Acute coronary syndrome: quick reference for loading doses and time targets

Overview

Acute coronary syndrome comprises STEMI, NSTEMI and unstable angina. Management begins in parallel with the diagnostic work-up. Obtain an interpretable 12-lead ECG within 10 minutes of first medical contact, attach continuous rhythm monitoring, secure intravenous access, assess the circulation and the bleeding risk, and exclude dangerous differential diagnoses [1,2].

STEMI and other ECG patterns suggesting acute coronary occlusion are time-dependent conditions. The decision on immediate reperfusion is based on symptoms, the ECG and haemodynamics. Do not wait for troponin. If clinical suspicion persists despite an initially non-diagnostic ECG, the ECG must be repeated, particularly with ongoing or recurrent pain [1,3,4].

This quick reference gives internationally established doses. Drug availability, thrombolysis regimens, renal function thresholds and the division of work between the ambulance service, the emergency department and the PCI laboratory may differ between Swedish regions. Always follow the local PCI and thrombolysis protocol where it specifies another approved regimen.

The first 10 minutes

1. Assess airway, breathing and circulation.
2. Obtain a 12-lead ECG within 10 minutes.
3. Attach defibrillator pads if the patient is unstable or at marked risk of arrhythmia.
4. Take a full blood count, electrolytes, creatinine, glucose, high-sensitivity troponin and, where needed, coagulation tests. Blood sampling must not delay reperfusion.
5. Give aspirin if acute coronary syndrome is likely and aortic dissection or active major bleeding is not suspected.
6. Call the PCI service immediately in STEMI, a STEMI equivalent or very high-risk NSTEMI.
7. Document symptom onset, first medical contact, the diagnostic ECG, the reperfusion decision, thrombolysis and PCI wire crossing. Exact times are needed for continued management and quality follow-up.

STEMI: time targets and choice of reperfusion

Primary PCI is the method of choice if PCI can be performed within 120 minutes of the STEMI diagnosis. With a longer expected delay and a symptom duration of less than 12 hours, immediate fibrinolysis is recommended in the absence of contraindications, followed by direct transfer to a PCI centre [1,5].

The 120-minute limit is a ceiling for the choice between primary PCI and fibrinolysis, not an acceptable routine target. The shorter the ischaemic time, the more myocardium can be salvaged. Call the PCI service in parallel with drug treatment and transport planning [1,5].

Symptom duration

• Under 12 hours: reperfusion is indicated in persisting STEMI.
• 12 to 48 hours: primary PCI should be considered even if symptoms have subsided, particularly with continuing ischaemia, heart failure, electrical instability or a large area of myocardium at risk.
• Over 48 hours: urgent PCI is still indicated with continuing ischaemia, shock, serious arrhythmia or acute heart failure. Routine opening of a persistently occluded infarct-related artery in a stable and asymptomatic patient is by contrast not recommended [1,5].

STEMI criteria and occlusion patterns on the ECG

Classic ST elevation criteria

New ST elevation at the J point in at least two anatomically contiguous leads indicates STEMI when the following thresholds are met [1,3]:

The thresholds support the diagnosis; they do not replace clinical judgement. Lesser ST elevation may be pathological if it is dynamic or accompanied by reciprocal changes, whereas marked ST elevation may be due to, for example, left ventricular hypertrophy, previous infarction, early repolarisation or pericarditis [4].

Left bundle branch block and ventricular pacing

New or presumed new left bundle branch block is not in itself a STEMI criterion. The timing of the left bundle branch block has low diagnostic precision. Assess instead symptoms, haemodynamics and ischaemic ECG signs, above all the modified Sgarbossa criteria [4,6].

Findings that strengthen the suspicion of acute coronary occlusion are:

• concordant ST elevation in a lead with a positive QRS
• concordant ST depression in V1 to V3
• disproportionately large discordant ST elevation in relation to the preceding S wave

The same principles can be applied in ventricular pacing. An unstable patient with a strong clinical suspicion should be discussed immediately with the PCI service even if the criteria are not fully met.

Posterior infarction

ST depression in V1 to V3, particularly together with tall R waves and upright T waves, may be the mirror image of posterior ST elevation. Record V7 to V9. ST elevation of at least 0.5 mm in at least two posterior leads supports the diagnosis of posterior infarction. Isolated posterior infarction should be managed as an acute occlusion syndrome [1,4].

Right ventricular infarction

In inferior STEMI, right-sided chest leads should be recorded early, above all V3R and V4R. ST elevation in V4R supports right ventricular infarction. The finding affects fluid, nitrate and anaesthetic management.

Other high-risk patterns

Immediate contact with the PCI service is also needed with:

• widespread ST depression in at least six leads with concomitant ST elevation in aVR or V1, particularly with circulatory compromise
• transient ST elevation with recurrent pain
• hyperacute T waves and dynamic changes suggesting early occlusion
• the de Winter pattern
• ongoing ischaemia with left bundle branch block, pacing or an ECG that is difficult to interpret
• refractory ischaemia despite the absence of classic STEMI thresholds

Acute loading doses for primary PCI

Antiplatelet therapy

Aspirin should normally be given to all patients with probable acute coronary syndrome. Enteric-coated tablets are unsuitable as a loading dose because absorption is slower. The standard maintenance dose is low-dose, since a higher long-term dose increases the bleeding risk without established additional ischaemic benefit [7].

Prasugrel and ticagrelor produce faster and more potent platelet inhibition than clopidogrel. In ISAR-REACT 5, cardiovascular death, infarction or stroke occurred in 6.9 percent with prasugrel compared with 9.3 percent with ticagrelor, with no statistically significant difference in major bleeding [8]. The result has influenced European recommendations, but the choice of agent must still be adapted to bleeding risk, previous stroke, age, body weight, planned surgery, the need for oral anticoagulation and the local PCI protocol.

Prasugrel must not be given after previous stroke or TIA. In patients aged 75 or over, or weighing less than 60 kg, particular caution is required and a lower maintenance dose may be appropriate. Prasugrel is not used as routine pretreatment in NSTEMI before the coronary anatomy is known [7,9].

Anticoagulation for primary PCI

Parenteral anticoagulation is given in addition to antiplatelet therapy. Unfractionated heparin is the commonest standard option in primary PCI [1,5,7].

ATOLL compared enoxaparin 0.5 mg/kg intravenously with unfractionated heparin in 910 patients with STEMI. The primary composite endpoint did not reach statistical significance, but several secondary ischaemic outcomes improved without an increase in major bleeding [10]. Fondaparinux, by contrast, must not be used as the sole anticoagulant in primary PCI because it can cause catheter thrombosis [7,11].

Avoid unnecessary switching between different heparins. Always check current or recently given anticoagulation, renal function, body weight and previous heparin-induced thrombocytopenia before a further dose is given.

Fibrinolysis when primary PCI cannot be reached in time

Fibrinolysis is relevant in clear STEMI with a symptom duration of less than 12 hours when primary PCI is not expected to be feasible within 120 minutes of diagnosis. The benefit is greatest with early presentation. Treatment should be given within 10 minutes of the decision to use fibrinolysis and must not be delayed by transport planning [1,5].

A pharmacoinvasive strategy means:

1. immediate fibrinolysis
2. direct transfer to a PCI centre
3. immediate rescue PCI if reperfusion fails
4. angiography within 2 to 24 hours after clinically successful fibrinolysis

In STREAM such a strategy gave a rate of death, shock, heart failure or reinfarction similar to primary PCI in early-presenting patients who could not reach PCI within an hour, but with a somewhat higher risk of intracranial haemorrhage [12].

Tenecteplase

Tenecteplase is given as a weight-based single intravenous bolus:

In older patients, particularly from the age of 75, a reduced dose is used in many modern pharmacoinvasive protocols. In STREAM-2, half-dose tenecteplase in older patients gave a reperfusion effect comparable to primary PCI, but intracranial haemorrhage still occurred and was more common than with primary PCI [13]. The exact age threshold and dose reduction should therefore follow the regional thrombolysis protocol and the current product information.

Antiplatelet therapy with fibrinolysis

Clopidogrel is the standard P2Y12 inhibitor in immediate conjunction with fibrinolysis. Prasugrel must not be given together with acute fibrinolysis. A switch to ticagrelor or prasugrel may become relevant later after PCI assessment and according to the local protocol.

Anticoagulation with fibrinolysis

Enoxaparin is a common option:

For the first two subcutaneous doses, a dose cap of 100 mg per dose under 75 years and 75 mg per dose from the age of 75 usually applies. Always check the creatinine clearance, not only the laboratory's eGFR.

Unfractionated heparin is an alternative, usually a 60 IU/kg intravenous bolus, to a maximum of 4,000 IU, followed by 12 IU/kg/hour, to a maximum of 1,000 IU/hour, adjusted according to the APTT. The choice is governed by the thrombolytic agent, age, renal function and the local protocol.

Contraindications to fibrinolysis

Absolute or strong contraindications include:

• previous spontaneous intracranial haemorrhage
• ischaemic stroke within the past few months
• known intracranial tumour, vascular malformation or other intracranial lesion with a high bleeding risk
• recent major head injury or intracranial surgery
• active clinically significant bleeding
• suspected aortic dissection
• severe uncontrolled hypertension
• recent major surgery or major trauma, depending on the timing and extent
• known severe coagulation disorder or ongoing anticoagulation with a significant effect

If fibrinolysis is contraindicated, the patient should be transferred for primary PCI even if the 120-minute target cannot be met.

Signs of failed fibrinolysis

Rescue PCI is indicated with:

• persisting or recurrent ischaemic symptoms
• less than a 50 percent reduction in ST elevation in the most affected lead after 60 to 90 minutes
• haemodynamic instability or cardiogenic shock
• acute heart failure
• malignant ventricular arrhythmia or other electrical instability

Do not routinely give a second dose of fibrinolysis when the first has failed. Call the PCI service and arrange immediate angiography.

Initial symptomatic and supportive treatment

Glyceryl trinitrate

Do not give glyceryl trinitrate in hypotension, shock, marked bradycardia or suspected critical preload dependence. Avoid nitrates for at least 24 hours after sildenafil or vardenafil and at least 48 hours after tadalafil, since the combination can cause profound hypotension [14].

In right ventricular infarction, nitrates have traditionally been regarded as contraindicated. A systematic review did not, however, find any statistically significant increase in serious complications after sublingual glyceryl trinitrate, although the evidence was very uncertain [15]. In practice, nitrates should be avoided in right ventricular infarction with hypotension or clear preload dependence. Right ventricular infarction without hypotension is a strong indication for caution rather than an absolute, well-founded contraindication.

Morphine

Morphine may be needed for severe pain that persists despite reperfusion planning and other symptomatic treatment, but it should not be given as a matter of routine. Opioids inhibit gastrointestinal motility and can delay the absorption of ticagrelor, prasugrel and clopidogrel.

In a meta-analysis, morphine was associated with higher platelet reactivity two hours after P2Y12 loading and a more than threefold increased risk of high residual platelet reactivity. The evidence base was, however, too small to determine whether this increased mortality or reinfarction [16]. Always document the time and dose if morphine is given.

Oxygen

Routine oxygen for normoxaemic patients is not indicated. In DETO2X-AMI, which included 6,629 patients with suspected infarction and a saturation of at least 90 percent, one-year mortality was 5.0 percent with oxygen and 5.1 percent with ambient air [17].

Give oxygen in:

• saturation below 90 percent
• respiratory failure
• pulmonary oedema with hypoxaemia
• shock with hypoxaemia
• another concurrent indication

Beta blockers

An oral beta blocker can be started during the first 24 hours once the patient is stable. Avoid early intravenous beta blockade in:

• acute heart failure or pulmonary oedema
• hypotension or signs of shock
• marked bradycardia
• high-grade AV block
• severe bronchospasm
• suspected acute ischaemia caused by cocaine or another sympathomimetic, without specialist assessment

NSTEMI and unstable angina

NSTEMI is diagnosed by a compatible clinical picture with a dynamic rise or fall in cardiac troponin and at least one sign of acute myocardial ischaemia. An isolated troponin rise is myocardial injury, not automatically a type 1 infarction [3].

Unstable angina means ischaemic symptoms without troponin dynamics meeting the criteria for infarction. The diagnosis has become less common since the introduction of high-sensitivity troponin assays.

Time to coronary angiography

ESC 2023 specifies immediate angiography in very high risk. Angiography within 24 hours should be considered in high risk, but the recommendation is not equivalent to requiring every troponin-positive patient to undergo angiography within exactly 24 hours regardless of comorbidity and clinical course [1,5].

A meta-analysis of 17 randomised trials with 10,209 patients showed that a generally early invasive strategy reduced recurrent ischaemia and length of stay but did not definitely reduce mortality or infarction compared with later angiography [18]. In VERDICT there was no overall significant benefit of angiography within 12 hours compared with 48 to 72 hours, but patients with a GRACE above 140 appeared to benefit more [19].

Troponin

Use high-sensitivity troponin and the laboratory's validated algorithm, usually:

• a sample on arrival and after 1 hour
• alternatively a sample on arrival and after 2 or 3 hours
• a further sample with persisting suspicion, very early symptom onset or values in the observation zone

The ESC 0/1-hour algorithm has high diagnostic sensitivity, but it does not replace clinical assessment. In a meta-analysis, sensitivity was about 98 percent depending on the assay. Patients in the observation zone had a substantial long-term risk and need further investigation [20].

A normal early troponin does not exclude:

• very early infarction
• unstable angina
• transient coronary occlusion
• posterior or right ventricular infarction
• other acute ischaemia where the reperfusion decision is already evident from the ECG and the clinical picture

P2Y12 inhibitors in NSTEMI

Give aspirin early when the diagnosis is likely and a dangerous bleeding diagnosis is not suspected. Routine loading with a P2Y12 inhibitor before angiography is by contrast not recommended when the coronary anatomy is unknown and an early invasive strategy is planned.

In a meta-analysis of seven randomised trials with 13,226 patients, pretreatment did not reduce cardiovascular events, infarction or cardiovascular death, but increased major bleeding with an odds ratio of 1.51. One additional major bleeding event occurred per approximately 63 patients pretreated [9]. In ACCOAST, pretreatment with prasugrel increased major bleeding without reducing ischaemic events [21].

Practical sequence when early angiography is planned:

1. give aspirin
2. give anticoagulation according to the chosen invasive strategy and the local protocol
3. hold routine P2Y12 loading until the anatomy is known
4. load with prasugrel, ticagrelor or clopidogrel once PCI has been decided, taking contraindications and bleeding risk into account

If angiography will be delayed by more than 24 hours, or if conservative treatment is planned, earlier P2Y12 treatment can be considered after individual assessment [7].

Anticoagulation in NSTEMI

Fondaparinux gave equivalent protection against ischaemic events but considerably less major bleeding than enoxaparin in OASIS-5. Among patients undergoing PCI, major bleeding was 2.4 percent with fondaparinux and 5.1 percent with enoxaparin [22]. Fondaparinux must be supplemented with unfractionated heparin during PCI to prevent catheter thrombosis [11,22].

Fondaparinux is excreted renally and must not be used in severe renal failure according to the product information. Enoxaparin requires dose adjustment in impaired renal function. Use the current weight and the calculated creatinine clearance.

PCI strategy and cardiogenic shock

Radial access is the first choice in invasive management when the operator is proficient in the technique. In MATRIX, radial access gave fewer composite clinical events than femoral access at one year, mainly through less bleeding [23].

In a stable STEMI patient with multivessel disease, complete revascularisation is recommended, either during the index admission or as a planned procedure shortly afterwards. In COMPLETE, complete revascularisation reduced cardiovascular death or infarction from 10.5 to 7.8 percent over a median follow-up of three years [24].

In cardiogenic shock a different principle applies. Acute PCI should initially be confined to the infarct-related artery unless there are particular reasons to treat further vessels. In CULPRIT-SHOCK, death or renal failure requiring dialysis at 30 days was less common with acute PCI of the culprit lesion alone than with immediate multivessel PCI, 45.9 compared with 55.4 percent [25].

Red flags and common pitfalls

Aortic dissection

Think of dissection with sudden maximal pain, radiation to the back, a difference in pulses, focal neurology, a new murmur of aortic regurgitation, pericardial fluid, unexplained shock or a widened mediastinum. Antithrombotic treatment and fibrinolysis can be catastrophic.

Where there is a concrete suspicion, urgent aortic imaging should take priority, usually CT angiography in a stable patient or transoesophageal echocardiography in an unstable patient. Routine CT before antithrombotic treatment is by contrast not justified in typical acute coronary disease without signs of dissection.

Pericarditis and myocarditis

Pericarditis often gives diffuse concave ST elevation and PR depression, without a clear anatomical coronary distribution. Localised myopericarditis can nevertheless mimic STEMI. Where there is uncertainty and possible acute coronary occlusion, the PCI service should be contacted rather than reperfusion delayed by an uncertain alternative diagnosis.

Takotsubo

Takotsubo cannot reliably be distinguished from STEMI on the ECG and troponin alone. Urgent angiography is often required to exclude coronary occlusion.

Right ventricular infarction

The patient may be markedly preload dependent. With hypotension and no pulmonary congestion, a cautious fluid bolus can be given with frequent reassessment. Avoid large uncontrolled fluid volumes, since concomitant left ventricular failure may be present. Avoid nitrates and high opioid doses in hypotension.

Women, older people and people with diabetes

Chest pain is still common, but dyspnoea, nausea, syncope, weakness, new confusion or marked fatigue may dominate. In studies, women have more often experienced delayed prehospital assessment and diagnosis [26]. In older people, frailty, renal function, body weight, cognitive status and bleeding risk should be assessed, but advanced age is not in itself a reason to withhold acute reperfusion [27].

Type 2 infarction and myocardial injury

Sepsis, rapid arrhythmia, pulmonary embolism, severe anaemia, hypertensive crisis and hypoxaemia can all produce troponin dynamics without acute atherothrombotic occlusion. The diagnosis of type 2 infarction requires both acute troponin dynamics and clinical signs of ischaemia caused by an imbalance between oxygen supply and demand. Automatic dual antiplatelet therapy is not justified without evidence of acute coronary thrombosis [3].

A normal troponin early on

Do not withdraw the diagnosis of STEMI because the troponin is normal. Troponin may be normal during the first few hours, and occlusion infarction is an ECG and clinical diagnosis that requires reperfusion before extensive necrosis has had time to develop.

Brief decision aid

Clear STEMI or suspected occlusion

1. Call the PCI service immediately.
2. Give aspirin.
3. Give P2Y12 loading and anticoagulation according to the local STEMI protocol.
4. Choose primary PCI if wire crossing can be achieved within 120 minutes.
5. If not, assess fibrinolysis and give it within 10 minutes of the decision.
6. Always transfer a thrombolysed patient to a PCI centre.

Suspected NSTEMI

1. Take serial ECGs and high-sensitivity troponin.
2. Give aspirin in the absence of contraindications.
3. Assess risk clinically and with GRACE.
4. In very high risk, immediate angiography.
5. In high risk, consider angiography within 24 hours.
6. Avoid routine P2Y12 pretreatment before early angiography.
7. Choose the anticoagulant according to the angiography plan, renal function and bleeding risk.

References

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