ST elevation myocardial infarction beta blocker therapy
| Myocardial infarction | |
| ICD-10 | I21-I22 |
|---|---|
| ICD-9 | 410 |
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| eMedicine | med/1567 emerg/327 ped/2520 |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor: Cafer Zorkun, M.D., Ph.D. [2]
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Mechanism of Benefit
Beta blockade has been associated with improved clinical outcomes among patients with ST elevation myocardial infarction. These agents exert the benefit via several mechanisms [1] [2] [3]:
- Beta blockers reduce myocardial oxygen demands
- Beta blockers reduce contractility which in turn reduces the risk of mechanical complications
- Beta blockers reduce the risk of lethal ventricular arrhythmias.
Blockade of cardiac beta1-receptors causes a decrease in heart rate, myocardial contractility, and velocity of cardiac contraction. The heart rate multiplied by the systolic blood pressure (i.e., the rate pressure product [RPP]) is reduced at rest and during exercise, and this action is reflected in a reduced myocardial oxygen demand (which is an important effect in the control of angina). [4] [5]
The main in vitro antiarrhythmic effect of beta blockers is the depression of phase 4 diastolic depolarization. Beta blockers are effective in abolishing arrhythmias produced by increased catecholamines. Maximum impulse traffic through the atrioventricular node (AV)is reduced, and the rate of conduction is slowed. Paroxysmal supraventricular tachycardia (PSVT) caused by AV nodal reentry is often abolished by beta blockers, which also slow the ventricular rate in atrial flutter and atrial fibrillation. There is a variable effect on ventricular arrhythmias, which may be abolished if induced by increased sympathomimetic activity, as is often seen in myocardial ischemia.
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.
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 increases acutely but falls to near normal with long term administration.[6] [7]
Clinical Trial Data
Although, the 2004 STEMI Guidelines recommendations were based on studies that showed a reduced incidence of subsequent reinfarction and recurrent ischemia in patients receiving both fibrinolytic therapy and intravenous beta blockers, uncertainty about the use of IV beta blockers in the setting of fibrinolytic therapy has increased following 2 later randomized trials of IV beta blockade; a post-hoc analysis of the use of atenolol in the GUSTO-I (Global Utilization of Streptokinase and [[t-PA] for Occluded Coronary Arteries) trial and a review of early beta-blocker therapy in myocardial infarction that did not find significant reductions in mortality.[8]
In the CAPRICORN study, carvedilol produced a marked reduction in cardiac deaths and events in early post MI patients. [9]
According to COMMIT-CCS 2 study caution is needed because beta blockers may increase cardiac mortality when used indiscriminately in patients, in whom the drugs are contraindicated, particularly IV use in patients who are hemodynamically unstable, with impending cardiogenic shock, pulmonary edema, or acute MI with HF.
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 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 scheduled treatment period.
Neither of the co-primary study end points was significantly reduced by allocation to metoprolol. For every 1000 patients treated, allocation to metoprolol was associated with 5 fewer episodes of reinfarction, 5 fewer episodes of ventricular fibrillation, but 11 more episodes of cardiogenic shock. The excess of cardiogenic shock was seen mainly from Days 0 to 1 after hospitalization, whereas the reductions in reinfarction and ventricular fibrillation appeared from day 2 onward.[10]
Allocation to metoprolol produced an average relative increase in cardiogenic shock of 30%, with higher rates for those >70 years of age, or with systolic blood pressure <120 mmHg, or with presenting heart rate >110 bpm, or with Killip class >1. On average across the whole study population, the absolute reduction in arrhythmia related deaths and the absolute increase in cardiogenic shock related deaths were of similar magnitude. No apparent difference was noted between the two treatment groups in the other attributed causes of death, either individually or in aggregate. Metoprolol allocation was associated with significantly more persistent hypotension and more cases of bradycardia.[11]
Though patients at high or low risk could be identified yet there is no possibility to identify any subgroups in which the benefits clearly outweighed the risks.
The results of the COMMIT-CCS 2 trial raise questions about the safety of early use of IV beta blockers, particularly in high risk populations, and led the writing group to reexamine the overall evidence base for beta blocker therapy. The evidence base for this therapy was developed more than 25 years ago in a treatment environment that differs from contemporary practice. Moreover, no study included an oral beta blocker only arm. [12] [13]
Dosing and Administration
It is reasonable to administer IV beta blocker therapy on Days 0 to 1 of hospitalization for STEMI when hypertension is present and the patient is not at an increased risk of cardiogenic shock on the basis of the risk factors defined above. Patients with sinus tachycardia or atrial fibrillation should have left ventricular function rapidly evaluated before administration of IV beta blockers (or other negative inotropes, such as non-dihydropyridine calcium channel blockers).
From Day 2 onward, when beneficial effects on reinfarction and ventricular fibrillation are seen, administration of 200 mg of controlled release oral metoprolol daily appears to be safe in hemodynamically stable patients with ST Elevation MI who are free of contra-indications. It is prudent to initiate a dose of 50 mg of metoprolol orally every 6 hours, transitioning to a dose equivalent to 200 mg/day orally or the maximum tolerated dose.
Beta blockers should not be administered to patients with STEMI precipitated by cocaine use because of the risk of exacerbating coronary spasm.
The following are relative contraindications to beta blocker therapy: heart rate <60 bpm, systolic arterial pressure <100 mmHg, moderate or severe LV failure, signs of peripheral hypoperfusion, shock, PR interval >0.24 second, second or third degree AV block, active asthma, or reactive airway disease.
Intravenous metoprolol can be given in 5 mg increments by slow intravenous administration (5 mg over one to two minutes), repeated every five minutes for a total initial dose of 15 mg. Patients who tolerate this regimen should then receive oral therapy beginning 15 minutes after the last intravenous dose (25 to 50 mg every six hours for 48 hours) followed by a maintenance dose of 100 mg twice daily.
Intravenous atenolol can be given in a 5 mg dose, followed by another 5 mg, 5 minutes later. Patients who tolerate this regimen should then receive oral therapy beginning 1 to 2 hours after the last intravenous dose (50 to 100 mg/day).
Esmolol (e.g., Brevibloc) (50 mcg/kg/min increasing to a maximum of 200 to 300 mcg/kg/min) can be used if an ultra short acting beta blocker is required. Beta blockers should be administered to all patients with ST elevation myocardial infarction without contraindications. Early intravenous use of a cardio selective agent, such as metoprolol or atenolol, is recommended.
Side Effects
Side effects of beta blockers treatment include:
- Cardiovascular System: 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.
- Respiratory System: Bronchospasm, laryngospasm, respiratory distress, respiratory arrest (rare with overdose) may occur.[14]
Guidelines (DO NOT EDIT)
Class I
1. Oral beta blocker therapy should be initiated in the first 24 h for patients who do not have any of the following (Level of Evidence: B):
a. Signs of heart failure,
b. Evidence of a low output state,
c. Increased risk for cardiogenic shock are age >70 years, systolic blood pressure <120 mmHg, sinus tachycardia >110 bpm or heart rate <60 bpm, and increased time since onset of symptoms of STEMI (the greater the number of risk factors present, the higher the risk of developing cardiogenic shock),
d. Other relative contraindications to beta blocker therapy (PR interval >0.24 seconds, second or third degree AV block, active asthma, or reactive airway disease).
2. Patients with early contraindications within the first 24 h of STEMI should be re-evaluated for beta blocker therapy as secondary prevention (Level of Evidence: C)
3. Patients with moderate or severe Left Ventricular failure should receive beta blocker therapy as secondary prevention with a gradual titration scheme (Level of Evidence: B).
Class IIa
1. It is reasonable to administer an IV beta blocker at the time of presentation to STEMI patients who are hypertensive and who do not have any of the following (Level of Evidence: B):
a. Signs of heart failure,
b. Evidence of a low output state,
c. Increased risk for cardiogenic shock are age >70 years, systolic blood pressure <120 mmHg, sinus tachycardia >110 bpm or heart rate <60 bpm, and increased time since onset of symptoms of STEMI (the greater the number of risk factors present, the higher the risk of developing cardiogenic shock),
d. Other relative contraindications to beta blocker therapy (PR interval >0.24 seconds, second or third degree AV block, active asthma, or reactive airway disease).
Class III
1. IV beta blockers should not be administered to STEMI patients who have any of the following (Level of Evidence: A):
a. Signs of heart failure,
b. Evidence of a low output state,
c. Increased risk for cardiogenic shock are age >70 years, systolic blood pressure <120 mmHg, sinus tachycardia >110 bpm or heart rate <60 bpm, and increased time since onset of symptoms of STEMI (the greater the number of risk factors present, the higher the risk of developing cardiogenic shock),
d. Other relative contraindications to beta blocker therapy (PR interval >0.24 seconds, second or third degree AV block, active asthma, or reactive airway disease).[15]
References
- ↑ Khan M G, Cardiac Drug Therapy 7th edition 2007
- ↑ Braunwald's Heart Disease, Libby P, 8th edition, 2007
- ↑ Hurst's The Heart, Fuster V, 12th edition, 2008
- ↑ Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet. 2005;366:1622–32.
- ↑ Lopez-Sendon J, Swedberg K, McMurray J, et al. Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J. 2004;25:1341–62.
- ↑ Krum H, Gu A, Wiltshire-Clement M, et al. Changes in plasma endothelin-1 levels reflects clinical response to β-blockade in chronic heart failure. Am Heart J 1996;131:337.
- ↑ Cruickshank JM, Degaute JP, Kuurne T, et al. Reduction of stress/catecholamine induced cardiac necrosis by B1 selective blockade. Lancet 1987;2:585.
- ↑ Khan M G, Cardiac Drug Therapy 7th edition 2007
- ↑ CAPRICORN: The Capricorn Investigators: Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction. Lancet 2001;357:1385.
- ↑ Khan M G, Cardiac Drug Therapy 7th edition 2007
- ↑ Khan M G, Cardiac Drug Therapy 7th edition 2007
- ↑ Antman E.M., Hant M., Armstrong P.W., et. al., 2007 Focused updates of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation published online Dec 10, 2007; DOI: 10.1161/CIRCULATION AHA.107.188209
- ↑ Khan M G, Cardiac Drug Therapy 7th edition 2007
- ↑ Savola J, Vehvilainen O, Vaatainen NJ. Psoriasis as a side effect of beta-blockers. BMJ 1987;295:637.
- ↑ Antman E.M., Hant M., Armstrong P.W., et. al., 2007 Focused updates of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Circulation published online Dec 10, 2007; DOI: 10.1161/CIRCULATION AHA.107.188209