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e188 Circulation August 14, 2007
phine use has been raised by data from a large observational
registry (n 443 hospitals) that enrolled patients with
UA/NSTEMI (n 57,039) (313). Those receiving morphine
(30%) had a higher adjusted likelihood of death
(propensity-adjusted OR 1.41, 95% CI 1.26 to 1.57),
which persisted across all subgroups (313). Although subject
to uncontrolled selection biases, these results raise a safety
concern and suggest the need for a randomized trial.
Meanwhile, the Writing Committee has downgraded the
recommendation for morphine use for uncontrolled ischemic
chest discomfort from a Class I to a Class IIa
recommendation.
3.1.2.3. BETA-ADRENERGIC BLOCKERS
Beta blockers competitively block the effects of catecholamines
on cell membrane beta receptors. Beta-1 adrenergic
receptors are located primarily in the myocardium;
inhibition of catecholamine action at these sites reduces
myocardial contractility, sinus node rate, and AV node
conduction velocity. Through these actions, they blunt the
heart rate and contractility responses to chest pain, exertion,
and other stimuli. They also decrease systolic blood pressure.
All of these effects reduce MVO 2. Beta-2 adrenergic
receptors are located primarily in vascular and bronchial
smooth muscle; the inhibition of catecholamine action at
these sites produces vasoconstriction and bronchoconstriction
(300). In UA/NSTEMI, the primary benefits of beta
blockers are due to inhibition of beta-1 adrenergic receptors,
which results in a decrease in cardiac work and myocardial
oxygen demand. Slowing of the heart rate also has a
favorable effect, acting not only to reduce MVO 2 but also to
increase the duration of diastole and diastolic pressure-time,
a determinant of forward coronary flow and collateral flow.
Beta blockers, administered orally, should be started early
in the absence of contraindications. Intravenous administration
may be warranted in patients with ongoing rest pain,
especially with tachycardia or hypertension, in the absence
of contraindications (see below) (Table 12).
Table 15. Properties of Beta Blockers in Clinical Use
The benefits of routine early intravenous use of beta
blockers in the fibrinolytic era have been challenged by 2
later randomized trials of intravenous beta blockade
(314,315) and by a post hoc analysis of the use of atenolol
in the GUSTO-I trial (316). A subsequent systematic
review of early beta-blocker therapy in STEMI found no
significant reduction in mortality (27). Most recently, the
utility of early intravenous followed by oral beta blockade
(metoprolol) was tested in 45,852 patients with MI (93%
had STEMI, 7% had NSTEMI) in the COMMIT study
(317). Neither the composite of death, reinfarction, or
cardiac arrest nor death alone was reduced for up to 28 d in
the hospital. Overall, a modest reduction in reinfarction and
ventricular fibrillation (which was seen after day 1) was
counterbalanced by an increase in cardiogenic shock, which
occurred early (first day) and primarily in those who were
hemodynamically compromised or in HF or who were
stable but at high risk of development of shock. Thus, early
aggressive beta blockade poses a substantial net hazard in
hemodynamically unstable patients and should be avoided.
Risk factors for shock were older age, female sex, time delay,
higher Killip class, lower blood pressure, higher heart rate,
ECG abnormality, and previous hypertension. There was a
moderate net benefit for those who were relatively stable
and at low risk of shock. Whether to start beta blockade
intravenously or orally in these latter stable patients is
unclear, and patterns of use vary. In an attempt to balance
the evidence base overall for UA/NSTEMI patients, beta
blockers are recommended in these guidelines to be initiated
orally, in the absence of contraindications (e.g., HF), within
the first 24 h. Greater caution is now suggested in the early
use of intravenous beta blockers, which should be targeted
to specific indications and should be avoided with HF,
hypotension, and hemodynamic instability.
The choice of beta blocker for an individual patient is
based primarily on pharmacokinetic and side effect criteria,
as well as on physician familiarity (Table 15). There are no
comparative studies between members of this class in the
Drugs Selectivity Partial Agonist Activity Usual Dose for Angina
Propranolol None No 20 to 80 mg twice daily
Metoprolol Beta1 No 50 to 200 mg twice daily
Atenolol Beta1 No 50 to 200 mg per d
Nadolol None No 40 to 80 mg per d
Timolol None No 10 mg twice daily
Acebutolol Beta1 Yes 200 to 600 mg twice daily
Betaxolol Beta1 No 10 to 20 mg per d
Bisoprolol Beta1 No 10 mg per d
Esmolol (intravenous) Beta1 No 50 to 300 mcg per kg per min
Labetalol* None Yes 200 to 600 mg twice daily
Pindolol None Yes 2.5 to 7.5 mg 3 times daily
Carvedilol None Yes 6.25 mg twice daily, uptitrated to a maximum of 25 mg twice daily
*Labetalol and carvedilol are combined alpha and beta blockers. Adapted from Table 25, Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients
with chronic stable angina. Available at: http://www.acc.org/qualityandscience (4).
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