acute%20coronary%20syndromes%20w_o%20persistent%20st-segment%20elevation
ACUTE CORONARY SYNDROMES W/O PERSISTENT ST-SEGMENT ELEVATION
Acute coronary syndromes refer to any constellation of clinical symptoms compatible with acute myocardial ischemia which may be life-threatening.
It encompasses unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI).
Unstable angina is the ischemic discomfort that presents without persistent ST-segment elevation on ECG and without the presence of cardiac markers in the blood.
Non-ST-segment elevation myocardial infarction is diagnosed if cardiac markers are positive with ST-segment depression or with nonspecific or normal ECGs.
The patient typically presents with ischemic-type chest pain that is severe and prolonged and may occur at rest or may be caused by less exertion than previous episodes.

Principles of Therapy

  • The timing of angiography can be classified into the following:
    • Immediate invasive strategy (<2 hours) in patients with at least one of the following: Acute heart failure with refractory angina or ST deviation, hemodynamic instability, life-threatening arrhythmias, MI mechanical complications, ongoing or recurrent chest pain unresponsive to medical therapy, recurrent dynamic ST- or T-wave changes
    • Early invasive strategy (<24 hours) in patients with at least one of the following: Changes in cardiac troponin level compatible with MI, dynamic ST- or T-wave changes, GRACE score of >140
    • Invasive strategy (<72 hours) in patients with at least one of the following: DM, early post-infarction angina, eGFR <60 mL/min/1.73 m2, LVEF <40%, previous CABG, recent PCI, GRACE score <140 and >109

Pharmacotherapy

Antiplatelet Agents 

Aspirin

  • Should be given promptly and continued daily in all patients with suspected acute coronary syndrome, unless there are contraindications
    • Initial loading dose of 160-325 mg (non-enteric formulation and should be chewed), followed by 75-100 mg (soluble/enteric coated formulation) daily to be continued indefinitely
  • Exerts antithrombotic effect by irreversible inhibition of cyclooxygenase-1 within platelets which prevents production of platelet-aggregating substance, thromboxane A2
  • Administration of daily Aspirin has been shown to consistently decrease risk of death and myocardial infarction (MI) in patients with unstable angina
  • Should be withheld 7-10 days prior to elective coronary artery bypass grafting

Cangrelor

  • Recommended for patients who may be considered for P2Y12-inhibitor-naive patients undergoing percutaneous coronary intervention
  • An intravenous (IV) adenosine triphosphate analogue that binds reversibly and with high affinity to the platelet P2Y12 receptor and has a short plasma half-life
  • Produces a highly effective inhibition of ADP-induced platelet aggregation immediately after IV bolus administration and allows for restoration of platelet function within 1-2 hours of infusion discontinuation in non-ST-segment elevation - acute coronary syndrome patients

Clopidogrel

  • Recommended in combination with Aspirin in unstable angina (UA)/non-ST segment elevation myocardial infarction (NSTEMI) patients wherein Ticagrelor or Prasugrel is unavailable or contraindicated
    • Initial dose of 300 mg, followed by 75 mg daily for at least 1 month and ideally up to 12 months
    • In patients with definite UA/NSTEMI undergoing percutaneous coronary intervention (PCI), an initial dose of 600 mg should be given immediately, followed by 150 mg daily for 6 days, then 75 mg daily may be given in patients not considered high risk for bleeding
  • Prodrug that actively biotransformed into molecules that bind irreversibly to the P2Y12 receptor which reduces platelet adhesion and aggregation
  • When combined with Aspirin, Clopidogrel has been shown to reduce cardiovascular (CV) death, MI and stroke in patients with UA/NSTEMI
  • If possible, discontinue at least 5 days before coronary artery bypass grafting (CABG)

Prasugrel

  • Recommended in combination with Aspirin only in P2Y12-inhibitor-naive patients (especially diabetics) in whom coronary anatomy is known and who will undergo PCI
    • Initial dose of 60 mg to be given at the time of PCI, followed by 10 mg daily for 12 months
  • Thienopyridine prodrug that requires conversion to its active metabolite that inhibit platelet activation and aggregation
  • Studies have shown that it is superior to Clopidogrel in reducing ischemic events including stent thrombosis
    • Has faster and consistent onset of action as compared to Clopidogrel
    • Studies have shown that it has increased risk for major bleeding, including fatal bleeding
  • Not recommended in patients with prior history of stroke or transient ischemic attack (TIA), >75 years old and weighs <60 kg
  • Should be withheld 7 days prior to elective CABG

Ticagrelor

  • Recommended in combination with Aspirin in UA/NSTEMI/STEMI patients with intermediate to high risk of ischemic events regardless of choice of therapy (invasive or conservative)
    • Initial dose of 180 mg then 90 mg 12 hourly for 12 months
    • Studies show that Aspirin >100 mg/day decreases the efficacy of Ticagrelor and thus, should be avoided; after any initial dose, use with Aspirin 75-100 mg/day
  • Nonthienopyridine, reversible, direct-acting oral antagonist of the P2Y12 receptor that does not require transformation to an active metabolite
  • 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
    • Has faster and consistent onset and offset of action as compared to Clopidogrel
    • Studies have shown that it has an increased risk of non-procedure-related bleeding but without an increased rate of overall major bleeding
  • Preferred over Clopidogrel for maintenance P2Y12 inhibitor therapy in the following:
    • Patients on medical therapy alone, ie without fibrinolytic therapy or revascularization, treated with dual antiplatelet therapy
    • Patients treated with dual antiplatelet therapy following implantation of a coronary stent
  • Should be withheld 5 days prior to elective CABG

Glycoprotein IIb/IIIa Inhibitors

  • May be considered as part of initial platelet therapy in patients with NSTEMI that have undergone early invasive therapy and DAPT and have intermediate/high risk
  • During PCI, it should be considered in bailout situations or thrombotic situations in patients previously treated with Prasugrel or Ticagrelor
  • Acts by occupying the GP IIb/IIIa receptors, preventing fibrinogen binding, thus reducing platelet aggregation
  • Several trials showed a consistent reduction of thrombotic complications, especially peri-procedural MI in patients undergoing PCI

Abciximab

  • Start and continue for 12 hours after PCI
  • Indicated only in patients in whom PCI is planned
  • Has a longer half-life than other GP IIb/IIIa inhibitors and excessive bleeding can occur in cardiac surgery patients

Eptifibatide or Tirofiban

  • Start and continue for 24 hours after PCI
  • May be used in patients with high-risk UA/NSTEMI in conjunction with standard therapy if PCI is not planned and if bleeding risk is low
  • Binds reversibly to GP IIb/IIIa receptor

If CABG is to be performed, discontinue GP IIb/IIIa antagonist at the time of or 4 hours prior to procedure

Anticoagulants

  • Anticoagulation is recommended for all UA/NSTEMI patients using any of the following: Unfractionated heparin, low molecular weight heparin, Bivalirudin or Fondaparinux
  • Prevents thrombus formation at the site of arterial injury, on the coronary guide wire, and in the catheters used for PCI

Unfractionated Heparin (UFH)

  • Dosing should be based on weight
  • Activated partial thromboplastin time (aPTT) should be maintained at 50-70 seconds
  • Enhances antithrombin III activity causing decrease in activity of clotting factors including thrombin and actor Xa; UFH also has antiplatelet function
  • Meta-analysis showed 44% risk reduction in death and MI with combination of UFH and Aspirin therapy compared to Aspirin alone

Low Molecular Weight Heparin (LMWH)

  • Recommended over UFH for UA/NSTEMI patients in whom early conservative or delayed invasive management is contemplated
  • Acute treatment with 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/NSTEMI patients in the absence of renal failure unless CABG is planned within 24 hours
    • Calculating creatinine clearance is essential in Enoxaparin therapy
  • 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
  • Advantages of LMWH over UFH
    • Monitoring of anticoagulant aPTT is not required
    • Ease of subcutaneous administration with LMWH
    • Lower risk of Heparin-induced thrombocytopenia (HIT) than UFH but similar risk for bleeding
  • LMWH should be discontinued if CABG is planned, use UFH instead during the operation
  • 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

Factor Xa Inhibitor 

Fondaparinux

  • Synthetic polysaccharide molecule and the only selective factor Xa inhibitor for clinical use
  • Recommended over Enoxaparin (LMWH) for UA/NSTEMI patients in whom early conservative or delayed invasive management is to be used
  • Acts by selective antithrombin-mediated inhibition of factor Xa
  • Can be given once daily because of 100% bioavailability and elimination half-life of 17 hours
  • No incidence of HIT has been reported
  • Should not be given if patient is likely to undergo CABG within 24 hours or if CrCl is <30 mL; use UFH instead
  • A large study comparing Fondaparinux with Enoxaparin in UA/NSTEMI patients showed less major bleeding in the use of Fondaparinux but similar occurrence of ischemic events in both groups

Direct Thrombin Inhibitors

Bivalirudin

  • Recommended as an alternative anticoagulant for urgent and elective PCI
  • It can also be used for treating HIT complicated by thrombotic events
  • Binds directly to thrombin (factor IIa), inhibiting the thrombin-induced conversion of fibrinogen to fibrin
  • Bivalirudin compared within UFH, in the setting of PCI, decreased the rate of major adverse cardiac events (eg death, MI or repeat revascularization) and rate of bleeding
  • Bivalirudin + glycoprotein IIb/IIIa inhibitors were comparable to UFH + glycoprotein IIb/IIIa inhibitors in protecting patients against ischemia during PCI and also showed lower bleeding complications

Argatroban

  • For prophylaxis or treatment of thrombosis in patients with HIT, including those undergoing PCI
  • Can be used in patients with renal insufficiency

Antianginal Agents

  • Antianginal agents required in the hospital, should be continued in patients who did not undergo coronary revascularization, in patients who had unsuccessful revascularization and in patients with recurrent symptoms after revascularization
    • Adjustment of doses may be required

Acute Anginal Episodes

  • All patients should be given short-acting sublingual nitrates and instructed on the proper use

Beta-Blockers

  • Recommended to be given within the first 24 hours in ACS patients with ongoing ischemic symptoms in the absence of contraindications (eg signs of HF, evidence of low-output state, increased risk for cardiogenic shock) and should be started early in treatment especially in patients who will undergo cardiac or noncardiac surgery
  • May be used to manage BP, angina and rhythm if needed
  • Acts by inhibition of catecholamine action that results in 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 their stimuli
  • Decreases myocardial O2 demand (by blocking the beta1-adrenergic receptor)
    • Reduction in HR also increases diastolic perfusion time, which may enhance LV perfusion
    • Studies of beta-blockers in UA have been small but larger randomized trials with other CAD patients (AMI, recent MI, stable angina with daily life ischemia and heart failure) have shown reductions in mortality and/or morbidity rates
    • Improve prognosis in patients after MI thus should be continued after ACS
  • Oral therapy should be dosed to HR of 50-60 bpm
  • Should continue indefinitely in all patients without contraindications
  • May lead to significant increase in survival

Nitrates

  • Sublingual nitrate followed by IV therapy should be used for the immediate relief of ischemia and associated symptoms
    • IV nitrate is recommended in patients whose symptoms are not relieved within 3 doses of sublingual nitrate, dynamic ECG changes are present, have left ventricular failure or have concomitant hypertension
    • Once patient has been pain-free for 12-24 hours of IV nitrate, attempt should be made to reduce IV dose and replace with topical/oral therapy
  • Topical or oral nitrates are acceptable alternatives for those without ongoing refractory ischemic symptoms
    • Oral/topical nitrates may be given after 12-24 hours of pain-free period after IV administration
  • Induce relaxation of the vascular smooth muscle in veins, arteries and arterioles which results in vasodilation
    • This reduces RV and LV preload along with afterload reduction which decreases cardiac work and myocardial O2 demand

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
    • May be considered in patients who are unable to tolerate adequate doses of one or both of these agents, in those with contraindications to beta-blockade, or in those with variant angina
    • Avoid Ca antagonists in those with significantly impaired LV function or AV conduction especially Verapamil
  • Ca antagonists exert negative inotropic effects, reduce smooth muscle tension in the peripheral vascular system which is associated with vasodilation
    • Decrease coronary vascular resistance and increase coronary blood flow
    • Cause dilation of the epicardial conduit vessels and the arteriolar resistance vessels
  • Clinical trials have shown Ca antagonists (eg Diltiazem, Verapamil) to be as effective as beta-blockers in relieving angina and improving exercise tolerance
    • Meta-analysis of Ca antagonists in UA has shown that this class of drug does not prevent the development of acute MI or reduce mortality
  • Trials in patients with acute CAD suggest that Verapamil and Diltiazem are the preferred Ca antagonists
    • Nifedipine or other Dihydropyridines should not be used without concomitant beta-blocker therapy (especially short-acting agents)
    • The choice of an individual Ca 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 physician’s familiarity with the specific agent

Opioids

  • Eg IV Morphine or Diamorphine
  • Recommended for patients whose symptoms are not relieved after 3 doses of sublingual nitrate or whose symptoms recur despite adequate anti-ischemic therapy
    • 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 HR and systolic BP, thus reducing myocardial O2 demand

High-intensity Statins

  • Assess fasting lipid profile in all patients and 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 

ACE Inhibitors1

  • Recommended in patients with chronic heart failure (CHF), LV dysfunction (EF <40%), hypertension, DM or stable chronic kidney disease
  • 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
    • Meta-analysis of 3 major trials supported benefit in using ACE inhibitors across the risk spectrum studied; these provide general benefit in stable CAD, but the benefit is proportional to disease-related risk, with low-risk patients having the least benefit

Angiotensin II Antagonists1

  • May be used in patients withMI or heart failure and reduced LV systolic function (EF <40%) who cannot take ACE inhibitors

Aldosterone Antagonists (Mineralocorticoid Receptor Antagonists)1

  • Eg Spironolactone, Eplerenone
  • Considered in patients after MI who have been treated with ACE inhibitors and beta-blockers and have decreased LV systolic function (EF <40%) and either with DM or heart failure
  • Contraindicated in severe renal failure and hyperkalemia

Other Agents

Nicorandil

  • May be used as an alternative to nitrates in stable angina patients but there is less data available for use in ACS
  • Activates the potassium ATP channel and increases coronary blood flow by dilation of coronary arteries and reduces myocardial O2 demand by reduction in afterload and a lesser extent, preload
  • The addition of this drug 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 decrease in 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

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
  • Contraindicated in patients with QT-prolonging conditions
  • Exerts antianginal effects by inhibiting the late sodium current without reducing HR 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 symptom relief but no significant reduction in CV death, MI or recurrent ischemia

Ivabradine

  • Approved for chronic stable angina and stable chronic heart failure but is currently being considered for patients with UA with contraindications to beta-blockers
  • Selectively inhibits cardiac pacemaker current If  which controls spontaneous diastolic depolarization in the sinoatrial node
  • Has been associated with decreased risk for revascularization

Trimetazidine

  • Exerts metabolic effects without hemodynamic changes
  • Use has been shown to improve LV function and has been associated with decreased mortality

1Please see Hypertension and Heart Failure - Chronic Disease Management Charts for dosing recommendations of ACE inhibitors, Angiotensin II antagonists and Aldosterone antagonists.

Non-Pharmacological Therapy

Risk Factor Management

  • It is important to assess the presence of coronary heart disease (CHD) 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 these risk factors appear to relate to poor outcomes in patients with established ACS

Blood Pressure (BP) Control

  • Primary goal: BP <130/80 mmHg; <130/80 mmHg in patients with DM or chronic kidney disease
  • BP should be monitored in all CHD patients
    • Start and maintain lifestyle modification (weight control, physical activity, diet modification, etc) in all patients with SBP ≥130 or DBP ≥80 mmHg
    • Start BP drug therapy which is tailored to patient’s requirements and characteristics (eg race, age, need for drugs with specific benefits) if above primary goals are exceeded
  • See Hypertension Disease Management Chart for more details

Lipid Management

  • Statins should be given to post UA/NSTEMI and postrevascularization patients before discharge from hospital, regardless of baseline LDL-C and diet modification
  • Cholesterol-lowering therapy should be started or intensified in UA/NSTEMI patients
    • May be initiated early (24-96 hr after hospital admission and continued after hospital discharge to provide life-long benefits)
    • Studies have shown that giving statins in acute treatment of UA/NSTEMI reduces major adverse cardiac events due to its pleotropic effects
    • In UA/NSTEMI patients with elevated LDL-C ≥2.6 mmol/L (100 mg/dL), titrate to achieve target LDL-C <1.81 mmol/L (70 mg/dL)
  • Nicotinic acid (Niacin) and fibric acid derivatives (Fenofibrate, Gemfibrozil) can be therapeutic options (after LDL-C lowering therapy) for patients with HDL-C <40 mg/dL and triglycerides >200 mg/dL
  • Lifestyle modification should be advised (diet <7% saturated fat intake and <200 mg/day cholesterol, physical activity and weight management)
  • Lipid-lowering therapy decreases vascular events and death after MI or UA in patients with average-high cholesterol
  • See Dyslipidemia Disease Management Chart for more details

Diabetes Management

  • Initiate appropriate pharmacological therapy and lifestyle modification to achieve near-normal fasting plasma glucose [<6.1 mmol/L (110-180 mg/dL)] or near-normal HbA1c (<6.5 -7%)
  • See Diabetes Mellitus Disease Management Chart for more details

Weight Management

  • Calculate BMI and measure waist circumference as part of patient assessment every visit
  • Goal BMI for Asian adults: 18.5-22.9 kg/m2, BMI for American/European adults: 18.5-24.9 kg/m2
  • Recommended waist circumference (measure horizontally at the iliac crest)
    • Asian men: <35 inches (90 cm); American/European men: <40 inches
    • Asian women: <31 inches (80 cm); American/European women: <35 inches
  • Initial goal of weight loss therapy should decrease the body weight by 10% from baseline; further weight reduction can be attempted if indicated after further assessment
  • Risk of coronary disease and mortality is increased in obese patients
    • Obesity also contributes to other CHD risk factors (eg hypertension, low HDL-C, glucose intolerance, etc)
    • The presence of abdominal obesity particularly raises CV risk
  • Encourage physical activity, caloric restrictions and behavioral programs to have the ideal body mass index

Increase in Physical Activity

  • Minimum goal: 30-60 minutes per day of moderate aerobic physical activity preferably everyday but at least 5 days per week, if tolerable
  • Assess risk preferably with exercise test prior to prescribing 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 and emotional well-being of patients after MI

Diet Modification

  • 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
  • Moderate alcohol consumption may be beneficial
  • If attempting to lower cholesterol with diet modification, please see Dyslipidemia Disease Management Chart for more specific recommendations
Digital Edition
Asia's trusted medical magazine for healthcare professionals. Get your MIMS Cardiology - Malaysia digital copy today!
DOWNLOAD
Editor's Recommendations
Most Read Articles
Jairia Dela Cruz, 05 Dec 2017
Discontinuation of aspirin may have detrimental consequences for long-term users, with a recent study reporting that cessation of use in the absence of major surgery or bleeding increases the risk of cardiovascular events.
19 Dec 2016
The prevalence of ECG for left ventricular hypertrophy (LVH) may vary depending on the criteria used across body mass index (BMI) categories in a low cardiovascular risk cohort, suggests a new study.
01 Mar 2015
Red yeast rice extracts have been used in traditional medicine for centuries.1 In recent times, an extract from red yeast rice, Xuezhikang® (XZK), has been studied for its role in dyslipidaemia and cardiovascular disease. This review will look at some of the clinical trials that have done so.
Pearl Toh, 8 hours ago
A higher dose of pitavastatin can benefit Japanese patients with stable coronary artery disease (CAD) compared with a low-dose pitavastatin, even though cardiovascular (CV) event incidence is known to be lower in Asian than Western patients, according to the REAL-CAD study presented at the AHA Scientific Sessions 2017.