-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
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.
: 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
50-200 mg twice daily
Often initiated with 12.5-25 mg every 6-8 h
12.5-200 mg daily
Short-acting tartrate preferred for ACS, however, mortality benefit shown for stable patients with CHF
ß1, ß2, α1
3.125-25 mg twice daily
Started low and titrate up; mortality benefit for LV dysfunction
25-200 mg daily
ß1, ß2, α1
200-600 mg twice daily
20-80 mg twice daily
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
: 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
In addition, a trial using nifedipine was stopped early because of concern for harm when taken without concomitant β
TABLE 7.2 Calcium Channel Blockers Used in ACS
Duration of Action
Immediate release: 30-90 mg every 6 h
Avoid with known or suspected LV dysfunction
Slow release: 120-360 mg three times daily
Immediate release: 80-160 mg every 8 h
Avoid with known or suspected LV dysfunction
Slow release: 120-480 mg daily
5-10 mg daily
5-10 mg daily
20-40 mg daily
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.
: 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.
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.
: 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
Duration of Effect
0.3-0.6 mg up to 1.5 mg
1 to 7 min
0.4 mg as needed
Similar to sublingual tablets however has a longer shelf life
0.2-0.8 mg per h every 12 h
8 to 12 h with intermittent therapy, efficacy improved with 12 h off period
5-200 mcg per min
Tolerance in 7 to 8 h
5-80 mg, every 8-12 h
Up to 8 h
Oral, slow release
40 mg, every 12-24 h
Up to 8 h
20 mg twice daily
12 to 24 h
Oral, slow release
60-240 mg daily
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.