Acute Coronary Syndromes (ACS)

Definition and Diagnostic Criteria

Acute coronary syndromes (ACS) are typically caused by the rupture or erosion of an unstable coronary artery atherosclerotic plaque which causes partial or complete coronary artery thrombosis and/or microemboli, resulting in diminished blood flow to the myocardium and subsequent myocardial ischemia

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Acute coronary syndromes include

   -Unstable angina pectoris (UAP)

   -Non–ST-elevation myocardial infarction (NSTEMI)

   -ST-elevation myocardial infarction (STEMI)

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The pathophysiology of ACS can be dynamic and thus patients can rapidly progress from one clinical condition (unstable angina, NSTEMI, STEMI) to another during the course of their presentation and initial evaluation and treatment. Thus serial ECG is essential if symptoms persist.

If obstruction is partial or transient, significant/detectable myocyte necrosis might not develop and the condition is named unstable angina (UAP). Unstable angina is defined by transient ischemia leading to diminished flow in the absence of significant myonecrosis detected by circulating troponin.

More prolonged or severe myocardial ischemia leads to elevated biomarkers of myocardial necrosis. If coronary occlusion causes myocardial cell death, the result is myocardial infraction (NSTEMI or STEMI).

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Diagnostic criteria for MI:​

Elevated troponin above the 99th percentile upper reference limit, with a rise/fall in serial measurements, and one of the following:

• Symptoms consistent with ischemia

• Ischemic ECG changes

• Development of pathological Q-waves

• New loss of viable myocardium or regional wall motion abnormality on imaging

• Coronary thrombus seen on angiography or autopsy
   

Patients who have troponin elevations without other features of ischemia (eg, new regional wall motion abnormality, angiographic stenosis, typical electrocardiographic changes) are diagnosed with myocardial injury. If such features are present, then patients are diagnosed with MI. 

Diagnostic criteria for unstable angina (UAP):

• Prolonged rest angina (usually > 20 minutes) or

• New-onset angina of at least CCS class 3 severity (within 1(–2) months) or

• Worsening angina: previously diagnosed angina that has become distinctly increased in frequency, duration, severity, or lower threshold. (eg, increased by ≥ 1 CCS class or to at least CCS class 3)

Types of MI

The term “myocardial infarction” (MI) was inconsistent until the WHO standardized terminology in the 1950s–1970s using ECG criteria. Since then, four Universal Definition of MI (UDMI) documents have refined the diagnosis:

• 2000: introduced biomarkers (troponin T/I) as key diagnostic tools.

• 2007: defined five MI types and required a troponin rise/fall with at least one value above the 99th percentile.

• 2012: added criteria for left bundle branch block, paced rhythms, and emphasized imaging and clinical context.

• 2018: updated for high-sensitivity troponin use, clarified chronic elevations, and distinguished myocardial injury, ischemia, and infarction.

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MI is classified into 5 etiological types:

1. Type 1: Plaque rupture/erosion with thrombosis/thrombus embolism leading to decreased myocardial blood flow and subsequent myocardial necrosis.

2. Type 2: Supply–demand mismatch without acute thrombosis (e.g., tachyarrhythmia, anemia, pulmonary edema, pneumonia, sepsis)

3. Type 3: Sudden cardiac death with suggestive symptoms before biomarkers are available or proven at autopsy

4. Type 4: PCI-related MI

5. Type 5: CABG-related MI
    

Special groups: spontaneous coronary dissection, Takotsubo syndrome

Differentiating between the types of MI is important, as management approaches are very different. For instance, patients with type 2 MI will likely not benefit from antiplatelet therapy targeted against thrombus formation, whereas this is a cornerstone of medical management for those with type 1 MI. Elevations in serum Tn inform the clinician about the presence of myocardial injury, but not the mechanism.

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Epidemiology

In Europe, the median age-standardized incidence of acute coronary syndrome is approximately 293.3 per 100,000 people. The incidence and prevalence of ACS vary significantly between different populations.

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More than half of all ACS patients are older than 75 years and over 60% of ACS patients are women.

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Prognosis

Among patients aged 35–74 who are hospitalized alive after an MI, the age-adjusted one-year mortality is approximately 15% in men and 13% in women.

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In a 2016 study, the 28-day age-adjusted case fatality rate in the 35–84 age group was 30–40% in men. Two-thirds of patients who die from a coronary event die at home, en route to the hospital, or in the emergency department. After hospital discharge (29–365 days post-MI), mortality is relatively low compared to the early phase.

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STEMI vs NSTEMI:

Early mortality (< 30 days after onset) is clearly higher in STEMI patients compared with NSTEMI patients.

However, one year after the event, mortality rates between the two groups clearly even out

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Long-term risk:

Even if the short-term risk of recurrent events is low, long-term prognosis can be poor.

The strongest predictors of arrhythmic sudden cardiac death are impaired left ventricular function, clinical heart failure, and documented ventricular tachycardia.

After MI, the risk of recurrent events remains elevated in the long term.

In European studies, the risk of a recurrent event (death, MI, or stroke) is about 20–25% in the first year, and 30–40% over three years.

Risk factors

Independent risk factors for coronary events and coronary artery disease include:

• Age

• Family history: coronary artery disease in a first-degree male relative before age 55, or female relative before age 65

• Male sex

• Smoking

• High LDL cholesterol

• Diabetes

• Hypertension

• Physical inactivity and prolonged sitting

• Chronic kidney disease

• Chronic inflammatory diseases, particularly rheumatic diseases
   

The probability of coronary artery disease is also increased by the presence of other known atherosclerotic vascular disease.

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Working Diagnosis

Working diagnoses when treating chest pain patients include:

• STEMI (ST-elevation myocardial infarction)

• NSTEMI (non-ST-elevation myocardial infarction)

• UAP (unstable angina pectoris)

• Other cardiac chest pain (e.g., myocarditis)

• Other non-cardiac chest pain

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A normal Coronary CT angiography ruling out both obstructive and non-obstructive plaque has a high NPV to exclude ACS and is associated with excellent clinical outcomes.

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Clinical Spectrum

ACS presentations range widely, from asymptomatic episodes to typical chest pain.

Typical chest pain:

• Pressure, heaviness, or tightness behind the sternum

• Ischemic chest pain is typically diffuse, central, and not localized to the “heart area” on the left chest wall.

• Often radiating to arms, neck, jaw, or upper abdomen

• not influenced by breathing or body position

• Characteristically lasts several minutes

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• Other associated symptoms:

  • Dyspnea (shortness of breath)

  • Sweating

  • Nausea or vomiting

  • Heartburn

  • Dizziness or syncope

  • Preceding symptoms may include crescendo angina (progressively worsening angina) or unstable episodes.

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In elderly and diabetic patients, atypical symptoms (e.g., dyspnea, fatigue, confusion) may be the only manifestations of MI.

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Risk Scoring Systems in ACS

Several risk scoring systems have been developed, such as GRACE and TIMI. These scores assume that the patient is experiencing an acute coronary syndrome.

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The European Society of Cardiology (ESC) recommends the use of the GRACE score for risk stratification and prognosis assessment in ACS.

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The study populations used to develop these scores are more than 10 years old, which may lead to an overestimation of risk in current practice.

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Clinical Findings

Sympathetic activation and pain often cause mild tachycardia and hypertension.

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Inferior wall infarction (or spontaneous/intentional reperfusion of such) may cause hypotension, bradycardia, or complete AV block, either due to a vagal reflex or ischemia of the conduction system.

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Myocardial infarction can lead to mitral regurgitation, either from localized ischemia (impaired papillary muscle relaxation) or papillary muscle rupture. Severe regurgitation due to chordal rupture may not produce a murmur, but causes rapid hemodynamic deterioration, often with refractory desaturation or pulmonary edema.

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A pericardial friction rub may occur due to pericardial irritation (Dressler’s syndrome), typically several days after infarction. Dresslers syndrome is becoming more rare because of modern reperfusion therapies.

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Free (lateral) wall or ventricular septal rupture can cause hemodynamic collapse. Ventricular septal rupture causes a loud pansystolic murmur.

Cardiogenic shock is suggested by tachycardia, tachypnea, dyspnea, pulmonary crackles, cool extremities, hypotension, low pulse pressure, confusion, and agitation.

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Echocardiography

Echocardiography is the most important non-invasive imaging tool. It should be performed before coronary angiography.

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All MI patients should undergo echocardiography during hospitalization as part of the comprehensive evaluation.

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In patients with ongoing or prolonged chest pain (>45 minutes), the absence of new regional wall-motion abnormalities on echocardiography effectively excludes major transmural myocardial ischaemia or infarction (large occlusive MI/STEMI-type events) (EACVI/ACCA position paper). ESC STEMI guidelines from 2012 state that absence of new wall-motion abnormality excludes major myocardial infarction, this of course does not apply to recent onset chest pain as WMA takes time to develop.

The above does not apply when pain is early, brief, or resolved, or in small infarcts, posterior/LCx involvement. . A normal echo also does not rule out NSTEMI or smaller ACS events, where high-sensitivity troponin remains the diagnostic standard.

Echocardiography should be used as an adjunct, particularly helpful when the ECG is nondiagnostic (e.g., LBBB, pacing, LVH). The presence of a new RWMA in that setting supports urgent angiography. ECHO should never delay reperfusion when STEMI is suspected.

Prior infarctions may appear as wall thinning or motion abnormalities.

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Echo is also useful in distinguishing conditions mimicking MI or causing ECG changes (e.g., aortic dissection, pericarditis, Takotsubo syndrome, tamponade, pulmonary embolism, valvular disease).

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Electrocardiography (ECG)

If the initial ECG is non-diagnostic, repeat recordings should be performed especially if symptoms persist, worsen or recur.

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Repeat ECFs may be needed every 15–30 minutes.

Always record 15–16 leads in suspected ACS (standard 12-lead + V4R + V7–V9).

V4R: to detect right ventricular infarction.

V7–V9: to detect posterior wall infarction (often manifests as ST depression in V1–V4).

An ECG recorded during cardiac chest pain in ACS is rarely normal.

Ischemia appears as ST elevation, ST depression, or T-wave changes.

Parallel lead groups include:

• Anterior: V1–V6

• Inferior: II, III, aVF

• Lateral: I, aVL, plus V7–V9
   

Pseudonormalization: a previously negative T-wave may become positive during ischemia.

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NSTEMI has a different and more variable pathophysiology than STEMI. ECG provides less anatomical information in NSTEMI; culprit lesion localization is not possible. Culprit lesion localization is based on the area of maximal ST elevation.

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Other serious conditions causing ST changes must be considered, including aortic dissection, pulmonary embolism, and acute intracranial events.

For Takotsubo syndrome, there are no specific ECG criteria; it may mimic a STEMI and diagnosis is made often via emergency angiography.

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ECG in STEMI

When a coronary artery becomes occluded, the T-wave quickly becomes tall and symmetrical.

Unless the artery reopens, in most cases there is development of ST-segment elevation or, in posterolateral infarction, maximal ST depression in leads V1–V4.

Evolution of changes in STEMI:

In STEMI, one can distinguish between pre-infarction syndrome and an evolving myocardial infarction:

• Pre-infarction syndrome: no Q wave yet, ST-segment elevation is present, and the T-wave is positive.

• Evolving MI: as the infarction develops, a pathological Q wave or T-wave inversion appears, ST elevation may persist.

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In the acute phase, a Q wave may result from altered direction of depolarization due to ischemia, rather than myocardial necrosis, and so Q waves may disappear during hospitalization (“healing” Q waves after reperfusion).

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When the occluded artery reopens, the T-wave becomes fully inverted and the ST segment usually normalizes, reflecting restoration of myocardial blood flow.
 

ST elevation may persist despite artery patency if microvascular circulation is impaired, for example due to distal embolization or tissue edema.

Localizing the culprit artery:

• In STEMI, the culprit vessel can be identified based on the lead with maximal ST elevation (the ischemic core area).

• Anatomical localization and culprit lesion identification by ECG requires the presence of ST elevation.
   

Special consideration:

If acute STEMI is suspected (typical prolonged chest pain) but the ECG shows bundle branch block or paced rhythm, immediate coronary angiography should be considered.

ECG in UAP and NSTEMI

In NSTEMI, ECG changes do not localize the culprit lesion.

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In 10–15% of ACS patients, the ECG is normal. However, an ECG recorded during anginal chest pain is only rarely normal.

Even a small ST depression (0.5 mm) in a patient with new or worsening chest pain strongly suggests an ischemic etiology.

Global ischemia pattern:

A characteristic ECG pattern of global ischemia helps identify patients who require very urgent treatment among the large group of suspected or confirmed ACS cases.
Findings include:

• ST depression in at least six leads (especially with maximal change in V4–V6)

• associated with negative T waves in those leads and ST elevation in lead aVR

This combination indicates severe three-vessel disease or left main coronary artery disease, and is associated with a high risk of major adverse events

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ECG in Previously Suffered Myocardial Infarction

A Q wave or QS complex seen on ECG is often a sign of prior infarction, provided there are no confounding factors affecting QRS interpretation.

A pathological Q wave may develop after STEMI, and this process can take 2–3 days.

A transmural infarction (extending through the full thickness of the myocardium) may occur even without Q waves. Conversely, a non-transmural lesion may sometimes present as an abnormal Q wave.

Diagnostic accuracy of a suffered MI improves when Q waves are present in multiple leads.

Important considerations in asymptomatic patients:

• A Q wave may also result from other causes, such as:

  • ventricular pre-excitation

  • cardiomyopathy

  • LVH or RVH

  • LBBB

  • left anterior fascicular block

  • abnormal heart position (e.g., horizontal orientation due to a high diaphragm)

  • electrode misplacement

​Therefore, before labeling an asymptomatic Q wave as evidence of a prior MI, other causes must be considered, electrode placement verified, and echocardiography should be performed to confirm or exclude myocardial injury.​

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Troponins

Troponins are structural proteins of cardiomyocytes that are released into circulation due to any myocardial injury.

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Troponin measurement is an essential complement in diagnosing and risk stratifying acute coronary syndrome (UAP vs NSTEMI/STEMI).

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In patients with MI, levels of cTn rise rapidly (usually within 1 h if using high- sensitivity assays) after symptom onset and usually remain elevated several days.

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Troponin levels should be measured at admission and again 1–3 hours after the first sample.

ESC high-sensitivity protocols:

The ESC 0/1-hour algorithms using high-sensitivity troponin T (hs-TnT) or I (hs-TnI) are highly sensitive, with a negative predictive value of 99.2–99.8% for ruling out NSTEMI.

It is recommended to use the 0 h/1 h algorithm or the 0 h/2 h algorithm. The ESC 0 h/3 h algorithm is an alternative for cases where the ESC 0 h/1 h or 0 h/2 h algorithms are not available.

The majority of currently used point-of-care (POC) tests cannot be considered high-sensitivity assays. Automated assays have been more thoroughly evaluated than POC tests and are currently preferred.

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Discharge after a 1-hour protocol is as safe as after a 3-hour protocol.

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Patients who don’t fit the ‘rule-out’ or ‘rule-in’ groups fall into the ‘observe’ group. These patients are diverse and have a mortality rate similar to rule-in cases. Therefore, individual risk assessment (e.g., risk scores) is crucial. A third cTn test at 3 hours, with potential echocardiography, is advised to guide further care. In cases of suspected ACS with diagnostic uncertainty, TTE can be useful to identify signs suggestive of ongoing ischaemia or prior MI.

Most patients in the observe zone with a high degree of clinical suspicion of ACS (e.g. relevant increase in cTn from presentation to 3 h) are candidates for invasive angiography. Most patients with a low to intermediate likelihood for ACS according to clinical judgment are candidates for non-invasive imaging.

A very low hs-troponin concentration combined with a normal ECG is sufficient to rule out MI if:

• at least 2 hours have passed since symptom onset, and

• the patient is asymptomatic.
   

Interpretation of elevated troponins:

Elevated troponin confirms myocardial injury, but not necessarily ischemic type 1 MI; other causes of injury must be considered. The PPV for MI in patients meeting the ‘rule-in’ pathway criteria in several studies has been ∼70–75%.

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A markedly elevated troponin (> 5× the 99th percentile) usually indicates myocardial infarction.

Mild elevations are often due to other acute or chronic conditions.

In patients with suspected NSTE-ACS, four factors affect hs-cTn levels besides the presence of MI:

• Age: levels can differ up to 300% between very young and very old healthy people.

• Renal function: patients with high vs. low eGFR can differ by up to 300%.

• Time since chest pain began: differences can exceed 300%.

• Sex: smaller effect, about 40%.

Even with these differences in baseline levels, absolute changes in hs-cTn are still of value in diagnosing MI. Using sex-specific hs-cTn cutoffs has shown mixed results and no clear clinical advantage. Until tools that adjust for all factors (e.g. age, kidney function, time from pain onset, and sex) are available, a single uniform cutoff remains the standard for early MI diagnosis.

Elevated hs-troponin values can also be detected in healthy individuals after strenuous physical exercise.

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Troponin kinetics:

• hs-TnT may remain elevated for 7–14 days

• hs-TnI for 4–7 days after symptom onset.

• hs-TnT may show a biphasic rise.

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Chronic Tn Elevation and Acute Myocardial Injury

Diagnosis of acute MI requires a dynamic change between two samples; a persistently elevated but stable value suggests chronic injury.

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There is no clear consensus on a specific threshold for acute injury in chronic Tn elevation. When the patient’s baseline Tn is >99th percentile URL, Tn increases ≥ 50% of the 99th percentile URL or changes > 20% of the baseline (often measured over 3-6h(-9h) interval) Tn can be considered acute. Chronic myocardial injury is often characterized by persistently elevated Tn values > 99th percentile URL not meeting the above criteria

No validated cutoff values of troponin specific to patients with chronic kidney disease are available. Hence, isolated measurements are difficult to interpret, especially when baseline levels are not known on presentation. Any acute kidney injury in which the serum creatinine level increases by 40% to 60% may result in a 20% rise in cardiac troponin, followed by a subsequent fall during the recovery phase of the kidney injury, mimicking the pattern seen in acute coronary syndrome

For patients with chronic kidney disease and signs that suggest acute coronary syndrome, tracking the rise and fall of cardiac troponin levels over the 3 hours after presentation with high-sensitivity assays, or over 6 hours with conventional assays, or up to 9 hours in those with end-stage renal disease, rather than documenting a single value or a rapid change over a 1-hour period, should be considered.

When initial levels are only mildly elevated (eg, high-sensitivity troponin T < 20 ng/L), any absolute change greater than 5 or 10 ng/L should also raise concern for acute coronary syndrome. Several studies have reported small absolute changes in troponin in patients with acute coronary syndrome, possibly as a result of plaque rupture occurring days before clinical presentation, when troponin samples are taken during the plateau phase of troponin release. Therefore, symptom duration should also be taken into account.

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General Initial Management in ACS

Oxygen therapy:

Routine oxygen therapy is not recommended if SpO₂ ≥ 90%.

Supplemental oxygen may even increase infarct size.

Oxygen should be given if there is measured hypoxemia (SpO < 90%), shock, or marked respiratory failure.

Target saturation: 94–98%, or 88–92% in severe COPD.

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Nitrates:

Relieve chest pain and acute ischemia.

No proven prognostic benefit.

In initial management fast-acting nitrate should be given provided systolic BP ≥ 100 mmHg.

Additional doses can be given every 5 minutes with BP monitoring.

If pain persists, or in hypertension/pulmonary edema, start nitrate infusion (target: systolic BP < 140 mmHg).

Nitrates should be used with caution in right ventricular infarction, severe aortic stenosis, or post-resuscitation.

Aspirin (ASA):

Cornerstone of ACS treatment.

Should generally be given even if already part of the patient’s home medication.

Beta-blockers:

Early routine IV beta-blockade does not improve prognosis in PCI-treated STEMI.

In hemodynamically stable patients, beta-blockers are safe and reduce ventricular arrhythmias.

Reduce catecholamine effects and oxygen consumption by lowering HR, BP, and contractility.

Beta-blockade increases cardiogenic shock risk in patients with unstable hemodynamics. Treatment should be approached with caution if left ventricular function is unknown.

Example: metoprolol 2.5–5 mg IV, if the patient is tachycardic or hypertensive and without acute HF, shock, or conduction disturbances.

Analgesia and sedation:

Adequate pain control reduces sympathetic drive, vasoconstriction, and myocardial workload.

Routine opioid use should be avoided.

For severe pain: morphine (or oxycodone) 4 mg IV, followed by 2–4 mg IV every 5 min as needed.

Benzodiazepines (e.g., diazepam 2.5 mg IV, lorazepam 1 mg IV) may be used for anxiety, reducing oxygen demand and opioid need.

For nausea: ondansetron 4 mg IV or droperidol 1.25 mg IV. Always check QT interval before use.

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Primary PCI and Fibrinolysis

The first-line treatment for STEMI patients is primary PCI (immediate percutaneous coronary intervention). PCI should be performed within 120 minutes from first medical contact. If this is not possible, fibrinolysis should be considered.

In anterior STEMI, fibrinolysis should be administered if PCI cannot be performed within 90 minutes.

Fibrinolysis can be given up to 12 hours after symptom onset if PCI is not available. Effectiveness decreases significantly beyond 3 hours from symptom onset. After 12 hours, fibrinolysis is not beneficial and may be harmful due to increased bleeding risk.

After fibrinolysis, patients should be transferred to a center with immediate PCI capability.

Efficacy of fibrinolysis is assessed by ECG and symptom resolution. Rescue PCI is indicated if fibrinolysis appears ineffective. A control ECG should be recorded within 60 minutes of starting fibrinolysis. Resolution of chest pain alone is unreliable as a measure of success of fibrinolysis.

In a study of 386 STEMI patients who underwent angiography 90 minutes after tPA fibrinolysis:

• Of those with complete ST resolution before angiography, 96% had reperfusion.

• With partial ST resolution, 84% had reperfusion.

• With complete chest pain relief prior to angiogram, 84% had reperfusion

• Surprisingly, 56% of those with no ST or symptom resolution still had open arteries.

ST resolution is used as a way to assess success of fibrinolysis even though it is not a completely accurate marker.

A ≥ 50% reduction in ST elevation (at the lead with maximal initial elevation) at 60 minutes strongly suggests successful reperfusion. Lack of such improvement indicates persistent occlusion or at least poor microvascular flow (due to edema, peripheral microthrombi).

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Fibrinolysis should not be repeated if unsuccessful. Instead, urgent coronary angiography and rescue PCI should be performed.

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Patients receiving fibrinolysis therapy should receive:

• Antiplatelets: ASA and an ADP receptor blocker clopidogrel

• Anticoagulant: enoxaparin or fondaparinux

• Fibrinolytic drug

If the patient has already received prasugrel or ticagrelor loading, fibrinolysis should only be given for vital indications (e.g., resuscitation, cardiogenic shock).

For elderly patients or those at high bleeding risk, immediate PCI is preferred to fibrinolysis. If fibrinolysis is used in patients > 75 years, consider half-dose tenecteplase to reduce the risk of intracranial bleeding.

After successful fibrinolysis, angiography should be performed within 2–24 hours

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Monitoring in Myocardial Infarction

Intensive or coronary unit care is required for patients with ongoing or extensive ischemia or hemodynamic instability.

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Invasive blood pressure monitoring is necessary only if the patient is hemodynamically unstable or if there is impaired oxygenation.

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Cardiogenic shock

Cardiogenic shock is the most severe form of heart failure, in which a critically reduced cardiac output leads to marked impairment of tissue perfusion.

Cardiogenic shock complicates 5–10% of acute myocardial infarctions. Early mortality remains high, around 40–50% despite advances in treatment.

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Patients are often tachycardic, hypotensive, confused, with increased respiratory rate, cold periphery, and frequently hypoxemia.

The majority of patients have multivessel coronary artery disease or acute left main stenosis.

Other causes include:

• Extensive myocardial necrosis.

• Severe ischemic myocardial stunning.

• Mechanical complications such as papillary muscle rupture, ventricular septal rupture, or free wall rupture.

In cases of mechanical complications, rapid diagnosis and urgent surgery are needed.

PCI is generally the first-line therapy, provided that rapid and sufficiently extensive revascularization can be achieved. In patients with severe multivessel disease, emergency CABG may be required.

Initial treatment focuses on optimizing hemodynamics with pharmacological support and mechanical circulatory support when necessary (e.g., intra-aortic balloon pump, ECMO), especially in refractory cases.​