Acute%20coronary%20syndromes%20w_out%20persistent%20st-segment%20elevation Treatment

Antiplatelet Agents

• In patients with ACS treated only with medical therapy, PCI or CABG, 12 months of dual antiplatelet therapy (Aspirin plus a P2Y₁₂ receptor inhibitor) is recommended
  • Consider continuing therapy >12 months in patients with previous MI and tolerant of dual antiplatelet therapy with no bleeding complication
  • Consider at least 1 month of dual antiplatelet therapy in patients treated only with medical therapy and at high risk of bleeding
  • Consider stopping therapy after 6 months in patients treated with PCI or CABG and at high risk of bleeding
• For long-term treatment, adding a 2nd 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 risk
• 12-month DAPT should be given in patients with ACS and chronic kidney disease with eGFR of 15 to <60 mL/min/1.73 m² with prior major adverse CV event and without high risk of bleeding   
  • Patients with eGFR of <60 mL/min/1.73 m² with high risk of bleeding may be given Aspirin or Clopidogrel
  • Shorten duration of DAPT in patients with eGFR of <15 mL/min/1.73 m² and high risk of bleeding  
• In patients >75 years old, shorten duration of DAPT (eg 1-6 months) in frail elderly patients or in those who are not frail but with high risk of bleeding
• P2Y₁₂ receptor inhibitors (Cangrelor, Clopidogrel, Prasugrel, Ticagrelor) are listed in alphabetical order

Aspirin

• Should be given promptly and continued daily in all patients with suspected ACS, 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
  • 75-100 mg of Aspirin is recommended in patients being treated with dual antiplatelet therapy
• 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 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 NSTE-ACS patients

Clopidogrel

• Recommended in combination with Aspirin in UA/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 NSTEMI undergoing an invasive management, an initial dose of 600 mg followed by 75 mg daily may be considered
• Prodrug that actively biotransforms 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
• Has a better safety profile as compared to Ticlopidine but with the same consistency and degree of P2Y₁₂ inhibition and risk of bleeding
• Preferred over other P2Y₁₂ inhibitors in elderly patients due to 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
• If possible, discontinue at least 5 days before elective CABG

Prasugrel

• Recommended in combination with Aspirin in P2Y₁₂-inhibitor-naive patients 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
• Should be considered the preferred P2Y12 inhibitor in NSTEMI patients who will undergo PCI
  • 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 side effects in patients with planned invasive evaluation when compared to Ticagrelor 
• 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 and degree of P2Y₁₂ inhibition 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); administer with caution in patients >75 years old and weigh <60 kg
• May be withheld for at least 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 initial choice of therapy (invasive or conservative, including pre-treatment with Clopidogrel)
  • Initial dose of 180 mg, then 90 mg 12 hourly for 12 months
  • Ticagrelor 60 mg 12 hourly for >12 months in combination with Aspirin may be preferred over Clopidogrel or Prasugrel in patients with MI and high risk of ischemia and tolerant of dual antiplatelet therapy with no bleeding complication
  • Studies show that Aspirin ≥300 mg/day decreases the efficacy of Ticagrelor; Aspirin 75-100 mg is recommended in patients being treated with dual antiplatelet therapy
• A member of the chemical class cyclopentyltriazolopyrimidines (CPTP), Ticagrelor is a 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 subset of patients with ACS:
  • 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
• May be withheld for at least 3 days prior to elective CABG

Glycoprotein IIb/IIIa Inhibitors

• Mainly used in patients with a large thrombus discovered during coronary angiography
• 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 
• Tirofiban or Eptifibatide
  • 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

Vorapaxar

• 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

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
• In patients who require oral anticoagulants (including older patients with increased thrombotic risk and acceptable bleeding risk), consider 1 month of triple therapy with Aspirin, Clopidogrel and an oral anticoagulant in patients who have undergone coronary stent implantation
• In non-ST elevation-ACS patients with atrial fibrillation who underwent PCI, risk of bleeding is lower with the use of direct oral anticoagulants and antiplatelet therapy than with standard triple therapy 

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

Unfractionated Heparin (UFH)

• Dosing should be based on weight
• Activated partial thromboplastin time (aPTT) should be maintained at 50-70 seconds or 1.5-2x normal
• Enhances antithrombin III activity causing decrease in activity of clotting factors including thrombin and actor Xa; UFH also has antiplatelet function

Factor Xa Inhibitors

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

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

• A parenteral selective factor Xa inhibitor which is a synthetic polysaccharide molecule
• 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 with the use of Fondaparinux but similar reduction in the risk of ischemic events in both groups

Rivaroxaban

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

Direct Thrombin Inhibitors

Argatroban

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

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 is comparable to UFH in protecting patients against ischemia during PCI and also showed lower bleeding complications

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 heart failure, 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 beats/minute
• 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 LV 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

• 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 
  • Long-term lipid management includes addition of Ezetimibe to a maximally tolerated statin dose after 4-6 weeks if LDL-C is not at goal; if despite this LDL-C is still not at goal, then PCSK9 inhibitors may be considered
• Patients >75 years old with clinical atherosclerotic CVD may be given moderate- or high-intensity statin therapy

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 with MI 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

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 I_f  which controls spontaneous diastolic depolarization in the sinoatrial node
• Has been associated with decreased risk for revascularization

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

Trimetazidine

• Exerts metabolic effects without hemodynamic changes
• In small trials, use has been shown to improve LV function and has been associated with decreased mortality

Proton Pump Inhibitors

• Given to patients at high risk of GI bleeding who are receiving Aspirin monotherapy, dual antiplatelet therapy, dual or triple antithrombotic therapy or oral anticoagulation monotherapy

¹Please see Hypertension and Heart Failure - Chronic disease management charts for dosing recommendations of ACE inhibitors, angiotensin II antagonists and aldosterone antagonists.

• 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 goal¹: BP <130/80 mmHg
• 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
• Please see Hypertension disease management chart for further information

¹Recommendations for BP treatment goals may vary between countries. Please refer to available guidelines from local health authorities

Lipid Management

• 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 
• Statins should be given to 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
  • Treatment goal is LDL-C level of <1.4 mmol/L (<55 mg/dL) and a reduction of at least 50% if baseline LDL-C level is >1.8 mmol/L (>70 mg/dL)
    • Consider adding Ezetimibe to further lower LDL-C in patients with LDL-C ≥1.8 mmol/L despite statin therapy at maximally tolerated dose, and a PCSK9 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) can be therapeutic options (after LDL-C lowering therapy) for patients with HDL-C <40 mg/dL and triglycerides >200 mg/dL to reduce residual risk in patients who have achieved LDL-C target goals
• Please see Dyslipidemia disease management chart for further information

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 HbA_1c (<6.5-7%)
• Less stringent glucose control may be more appropriate in patients with more advanced CVD, older age, longer diabetes duration, and significant comorbidities
• Please see Diabetes Mellitus disease management chart for further information

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 in (90 cm); American/European men: <40 in (102 cm)
  • Asian women: <31.5 in (80 cm); American/European women: <35 in (88 cm)
• 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
• If attempting to lower cholesterol with diet modification, please see Dyslipidemia disease management chart for more specific recommendations