Medications Used in the Management of Acute Coronary Syndrome



Medications Used in the Management of Acute Coronary Syndrome


Michael Jolly

A. Michael Lincoff



The pharmacologic management of an acute coronary syndrome (ACS) has evolved dramatically over the past two decades into a heavily evidence-based discipline. Contemporary treatment strategies have become more targeted, focusing on the unique pathophysiologic underpinnings of this disorder. In addition, new therapeutic approaches are rigorously tested and proven in large clinical trials before becoming standard therapy. As our armamentarium of new therapeutics continues to grow, our diagnostic and management strategies will necessarily change over time. As such, practitioners caring for patients with ACS must become lifelong students of this exciting and dynamic field to provide the best care for their patients in the years to come.

Appropriate medical therapy is indicated for all patients presenting with or suspected of having ACS. The goals of initial medical therapy are 4-fold: to relieve pain, to halt the progression of disease, to reduce morbidity, and to improve survival. Because the term ACS encompasses a spectrum of severity with a common pathophysiology, the difficulty in the pharmacologic management comes in determining where in the spectrum a particular patient falls and to balance the risks and benefits in treating that patient to achieve the desired goals.

Once the diagnosis of ACS is established, the patient should be quickly stratified by risk into one of several treatment strategies. Medical therapy should be immediately started in a rational manner to achieve the initial goals of treatment, namely, to interrupt platelet activation/aggregation, thrombus formation, and to relieve pain. Patients diagnosed with ST-segment elevation myocardial infarction (STEMI) should be emergently strategized to primary PCI or fibrinolytic therapy, whereas those with UA/NSTEMI should be risk-stratified into either an early invasive or an initial conservative approach. Regardless of what treatment strategy is initiated, patients should be continuously evaluated for highrisk features of disease, adverse hemodynamic consequences, and treatment failure. Such features often mandate deviation from the initial management strategy to a more aggressive one. It is important to note that as a patient transitions from one treatment strategy to another, the pharmacologic approach can vary substantially.

In general, the pharmacologic approach to managing ACS should be prioritized with an emphasis on rapid treatment with medications known to provide morbidity and mortality benefit. Guidelines for treatment are useful; however, they cannot address every possible nuance experienced in clinical practice. Health care providers must have a thorough understanding of their institutional capabilities and preferences as well as familiarity with the drugs, doses, indications, and side effects to provide patients with optimal benefit and minimal harm.


ANTI-ISCHEMIC AND ANALGESIC THERAPY


ß-ADRENERGIC BLOCKERS

Rationale: β-Blockers are used to inhibit the actions of catecholamines on the β1 adrenergic receptors located in the myocardium. Inhibition of these receptors leads to a reduction in myocardial contractility, AV node conduction, sinus node rate, and an overall reduction in systolic blood pressure. The net effect of these actions results in a decrease in cardiac work and myocardial oxygen demand. In addition, β-blockers increase diastolic pressure time, which may be important in increasing coronary blood flow. In patients with ACS undergoing PCI, a large meta-analysis showed a significant reduction in mortality at 30 days and 6 months for patients who received β-blocker therapy.1 However, the Clopidogrel and Metoprolol in Myocardial Infarction (COMMIT) failed to demonstrate a mortality benefit with the early use of β-blockers in patients with myocardial infarction.2 This finding has been attributed to injudicious use of β-blockers in patients with heart failure or other risk factors for cardiogenic shock and has been instructive in the most recent guidelines involving recommendations for β-blocker usage in ACS. However, in contrast to the early aggressive use of β-blockers for acute MI, the Carvedilol Post-Infarct Survival Control in left ventricular dysfunction (CAPRICORN) trial demonstrated a reduction in all-cause mortality, cardiovascular mortality, and nonfatal MI when 1,959 patients with acute MI and LV dysfunction were randomized to receive to low-dose carvedilol versus placebo and treated with a more gradual up-titration strategy.3

Indications: ACS (without contraindications), stable angina, compensated chronic heart failure.

Dosing: Multiple preparations available including intravenous and oral, β1 and nonselective, short and long acting (Table 7.1).

Side effects: Hypotension, bradycardia, AV block, congestive heart failure (CHF), bronchospasm, paradoxical Hypertention in setting of active cocaine use.

Contraindications: High-grade AV block, active bronchoconstriction, hypotension, bradycardia, severe LV dysfunction or heart failure (rales, S3 gallop), or in patients with MI at high risk for cardiogenic shock (older age, female sex, relative hypotension, high Killip class, and reflexive tachycardia).









TABLE 7.1 ß-Blockers Used in ACS













































Drugs


Selectivity


Dose


Comment


Metoprolol tartrate


ß1


50-200 mg twice daily


Often initiated with 12.5-25 mg every 6-8 h


Metoprolol succinate


ß1


12.5-200 mg daily


Short-acting tartrate preferred for ACS, however, mortality benefit shown for stable patients with CHF


Carvedilol


ß1, ß2, α1


3.125-25 mg twice daily


Started low and titrate up; mortality benefit for LV dysfunction


Atenolol


ß1


25-200 mg daily



Labetalol


ß1, ß2, α1


200-600 mg twice daily



Propranolol


ß1, ß2


20-80 mg twice daily



Esmolol


ß1


50-300 mcg/kg/min



Adapted from Gibbons RJ, Abrams J, Chatterjee K, et al.; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003;41:159-168.


Recommendations: The acute use of β-blockers in ACS is recommended in all patients without contraindications, especially in patients with ongoing angina and hypertension. Short-acting, β1 selective agents are typically used to minimize side effects and allow for dose titration. A typical regimen would include metoprolol 5 mg IV, repeated every 5 minutes, up to a total of 15 mg. Oral therapy can be started at metoprolol 25 to 50 mg every 6 hours and titrated to achieve the desired heart rate (HR) or BP. Frequent HR and BP checks, continuous ECG monitoring, and routine auscultation for rales and bronchospasm should be performed (preferably in an ICU setting). Once stabilized, patients should receive maintenance doses up to 100 mg twice daily. In patients with LV dysfunction, β-blockers with proven mortality benefit such as bisoprolol, carvedilol, and metoprolol succinate should be utilized for long-term management.


CALCIUM CHANNEL BLOCKERS

Rationale: Calcium channel blockers (CCBs) inhibit myocardial and vascular smooth muscle contraction by reducing transmembrane inward calcium flux. In ACS, CCBs are useful in decreasing myocardial oxygen demand (by decreasing afterload, contractility, and HR) and in coronary vasodilatation. Meta-analyses of UA/NSTEMI trials involving CCBs have suggested no overall benefit in death or nonfatal MI.4 Retrospective studies of verapamil and diltiazem have shown increased mortality in patients with LV dysfunction.5,6 In addition, a trial using nifedipine was stopped early because of concern for harm when taken without concomitant β-blockers.7








TABLE 7.2 Calcium Channel Blockers Used in ACS















































Drug


Dose


Duration of Action


Comment


NON DIHYDROPYRIDINES


Diltiazem


Immediate release: 30-90 mg every 6 h


Short


Avoid with known or suspected LV dysfunction



Slow release: 120-360 mg three times daily


Long



Verapamil


Immediate release: 80-160 mg every 8 h


Short


Avoid with known or suspected LV dysfunction



Slow release: 120-480 mg daily


Long



DIHYDROPYRIDINES


Amlodipine


5-10 mg daily


Long



Felodipine


5-10 mg daily


Long



Nisoldipine


20-40 mg daily


Short



Indications: In ACS, considered second-line therapy in β-blocker-intolerant patients for relief of angina, blood pressure control, and rate control of supraventricular arrhythmias. CCBs are considered adjuncts to β-blockers and nitrates for the relief of ischemic symptoms. They are generally the preferred treatment for patients with cocaine-induced myocardial ischemia or variant angina.

Dosing: Multiple preparations both intravenous and oral, short and long acting (Table 7.2).

Side effects: Hypotension, bradycardia, myocardial depression (diltiazem and verapamil), flushing, edema, or headache.

Contraindications: Hypotension, AV conduction abnormalities, LV dysfunction or CHF (especially diltiazem and verapamil).


Recommendations: In patients with contraindications to β-blockers or in those where β-blockers and nitrates have failed to achieve relief of ischemia or rate control with supraventricular arrhythmias, CCBs can be used to further reduce blood pressure and chest pain. Caution should be exercised when CCBs and β-blockers are used concomitantly because of depressed AV nodal conduction. Diltiazem and verapamil should be avoided in patients with LV dysfunction. Use of dihydropyridines such as amlodipine and felodipine appear to be safe with LV dysfunction, although their benefit remains undefined in the treatment of ACS; nifedipine should be avoided altogether.


NITRATES

Rationale: Despite a paucity of rigorous clinical trial data, nitrates continue to remain important in the treatment of hypertension and chest pain in patients with ACS. Nitrates cause a reduction of myocardial oxygen demand while enhancing myocardial oxygen delivery and affect both peripheral and coronary vascular beds. Nitroglycerin increases venous capacitance thereby decreasing preload and reducing ventricular wall tension. Furthermore, nitroglycerin promotes the dilation of the coronary arteries and possibly has a mild inhibitory effect on platelet aggregation (although the clinical significance of this is not known).

Indications: Angina, hypertension, CHF, variant angina.

Dosing: Nitroglycerine (NTG) is available in multiple preparations including sublingual tablets and spray, transdermal, and intravenously (Table 7.3).

Side effects: Headaches, hypotension, and tachyphylaxis are common with NTG usage.

Contraindications: NTG is contraindicated after the use of phosphodiesterase inhibitors used for the treatment of erectile dysfunction such as sildenafil, tadalafil, and vardenafil as concominant use can induce profound hypotension. In addition, nitrates should be avoided in patients suspected of having an RV infarct as its usage can result in severe hypotension even with low doses.

Recommendations: NTG use is typically initiated with three 0.4 mg sublingual NTG tablets taken 5 minutes apart with the concomitant administration of either an oral or an intravenous β-blocker. For patients with ongoing chest pain, hypertension, or decompensated heart failure, it is appropriate to switch to intravenous NTG. This is given at 10 mcg per minute through continuous infusion via nonabsorbing tubing and can be uptitrated by 10 mcg per minute every 3 to 5 minutes to achieve symptomatic relief or desired blood pressure response. Although there is no published maximal ceiling dose, 200 mcg per minute is typically used as there is unlikely to be measurable clinical benefit beyond this rate. For blood pressure titrations, NTG should not be titrated to <110 mm Hg in previously normotensive patients or to >25% lower than the starting mean arterial blood pressure (MAP) in hypertensive patients. NTG should generally be avoided in patients with starting systolic blood pressures of <90 mm Hg, in patients with marked bradycardia or tachycardia, or in patients who present with systolic blood pressures 30 mm Hg or more below their baseline. After a patient has been stable or chest pain free for 12 to 24 hours, it is prudent to attempt weaning intravenous NTG or transitioning to an oral preparation if still indicated.








TABLE 7.3 Nitrate Preparations Used in ACS
















































Compound


Route


Dose


Duration of Effect


Nitroglycerin


Sublingual tablets


0.3-0.6 mg up to 1.5 mg


1 to 7 min



Spray


0.4 mg as needed


Similar to sublingual tablets however has a longer shelf life



Transdermal


0.2-0.8 mg per h every 12 h


8 to 12 h with intermittent therapy, efficacy improved with 12 h off period



Intravenous


5-200 mcg per min


Tolerance in 7 to 8 h


Isosorbide dinitrate


Oral


5-80 mg, every 8-12 h


Up to 8 h



Oral, slow release


40 mg, every 12-24 h


Up to 8 h


Isosorbide mononitrate


Oral


20 mg twice daily


12 to 24 h



Oral, slow release


60-240 mg daily




MORPHINE

Rationale: Although there is a lack of randomized clinical trials, morphine sulfate provides analgesic and anxiolytic effects that might partially counteract the adrenergic drive associated with ACS. In addition, it causes mild venodilation, a modest reduction in HR through increased vagal tone, and decreased BP that lowers myocardial oxygen demand.

Dosing: Morphine sulfate 1 to 5 mg IV PRN.

Side effects: Nausea, vomiting, respiratory depression, and hypotension.

Recommendations: Morphine should be considered for anginal relief in patients not sufficiently controlled with nitrates, β-blockers, or CCBs and is often given in preparation for further invasive testing.


ANCILLARY THERAPIES


ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS

Rationale: Inhibition of the renin-angiotensin-aldosterone system has salutary effects on BP, afterload reduction, and LV remodeling associated with MI-induced LV dysfunction. ACE inhibitors have a proven track record in multiple clinical trials for decreasing mortality particularly in patients with depressed ejection fractions, chronic coronary artery disease (CAD), and
diabetes.8,9,10,11 and 12 In addition, the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial demonstrated that valsartan was as effective as captopril in the reduction of death following MI in patients with demonstrable LV dysfunction or clinical heart failure.13 Therefore, in addition to their proven clinical role in stable CHF, angiotensin II receptor blockers (ARBs) appear to also offer benefit in the ACS setting.

Indications: ACS with concurrent pulmonary congestion or LVEF ≤40%, in absence of contraindications. ARBs should be given to patients intolerant of ACE inhibitors.

Dosing: Multiple preparations both short and long acting. Intravenous forms not recommended for ACS (Table 7.4).

Side effects: Hypotension, hyperkalemia, angioedema and cough (ACE inhibitors).

Contraindications: Hemodynamic instability, renal failure, hyperkalemia.

Recommendations: Typically initiated early, within the first 24 hours of hospital stay, in patients without contraindications. Use of short-acting formulations (i.e., captopril 12.5 mg every 8 hours) allows for dose titration. Once stable, once-daily dosing can be initiated. Intravenous ACE inhibitors should be avoided in the management of ACS.


ALDOSTERONE RECEPTOR ANTAGONISTS

Rationale: Aldosterone receptor antagonists have been shown to prevent deleterious ventricular remodeling after acute MI, decrease the rate of death, and reduce hospitalizations in patients with chronic severe heart failure. The Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial further expanded the beneficial role in renin-angiotensin-aldosterone blockade by demonstrating a reduction in morbidity and mortality for patients presenting with acute MI complicated by LV dysfunction when treated with eplerenone.








TABLE 7.4 ACE Inhibitors and ARBs Used in ACS



















































































































Drug


Starting Dose


Typical Dose


Maximum Dose


Comments


ACE INHIBITORS


Benazepril


10 mg


20-40 mg


80 mg


May use BID dosing


Captopril


6.25-12 mg BID-TID


25-50 mg BID-TID


450 mg daily


Target dose in HF: 50 mg TID


Enalapril


2.5-5 mg daily-BID


10-40 mg


40 mg


Target dose in HF: 10 mg BID


Fosinopril


10 mg


20-40 mg


80 mg



Lisinopril


2.5-5 mg


10-40 mg


80 mg


Target dose in HF: 20 mg daily


Moexipril


7.5 mg


7.5-30 mg


30 mg



Perindopril


4 mg


4-8 mg


16 mg



Quinapril


10 mg


20-80 mg


80 mg


Target dose in HF: 20 mg daily


Ramipril


2.5 mg


2.5-20 mg


20 mg



Trandolapril


1 mg


2-4 mg


8mg


Reduce dose in hepatic dysfunction


ARBs


Candesartan


8-16 mg


16-32 mg


32 mg



Eprosartan


600 mg


600-800 mg


800 mg



Irbesartan


75-150 mg


150-300 mg


300 mg



Losartan


25-50 mg


50-100 mg


100 mg


Reduce dose in hepatic dysfunction


Valsartan


20 mg


160 mg


320 mg



Olmesartan


20 mg


20-40 mg


40 mg



Telmisartan


20-40 mg


40-80 mg


80 mg



Indications: ACS with concurrent pulmonary congestion or LVEF ≤40%, in absence of contraindications.

Dosing: Eplerenone 25 mg PO daily with gradual up-titration to a maximum of 50 mg PO daily. Frequent monitoring of electrolytes, especially potassium and creatinine, is essential.

Side effects: Hypotension, hyperkalemia, and renal dysfunction.

Contraindications: Hemodynamic instability, and renal failure, hyperkalemia.

Recommendations: Given the totality of evidence to date, ACE inhibitors and ARBs remain preferred first-line therapy agents for renin-angiotensin-aldosterone blockade for patients with ACS and concurrent LV dysfunction. However, the addition of an aldosterone receptor blocker such as eplerenone may be considered in patients already receiving optimal medical treatment in the absence of contraindications.


HMG-COA REDUCTASE INHIBITORS (STATINS)

Rationale: Statins have been widely studied in both primary and secondary preventions for CAD. The “pleiotropic” effects of statins include not only their well-established ability to lower
LDL but also their anti-inflammatory, antioxidant, and antithrombotic properties. In the setting of ACS, PROVE IT-TIMI 22 showed a significant 16% reduction in the hazard ratio for death, MI, UA, revascularization, and stroke in patients treated with intensive lipid-lowering therapy (atorvastatin 80 mg) compared with standard therapy (pravastatin 40 mg).14

Indications: STEMI and UA/NSTEMI

Dosing: Multiple agents, however, atorvastatin most studied for ACS. Typically given at 40 to 80 mg PO daily (Table 7.5).

Side effects: Dyspepsia, rash/pruritis, myalgias, hepatotoxicity, and rhabdomyolysis (rare).

Contraindications: Caution when used with cytochrome P450 inhibitors and in the setting of elevated transaminases.

Recommendations: Statins at high doses should be considered early in the course of patients presenting with ACS. LDL target goals for the ACS population should be <100 mg per dl and probably <70 mg per dl in high-risk patients and diabetics. Statins should be considered standard therapy for secondary prevention in the absence of contraindications.


ANTIPLATELET MEDICATIONS


ASPIRIN

Rationale: Aspirin (ASA) is a potent, irreversible platelet COX-1 inhibitor that inhibits the production of thromboxane A2 and resultantly decreases platelet aggregation at the site of intimal injury and thrombus formation. Although it is a relatively weak inhibitor of overall platelet aggregation, ASA confers a significant reduction in mortality.15,16,17,18 and 19

Indications: ACS (diagnosed or suspected), chronic CAD.

Dosing: Initial dosing should be 162 to 325 mg given orally as a nonenteric coated, chewable tablet to allow for rapid buccal absorption. In case of active nausea or vomiting, a 300 mg rectal suppository should be promptly administered.

Side effects: Nausea, vomiting, dyspepsia, gastrointestinal/genitourinary and bleeding.

Contraindications: The only contraindication is patients with true ASA allergy (anaphylaxis, hives, nasal polyps, or bronchospasm). Such patients should be given a thienopyridine such as clopidogrel, with strong consideration given for ASA desensitization treatment.

Recommendations: Aspirin 325 mg should be administered to all persons as soon as ACS is diagnosed or suspected, typically in the ambulance or the emergency department. In general, therapy with ASA should be continued indefinitely after the first presentation with ACS at a low dose of 75 to 81 mg daily. Patients who are treated with PCI should typically remain on 325 mg dosing for the first month for bare-metal stent (BMS) or 3 to 6 months for drug-eluting stent (DES) before converting to a low-dose regimen.








TABLE 7.5 Statins Used in ACS
























Drug


Dose


Atorvastatin


10-80 mg daily


Fluvastatin


20-80 mg daily


Lovastatin


10-80 mg daily


Pravastatin


10-80 mg daily


Rosuvastatin


5-40 mg daily


Simvastatin


10-80 mg daily



THIENOPYRIDINES AND ADP RECEPTOR INHIBITORS

Thienopyridines are inhibitors of ADP-induced platelet aggregation and along with ASA have become important therapies in the treatment of ACS. Three thienopyridines have received FDA approval in the United States for use in ACS: ticlopidine, clopidogrel, and prasugrel. Ticagrelor, a novel ADP receptor inhibitor, had recently been approved by the FDA. Each of these drugs works by inhibiting the P2Y12

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May 27, 2016 | Posted by in CARDIAC SURGERY | Comments Off on Medications Used in the Management of Acute Coronary Syndrome
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