapy with initial stabilisation of symptoms does not mitigate the need for early angiography.

 

12 TIMI risk scores and 14-day cardiac event rates

 

 

§                     All patients with NSTEACS should have their risk stratified to direct management decisions.

§                     All patients with NSTEACS should be given aspirin unless contraindicated.

§                     Patients with high-risk NSTEACS should be treated with aggressive medical management (including aspirin and clopidogrel, unfractionated heparin or subcutaneous enoxaparin, intravenous tirofiban or eptifibatide, and a β-blocker), and arrangements should be made for coronary angiography and revascularisation, except in those with severe comorbidities.

§                     Patients with intermediate-risk NSTEACS should undergo an accelerated diagnostic evaluation and further assessment to allow reclassification into low-risk or high-risk categories.

§                     Patients with low-risk NSTEACS, after an appropriate period of observation and assessment, may be discharged on upgraded medical therapy for urgent outpatient cardiac follow-up.

 

Long-term management after control of myocardial ischaemia

 

§                     Before discharge of patients who have had an ACS, therapy with an appropriate medication regimen should be initiated, including antiplatelet agent(s), β-blocker, angiotensin-converting enzyme inhibitor, statin and other therapies as appropriate.

§                     Implantable cardiac defibrillators should be considered in some patients who, despite optimal medical therapy, have persistently depressed left ventricular function more than 6 weeks after STEMI.

§                     Patients should be given advice on lifestyle changes that will reduce the risk of further coronary heart disease events, including smoking cessation, good nutrition, moderate alcohol intake, regular physical activity and weight management, as appropriate.

§                     All patients should have access, and be actively referred, to comprehensive ongoing prevention and cardiac rehabilitation services.

§                     All patients should be provided with a written action plan for chest pain.

§                     Depression and coronary heart disease frequently coexist, and in patients with heart disease, depression, social isolation and lack of social support are more likely to lead to poorer outcomes. All patients with coronary heart disease should be assessed for depression and level of social support.

 

Appendix: Implantable cardiac defibrillator (ICD) implantation after ST-segment-elevation myocardial infarction (STEMI): proposed management algorithm104,105

This algorithm is for suggested management in an area which is still evolving.There may be considerable resource issues that will need to be explored, and cost-effectiveness data are currently lacking. Other factors such as comorbidities and conditions that significantly shorten life expectancy and reduce quality of life should be considered before ICD implantation. The evidence for benefit is strongest in patients with a left-ventricular ejection fraction ≤ 30% and New York Heart Association Class II or III heart failure.

* Patients with sustained ventricular tachyarrhythmias or unexplained syncope after STEMI and an ejection fraction > 35% should also be considered for electrophysiological evaluation.

 

Overview of keypoints

Acute coronary syndrome (ACS) refers to a group of clinical conditions caused by myocardial ischemia including unstable angina pectoris (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI) (Fig. 1).

 

Figure 1. The spectrum of acute coronary syndrome.

ECG = electrocardogram; NSTEMI = non-ST-elevation myocardial infarction; STEMI = ST-elevation myocardial infarction

From Hamm et al. Eur Heart J 2011;32:2999-3054.

 

Definition and terminology

Patients presenting with acute chest pain and persistent (>20 min.) ST-elevation on electrocardiogram (ECG) will have the working diagnosis of ST-elevation ACS. Most of these patients will ultimately develop STEMI and progress to Q wave myocardial infarction (MI). Patients with acute chest pain, but without persistent ST-segment elevation (presenting with persistent or transient ST depression or T-wave inversion, flat T waves, pseudo-normalization of T waves or normal ECG) will have the working diagnosis of non-ST-elevation ACS. On the basis of troponin measurements patients with non-ST-elevation ACS will be further qualified as having NSTEMI or UA.

The distinction betweeon–ST segment elevation ACS and ST-segment elevation ACS is clinically important because rapid recanalization therapy is critical for improving the outcome in ST elevation ACS/STEMI, but is less urgent ion–ST-segment elevation ACS.

MI is defined pathologically as myocardial cell death due to prolonged ischemia. In the clinical setting, these conditions are met when the following criteria are present: detection of a rise and/or fall of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit (URL) together with evidence of myocardial ischemia as recognized by at least one of the following:

– symptoms of ischemia;

– ECG changes of new ischemia (ST-elevation or depression) or development of pathologic Q waves; or

– imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

 

Pathophysiology

Acute coronary syndrome represents a life-threatening manifestation of atherosclerosis. ACS most frequently develops as a result of plaque rupture or erosion with overlying thrombosis. A thin fibrous cap is more likely to rupture than a thick one. Factors such as the lipid and tissue factor content of the plaque, the severity of the plaque rupture, the degree of inflammation at the site, the blood flow in the area, and the patient’s antithrombotic and prothrombotic balance are important in determining whether a given plaque rupture will result in ACS.

Less frequent pathophysiological causes of ACS include dynamic obstruction due to coronary vasospasm as in Prinzmetal angina or in cocaine use, coronary dissection, secondary UA in patients with fever, thyrotoxicosis, severe anemia, hypoxemia or hypotension.

 

Clinical presentation

The typical clinical presentation of ACS is prolonged (>20 min.) retrosternal pressure or heaviness radiating to the left arm, neck or jaw. These complaints may be accompanied by other symptoms such as diaphoresis, nausea, abdominal pain and syncope(Table 1).

Table 1. Likelihood that signs and symptoms represent an ACS

 

 

 

Atypical presentations include epigastric pain, neck, jaw, ear, arm discomfort. Some patients, especially those who are elderly or who have diabetes, present with no pain, complaining only of episodic shortness of breath, severe weakness, light-headedness, diaphoresis, or nausea and vomiting. Elderly persons may also present only with altered mental status (Table 2).

Table 2. Killip Classification in acute MI

 

 

The physical examination is frequently normal. Worrisome findings include hypotension, new jugular venous distension, pulmonary edema, or a new systolic murmur. An important goal of the physical examination is to exclude non-cardiac causes of chest pain (e.g., pulmonary embolism, aortic dissection, pericarditis, valvular heart disease, pneumothorax, pneumonia, or pleural effusion). The Killip classification system (Table 2) and TIMI risk score (Table 3) are helpful in using physical exam findings to assess a patient’s 30-day mortality.

Table 3. TIMI risk score for ST-elevation MI

 

 

Diagnosis

The diagnosis is based on a combination of history, ECG, and biochemical markers of cardiac injury.

ECG. ST segment elevation of ≥2 mm in two adjacent chest leads and of ≥1 mm in adjacent limb leads suggests of STEMI. Other associated findings may include tall peaked T waves and reciprocal ST-segment depression. Pathological Q waves indicating significant transmural myocardial damage should be ≥25% of the R wave, ≥0.04 sec in duration. The infarction site can be localized from ECG changes (Table 4).

Patients with UA/NSTEMI may have a normal ECG or may have changes ranging from new T wave inversions, ST segment depression, or normalization of previously inverted T waves (pseudonormalization).

 

Table 4. Localization of infarcts from ECG changes

 

 

Biochemical markers of cardiac injury

Creatine kinase (CK). Levels twice the upper limit of normal are taken as being abnormal. Serum levels rise within 4-8 hours post-STEMI and fall to normal within 3-4 days. CK-MB isoenzyme is more specific for myocardial disease.

Cardiac troponins (TnT, TnI). Serum levels start to rise by 3 hours post-MI, and elevation may persist up to 7-14 days. Troponins can also be elevated ion-ischaemic myocardial damage such as myocarditis, cardiomyopathy, pericarditis.

 

Treatment

Stabilizing measures are similar in all patients with ACS. Patients should be placed in an environment with continuous ECG monitoring and defibrillation capacity. Patients should receive aspirin 300 mg orally, analgesia, secure i.v. access and oxygen. Intramuscular injections and not be given as they cause rise in total CK and risk of bleeding with thrombolysis/anticoagulation.

STEMI

Patients presenting with ST-segment elevation or left bundle branch block on ECG benefit significantly from immediate reperfusion and are treated as one group under the term STEMI.

1. Relief of pain, breathlessness and anxiety.

Titrated i.v. opioids (e.g. morphine) are the analgesics most commonly used in this context. Repeated doses may be necessary. Side-effects include nausea and vomiting, hypotension with bradycardia, and respiratory depression. Anti-emetics (e.g., metoclopramide 10 mg i.v.) may be administered concurrently with opioids to minimize nausea. 

Nitrates (sublingual or intravenous) may lessen pain and can be given, providing the patient is not hypotensive.

Oxygen (at 2-5 L/min for at least 2-3 hours by mask or nasal prongs) should be administered to those who are breathless, hypoxic (SaO₂<95%), or who have heart failure. Non-invasive monitoring of blood oxygen saturation greatly helps when deciding on the need to administer oxygen or ventilatory support.

Anxiety is a natural response to the pain and the circumstances surrounding a heart attack. Reassurance of patients and those closely associated with them is of great importance. If the patient becomes excessively disturbed, it may be appropriate to administer a tranquillizer, but opioids are frequently all that is required.

2. Correction of electrolytes. Potassium and magnesium should be supplemented as both low potassium and magnesium may be arrhythmogenic.

3. Strategies to limit infarct size (beta-blockade, ACE-inhibitors, reperfusion).

Beta-blockade. Metoprolol i.v. 1-2 mg at a time repeated at 1-2 min. intervals to a maximum dose of 15-20 mg under continuous ECG and BP monitoring. Aim at a pulse rate of 60 bpm and systolic BP 100-110 mmHg.

ACE-inhibitors. After receiving aspirin, beta-blockade (if appropriate), and reperfusion, patients with STEMI should receive an ACE-inhibitor within the first 24 hours of presentation.

Reperfusion.

Primary percutaneous coronary intervention (PCI) is the current gold standard  reperfusion strategy for the treatment of STEMI and demonstrates superior outcome in comparison with thrombolysis. In settings where primary PCI cannot be performed within 120 min of first medical contact by an experienced team, thrombolysis should be considered, particularly if it can be given pre-hospital (e.g. in the ambulance) and within the first 120 min of symptom onset. As an adjuct to thrombolysis, rescue PCI should be reserved for patients who remain symptomatic post thrombolysis or develop cardiogenic shock.

Thrombolysis (fibrinolysis). Fibrinolytic therapy (Table 5) is recommended within 12 h of symptom onset if primary PCI cannot be performed within 90 min of being able to administer fibrinolysis and within 120 min from first medical contact and there are no contraindications (Table 6). The later the patient presents (particularly after 6 h), the more consideration should be given to transfer for primary PCI (in preference to fibrinolytic therapy) as the efficacy and clinical benefit of fibrinolysis decrease over time, which, in later presentations, has the effect of increasing the acceptable time delay before transfer for primary PCI.

 

Table 5. Dose and administration of thrombolytic agents

 

Streptokinase is the first-generation fibrinolytic agent which is an indirect plasminogen activator and therefore relatively nonspecific for fibrin. In comparative trials, it had the lowest rate of intracranial hemorrhage. streptokinase is antigenic and allergic reactions occur on 5 to 6 % of patients.

Alteplase represents a second-generation fibrinolytic. Of all current fibrinolytics, it has the shortest half-life (4 to 8 minutes) and therefore is administered as a bolus followed by an infusion over 90 minutes or longer.

Reteplase and tenecteplase are the third-generation fibrinolytics. They are the mutants of alteplase with a longer half-life and offer the convenience of bolus administration.

 

Table 6. Contraindications for use of thrombolytic agents in acute MI

 

4. Additional therapies

Heparin. Unfractionated heparin (UFH) should be used routinely with rt-PA and its derivatives for 24-48 hours for a target aPTT (activated partial thromboplasin time) 50-70 sec or 1.5-2.0 times control (to be monitored at 3, 6, 12 and 24 h). Low molecular weight heparin (LMWH) can be used as an alternative to UFH.

Clopidogrel (loading dose of 600 mg orally followed by a maintenance dose of 75 mg/day) should be administerd to all patients undergoing primary PCI. If coronary stents are used, patients should remain on clopidogrel for at least 1 month in bare-metal stents and 12 months in coated stents.

Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) are recommended routinely in the context of STEMI treated with primary PCI.

 

NSTEMI/UA

Timing of angiography and revascularization should be based on patient risk profile. The GRACE risk score provides the most accurate stratification of risk both on admission and at discharge due to its good discriminative power. However, the complexity of the estimation requires the use of computer or personal digital assistant software for risk calculations, which can also be performed online:

 

 

Cardiac catheterization followed by revascularization has been shown to prevent recurrent ischaemia and/or improve short- and long-term outcomes. Several risk factors (troponin elevation, diabetes, ST-segment depression, renal insufficiency, etc.) have been identified to predict the long-term benefit of an invasive strategy. Depending on the acuteness of risk, the timing of angiography can be tailored, according to four categories:

– invasive (<72 h);

– urgent invasive (<120 min);

– early invasive (<24 h);

– primarily conservative.

 

Urgent invasive strategy (<120 min after first medical contact)

This should be undertaken for very high risk patients. These patients are characterized by:

– refractory angina (indicating evolving MI without ST abnormalities);

– recurrent angina despite intense antianginal treatment, associated with ST depression (2 mm) or deep negative T waves;

– clinical symptoms of heart failure or haemodynamic instability (‘shock’);

– life-threatening arrhythmias (ventricular fibrillation or ventricular tachycardia).

 

Early invasive strategy (<24 h after first medical contact)

Most patients initially respond to the antianginal treatment, but are at increased risk and need angiography followed by revascularization. High risk patients as identified by a GRACE risk score >140 and/or the presence of at least one primary high risk criterion should undergo invasive evaluation within 24 h. High risk criteria include:

– relevant rise or fall in troponin;

– dynamic ST- or T-wave changes (symptomatic or silent);

– diabetes mellitus;

-renal insufficiency (eGFR<60mL/min/1.73m²);

– early postinfarction angina;

-recent PCI;

– prior CABG;

– intermediate to high GRACE risk score

 

 

Invasive strategy (<72 h after first medical contact)

In lower risk subsets with a GRACE risk score of <140 but with at least one high risk criterion, the invasive evaluation can be delayed without increased risk but should be performed during the same hospital stay, preferably within 72 h of admission. Thus, such patients should undergo elective invasive evaluation at the first opportunity depending on the local circumstances.

 

Conservative strategy (no or elective angiography)

Patients that fulfill all of the following criteria may be regarded as low risk and should not routinely be submitted to early invasive evaluation:

·                     No recurrence of chest pain.

·                     No signs of heart failure.

·                     No abnormalities in the initial ECG or a second ECG (at 6–9 h).

·                     No rise in troponin level (at arrival and at 6–9 h).

·                     No inducible ischaemia.

 

In other low risk patients without recurrent symptoms a non-invasive assessment of inducible ischaemia should be performed before hospital discharge. Coronary angiography should be performed if the results are positive for reversible ischaemia.

 

Medical management

All patients should be treated with adequate analgesia, i.v. nitrates, beta-blockers and statins (if not contraindicated). Other agents can also be added depending on the clinical picture.

1. Anti-ischaemic agents

Anti-ischaemic drugs either decrease myocardial oxygen demand (by decreasing heart rate, lowering blood pressure, reducing preload, or reducing myocardial contractility) or increase myocardial oxygen supply (by inducing coronary vasodilatation).

Beta-blockers competitively inhibit the myocardial effects of circulating catecholamines and reduce myocardial oxygen consumption by lowering heart rate, blood pressure, and contractility. Beta-blockers should be started on presentation, initially using a short-acting agent (e.g., metoprolol 12.5-50 mg t.i.d) which, if tolerated, may be converted to a longer-acting agent. Aim for HR of ≈ 50-60 bpm.

Nitrates

E.g., glyceryl trinitrate (GTN) infusion (50 mg in 50 mL 1 M saline at 1-10 mL/h). Tolerance to continuous infusion develops within 24 hours, therefore the lowest eficaceous dose should be used.

The use of nitrates in unstable angina is largely based on pathophysiological considerations and clinical experience. The therapeutic benefits of nitrates and similar drug classes such as syndonimines are related to their effects on the peripheral and coronary circulation. The major therapeutic benefit is probably related to the venodilator effects that lead to a decrease in myocardial preload and LV end-diastolic volume, resulting in a decrease in myocardial oxygen consumption. In addition, nitrates dilate normal as well as atherosclerotic coronary arteries and increase coronary collateral flow.

Nitrates should not be given to patients on phosphodiesterase-5 inhibitors (sildenafil, vardenafil, or tadalafil) because of the risk of profound vasodilatation and critical blood pressure drop.

Calcium channel blockers

Calcium channel blockers are vasodilating drugs. In addition, some have direct effects on atrioventricular conduction and heart rate. There are three subclasses of calcium blockers, which are chemically distinct and have different pharmacological effects: dihydropyridines (such as nifedipine), benzothiazepines (such as diltiazem), and phenylethylamines (such as verapamil). The agents in each subclass vary in the degree to which they cause vasodilatation, decrease myocardial contractility, and delay atrioventricular conduction. Atrioventricular block may be induced by non-dihydropyridines. Nifedipine and amlodipine produce the most marked peripheral arterial vasodilatation, whereas diltiazem has the least vasodilatory effect. All subclasses cause similar coronary vasodilatation. Therefore, calcium channel blockers are the preferred drugs in vasospastic angina. Diltiazem and verapamil show similar efficacy in relieving symptoms and appear equivalent to beta-blockers.

E.g., diltiazem 60-360 mg orallt, verapamil 40-120 mg orally t.i.d. Amlodipine/felodipine 5-10 mg PO can also be used.

Other antianginal drugs

Nicorandil, a potassium channel opener, reduced the rate of the primary composite endpoint in patients with stable angina, but was never tested in ACS patients. Ivabradine selectively inhibits the primary pacemaker current in the sinus node and may be used in selected patients with β-blocker contraindications.

Ranolazine exerts antianginal effects by inhibiting the late sodium current. It was not effective in reducing major cardiovascular events in a clinical trial, but reduced the rate of recurrent ischaemia.

Statins  (e.g., atorcvastatin 80 mg qd) have been shown to reduce mortality and recurrent MI in the acute setting.

 

2. Antiplatelet agents

Platelet activation and subsequent aggregation play a dominant role in the propagation of arterial thrombosis and consequently are the key therapeutic targets in the management of ACS. Antiplatelet therapy should be instituted as early as possible when the diagnosis of NSTE-ACS is made in order to reduce the risk of both acute ischaemic complications and recurrent atherothrombotic events. Platelets can be inhibited by three classes of drugs, each of which has a distinct mechanism of action.

Aspirin (acetylsalicylic acid) targets cyclo-oxygenase (COX-1), inhibiting thromboxane A₂ formation and inducing a functional permanent inhibition in platelets. However, additional complementary platelet aggregation pathways must be inhibited to ensure effective treatment and prevention of coronary thrombosis. ADP binding to the platelet P2Y₁₂ receptor plays an important role in platelet activation and aggregation, amplifying the initial platelet response to vascular damage. The antagonists of the P2Y₁₂receptor are major therapeutic tools in ACS. The prodrug thienopyridines such as clopidogrel and prasugrel are actively biotransformed into molecules that bind irreversibly to the P2Y₁₂ receptor. A new class of drug is the pyrimidine derivative ticagrelor, which without biotransformation binds reversibly to the P2Y₁₂ receptor, antagonizing ADP signalling and platelet activation. I.v. GP IIb/IIIa receptor antagonists (abciximab, eptifibatide, and tirofiban) target the final common pathway of platelet aggregation.

Aspirin

A daily maintenance dose of 75–100 mg should be continued indefinitely. It has the same efficacy as higher doses and carries a lower risk of gastrointestinal intolerance.

P2Y₁₂ receptor inhibitors include thienopyridines (clopidogrel, prasugrel) and triazolopyrimidine (ticagrelor). Of note, ticlopidine was the first thienopyridine investigated in ACS, but was replaced by clopidogrel because of side effects. Today ticlopidine may still be used in patients who are allergic to clopidogrel, although cross-reactions are possible.

A loading dose of clopidogrel 300-600 mg followed by 75 mg daily maintenance for 9–12 months in addition to aspirin should be given to all patients with NSTE-ACS. The 600 mg loading dose of clopidogrel has a more rapid onset of action and more potent inhibitory effect than the 300 mg dose. Clopidogrel should be withheld for 5-7 days in patients requiring CABG to reduce hemorrhagic complications.

Alternative regimens:

prasugrel loading dose of 60 mg followed by a maintenance dose 10 mg daily

ticagrelor loading dose of 180 mg followed by a maintenance dose 90 mg b.i.d.

 

Glycoprotein IIb/IIIa receptor inhibitors

The three GP IIb/IIIa receptor inhibitors approved for clinical use are i.v. agents belonging to different classes: abciximab is a monoclonal antibody fragment; eptifibatide is a cyclic peptide; and tirofiban is a peptidomimetic molecule.

these agents should be used in conjunction with aspirin, clopidogrel and LMWH or UFH. Eptifibatide or tirofiban should be used in high-risk patients with ongoing ischemia and elevated troponins in whom invasive strategy is not planned/available (<24 hours). In patients with an early invasive strategy, all GP IIb/IIIa receptor inhibitors can be used. Infusion is generally continued for 12 hours post-PCI.

Administration regimens:

Abciximab (ReoPro) – bolus of 0.25 mg/kg i.v. over 1 minute followed by i.v. infusion 0.125 mcg/kg/min (maximum 10 mcg/min) for 12 hours;

Eptifibatide (Integrilin) – bolus 180 mcg/kg followed by i.v. infusion 2 mcg/kg/min;

Tirofiban (Aggrastat) – 400 ng/kg/min for 30 minutes followed by i.v. infusion 100 ng/kg/min.

 

3. Anticoagulants

Several anticoagulants, which act at different levels of the coagulation cascade, have been investigated or are under investigation in NSTE-ACS:

Indirect inhibitors of coagulation (need antithrombin for their full action)

                    Indirect thrombin inhibitors: UFH

                   LMWHs

                    Indirect factor Xa inhibitors: LMWHs

                   fondaparinux

Direct inhibitors of coagulation

                    Direct factor Xa inhibitors: apixaban, rivaroxaban, otamixaban

                    Direct thrombin inhibitors (DTIs): bivalirudin, dabigatran

                    

All patients should be given a LMWH or fondaparinux or UFH.

LMWH should be used in conjunction with aspirin and clopidogrel and continued for 2-5 days after the last episode of pain and ischemic ECG changes.

E.g., enoxaparin 1 mg/kg bid (100 U/kg twice daily).

Fondaparinux is the only selective activated factor X (factor Xa) inhibitor available for clinical use. Fondaparinux is a synthetic pentasaccharide structurally similar to the antithrombin-binding sequence common to all forms of heparin. In ACS, a 2.5 mg fixed daily dose of fondaparinux is recommended.

UFH should be used as an alternative to LMWH and fondaparinux in conjunction with aspirin and clopidogrel. A weight-adjusted dose of UFH is recommended, at an initial bolus of 60–70 IU/kg with a maximum of 5000 IU, followed by an initial infusion of 12–15 IU/kg/h, to a maximum of 1000 IU/h. The therapeutic window is narrow, requiring frequent monitoring of aPTT, with an optimal target level of 50–75 s, corresponding to 1.5–2.5 times the upper limit of normal. At higher aPTT values, the risk of bleeding complications is increased, without further antithrombotic benefits.

In the PCI setting, UFH is given as an i.v. bolus either under activated clotting time (ACT) guidance (ACT in the range of 250–350 s, or 200–250 s if a GP IIb/IIIa receptor inhibitor is given) or in a weight-adjusted manner (usually 70–100 IU/kg, or 50–60 IU/kg in combination with a GP IIb/IIIa receptor inhibitors).

Bivalirudin plus a provisional GP IIb/IIIa receptor inhibitor showed similar efficacy to heparin/LMWHs plus systematic GP IIb/IIIa receptor inhibitors, while significantly lowering the risk of major haemorrhagic complications. However, no significant difference in short- or long-term outcomes was observed between these two anticoagulation strategies. Bivalirudin is currently approved for urgent and elective PCI at a dose of 0.75 mg/kg bolus followed by 1.75 mg/kg/h. In NSTE-ACS patients, bivalirudin is recommended at a dose of 0.1 mg/kg i.v. bolus followed by an infusion of 0.25 mg/kg/h until PCI. Bivalirudin plus provisional

GP IIb/IIIa receptor inhibitors are recommended as an alternative to UFH plus GP

IIb/IIIa receptor inhibitors in patients with an intended urgent or early invasive

strategy, particularly in patients with a high risk of bleeding.

At discharge from hospital, the following measures are necessary:

1. Aspirin: continue life long;

2. P2Y12 inhibitor: continue for 12 months (unless at high risk of bleeding);

3. Beta-Blocker: if LV function is depressed;

4. ACE inhibitor/ARB: if LV function is depressed. Consider for patients devoid of depressed LV function;

5. Aldosterone antagonist/ eplerenone: if depressed LV function (LVEF ≤35%) and either diabetes or heart failure, without significant renal dysfunction;

6. Statin: titrate to achieve target LDL-C levels <1.8 mmol/L (<70 mg/dL)

7. Lifestyle: risk-factor counselling, referral to cardiac rehabilitation / secondary prevention programme.

 

 

References.

A – Basic:

1. Davidson’s Principles and practice of medicine (21^st revised ed.) / by Colledge N.R., Walker B.R., and Ralston S.H., eds. – Churchill Livingstone, 2010. – 1376 p.

2. Harrison’s principles of internal medicine (18^th edition) / by Longo D.L., Kasper D.L., Jameson J.L. et al. (eds.). – McGraw-Hill Professional, 2012. – 4012 p.

3.  The Merck Manual of Diagnosis and Therapy (nineteenth Edition)/ Robert Berkow, Andrew J. Fletcher and others. – published by Merck Research Laboratories, 2011.

4.  Web -sites:

a)   http://emedicine.medscape.com/

b)  http://meded.ucsd.edu/clinicalmed/introduction.htm

 

B – Additional:

1. Braunwald’s Heart Disease: a textbook of cardiovascular medicine (9^th ed.) / by Bonow R.O., Mann D.L., and Zipes D.P., and Libby P. eds. – Saunders, 2012. – 2048 p.

2. Braunwald’s Heart Disease: review and assessment (9^th ed.) / Lilly L.S., editor. – Saunders, 2012. – 320 p.

3. Cardiology Intensive Board Review. Question Book (2^nd ed.) / by Cho L., Griffin B.P., Topol E.J., eds. – Lippincott Williams & Wilkins, 2009. – 385 p.

4. Cleveland Clinic Cardiology Board Review / Griffin B.P., Kapadia S.R., Rimmerman C.M., eds. – Lippincott Williams & Wilkins, 2012. – 952 p.

5. Hurst’s the Heart (13^th ed.) / by Fuster V., Walsh R.A., Harrington R., eds. – McGraw-Hill, 2010. – 2500 p.

5. Oxford Handbook of Cardiology (2^nd ed.) / by Ramrakha P., Hill J., eds. – Oxford University Press, 2012. – 851 p.