Acute Coronary Syndromes w/out Persistent ST-Segment Elevation : Management

Content on this page:

Evaluation

Pharmacological therapy

Nonpharmacological

Content on this page:

Evaluation

Pharmacological therapy

Nonpharmacological

Evaluation

Repeat Tests

ECG

Perform serial ECGs or if the patient experiences a new episode of chest pain, a 12-lead ECG is obtained and compared with the ECG taken without symptoms. ECG recordings may be repeated at least 6 to 9 hours and 24 hours after presentation. More than 24-hour rhythm monitoring is recommended in NSTEMI patients at increased risk for cardiac arrhythmia while <24-hour monitoring is sufficient for those at low risk for cardiac arrhythmia.

Biochemical Markers

A conventional cTn assay of <99th percentile should be repeated 3-6 hours later (1 to 3 hours later if using hs-cTn). The patient is admitted if there is a >99th percentile or >50% change in the levels of cTn within a 3-hour period*.

If the change in cTn levels is <99th percentile or <50% within a 3-hour period*, consider the following:

Admitting the patient if there is still pain and/or a HEART score of >3** or thrombolysis in MI (TIMI) score of ≥2**
Discharge the patient for early outpatient cardiology consult if without pain and HEART score <3** or TIMI score is 0 or 1**

*If the initial baseline cTn or hs-cTn is markedly >99th percentile, a change of >20% is significant; if the baseline is less than or around the 99th percentile, a change of at least 50% is required to be significant.
**Use HEART score for scoring if cTn is used. Use modified HEART score or TIMI score if hs-cTn is used.

Further Testing

Further testing may be performed prior to discharge or as an outpatient to ascertain diagnosis. A stress test may be performed to provoke ischemia. Evaluation of LV function is considered if ischemia is present. However, if stress test is negative and history is still suggestive of ischemic pain, a nuclear scan, cardiac MRI or a CT coronary angiogram may be considered. If the stress test is negative and history is not suggestive of ischemic pain, an alternative diagnosis should be sought. A treadmill ECG, stress myocardial perfusion imaging, or stress echocardiography before discharge or within 72 hours after discharge is suggested in patients with possible ACS who have normal serial ECGs and cTn. Lastly, the patient is treated appropriately.

Evaluation for Risk Stratification

Medical history, physical exam, ECG, biochemical markers, and assessment of renal function can be used to estimate the risk of death and non-fatal cardiac ischemic events. The assessment of risk is useful in the selection of site of care (eg intensive care unit [ICU], monitored unit, outpatient), and in the selection of treatment. Risk assessment should be done repeatedly. Patients with ACS and with ongoing angina, hemodynamic instability, uncontrolled arrhythmias, suboptimal reperfusion, or cardiogenic shock should be admitted to a cardiac ICU to reduce CV events.

Patients with high likelihood of ACS secondary to CAD are at greater risk of untoward cardiac events than patients at less risk of CAD. High-likelihood signs and symptoms of CAD include chest or left arm pain or discomfort as chief symptom reproducing prior to the documented angina, known or prior history of CAD including MI, presence of transient mitral regurgitation, murmur, hypotension, diaphoresis, pulmonary edema or rales, elevated cardiac markers, and ECG result of a new or presumably new, transient ST-segment deviation or T-wave inversion in multiple precordia leads.

Prognostic information to predict short- or mid-term risk ischemic events commonly use the Global Registry of Acute Coronary Events (GRACE), the TIMI score, the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) risk score, and the National Cardiovascular Data Registry-Acute Coronary Treatment and Intervention Outcomes Network (NCDR-ACTION).

Very High-Risk Criteria

Acute heart failure
Arrhythmias (life-threatening) or cardiac arrest
Hemodynamic instability or cardiogenic shock
Mechanical complications of MI
Recurrent dynamic ST-T wave changes with or without intermittent ST-elevation
Recurrent or ongoing chest pain refractory to medical treatment

High-Risk Criteria

Dynamic ST- or T-wave changes (symptomatic or silent)
Rise or fall in cTn compatible with MI (confirmed diagnosis of NSTEMI based on ESC hs-cTn algorithms)
GRACE score >140
Transient ST-segment elevation
TIMI score >4

Intermediate-Risk Criteria

DM
Renal insufficiency (eGFR <60 mL/min/1.72 m²)
Left ventricular ejection fraction (LVEF) <40% or congestive heart failure (CHF)
Early post-infarction angina
Previous revascularization (PCI/CABG)
GRACE score >109 and <140
TIMI risk score 3 and 4

Low-Risk Criteria

Any characteristics not mentioned in above criteria

Stress Test

A stress test may be performed in patients with low and intermediate risk who have no ischemia at rest or with low level activity for a minimum of 12 to 24 hours prior to discharge or as an outpatient. This confirms or establishes the diagnosis of CAD and assesses risk for future CV events. Patients with significant ischemia during exams should be considered for coronary angiography.

Pharmacological therapy

Antiplatelet Agents¹

The choice of antiplatelet agent and duration of therapy is based on the patient’s bleeding risk and anticipated management strategy. For patients undergoing PCI, Aspirin plus Prasugrel or Ticagrelor is recommended. For patients undergoing CABG, Aspirin plus Clopidogrel or Ticagrelor is recommended. For patients without planned invasive evaluation, Aspirin plus Ticagrelor is recommended. In patients with ACS treated only with medical therapy, PCI, or CABG, 12 months of dual antiplatelet therapy (DAPT) (Aspirin plus P2Y₁₂ receptor inhibitor) is recommended unless with contraindications. Continuing therapy for >12 months is considered in patients with previous MI and are tolerant of DAPT with no bleeding complication. At least 1 month of DAPT is considered in patients treated only with medical therapy and are at high risk of bleeding. Aspirin or P2Y₁₂ inhibitor monotherapy after 1 month of DAPT may be considered in patients with high bleeding risk. Consider stopping therapy after 6 months in patients treated with PCI or CABG and are at high risk of bleeding. Abbreviated DAPT strategies (shortening DAPT to 3 to 6 months in patients with high bleeding risk followed by P2Y₁₂ inhibitor monotherapy within the first 12 months of ACS) may be considered in patients who are event-free after 3 to 6 months of DAPT and without high risk of ischemic events, with DAPT duration guided by patient’s ischemic and bleeding risks. DAPT for 1 to 3 months is recommended in patients with high bleeding risk who will undergo PCI for ACS or elective PCI followed by maintenance single antiplatelet therapy (SAPT, Aspirin or P2Y₁₂ inhibitor monotherapy) thereafter in those without any ischemic or bleeding events in the first month. Patients with ACS who stop DAPT to undergo CABG should resume DAPT after CABG for at least 12 months.

Discontinuation of antiplatelet treatment after 12 months is recommended in patients treated with an oral anticoagulant. For long-term treatment, adding a second antithrombotic agent to Aspirin should be considered in patients at high risk of ischemic events without high risk for bleeding and may be considered in patients with moderate ischemic risk without high risk of bleeding. Twelve-month DAPT should be given in patients with ACS and chronic kidney disease (CKD) with eGFR of 15 to <50 mL/min/1.73 m² with prior major adverse CV event and without high risk of bleeding. Patients with an eGFR of <60 mL/min/1.73 m² with high risk of bleeding may be given Aspirin or Clopidogrel. The duration of DAPT is shortened in patients with an eGFR of <15 mL/min/1.73 m² and at high risk of bleeding. In patients >75 years old, the duration of DAPT is shortened (eg 1 to 6 months) in frail elderly patients or in those who are not frail but with high risk of bleeding.

Pretreatment with P2Y₁₂ inhibitor may be considered in the following patients:

Those who will undergo primarily PCI
- In patients with ACS who are undergoing PCI, Prasugrel or Ticagrelor is recommended over Clopidogrel
- Patients with ACS who will proceed to PCI and did not receive pretreatment P2Y12 inhibitor should have a loading dose at the time of PCI
With NSTE-ACS who will undergo early invasive procedure and without high risk of bleeding

Upstream treatment with Clopidogrel or Ticagrelor may be considered to reduce major adverse CV events in patients with NSTE-ACS who are scheduled for an invasive strategy with timing of angiography to be >24 hours.

Measures to reduce bleeding risk in patients with ACS who underwent PCI and require antiplatelet therapy include:

Use of a proton pump inhibitor in patients at risk of GI bleeding
Transition to Ticagrelor monotherapy 1 to 3 months after PCI in patients who have tolerated DAPT with Ticagrelor
Discontinuation of Aspirin from triple therapy (DAPT plus oral anticoagulant) 1 to 4 weeks after PCI with continued use of P2Y₁₂ inhibitor (preferably Clopidogrel) and oral anticoagulant in patients who require long-term anticoagulation
P2Y₁₂ inhibitor de-escalation or switching from Prasugrel or Ticagrelor to Clopidogrel after 1 month of DAPT
- The risk of ischemic events is increased and is therefore not recommended in the first 30 days after the index ACS event

Aspirin

Aspirin should be given promptly and continued daily in all patients with suspected ACS, unless there are contraindications. The initial loading dose of 162 to 325 mg (non-enteric-coated formulation and should be chewed) is followed by 75 to 100 mg (non-enteric-coated formulation) daily, to be continued indefinitely. A 75 to 100 mg dose of Aspirin is recommended in patients being treated with DAPT. Aspirin exerts antithrombotic effect by irreversible inhibition of cyclooxygenase-1 within platelets which prevents the production of platelet-aggregating substance, thromboxane A₂. Administration of daily Aspirin has been shown to consistently decrease risk of death and MI in patients with UA. Aspirin may be withheld 7 to 10 days prior to elective CABG.

Cangrelor

Cangrelor is recommended for patients who may be considered for P2Y₁₂ inhibitor-naïve patients undergoing PCI. It is an intravenous (IV) adenosine triphosphate analogue that binds reversibly and with high affinity to the platelet P2Y₁₂ receptor. It has a short plasma half-life. Lastly, Cangrelor produces a highly effective inhibition of ADP-induced platelet aggregation immediately after IV bolus administration and allows for restoration of platelet function 1 to 2 hours of infusion discontinuation in NSTE-ACS patients.

Clopidogrel

Clopidogrel is recommended in combination with Aspirin in UA or NSTEMI patients when Ticagrelor or Prasugrel is unavailable, cannot be tolerated or contraindicated. An initial dose of 300 mg is followed by 75 mg daily for at least 1 month and ideally up to 12 months. In patients with definite NSTEMI undergoing an invasive management, an initial dose of 600 mg followed by 75 mg daily may be considered.

When combined with Aspirin, Clopidogrel has been shown to reduce CV death, MI, and stroke in patients with UA or NSTEMI. Clopidogrel is recommended over Prasugrel in combination with Aspirin as part of DAPT in patients with medically managed ACS without coronary revascularization intervention. The risk of TIMI major or minor bleeding is higher in patients <75 years old taking Prasugrel compared to Clopidogrel.

Clopidogrel is a prodrug that actively biotransforms into molecules that bind irreversibly to the P2Y₁₂ receptor which reduces platelet adhesion and aggregation. Additionally, it has a better safety profile as compared to Ticlopidine but with the same consistency and degree of P2Y₁₂ inhibition and risk of bleeding. It is also preferred over the other P2Y₁₂ inhibitors in elderly patients due to the lower risk of bleeding. In ACS patients on long-term Clopidogrel, switching to Ticagrelor from Clopidogrel may be considered early following hospital admission regardless of the loading dose and timing of Clopidogrel therapy. Lastly, Clopidogrel should be discontinued at least 5 days before elective CABG if possible while for urgent CABG, discontinuation for at least 24 hours is ideal and proceeding earlier than 5 days may be reasonable.

Prasugrel

Prasugrel is recommended in combination with Aspirin in P2Y₁₂ inhibitor-naïve patients in whom coronary anatomy is known and who will undergo PCI. An initial dose of 60 mg is given at the time of PCI, followed by 10 mg daily for 12 months. Prasugrel should be considered as the preferred P2Y₁₂ inhibitor in NSTEMI patients who will undergo PCI. Notably, in the Intracoronary stenting and Antithrombotic regimen Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial, Prasugrel showed significantly lower incidence in mortality, MI, or stroke without any increase in bleeding, and less treatment discontinuation due to the side effects in patients with planned invasive evaluation when compared to Ticagrelor. It is a thienopyridine prodrug that requires conversion to its active metabolite that inhibits platelet activation and aggregation. It is also the suggested P2Y₁₂ inhibitor in combination with Aspirin as DAPT over Clopidogrel-based DAPT in patients with recent ACS after CABG. Studies have shown that Prasugrel is superior to Clopidogrel in reducing ischemic events including stent thrombosis. It has faster and consistent onset of action and degree of P2Y₁₂ inhibition as compared to Clopidogrel. Studies have also shown that it has increased risk for major bleeding, including fatal bleeding. Prasugrel is not recommended in patients with prior history of stroke or transient ischemic attack (TIA). It should be administered with caution in patients ≥75 years old and weigh <60 kg. Lastly, it may be withheld for at least 7 days prior to elective CABG while for urgent CABG, withholding for at least 24 hours is ideal and proceeding earlier than 7 days may be reasonable.

Ticagrelor

Ticagrelor is recommended in combination with Aspirin in UA, NSTEMI, and STEMI patients with intermediate to high risk of ischemic events regardless of initial choice of therapy (invasive or conservative, including pre-treatment with Clopidogrel). An initial dose of 180 mg is then followed by a dose of 90 mg every 12 hours for 12 months. A dose of 60 mg every 12 hours for >12 hours in combination with Aspirin may be preferred over Clopidogrel or Prasugrel in patients with MI and at high risk of ischemia and tolerant of DAPT with no bleeding complication. Studies show that Aspirin ≥300 mg per day decreases the efficacy of Ticagrelor. Therefore, Aspirin at a dose of 75 to 100 mg is recommended in patients being treated with DAPT.

Ticagrelor is a member of the chemical class cyclopentyltriazolopyrimidines (CPTP). It is a reversible, direct-acting oral antagonist of P2Y₁₂ receptor that does not require transformation to an active metabolite. It is superior to Clopidogrel in reducing clinical events. Studies have shown that it has lower rates of MI, definite stent thrombosis, vascular death, and all-cause mortality. Ticagrelor has faster and consistent onset and offset of action as compared to Clopidogrel. Studies have also shown that Ticagrelor has an increased risk of non-procedure-related bleeding but without an increased rate of overall major bleeding.

Ticagrelor is preferred over Clopidogrel for maintenance P2Y₁₂ inhibitor therapy in the following subset of patients with ACS:

Patients on medical therapy alone, ie without fibrinolytic therapy or revascularization, treated with DAPT
Patients treated with DAPT following implantation of a coronary stent

Ticagrelor is the suggested P2Y₁₂ inhibitor in combination with Aspirin as DAPT over Clopidogrel-based DAPT in patients with recent ACS after CABG. It is also preferred over Prasugrel for use as part of DAPT after CABG in patients with ACS. It may be withheld for at least 3 to 5 days prior to elective CABG. For urgent CABG, withholding for at least 24 hours is ideal and proceeding earlier than 5 days may be reasonable.

Acute Coronary Syndromes w.out Persistent ST-Segment Elevation_Management 1

Glycoprotein IIb/IIIa Inhibitors

Glycoprotein IIb/IIIa inhibitors are mainly used an adjunctive agent in patients with a large thrombus at the time of PCI or discovered during coronary angiography. They act by occupying glycoprotein IIb/IIIa receptors, preventing fibrinogen binding, thus reducing platelet aggregation. During PCI, it should be considered in bailout situations or thrombotic situations in patients previously treated with Prasugrel or Ticagrelor. They should also be considered if there is evidence of no-reflow or a thrombotic complication during PCI. Several trials showed a consistent reduction of thrombotic complications, especially peri-procedural MI in patients undergoing PCI. Adding a glycoprotein IIb/IIIa inhibitor may be considered in patients not treated with an invasive approach but are at very high risk. For patients undergoing an invasive approach and are at very high risk, consider adding a glycoprotein IIb/IIIa inhibitor before (Eptifibatide or Tirofiban) or after (Abciximab or Eptifibatide) diagnostic angiography.

Abciximab is started and continued for 12 hours after PCI. It is indicated only in patients in whom PCI is planned. It has a longer half-life than other glycoprotein IIb/IIIa inhibitors and excessive bleeding can occur in cardiac surgery patients.

Tirofiban or Eptifibatide binds reversibly to glycoprotein IIb/IIIa receptors. They are started and continued for 24 hours after PCI. They may be used in patients with high-risk UA or NSTEMI in conjunction with standard therapy if PCI is not planned and if the bleeding risk is low.

Dose adjustment is necessary with glycoprotein IIb/IIIa inhibitors in older patients. It must be noted that if CABG is to be performed, glycoprotein IIb/IIIa inhibitor is discontinued at the time of or 4 hours prior to the procedure.

Vorapaxar

Vorapaxar is a protease activated receptor-1 (PAR-1) antagonist that inhibits platelet activation. Studies showed that Vorapaxar, when given with other antiplatelet agents, significantly reduced incidences of MI, stroke, and death caused by cardiovascular disease.

¹P2Y12 receptor inhibitor (Cangrelor, Clopidogrel, Prasugrel, Ticagrelor) are listed in alphabetical order.

Anticoagulants

Parenteral anticoagulation is recommended for all UA and NSTEMI patients as soon as possible after diagnosis regardless of the initial treatment strategy using Unfractionated Heparin (UFH), low-molecular-weight Heparin (LMWH), Bivalirudin or Fondaparinux. They are initiated upstream (ie at the time of diagnosis and before coronary angiography). It must be noted that parenteral anticoagulation is continued until revascularization to reduce ischemic events in patients with ACS undergoing coronary revascularization (eg PCI or CABG) during the same admission. Anticoagulants prevent thrombus formation at the site of arterial injury, on the coronary guide wire, and in the catheters used for PCI. The choice of parenteral anticoagulant is influenced by the patient’s renal function, site of vascular access and concomitant use of other antiplatelet or anticoagulant agents. In patients with NSTE-ACS in whom an early invasive approach is not anticipated, either Enoxaparin or Fondaparinux are recommended alternative agents to UFH to reduce ischemic events. An oral anticoagulant plus a single antiplatelet agent for up to 12 months should be considered in patients requiring anticoagulation and treated medically. In patients who require oral anticoagulants (including older patients with increased thrombotic risk and acceptable bleeding risk), 1 month of triple therapy is considered with Aspirin, Clopidogrel, and an oral anticoagulant in patients who have undergone coronary stent implantation. Anticoagulation in combination with SAPT should be resumed as soon as possible after CABG in patients with ACS undergoing CABG with an established indication for oral anticoagulation, triple antithrombotic therapy should be avoided.

In NSTE-ACS patients with atrial fibrillation who underwent PCI, the risk of bleeding is lower with the use of direct oral anticoagulants and antiplatelet therapy than with standard triple therapy. After an ACS event, dual antithrombotic therapy with non-vitamin K antagonist oral anticoagulation (NOAC) at the recommended dose for stroke prevention and a single oral antiplatelet agent (preferably Clopidogrel) for up to 12 months is recommended in patients with atrial fibrillation and a CHA₂DS₂-VASc score of ≥1 in men and ≥2 in women after up to 1 week of initial triple antithrombotic therapy (NOAC plus DAPT). The indication for oral anticoagulants should be re-assessed in patients with ACS and treatment should be continued in the presence of paroxysmal, persistent, or permanent atrial fibrillation with a CHA₂DS₂-VASc score of ≥1 in men and ≥2 in women, mechanical heart valve or with a recent or history of recurrent or unprovoked deep vein thrombosis or pulmonary embolism. Dose adjustment is necessary with UFH or LMWH in older patients.

Low-Molecular-Weight Heparin (LMWH)

LMWH is recommended over UFH for UA and NSTEMI patients in whom early conservative or delayed invasive management is contemplated. It may be used as an alternative to UFH for patients with NSTE-ACS who will undergo immediate or early angiography with or without PCI to reduce ischemic events. Acute treatment with subcutaneous (SC) LMWH is considered at least as effective as IV UFH. Enoxaparin twice daily has shown better outcomes (reduced death, MI, or recurrent angina) when compared to UFH and is considered preferable in UA or NSTEMI patients in the absence of renal failure unless CABG is planned within 24 hours. It must be noted that calculating creatinine clearance (CrCl) is essential in Enoxaparin therapy. IV Enoxaparin should be considered as anticoagulant for PCI in patients with NSTE-ACS who received SC Enoxaparin while awaiting coronary angiography. Similar to Heparin, these compounds enhance the action of antithrombin III, but they have a higher ratio of anti-factor Xa to antithrombin activity than Heparin.

The advantages of LMWH over UFH include the fact that monitoring anticoagulant activated partial thromboplastin time (aPTT) is not required, the ease of SC administration with LMWH, and the lower risk of Heparin-induced thrombocytopenia (HIT) than UFH but similar risk for bleeding. LMWH should be discontinued if CABG is planned, and UFH is used instead during the operation. Lastly, studies have shown significant reduction in total ischemic event rate, recurrent angina rate, need for revascularization, MI or death during treatment period using combination of Aspirin and LMWH.

Acute Coronary Syndromes w.out Persistent ST-Segment Elevation_Management 2

Unfractionated Heparin (UFH)

UFH is recommended for patients with NSTE-ACS who will undergo immediate or early angiography with or without PCI. Bolus UFH is recommended during PCI if the patient is on a NOAC or if the international normalized ratio (INR) is <2.5 in vitamin K antagonist (VKA)-treated patients. UFH works by enhancing antithrombin III activity causing a decrease in the activity of clotting factors including thrombin and factor Xa. UFH also has an antiplatelet function. The dosing of UFH should be based on weight. The aPTT should be maintained at 50 to 70 seconds or 1.5 to 2 times the normal.

Factor Xa Inhibitors

In patients with NSTE-ACS and atrial fibrillation undergoing PCI or medical management, direct oral anticoagulants (eg Apixaban, Dabigatran, Rivaroxaban) are preferred over VKA if without contraindications.

Apixaban

Apixaban may be considered in patients with atrial fibrillation together with Clopidogrel for at least 6 months. Combination therapy has less bleeding and fewer hospitalizations with no significant differences in the incidence of ischemic events when compared to regimens that included Aspirin, Warfarin, or both.

Fondaparinux

Fondaparinux is a parenteral selective factor Xa inhibitor which is a synthetic polysaccharide molecule. It is recommended over Enoxaparin (LMWH) for UA or NSTEMI patients in whom early conservative or delayed invasive management is to be used. A large study comparing Fondaparinux with Enoxaparin in UA and NSTEMI patients showed less major bleeding with the use of Fondaparinux but with similar reduction in the risk of ischemic events in both groups. It acts by selective antithrombin-mediated inhibition of factor Xa. It can be given once daily because of its 100% bioavailability and elimination half-life of 17 hours. There has been no incidence of HIT reported with the use of Fondaparinux. However, it should not be given if the patient is likely to undergo CABG within 24 hours or if CrCl is <30 mL. In such cases, UFH is used instead. A large study comparing Fondaparinux with Enoxaparin in UA and NSTEMI patients showed less major bleeding with the use of Fondaparinux but with similar reduction in the risk of ischemic events in both groups. It should also not be used as the sole anticoagulant to support PCI due to the risk of catheter thrombosis.

Rivaroxaban

Low-dose Rivaroxaban is considered for approximately 1 year after stopping parenteral anticoagulation in NSTEMI patients without prior TIA or stroke history, and those at high risk of ischemia and low-risk of bleeding on Aspirin and Clopidogrel. Low-dose Rivaroxaban may also be considered for >1 year in patients with recurrent ischemia.

Direct Thrombin Inhibitors

Argatroban

Argatroban can be used as prophylaxis or treatment of thrombosis in patients with HIT, including those undergoing PCI. It can also be used in patients with renal insufficiency.

Bivalirudin

Bivalirudin is recommended as an alternative anticoagulant to UFH for urgent and elective PCI to reduce bleeding. It can also be used for treating HIT complicated by thrombotic events. It binds directly to thrombin (factor IIa), thus inhibiting the thrombin-induced conversion of fibrinogen to fibrin. Compared to UFH, in the setting of PCI, Bivalirudin decreased the rate of major adverse cardiac events (eg death, MI, or repeat revascularization) and rate of bleeding. Bivalirudin is comparable to UFH in protecting patients against ischemia during PCI and showed lower bleeding complications.

Antianginal Agents

Antianginal agents required in the hospital should be continued after discharge in patients who did not undergo coronary revascularization, in patients who had unsuccessful revascularization, and in patients with recurrent symptoms after revascularization. Notably, adjustment of doses may be required (ie recurrent ischemia).

Acute Anginal Episodes

All patients should be given short-acting sublingual nitrates and instructed on their proper use prior to discharge.

Beta-Blockers

Beta-blockers are recommended to be given within the first 24 hours in ACS patients with ongoing ischemic symptoms in the absence of contraindications (eg signs of heart failure, evidence of a low-output state or hemodynamic compromise, increased risk for cardiogenic shock, bradycardia or severe reactive airway disease) to reduce the risk of reinfarction and ventricular arrhythmias, and should be started early in the treatment especially in patients who will undergo cardiac or non-cardiac surgery. They are also recommended in patients with ACS with LVEF ≤40% regardless of heart failure symptoms. They may be used to manage BP, angina, and rhythm if needed. Beta-blockers act by inhibition of catecholamine action that results in the reduction of myocardial contractility, sinus node rate, and AV node conduction. This causes a blunted effect on HR and contractility responses to chest pain, exertion, and other stimuli. They decrease myocardial oxygen demand by blocking the beta1-adrenergic receptor. The reduction in heart rate also increases diastolic perfusion time, which may enhance LV perfusion. Beta-blockers also improve prognosis in patients after MI, thus they should be continued after ACS. Oral therapy should be dosed to achieve a heart rate of 50 to 60 beats per minute. Beta-blockers are avoided in patients with cocaine-associated MI due to the potential of exacerbation of coronary artery vasoconstriction in acute MI.

Nitrates

Sublingual nitrate followed by IV therapy should be used for the immediate relief of ischemia and associated symptoms. Sublingual nitrate is used in hemodynamically stable patients with SBP ≥90 mmHg. IV nitrate is recommended in patients whose symptoms are not relieved with three doses of sublingual nitrate, dynamic ECG changes are present, have LV failure, or have concomitant hypertension or pulmonary edema. Once the patient has been pain-free for 12 to 24 hours of IV nitrate, attempt should be made to reduce the IV dose, and replacement with a topical or oral therapy should be done. They are useful in the first 24 to 48 hours in patients with recurrent ischemia, heart failure or hypertension. They induce relaxation of the vascular smooth muscle in veins, arteries, and arterioles which results in vasodilation, reducing RV and LV preload along with afterload reduction, thus decreasing cardiac work and myocardial oxygen demand. Topical or oral nitrates are acceptable alternatives for those without ongoing refractory ischemic symptoms. It must be noted that their use is contraindicated in patients with recent intake (within previous 24 hours) of phosphodiesterase inhibitors (eg Sildenafil, Tadalafil, Vardenafil) due to the potential for vasodilation and hypotension and increased risk of MI or death.

Calcium Antagonists

Calcium antagonists may be used to control ongoing or recurring ischemia-related symptoms in patients who are already given adequate doses of nitrates and beta-blockers. They may be considered in patients who are unable to tolerate adequate doses of one or both agents, in those with contraindications to beta-blockade, or in those with variant angina. Importantly, calcium antagonists are avoided in those with significantly impaired LV function or AV conduction, especially Verapamil. They exert negative inotropic effects and reduce smooth muscle tension in the peripheral vascular system. The latter leads to vasodilation. This also leads to a decrease in coronary vascular resistance and increase coronary blood flow. Calcium antagonists also cause dilation of the epicardial conduit vessels and the arteriolar resistance vessels.

Clinical trials have shown calcium antagonists (eg Diltiazem, Verapamil) to be as effective as beta-blockers in relieving angina and improving exercise tolerance. Meta-analysis of calcium antagonists in UA has shown no difference in the incidence of subsequent MI or death, and data are conflicting whether mortality is reduced in patients with NSTEMI. Verapamil and Diltiazem are the preferred calcium antagonists. Notably, Nifedipine or other Dihydropyridines should not be used without concomitant beta-blocker therapy (especially short-acting agents). Lastly, the choice of an individual calcium antagonist is based primarily on the type of agent, hemodynamic state of the patient, risk of side effects on cardiac contractility, AV conduction and sinus node function, and the physician’s familiarity with the specific agent.

Opioids

Example drugs: IV Morphine, Diamorphine

Opioids are recommended for patients whose symptoms are not relieved after three doses of sublingual nitrate or whose symptoms recur despite adequate anti-ischemic therapy. They may be administered along with IV nitrate with careful BP monitoring and in the absence of hypotension or intolerance. Potent analgesic and anxiolytic opioids also cause venodilation and may produce modest reductions in heart rate and systolic BP, thus reducing myocardial oxygen demand. A study recommends using Morphine with caution in patients with NSTE-ACS.

High-intensity Statins

Fasting lipid profile should be assessed in all patients within 24 hours of hospitalization for those patients who present with an acute event. High-intensity statin therapy should be started upon admission in all NSTE-ACS patients and maintained long term if there are no contraindications. The addition of a non-statin lipid-lowering agent (eg Ezetimibe, proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors, Inclisiran, Bempedoic acid) is recommended for patients with ACS on maximally tolerated statin with a low-density lipoprotein cholesterol (LDL-C) level of ≥1.8 mmol/L (≥70 mg/dL). Lipid-lowering therapy may be further intensified if LDL-C level is ≥1.4 to <1.8 mmol/L (55 to <70 mg/dL) and patient is on a maximally tolerated statin. High-intensity statin therapy is continued in patients with LDL-C level <1.4 mmol/L (<55 mg/dL). The addition of a non-statin lipid-lowering agent is recommended in patients who are statin intolerant. Patients >75 years old with clinical atherosclerotic CVD may be given moderate- or high-intensity statin therapy. Lastly, lipid profile is re-evaluated 4 to 8 weeks after post-discharge; treatment is modified as necessary to reach target lipid levels.

ACE Inhibitors²

ACE inhibitors are recommended in high-risk patients with ACS with heart failure symptoms, LVEF ≤40%, hypertension, DM or CKD. They exhibit cardioprotective effects by promoting vasodilatory, antiproliferative, antiaggregatory, and antithrombotic effects. Studies have shown reduction in cardiac events in patients with LV dysfunction with known CAD treated with ACE inhibitors.

Angiotensin II Antagonists²

Angiotensin II antagonists are recommended in high-risk patients with ACS with LVEF ≤40%, hypertension or DM. They may be used in patients with MI or heart failure and reduced LV systolic function (EF <40%) who cannot take ACE inhibitors.

Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists)²

Example drugs: Spironolactone, Eplerenone

Aldosterone antagonists are recommended in patients with ACS with LVEF ≤40% and DM and/or heart failure. They are contraindicated in patients with severe renal failure and hyperkalemia.

²Please see Hypertension and Hear Failure – Chronic disease management charts for dosing recommendations of ACE inhibitors, angiotensin II antagonists, and aldosterone antagonists.

Other Agents

Ivabradine

Ivabradine has been approved for chronic stable angina and stable chronic heart failure but is currently being considered for patients with UA with contraindications to beta-blockers. It selectively inhibits the cardiac pacemaker current If which controls spontaneous diastolic depolarization in the sinoatrial node. It has been associated with decreased risk for revascularization.

Nicorandil

Nicorandil may be used as an alternative to nitrates in stable angina patients but there is less data available for its use in ACS. It activates the potassium adenosine triphosphate (ATP) channel and increases coronary blood flow by dilation of the coronary arteries and reduces myocardial oxygen demand by reduction in the afterload and to a lesser extent, the preload. The addition of Nicorandil to conventional therapy significantly reduced the number of episodes of transient MI (mostly silent) and of ventricular and supraventricular tachycardia in a small pilot study. Another study showed a decrease in the occurrence rate of coronary death, non-fatal MI, or unplanned hospital admission due to cardiac pain in chronic stable angina, but not in the setting of NSTEMI.

Proton Pump Inhibitors

Proton pump inhibitors are given to patients at high risk of GI bleeding who are receiving Aspirin monotherapy, DAPT, dual or triple antithrombotic therapy or oral anticoagulation monotherapy.

Ranolazine

Ranolazine can be used alone or in combination with Amlodipine, beta-blockers or nitrates for the treatment of chronic angina that is not responsive to standard antianginal treatment. It is contraindicated in patients with QT-prolonging conditions. It exerts antianginal effects by inhibiting the late sodium current without reducing the heart rate or BP and reduces the adverse effects of intracellular sodium and calcium overload that accompany myocardial ischemia. Results of a large study suggested safety and symptoms relief but no significant reduction in CV death, MI or recurrent ischemia.

Trimetazidine

Trimetazidine exerts metabolic effects without hemodynamic changes. In small trials, its use has been shown to improve LV function and has been associated with decreased mortality.

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Nonpharmacological

Invasive Strategies

The timing of invasive strategy can be classified into immediate invasive, early invasive or invasive. Immediate invasive strategy (<2 hours) is considered in very high-risk patients with at least one of the following: Acute heart failure with refractory angina or ST deviation, hemodynamic instability, life-threatening arrhythmias, cardiogenic shock, MI, mechanical complications, ongoing or recurrent chest pain unresponsive to medical therapy, recurrent dynamic ST- or T-wave changes.

Early invasive strategy (<24 hours) may be considered in high-risk patients with at least one of the following criteria: Changes in cTn level compatible with MI (confirmed NSTEMI diagnosis based on current recommended ESC hs-cTn algorithms) despite optimized medical therapy, dynamic ST- or T-wave changes, transient ST-segment elevation, GRACE score >140.

Invasive strategy (<72 hours) is considered in intermediate-risk patients with at least one of the following: DM, early post-infarction angina, absence of ongoing ischemic symptoms, stable or downtrending cTn levels, eGFR <60 mL/min/1.73 m², LVEF <40%, previous coronary artery bypass grafting (CABG), recent percutaneous coronary intervention (PCI), GRACE score 109-140.

Invasive strategy (coronary angiography prior to hospital discharge) is considered in low-risk patients with at least one of the following: Absence of ongoing ischemic symptoms or dynamic ST-segment changes, cTn <99th percentile, TIMI score<2, GRACE score <109.

To reduce major adverse CV events, patients with NSTE-ACS who are at intermediate or high risk of ischemic events are recommended to have an invasive approach with intent to proceed with revascularization during hospitalization, while those with NSTE-ACS who are at low risk of ischemic events are recommended to have a routine invasive or selective invasive approach with further non-invasive risk stratification (eg stress testing or cardiac CT angiography) prior to coronary angiography to identify those who may need revascularization. Routine invasive approach is a strategy of performing coronary angiography with intent of performing coronary revascularization by PCI or CABG.

Invasive strategies are recommended for patients with high index of suspicion for UA. Selective invasive strategy is recommended in patients without very high- or high-risk features and with low index suspicion for UA. Invasive strategies are also recommended for cancer patients with high-risk ACS with expected survival of ≥6 months. Antiplatelet therapy should be given to patients with multivessel disease who are not eligible for revascularization.

Coronary Angiography

Coronary angiography is recommended in patients with intermediate- to high-risk features not responsive to intensive medical therapy. Angiography is contraindicated when risks of revascularization outweigh the benefits (eg liver or pulmonary or renal failure, cancer), and in patients, especially women, with acute chest pain and a low risk of ACS who have negative troponin. Coronary angiography is recommended to be done immediately in patients with refractory or recurrent angina associated with dynamic ST-deviation, heart failure, life-threatening arrhythmias or hemodynamic instability despite medical therapy. Angiography within 48 hours of the diagnosis is reasonable in patients undergoing an invasive strategy. Non-invasive imaging is a reasonable option for obstructive CAD assessment in those who cannot undergo invasive angiography. A radial approach is preferred for both coronary angiography and PCI due to lower bleeding, vascular complications and mortality.

Revascularization

Revascularization relieves angina or ongoing MI and prevents progression of MI to death. Complete revascularization is recommended in patients with NSTE-ACS during the index PCI procedure or within 45 days. The choice of revascularization procedure (PCI versus CABG) will depend on the extent and severity of lesion based on coronary angiography, complexity of CAD, the condition of the patient, and coexisting illness, particularly in patients with multivessel CAD (ie stenosis of ≥50% in ≥2 epicardial arteries).

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The appropriate use criteria for revascularization recommended by the American College of Cardiology (ACC), American Association for Thoracic Surgery (AATS), American Heart Association (AHA), American Society of Echocardiography (ASE), American Society of Nuclear Cardiology (ASNC), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Cardiovascular Computed Tomography (SCCT), and the society of Thoracic Surgeons (STS) is as follows:

Patients with evidence of cardiogenic shock with ≥1 coronary arteries for immediate revascularization
- Risk versus benefit ratio should be considered in this group of patients
Stable patients at immediate- or high-risk for clinical event and with ≥1 coronary arteries for revascularization
May be considered in stable patients with low risk for clinical events and with ≥1 coronary arteries for revascularization

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PCI is found to be beneficial in patients with one- to two-vessel CAD, with or without significant proximal left anterior descending CAD, but with a large area of viable myocardium and high-risk criteria on non-invasive testing. PCI is recommended in patients with spontaneous coronary artery dissection with signs and symptoms of ongoing myocardial ischemia, a large myocardial area in jeopardy and reduced antegrade flow. It is preferred in patients with very high-risk NSTE-ACS requiring immediate revascularization. PCI of a non-infarct-related artery must be based on angiographic severity. The PCI of significant non-culprit lesions is recommended to reduce the risk of major adverse CV events in stable patients with NSTE-ACS and multivessel CAD. A drug-eluting stent is recommended over bare metal stents to those undergoing revascularization by PCI. Intracoronary imaging (eg intravascular ultrasound or optical coherence tomography) is recommended to guide PCI in patients with ACS with complex coronary lesions or during coronary stent implantation in the left main artery to reduce ischemic events.

CABG is preferred over multivessel PCI in patients with NSTE-ACS and multivessel disease in the following: Significant left main coronary artery stenosis with high-complexity CAD, multivessel CAD with complex or diffuse CAD, multivessel CAD or complex left main CAD with severe LV dysfunction, DM and multivessel disease with left anterior descending artery involvement.

Supportive Therapy

Bed Rest

Bed rest is usually prescribed initially in patients with UA or NSTEMI while ischemia is ongoing. The patient can be mobilized to bedside commode or chair when symptom-free. Ambulation as tolerated may begin once the patient has been hemodynamically stable without attendant complications or recurrent symptoms for 12 to 24 hours. Subsequent activity should not be inappropriately restricted. The focus should be on the prevention of recurrent symptoms, and activity may be increased once the patient responds to therapy. Prophylaxis for venous thromboembolism is considered in NSTEMI patients with bed rest of >24 hours.

Supplemental Oxygen (O₂)

Supplemental O₂ is given to all patients with overt pulmonary congestion or arterial O₂ saturation of <90% or respiratory distress or other high-risk features of hypoxemia. It is considered in all patients with ACS for the first 6 hours of therapy.

Blood Transfusion

Red blood cell (RBC) transfusion is considered in unstable patients (eg acute MI patients with ongoing bleeding, signs of ischemia or infarction, or shock due to anemia) to improve perfusion and compensate for ongoing blood loss. Transfusion in stable patients should be individualized. Patients may benefit from transfusion if the hemoglobin is low (<8 g/dL). Maintaining a hemoglobin level of ≥10 g/dL through RBC transfusion may be reasonable for patients with ACS and acute or chronic anemia who are not experiencing active bleeding.

Patient and Caregiver Education

Patient counseling tends to improve patient compliance and outcomes. It assesses the functional capacity and the ability to carry out daily activities or work of the patient. The patient and caregivers are educated about UA and CVD. It is important that the nature of the disease, drug regimens, lifestyle modifications, and symptoms of angina are discussed.

Before hospital discharge, instructions are provided with respect to the medication type, purpose, dose, frequency, side effects, and the importance of treatment adherence. Patients and caregivers should be instructed on what steps to take if anginal symptoms occur. The patient should be instructed to take sublingual nitrate and to seek emergency medical attention if three doses of nitrate fail to relieve the pain. It is important to explain to the patient that if anginal symptoms change (eg pain more frequent, or occurs at rest, etc), they should contact their physician.

Education should be part of every patient encounter and should be tailored to the patient’s level of understanding. It may be best to develop a plan with the patient and hold discussions over time so that the patient is not overwhelmed by changing several behaviors all at one time (eg smoking, diet, exercise, etc). Enlisting family members into the educational process to assist in achieving risk-factor modifications may be helpful such as cooking low-fat meals for the entire family or family exercise to further support the patient in changing risk behavior. This is particularly important when screening family members reveals common risk factors (eg hyperlipidemia, hypertension, and obesity). Information on the schedule for follow-up after discharge is also given. Low-risk medically treated patients and revascularized patients should return in 2 to 6 weeks. Higher risk patients should return within 2 weeks. Pneumococcal and annual influenza vaccinations are also recommended if without contraindications. The patient’s need for treatment of chronic musculoskeletal pain or discomfort should be assessed. Pain relief should begin with Paracetamol, small doses of narcotics or non-acetylated salicylates. Stress management is advised to improve patient outcomes. Symptoms of depression and anxiety are addressed. Antioxidant vitamins (eg vitamin E, C, or beta-carotene) and folic acid with or without vitamins B6 and B12, should not be used for secondary prevention in UA and NSTEMI patients.

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Activity

Daily walking may be encouraged immediately after discharge. Exercise training can be started within 1 to 2 weeks after PCI or CABG to relieve ischemia. The safety and timing of resumption of sexual activity is also discussed. This is usually 1 to 2 weeks for low-risk patients and 4 weeks for post-CABG. Advice on the resumption of driving (usually 1 week) is given if stressful driving conditions are avoided. The timing of returning to work is also recommended. Lastly, air travel may be resumed within 2 weeks of discharge, if the patient travels with a companion, sublingual GTN is carried and is taken to the airport to avoid rushing. Patients with a more complicated course may return to usual activities in 2 to 3 weeks.

Risk Factor Management

It is important to assess the presence of CAD risk factors and to treat these effectively. There is evidence that the treatment of risk factors reduces the risk of coronary disease events. The presence of risk factors appears to relate to poor outcomes in patients with established ACS. Patients should undergo further risk assessment before discharge.

Smoking Cessation

There are observational studies that show cigarettes smoking increases the risk for CV disease events, insulin resistance, and DM. There is a dose-dependent relationship between cigarettes smoked and CV risks. The primary goal is complete smoking cessation. Smoking cessation is associated with reduced risk of re-infarction by 30-40% and death by 35-45% after ACS. It is important to assess the patient’s tobacco use and to strongly urge the patient and family to stop smoking. Patients who are willing to quit should be identified. A quit plan should be developed and pharmacological therapy (eg nicotine replacement, Bupropion, Varenicline) counseling and formal cessation programs should be provided, if needed. Aside from smoking cessation, avoidance of exposure to environmental smoke is also recommended.

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BP Control

The primary BP goal³ is <130/80 mmHg. BP should be monitored in all CAD patients. Lifestyle modification (weight control, physical activity, diet modification, etc) should be started and maintained in all patients with a systolic BP (SBP) of ≥130 or a diastolic BP (DBP) ≥80 mmHg. BP drug therapy is started which is tailored to the patient’s requirements and characteristics (eg race, age, need for drugs with specific benefits) if above primary goals are exceeded.

³Recommendations for BP treatment goals may vary between countries. Please refer to available guidelines from local health authorities.

Please see Hypertension disease management chart for further information

Lipid Management

Lifestyle modification should be advised (diet <7% saturated fat intake and <200 mg/day of cholesterol, physical activity, and weight management). Lipid-lowering therapy decreases vascular events and death after MI or UA in patients with average-high cholesterol. Cholesterol-lowering therapy should be started or intensified in UA and NSTEMI patients. Therapy may be initiated early (24 to 96 hours after hospital admission) and continued after hospital discharge to provide life-long benefits. Studies have shown that giving statins in acute treatment of UA and NSTEMI reduces major adverse cardiac events due to its pleotropic effects. The treatment goal is LDL-C level of <1.4 mmol/L (<55 mg/dL) and a reduction of at least 50% if the baseline LDL-C level is >1.8 mmol/L (>70 mg/dL). Ezetimibe is considered to further lower LDL-C in patients with LDL-C of ≥1.8 mmol/L (≥70 mg/dL) despite statin therapy at maximally tolerated dose. A PSCK9 inhibitor may be considered if LDL-C is not at goal with Ezetimibe and a maximally tolerated statin.

Nicotinic acid (Niacin) and fibric acid derivatives (Fenofibrate, Gemfibrozil) may be therapeutic options, after LDL-C lowering therapy) for patients with high-density lipoprotein-cholesterol (HDL-C) <1 mmol/L (<40 mg/dL) and triglycerides >2.3 mmol/L (>200 mg/dL) to reduce residual risk in patients who have achieved LDL-C target goals. In patients with ACS and triglyceride levels of 1.5 to 5.6 mmol/L (135 to 499 mg/dL) despite statin therapy, Icosapent ethyl may be used in combination with a statin.

Please see Dyslipidemia disease management chart for further information

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Diabetes Management

Appropriate pharmacological and lifestyle modification are initiated to achieve a near-normal fasting plasma glucose (<6.1 mmol/L [110 to 180 mg/dL]) or near-normal HbA1C (<6.5-7%). The choice of long-term glucose-lowering agent must be based on the presence of comorbidities (eg heart failure, CKD, obesity). Glucose-lowering therapy should be considered in patients with ACS with persistent hyperglycemia while avoiding hypoglycemia episodes. Frequent monitoring of blood glucose is recommended in patients with known DM or hyperglycemia (glucose levels of ≥11.1 mmol/L [≥200 mg/dL]). Less stringent glucose control may be more appropriate in patients with more advanced CAD, older age, longer diabetes duration, and significant comorbidities.

Please see Diabetes Mellitus disease management chart for further information

Weight Management

Body mass index (BMI) is calculated, and waist circumference measured as part of patient assessment every visit. The goal BMI for Asian adults is 18.5 to 22.9 kg/m². While the BMI for Americans and European adults is 18.5 to 24.9 kg/ m². The recommended waist circumference, which is measured horizontally at the iliac crest, is <35 inches (90 cm) for Asian men, <40 inches (102 cm) for American and European men, <31.5 inches (80 cm) for Asian women, and <35 inches (88 cm) for American and European women. The initial goal of weight loss therapy should decrease the body weight by 10% from baseline. Further reduction in weight can be attempted if indicated after further assessment. It is important to note that the risk of coronary disease and mortality is increased in obese patients. Furthermore, obesity contributes to other CAD risk factors (eg hypertension, low HDL-C, glucose intolerance, etc). The presence of abdominal obesity particularly raises CV risk. Physical activity, caloric restrictions, and behavioral programs are encouraged to have the ideal BMI.

Increase in Physical Activity

The minimum goal of physical activity is 30 to 60 minutes per day of aerobic physical activity, preferably everyday but at least 5 days per week, if tolerable. Risk is assessed preferably with an exercise test prior to prescribing an exercise program. Cardiac rehabilitation and secondary prevention programs with supervised exercise training are recommended for patients with multiple risk factors and those moderate- to high-risk patients. Cardiac rehabilitation programs can contribute in decreasing mortality and improving physical activity and emotional well-being of patients after MI.

Diet Modification

A diet low in saturated fat, low in salt, high in polyunsaturated fat, and high in fresh fruits and vegetables may assist in preventing recurrent CV events. If one is attempting to lower cholesterol with diet modification, please see Dyslipidemia disease management chart for more specific recommendations.

Acute Coronary Syndromes w/out Persistent ST-Segment Elevation Management

Evaluation

Pharmacological therapy

Nonpharmacological