ST elevation myocardial infarction beta blocker therapy
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Mechanism of Benefit of Beta-Blockers in STEMI
- Beta-blockers reduce myocardial contractility, the velocity of myocardial contraction and heart rate all of which in turn reduces the risk of mechanical complications.
- Beta-blockers reduce the risk of lethal ventricular arrhythmias by depressing phase 4 of diastolic depolarization and reducing the risk of arrhythmias induced by catecholamines.
- Beta-blockers reduce the heart rate multiplied by the systolic blood pressure (i.e., the rate pressure product [RPP]) at rest and during exercise, which reduces myocardial oxygen demand. This in turn limits infarct size and reinfarction.
- Beta-blockers increase diastolic filling time which may improve perfusion of the subendocardial tissue which may improve ischemia and thereby limit infarct size.
- Beta-blockers reduce the activity of the renin-angiotensin system by reducing renin release from the juxta glomerular cells. Also, beta-blockade augments atrial and brain natriuretic peptide (BNP). Beta blockers interfere with sympathetic vasoconstrictor nerve activity; this action is partly responsible for their antihypertensive effect. Cardiac output usually falls and remains slightly lower than normal with administration of non intrinsic sympathomimetic activity (ISA) agents. Systemic vascular resistance (SVR) increases acutely but falls to near normal with long term administration. This acute rise in SVR may explain why acute beta-blockade in STEMI has been associated with worse outcomes among patients with congestive heart failure or cardiogenic shock in the COMMIT study. 
Early Trial Data Obtained Prior to the Advent of Fibrinolytics and ACE Inhibition
Early clinical trail data in the 1980s demonstrated improved outcomes among STEMI patients who were administered beta-blockers. These data were obtained prior to the widespread administration of angiotensin converting enzyme (ACE) inhibitors, and in some trials, prior to the advent of fibrinolytic agents. 
In ISIS 1 patients were randomized to treatment with either atenolol (5-10 mg iv immediately, followed by 100 mg/day orally for 7 days) or placebo (n=16,027).  Atenolol administration was associated with a 15% relative risk reduction in cardiovascular mortality over the first seven days (3.89% versus 4.57%, 2p = 0.04). The combined endpoint of death, cardiac arrest, and reinfarction was also signifcantly reduced (2p < 0.0002). There was a consistent benefit across all subgroups. Following the initial treatment over the first 7 days, the benefit was maintained and slightly fewer events were accrued such at that 1 year, cardiovascular death was significantly lower among patients treated with atenolol (10.7% versus 12.0%, 2p < 0.01).
In the Metoprolol In Acute Myocardial Infarction (MIAMI) trial, STEMI patients were randomized to receive either metoprolol (up to 15 mg IV in 3 divided doses followed by 50 mg orally every six hours for 48 hours and then 100 mg twice per day thereafter) or placebo (n=5,700 patients). There was a favorable trend in mortality at 15 days (4.3% vs 4.9%) which was sustained over time. The benefits of metoprolol were greater in high risk patients. 
Randomized Trial Data Supporting the Administration of Beta Blockers in the Modern Era
While the prior studies evaluated the benefit int he era prior to fibrinolytic administration, data from the era in which fibrinolytic agents are administered show mixed results. Among those trails that demonstrate a benefit, the risk of recurrent ischemia and reinfarction were reduced. There is subgroup data to suggest a reduction in mortality if beta-blockers are administered within 2 hours of symptom onset.
The Thrombolysis In Myocardial Infarction Phase II (TIMI-II) Trial
In the TIMI-II trial, IV alteplase treated patients were randomized to receive either metoprolol, 15 mg IV which was then followed by oral metoprolol, 50 mg twice per day for 1 day and then 100 mg twice per day thereafter versus placebo. Metoprolol administration was associated with a lower rate of nonfatal reinfarction and recurrent ischemia. The composite end point of death or reinfarction, occurred less often in those given immediate IV metoprolol was significantly reduced among patients who were treated within 2 hours of symptom onset.
Randomized Trial Data That Do Not Support the Administration of Beta Blockers in the Modern Era
Thrombolysis in Myocardial Infarction (TIMI) II-B Study 
In TIMI IIB, a subgroup of 1,434 patients treated with rt-PA who were elligible for beta-blockers were subrandomized to treatment with either immediate IV beta-blockade (5 mg intravenously at 2-minute intervals over 6 minutes, for a total intravenous dose of 15 mg, followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter)(n=720) or delayed administration (Metoprolol, 50 mg orally twice on day 6, followed by 100 mg orally twice a day thereafter)(n=714). The pre-specified primary end point of pre-discharge ejection fraction was nearly identical in both groups (50.5%) and there was no difference in mortality. Early administration was associated with a reduction in the risk of reinfarction (2.7% versus 5.1%, p = 0.02) and recurrent substernal chest discomfort (18.8% versus 24.1%, p less than 0.02) through 6 days.
Short-term effects of early intravenous treatment with a beta-adrenergic blocking agent or a specific bradycardiac agent in patients with acute myocardial infarction receiving thrombolytic therapy 
Alteplase treated patients were randomized to atenolol (5 to 10 mg intravenously followed by 25 to 50 mg orally every 12 hours, n=100) or alinidine (20 to 40 mg intravenously followed by 20 to 40 mg orally every 8 hours, n=98) or placebo (n=94). Neither atenolol nor alinidine were associated with improvements in coronary artery patency, arrhythmias, global ejection fraction, regional wall motion, enzymatic or scintigraphic infarct size at 10 to 14 days. Atenolol was associated with a greater incidence of nonfatal pulmonary edema (6% vs. 1% in the alinidine group and 0% in the placebo group, p = 0.021).
Clopidogrel and Metoprolol in Myocardial Infarction Trial / Second Chinese Cardiac Study (COMMIT-CCS 2)
The COMMIT-CCS 2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial / Second Chinese Cardiac Study) randomized 45,852 patients within 24 hours of onset of suspected MI to receive either metoprolol (up to 3 doses of 5 mg IV each in the first 15 minutes, followed by 200 mg orally daily) or matching placebo.  Fifteen minutes after the IV doses, a 50 mg tablet of metoprolol or placebo was administered orally and repeated every 6 hours during days 0 to 1 of hospitalization. From day 2 onward, 200 mg of controlled release metoprolol or placebo was administered orally daily (this is the FDA approved regimen for metoprolol in MI) until discharge from the hospital or up to a maximum of 4 weeks in hospital (in survivors, the mean was 15 days). The 2 pre-specified co-primary outcomes were the composite of death, reinfarction or cardiac arrest and death from any cause during the treatment phase of the study.
Administration of metoprolol was not associated with a reduction in either of the co-primary end points. If one were to treat 1,000 patients, treatment with metoprolol was associated with 5 fewer episodes of reinfarction, 5 fewer episodes of ventricular fibrillation, but these benefits came at the cost of 11 more episodes of cardiogenic shock(a 30% relative increase). In addition to the increased risk of cardiogenic shock, Metoprolol administration was also associated with an increased risk of hypotension and bradycardia. The excess risk of cardiogenic shock was observed early, predominantly during the first day after treatment. In contrast, the reductions in reinfarction and ventricular fibrillation appeared slowly over time.
The following subgroups of patients in COMMIT-CCS 2 were identified as being at higher risk of development of cardiogenic shock:
- Age over 70
- Systolic blood pressure < 120 mm Hg
- Pulse on admission > 110 beats per minute
- Killip class >1.
The ACC / AHA guidelines committee recommends that clinicians identify those patients at higher risk of cardiogeneic shock, and avoid therapy in these patients.
Non-Randomized Data from the Modern Era That Do Not Support the Administration of Beta Blockers in the Modern Era
GUSTO 1 Substudy
Non-randomized analyses of the benefit of beta-blockers are difficult to interpret in so far as those patients who were administered beta-blockers were healthier, and their administration was prohibited in patients with heart failure in trials such as GUSTO 1.  Despite design elements which favored outcomes among patient administered beta-blockers (healthier patients were treated with beta-blockers and heart failure patients were excluded), the administration of intravenous atenolol combined with late oral administration was associated with higher mortality than late oral administration alone in a retrospective analysis from GUSTO 1,.  The authors concluded that late oral administration of atenolol might be sufficient and may offer just as good of outcomes as that coupled with early IV administration.
- Cocaine-induced MI
- Left ventricular failure
- Cardiogenic shock or risk of cardiogenic shock (at risk patients include those who are over age 70, patients with a systolic blood pressure < 120 mm Hg, patients with a pulse on admission of > 110 beats per minute, and patients with Killip class > 1)
- Heart rate <60
- Systolic blood pressure < 100 mmHg
- PR interval >0.24 second
- Second or third degree AV block
- Active asthma, or reactive airway disease.
Dosing and Administration
Early Beta-Blocker Therapy in the First 24 Hours
Among patients who are not deemed to be at high risk of subsequently developing cardiogenic shock (at risk patients include those who are over age 70, patients with a systolic blood pressure < 120 mm Hg, patients with a pulse on admission of > 110 beats per minute, and patients with Killip class > 1), the ACC / AHA guidelines indicate that "it is reasonable to administer IV beta blocker therapy on Days 0 to 1 of hospitalization for STEMI when hypertension is present." If a patient is in sinus tachycardia or atrial fibrillation, then the patient should be rapidly evaluated to ascertain whether left ventricular failure is present before drugs with negative inotropic properties such as beta-blockers are administered.
The dose of intravenous metoprolol is 5 mg over one to two minutes, which is repeated every five minutes for a total initial dose of 15 mg. Once it is established that a patient can tolerate this dose, they can then be transitioned to oral therapy. The first oral dose can be administered 15 minutes after the third IV dose. The initial oral dose is 25 to 50 mg every six hours for 48 hours. If this dose is well tolerated, the maintenance dose is 100 mg twice daily.
The dose of intravenous atenolol is a 5 mg initial dose. 5 minutes later this initial dose is then followed by another 5 mg dose. If the patient tolerates these doses, then the maintenance dose of 50 to 100 mg per day is begun 1 to 2 hours following the last intravenous dose.
The dose of Esmolol (Brevibloc) is 50 mcg/kg/min which can be increased to a maximum dose of 200 to 300 mcg/kg/min. This agent can be used to test the response to beta-blockade as its action is rapidly reversible.
Beta-Blocker Therapy After the First 24 Hours
If a patient does not have significant left ventricular failure, then long term dosing with a beta-blcoker such as metoprolol is a reasonable choice. Dosing of metoprolol is often initiated with a 50 mg dose every 6 hours. if this dose is tolerated, the patient can then be administered 200 mg of controlled release oral metoprolol daily.
Beta-Blocker Therapy in the Patient with Left Ventricular Dysfunction Post MI
The Carvedilol Post-infarct Survival Controlled Evaluation trial (CAPRICORN) evaluated the safety and efficacy of beta-blockade with carvedilol in patients with either transient or sustained LV dysfunction following an MI.  Patients with a left-ventricular ejection fraction (LVEF) of <= to 40% were randomized to treatment with either carvedilol (6.25 mg, n=975) which was increased to 25 mg BID over the next 6 weeks or placebo (n=984). Patients in the study were allowed background therapy with ACE inhibitors. The primary endpoint of death or rehospitalization did not differ between treatment arms but all cause mortality was lower among patients treated with carvedilol (12% vs 15%, HR 0.77 [0.60-0.98], p=0.03).
- Cardiovascular: Precipitation of Heart Failure, AV block, hypotension, severe bradycardia, intermittent claudication, cold extremities, Raynaud’s phenomenon, and dyspnea may occur.
- Central Nervous System: Depression may occur, especially with propranolol, and psychosis can occur. Dizziness, weakness, fatigue, vivid dreams, insomnia, and rare loss of hearing may occur.
- Gastrointestinal: Nausea, vomiting, and epigastric distress are possible.
- Respiratory: Bronchospasm, laryngospasm, respiratory distress, respiratory arrest (rare with overdose) may occur.
2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: Executive Summary(DO NOT EDIT)
Beta Blockers (DO NOT EDIT)
|"1. Oral beta blockers should be initiated in the first 24 hours in patients with STEMI who do not have any of the following: signs of HF, evidence of a low output state, increased risk for cardiogenic shock*, or other contraindications to use oral beta blockers (PR interval more than 0.24 seconds, second- or third-degree heart block, active asthma, or reactive airway disease). (Level of Evidence: B) "|
|"2. Beta blockers should be continued during and after hospitalization for all patients with STEMI and with no contraindications to their use. (Level of Evidence: B) "|
|"3. Patients with initial contraindications to the use of beta blockers in the first 24 hours after STEMI should be reevaluated to determine their subsequent eligibility. (Level of Evidence: C) "|
|"4. Risk factors for cardiogenic shock (the greater the number of risk factors present, the higher the risk of developing cardiogenic shock) are age 70 years, systolic blood pressure 120 mm Hg, sinus tachycardia 110 bpm or heart rate 60 bpm, and increased time since onset of symptoms of STEMI "|
|"1. It is reasonable to administer intravenous beta blockers at the time of presentation to patients with STEMI and no contraindications to their use who are hypertensive or have ongoing ischemia. (Level of Evidence: B) "|
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