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Feature: ACUTE CORONARY SYNDROME

Mnemonic to assist in the treatment of NSTE-ACS

Hussein, Mohamed El PhD, RN, NP; Hakkola, Jonah

Author Information
doi: 10.1097/01.NPR.0000718512.98673.72
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Figure
Figure

Amnemonic is a technique of encoding information that helps individuals remember and retrieve specific information pertaining to a subject. Mnemonics offer NPs a strategy that aids in effective data retrieval from memory to provide standard care.1 To help NPs in the pharmacologic management of patients with non-ST-segment elevation (NSTE)-acute coronary syndrome (ACS), we are proposing “The 5 As of NSTE-ACS Treatment” (see 5 As of NSTE-ACS Treatment) as a rapid recall tool where each “A” represents a pharmacologic standard of care for patients with NSTE-ACS. The five As in the mnemonic are anti-ischemic, anticoagulant, antiadrenergic (beta-adrenergic blockers [BB]), angiotensin-converting enzyme (ACE) inhibitors, and antihyperlipidemic therapies.

Pathophysiology

ACS is a subcategory of coronary artery disease (CAD) that usually has a symptomatic presentation and develops from atherosclerosis in the myocardial vasculature.2 Atherosclerosis is a condition in which lipid-laden macrophages accumulate in the walls of coronary arteries, leading to plaque formation.3 In cases of NSTE-ACS, the plaque causes partial or intermittent occlusion of coronary arteries resulting in ischemia or infarction of the myocardium.3 NSTE-ACS encompasses NSTE myocardial infarction (NSTEMI) and unstable angina.3

Diagnosis

The American Heart Association (AHA) and the American College of Cardiology (ACC) guidelines recommend that NPs perform a rapid assessment of patients presenting with chest pain or shortness of breath to rule out NSTE-ACS.4 Other atypical presentations may warrant consideration for NSTE-ACS as well, including diaphoresis, nausea, abdominal pain, syncope, and unexplained fatigue.4 Diagnosis of NSTE-ACS with a 12-lead ECG should occur within 10 minutes of first medical contact.4 Although rare, NSTE-ACS can occur in the presence of a normal ECG.4 Cardiac troponin levels should be measured to confirm the diagnosis and guide risk stratification.5 The patient's clinical picture must also be considered along with the ECG and troponin levels during diagnosis.4 Depending on the patient's hemodynamic status and whether the patient's chest pain is responsive or resistant to I.V. nitroglycerin, the NP may choose to either activate the cardiac catheterization lab and redirect the patient to percutaneous coronary intervention (PCI) or to treat the patient medically.4 Acutely, many patients are treated medically by an ischemia-guided strategy and invasive diagnostic or therapeutic interventions are often performed at a later stage if indicated, although an early invasive strategy may be appropriate in some cases.4 A recent study termed “the ISCHEMIA trial” randomized patients with stable ischemic heart disease to either routine invasive therapy (coronary angiography and PCI or coronary artery bypass grafting) (n = 2,588) versus medical therapy (n = 2,591).6 The researchers concluded that there was no significant reduction in major adverse ischemic events from routine invasive therapy when compared with optimal medical therapy among patients with stable ischemic heart disease (P = .34).6

The mnemonic

Anti-ischemics

Anti-ischemics are drugs used either to decrease myocardial oxygen demand or improve coronary artery blood flow in NSTE-ACS and decrease the frequency and intensity of chest pain episodes.4 It is key for the NP to be aware of the current recommendations for anti-ischemic pharmacologic therapy.

Anti-ischemics include nitrates, calcium channel blockers (CCBs), and beta-adrenergic blockers (BBs).4 BB therapy is discussed in a later section. Nitroglycerin (NTG) is a commonly prescribed organic nitrate used for the treatment of NSTE-ACS-related chest pain.7 Guidelines recommend that patients with NSTE-ACS and ongoing ischemic pain receive sublingual (SL) NTG every 5 minutes, up to three doses.4 NTG should not be given to patients who have recently received a phosphodiesterase inhibitor, such as sildenafil within the last 24 hours or tadalafil within the last 48 hours.4

A seminal double-blind randomized controlled trial (RCT) by Karlberg and colleagues (N = 143) examined the efficacy of I.V. NTG for reduction of ischemic events of NSTE-ACS.8 Thirteen of 73 patients receiving I.V. NTG experienced more than two new occurrences of angina lasting less than 20 minutes and responding to SL NTG or one new episode of angina lasting greater than 20 minutes and not responding to SL NTG in comparison to 25 of 70 patients in the placebo group (P < .03).8 If chest pain does not subside with SL NTG therapy, or if there is ongoing ischemia, heart failure, or hypertension, the NP should consider prescribing I.V. NTG.4,5

Another class of anti-ischemics are CCBs, which are classified as either dihydropyridine (DHP) (such as amlodipine or nifedipine) or non-DHP (such as verapamil or diltiazem).9 DHPs inhibit calcium ions from entering the coronary arteries' vascular smooth muscles producing vasodilation, thus increasing myocardial oxygen delivery.9 Non-DHPs decrease heart rate and contractility, therefore, decreasing myocardial oxygen demand and relieving symptoms.9 CCB classification is based on their affinity to bind sites on the calcium channel (CC) pores. DHPs have greater selectivity to CC in the blood vessels, whereas non-DHPs decrease heart rate through inhibition of the CC in the atrioventricular (AV) node.9

CCBs are an antianginal agent alternative to BB therapy.10 The AHA/ACC guideline recommends non-DHP CCBs as initial therapy when BBs are contraindicated, or for those who continue to have ischemia despite use of BB and nitrates, provided there are no contraindications to its use, such as severe left ventricular dysfunction or second- or third-degree AV block.4 The NP is advised to avoid combining non-DHPs and BBs as concomitant therapy with these two classes can have synergistic effects on AV nodal inhibition.9 Amlodipine, a DHP CCB, may be a viable antianginal agent alternative to or in conjunction with BB therapy due to its long half-life and tolerability.10 In terms of antianginal therapy with DHPs, concomitant therapy with BBs should be started within 24 hours for patients with NSTE-ACS who do not have signs of heart failure.4,9

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Anti-ischemics Anticoagulants/Antiplatelets Antiadrenergics (BBs) ACE inhibitors Antihyperlipidemics
Nitrates:
  1.  NTG SL every 5 minutes (maximum three doses) for ongoing ischemic pain.4

  2.  CCB: alternative antianginal agent to BBs in certain situations.4

  3.  DHP (such as amlodipine, nifedipine) may be used concomitantly with BBs.4,9

  4.  Non-DHP (such as verapamil, dilti-azem)—avoid combining with BB.9

    Oxygen:

  5.  for oxygen saturation <90%, respiratory distress, or high-risk features of hypoxemia.9

Anticoagulants
  1.  LMWH:

  2. Enoxaparin: Recommended when an invasive approach is not planned.15

  3. or

  4. UFH:I.V. bolus followed by an I.V. infusion to maintain a therapeutic aPTT.15

  5.  Oral anticoagulants (warfarin, apixaban, others):

  6. For some patients, transition from parenteral to oral anticoagulant therapy to be continued upon discharge is indicated.4

    Antiplatelets

  7.  ASA: chewed/crushed to all patients with confirmed or suspected NSTE-ACS as soon as possible and continued indefinitely23

  8.  DAPT: for 1 year following NSTE-ACS event24

  9.  For those receiving PCI: ASA and either ticagrelor or prasugrel.24

  10.  For those not treated with an invasive strategy:

  11.  ASA and ticagrelor.4

  12.  Morphine sulfate:

  13.  After all anti-ischemic medications have been maximized.4

  1. Improve survival when initiated within 24 hours of NSTE-ACS and can control dysrhyth-mias.5,28

    Nonselective BB:

  2.  Carvedilol

  3. More effective than selective beta-1 blockers when combined with DAPT.27

    Selective beta-1 blockers:

  4.  Metoprolol

  5.  Bisoprolol

  1. Improve survival following NSTE-ACS by decreasing the afterload and myocardial oxygen demand.5,26

  2. Start within 24 hours of symptoms.26

  3. Refer to ACEi therapy post-MI

  1. High-intensity atorvastatin or rosuvastatin: recommended for all patients with NSTE-ACS to reduce atherosclerotic CVD risk unless contraindicated.31

    Goals:

  2.  LDL-C < 2.0 mol/L (77 mg/dL) or >50% reduction

  3.  or

  4.  apoB < 0.8 g/L

  5.  or

  6.  non-HDL-C < 2.6 mmol/L (100 mg/dL).30

NTG, nitroglycerin; SL, sublingual; CCB, calcium channel blockers; BBs, beta-blockers; DHP, dihydro-pyridine; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; aPTT, activated partial thromboplastin time; DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention; ASA, aspirin/acetylsalicylic acid; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; apoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol

Pavasini and colleagues conducted a systematic review to compare the efficacy of antianginal drugs, and concluded that CCBs, specifically amlodipine, result in better total exercise and activity tolerance in patients in comparison to long-acting nitrates.11 CCBs are associated with an 18% reduction in the risk of angina.9

Oxygen therapy is a vital component of the anti-ischemic therapy of NSTE-ACS. The current AHA/ACC NSTE-ACS guideline recommends the use of oxygen therapy for patients with an oxygen saturation of less than 90%, respiratory distress, or high-risk features of hypoxemia.4,9 In a 2017 RCT by Hofmann and colleagues, enrolled patients (N = 6,629) randomly received either oxygen therapy or room air.12 The room air group experienced a greater frequency of hypoxemia than those receiving oxygen (7.7% versus 1.9%, P < .001), yet there was no significant difference in median troponin levels (P = .97) or 1-year all-cause mortality (P = .80).12

Anticoagulants and antiplatelets

Anticoagulants. One of the primary causes of NSTE-ACS is the development of a thrombus in one of the coronary arteries either due to the rupture or erosion of a plaque.13 Injury of the endothelium exposes collagen and activates von Willebrand factor, leading to platelet activation.10 Anticoagulants inhibit clotting factors, thus reducing the likelihood of clot development or growth.7 Combined with antiplatelet therapy, such as acetylsalicylic acid/aspirin (ASA), ticagrelor, or clopidogrel, anticoagulants reduce the recurrence of ischemic events and death.14 The NP should incorporate parenteral anticoagulant therapy, such as low-molecular-weight heparin (LMWH), into the treatment of the patient with NSTE-ACS regardless of the initial treatment strategy.4,7 Transition to oral anticoagulant therapy (such as warfarin or apixaban, among others) to be continued upon discharge is indicated for some patients.4

Unfractionated heparin (UFH) is given as an I.V. bolus followed by an I.V. infusion to maintain a therapeutic activated partial thromboplastin time (aPTT).15 Enoxaparin, a LMWH, is another option and is recommended for patients with NSTE-ACS when an invasive approach is not planned.15 Both UFH and LMWH have proved to be effective therapies in the treatment of NSTE-ACS in many clinical trials and are the conventionally accepted drugs of choice.16 LMWH remains the most common anticoagulant choice, as it has a longer half-life. Dalteparin's half life is 2.1-5 hours,17 and enoxaparin's is 4.5-7 hours18 compared with 0.5-2 hours for UFH,19 coupled with higher bioavailability and easier administration.16

Xiao and colleagues identified data from 859 US hospitals between the years 2010 and 2016 on patients diagnosed with ACS (N = 1,048,053), including 582,134 patients with NSTEMI and 219,259 patients with unstable angina, to compare effects of monotherapy with enoxaparin versus UFH.20 In comparison to UFH, patients with NSTEMI who were treated with enoxaparin experienced lower rates of myocardial infarction (MI) (odds ratio [OR] = 0.95; 95% confidence interval [CI]: 0.92, 0.99), recurrent angina (OR = 0.88; 95% CI: 0.78, 0.98), in-hospital mortality (OR = 0.88; 95% CI: 0.81, 0.95), and composite ischemic complications (OR = 0.95; 95% CI: 0.92, 0.98).20 Treatment with enoxaparin in comparison to UFH decreased the odds of major bleeding across all ACS patients (NSTEMI: OR = 0.68, 95% CI: 0.64, 0.72; unstable angina: OR = 0.77, 95% CI: 0.66, 0.91).20 The selection of appropriate anticoagulant drugs for NSTE-ACS therapy by the NP can optimize outcomes in the clinical settings.20

A 2019 RCT with a 2x2 factorial design by Windecker and colleagues compared the use of the oral anticoagulant apixaban versus vitamin K antagonist (VKA) plus ASA versus placebo in patients with atrial fibrillation presenting with ACS who were receiving a P2Y12 inhibitor (such as clopidogrel or ticagrelor).21 The researchers concluded that a combination of apixaban and a P2Y12 inhibitor is significantly safer and as effective as regimens incorporating VKAs and/or ASA.21

Antiplatelets. Platelet inhibition is a core component in the treatment of NSTE-ACS.22 Thrombosis Canada recommends that an initial dose of ASA chewed or crushed be given to all patients with suspected NSTE-ACS and continued on a daily basis indefinitely.23 For patients undergoing PCI following an NSTE-ACS event, the Canadian Cardiovascular Society recommends dual antiplatelet therapy (DAPT) for 1 year.24 ASA alongside ticagrelor or prasugrel is preferred over ASA plus clopidogrel for those patients.24 ASA plus ticagrelor for up to 1 year is preferred over ASA plus clopidogrel for those not treated with an invasive strategy.4

A prospective cohort study (N = 45,073) conducted by Sahlén and colleagues compared the outcomes of patients treated with ticagrelor (n = 11,954) versus clopidogrel (n = 33,119) post-ACS at 24 months.22 The sample included 64.5% patients who were post-NSTE-ACS. The analyzed data concluded that the cumulative probability of death, MI, and stroke was 11.7% for patients on ticagrelor and 22.3% with clopidogrel (adjusted hazard ratio 0.85 [95% CI: 0.78-0.93]).22 However, bleeding outcomes requiring admission were identified at 5.5% for ticagrelor versus 5.2% for clopidogrel, suggesting a higher bleeding risk for ticagrelor.22 The authors concluded that ticagrelor treatment in real-world outcomes is consistent with previously conducted RCTs, such as the PLATelet inhibition and patient Outcomes (PLATO) trial, and demonstrates the effectiveness of ticagrelor therapy over clopidogrel for patients with acute ACS, including those with NSTE-ACS.22

Morphine sulfate is currently accepted as a viable pharmacologic intervention for the management of persistent chest pain and after all anti-ischemic medications have been maximized.4 However, an RCT conducted by Hobl and colleagues examined the potential drug interactions between clopidogrel and morphine in healthy subjects (N = 24).25 The researchers concluded that morphine slows clopidogrel absorption (P = .025) and delays maximal platelet aggregation inhibition by about 2 hours (P < .001).25 Furthermore, higher residual platelet aggregation was seen 1-4 hours after morphine injection (P < .005).25 The NP should be aware of potential adverse reactions and interactions before prescribing morphine to patients with NSTE-ACS.5

Antiadrenergic (BBs)

Current guidelines continue to support the use of BBs in the treatment of NSTE-ACS.4 Through directly blocking beta-1 myocardial adrenergic receptors, the purpose of BB therapy in NSTE-ACS lies within its negative inotropic and chronotropic effects, which reduce myocardial oxygen demands.5,9 BBs have been shown to improve survival when given within 24 hours of an NSTE-ACS by reducing the infarct size.5 In addition, BBs can control dysrhythmias that may follow an NSTE-ACS by slowing impulse conduction through the heart.4 Contraindications for oral BB therapy include signs of heart failure, evidence of low-output state, risk for cardiogenic shock, as well as any contraindications to beta blockade.4 Furthermore, I.V. BB therapy may be harmful for patients with risk factors for shock.4

A study by Ilardi and colleagues compared the effects of metoprolol and carvedilol on residual platelet reactivity or continued platelet reactivation even after receiving a loading dose of an antiplatelet agent in patients with NSTE-ACS.26 The authors concluded that patients (N = 100) receiving DAPT (ASA and ticagrelor) benefit more from a nonselective BB (P = .04) such as carvedilol (n = 50) in comparison to the selective beta-1 blocker metoprolol (n = 50), with respect to platelet aggregation. Current guidelines recommend either metoprolol or bisoprolol (selective beta-1 blockers) or carvedilol (beta-1 and alpha-1 blocker) as early treatment and secondary prevention for NSTE-ACS.5

In a meta-analysis by Chatterjee and colleagues, 16 studies (N = 73,396) comparing I.V. BB therapy within 12 hours of presentation of ACS to standard therapy and/or placebos were analyzed.27 Administration of BB within 12 hours resulted in an average 8% decrease in in-hospital mortality (P = .04), a significant reduction in risk of ventricular tachyarrhythmias (P = .0003) and myocardial reinfarction (P = .004) with no increase in risk of cardiogenic shock (P = .91) or stroke (P = .38).27

Abi Khalil and colleagues examined the prognostic impact of BB therapy in patients with ACS (N = 7,407) without heart failure.28 They concluded that there was a significant reduction in cumulative mortality (P = .002), risk of mitral regurgitation (P = .0001), ventricular tachycardia and/or ventricular fibrillation (P = .001), cardiogenic shock (P = .001), and acute heart failure (P = .001) in patients on BB therapy on admission as compared with those who were not.28 Nevertheless, both the control and study groups retained similar risk for transient ischemic attacks and stroke.28

ACE inhibitors

ACE inhibitors (ACEi) have been shown to improve survival following an NSTE-ACS by decreasing the afterload and myocardial oxygen demand.5 To be effective, ACEi therapy should begin within 24 hours of symptoms; however, the NP should use ACEi cautiously as therapy may cause hypotension and renal dysfunction.4 Using ACEi in NSTE-ACS is associated with a statistically significant reduction in 30-day mortality.4

-
Contraindications 34,35
  1. Pregnancy: ACEi can cause injury and death to the developing fetus (boxed warning)

  2. Hypersensitivity to any ACEi

  3. Angioedema related to prior ACEi therapy

  4. Hereditary or idiopathic angioedema (enalapril)

  5. Concomitant therapy with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2)

  6. Concomitant therapy alongside or within 36 hours of neprilysin inhibitor therapy (such as sacubitril [found in combination drug sacubitril/valsartan])

  7. Caution: Renal impairment, hepatic impairment, hypovolemia, hyponatremia, and concurrent diuretic therapy

Warnings and precautions34,35
  1. Anaphylactoid reactions, including angioedema

  2. Cholestatic jaundice progressing to hepatic failure

  3. Cough

  4. Hematologic effects including neutropenia, leukopenia, anemia, and thrombocytopenia

  5. Hyperkalemia

  6. Hypotension/Syncope

  7. Proteinuria

  8. Renal function deterioration

  9. Use with caution in patients with aortic stenosis/hypertrophic cardiomyopathy

  10. May cause hypotension in patients undergoing major surgery or during anesthesia

ACEi, ACE inhibitor; MI, myocardial infarction; GFR, glomerular filtration rate
Not a complete list of all contraindications, warnings, precautions, and adverse reactions. Refer to drug labels for complete prescribing information.

It is suggested that NPs initiate ACEi therapy for patients who have experienced an NSTE-ACS event. Alternatively, an angiotensin-receptor blocker (ARB) can be considered in cases where the patient cannot tolerate an ACEi (see ACEi therapy post-MI).5 Unless contraindicated, it is recommended that NPs initiate and continue ACEi therapy in patients with left ventricular ejection fraction <0.40, hypertension, diabetes mellitus, or stable chronic kidney disease.4

Hoang and colleagues conducted a meta-analysis to study the effects of treatment with ACEi or ARBs in patients with CAD but without heart failure. Fifteen relevant trials were identified (10 ACEi and 5 ARB; N = 78,761).29 ACEi treatment was associated with a significant reduction in non-fatal MI (relative risk [RR] 0.83; 95% CI 0.75-0.91) and other major endpoints including stroke, cardiovascular mortality, and all-cause mortality.29

Antihyperlipidemics

The Canadian Cardiovascular Society guidelines identify high-dose statins as the first-line treatment for dyslipidemia management in all patients with NSTE-ACS, with goals of low-density lipoprotein cholesterol (LDL-C) less than 2.0 mmol/L (77 mg/dL) or greater than 50% reduction, or apolipoprotein B (apoB) less than 0.8 g/L, or non-high-density lipoprotein cholesterol (non-HDL-C) less than 2.6 mmol/L (100 mg/dL).30 Current guidelines recommend high-intensity atorvastatin or rosuvastatin to effectively reduce atherosclerotic cardiovascular disease risk.31

In a retrospective longitudinal study conducted using data from Swedish electronic medical records between the years 1992 and 2012, Rockberg and colleagues identified patients (N = 31,104) with history of one ACS event and analyzed their outcomes on high-dose statin therapy.32 The authors determined that there was a lower risk of subsequent events at 5 years in comparison to the control group (high-dose statin hazard rate: 20.94; no statin hazard rate: 37.82) and at 10 years (high-dose statin hazard rate: 11.55; no statin hazard rate: 27.51).32

Conclusion

By using this mnemonic strategy specific to the pharmacologic interventions for ACS, the NP can rapidly recall and integrate evidence-based treatment plans in clinical practice. The “5 As of NSTE-ACS Treatment” is a tool that succinctly summarizes these strategies in an easy-to-remember outline, with the intent of directly impacting patient care in an area that heavily relies on rapid-response times from the healthcare team. It is imperative to acknowledge the complexity and the related challenges of managing patients with NSTE-ACS. Finally, while the mnemonic follows a guideline-driven algorithm to meet the needs of most patients, individual circumstances must be taken into consideration. For example, heart disease is different among males and females and, although there are no absolute guidelines for males versus females in NSTE-ACS, there are documented differences in presentation and outcome.33 Therefore, clinical judgment is crucial to the NP's practice and should always be incorporated in conjunction with the mnemonic.

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      Keywords:

      ACE inhibitors; acute coronary syndrome; anti-ischemic; beta-blockers; calcium channel blockers (CCB); non-ST-segment elevation

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