Anti-ischemia Therapy
The agents used for treating ischemia in patients with unstable angina/NSTEMI include nitrates, morphine sulfate, and beta blockers (e.g., metoprolol) [see Table 6].
Nitrates Nitroglycerin is an endothelium-independent general arterial and venous dilator. It decreases myocardial oxygen demand through increased venous capacitance and peripheral artery dilation—factors that reduce preload and afterload, respectively, and thereby reduce myocardial wall stress. Epicardial coronary vasodilation and increased collateral flow act to enhance myocardial oxygen delivery.
No large, placebo-controlled clinical trials addressing reductions in major cardiac events or symptoms in unstable angi-na/NSTEMI have been performed. Multiple small, uncontrolled trials, a well-characterized biologic effect, and decades of experience have made nitrates a standard of care in the early treatment of these patients.
Table 6 Anti-ischemia Therapy
|
Drug |
Dosage |
Route |
Duration |
Adverse Effects |
Adverse Drug Reactions |
Contraindications |
|
Nitrates |
S.L.: 0.4 mg q. 5 min x 3; I.V.: 10 mg/min, titrate up q. 5 min; paste: 2-6 cm; patch: 0.4 mg/hr |
S.L., I.V., paste, patch |
15-20 min until side effects occur or symptoms resolve |
Hypotension, headache, nausea, tolerance |
None |
Hypotension; sildenafil or vardenafil within 24 hr of nitrate use |
|
Morphine sulfate |
1-5 mg every 10-15 min |
I.V. |
Until side effects or symptoms resolve |
Hypotension, respiratory depression, rash, pruritus, nausea |
None |
Severe ventilatory failure, hypotension |
|
Metoprolol* |
5 mg q. 5 min to max 3 doses, then 25-100 mg b.i.d. with titration |
I.V., then oral |
Symptom resolution (if MI, then indefinite) |
Hypotension, bradycar-dia, bronchospasm, worsened claudication |
None |
Hypotension, bradycar-dia, asthma, decompen-sated heart failure |
*Other beta blockers are equally effective, although agents with intrinsic sympathomimetic activity should be avoided. Calcium channel blockers may be used for patients in whom beta blockers are contraindicated. MI—myocardial infarction
In the emergency department, the initial nitrate dosage in a nonhypotensive patient is typically 0.4 mg of sublingual nitro-glycerin (tablet or spray) repeated approximately every 5 minutes if ischemic symptoms do not subside. If this fails to terminate the ischemia, intravenous nitroglycerin at an infusion rate of 10 |ig/min is recommended. The dose is titrated upward in increments of 10 to 20 |ig/min until symptoms or signs of ischemia subside, hypotension develops, or the recommended maximal dose of 200 |ig/min is achieved. After the acute period, topical nitrates, such as a 0.4 mg/hr nitrate patch, can be used for long-term therapy if necessary.
Nitroglycerin can result in significant hypotension, necessitating withdrawal of the agent. It should be avoided in patients who have taken sildenafil (Viagra) or vardenafil (Levitra) in the past 24 hours, because very severe hypotension can occur. Nitrate tolerance develops with prolonged nitrate administration, so patients should have nitrate-free intervals. Other adverse reactions, including intermittent headaches and nausea, are common.
A class I recommendation and level C evidence support the use of nitroglycerin to terminate or prevent ischemic episodes. Nitroglycerin therapy should serve as a bridge to the use of other evidence-based therapies, such as revascularization.
Morphine sulfate Almost a century of experience in acute coronary syndrome (albeit in the absence of clinical trial data) has established morphine sulfate as a useful adjunct to the early management of unstable angina/NSTEMI. Besides its potent analgesic and anxiolytic effect, morphine sulfate causes venodi-lation and mild arterial dilation, leading to reduced preload and afterload, and it may increase vagal tone to modestly reduce heart rate. These effects make it useful for treating patients with severe pulmonary congestion.
Morphine sulfate is given in a dose of 1 to 5 mg intravenously every 10 to 15 minutes until ischemic symptoms dissipate. At the same time, consideration for intravenous nitroglycerin treatment should be made. Morphine sulfate often causes hypotension, nausea, vomiting, and respiratory depression. Effects are quickly reversible with naloxone. A class I recommendation and level C evidence support the use of morphine sulfate to relieve chest pain that is refractory to sublingual nitroglycerin, to reverse acute pulmonary edema, and to ease severe agitation.
Beta blockers Beta blockers reduce myocardial oxygen demand by reducing heart rate and contractility. Slowing of the heart rate may also permit increased coronary filling during a prolonged diastole.
Much of the evidence in favor of beta-blocker therapy for unstable angina/NSTEMI is extrapolated from the large benefit shown in major clinical trials of acute MI. A meta-analysis of trials of threatened or evolving MI revealed a 13% reduction in progression to acute MI,74 but there was insufficient power for mortality analysis.
There is no evidence of any difference in efficacy between the various beta blockers available, although agents with intrinsic sympathomimetic activity should be avoided. The dose will vary with the agent selected. In unstable angina/NSTEMI, intravenous loading doses titrated to a target resting heart rate of 50 to 60 beats/min may be used, with rapid conversion to an oral regimen. In patients who may have difficulty tolerating the adverse effects of beta blockers, the initiating dose should be small and titration should proceed more slowly.
Bronchospasm and severe asthma are contraindications to the use of beta blockers. Significant sinus bradycardia, AV nodal block, and hypotension can also occur, typically in patients with preexisting disease of cardiac conductive tissue.
A class I recommendation and level B evidence support the use of beta blockers in patients with ongoing chest pain; in such patients, an initial intravenous dose is followed by oral therapy.
Calcium channel blockers These agents are primarily vasodilators, but they also have effects on atrioventricular nodal conduction and left ventricular contractility. The dihydropyri-dine calcium channel blockers (e.g., nifedipine and amlodipine) have the most peripheral vasodilatory capability and the least negative inotropic effect.
To date, the trial data generally suggest that calcium channel blockers offer symptom relief in patients with unstable angina, but a meta-analysis found no improvements with regard to death or the occurrence of MI.75 Nifedipine, compared with a beta blocker (metoprolol), demonstrated a trend toward increased MI.76 In unstable angina/NSTEMI, the nondihydropyri-dine agents are used for coronary artery spasm and may be chosen for patients who cannot tolerate beta blockade.
Doses of calcium channel blockers vary with the agent chosen. For diltiazem, the usual immediate dose is a 20 mg/kg intravenous bolus, followed 15 minutes later by a 20 to 25 mg/kg bolus. Thereafter, the drug is administered orally, in a dosage of 30 mg three to four times a day, titrated to a total daily dose of 360 mg if necessary. Long-acting formulations exist as well.
Hypotension occurs with all calcium channel blockers. Brady-cardia and negative inotropic effects accompany the nondihy-dropyridine agents; these agents should be avoided in patients with heart failure. The dihydropyridine agents may cause reflex tachycardia and other sympathomimetic effects.
Recommendations for the use of calcium channel blockers are as follows:
1. Nondihydropyridine calcium channel blockers (i.e., verap-amil, diltiazem) may be initiated in patients with continuing or frequently recurring ischemia for whom beta block-ers are contraindicated, in the absence of severe left ventricular dysfunction or other contraindications of calcium channel blockade. This class I recommendation is supported by level B evidence.
2. Extended-release forms of nondihydropyridine calcium channel blockers may be used instead of a beta blocker (class IIa recommendation, level B evidence).
3. Immediate-release dihydropyridine calcium channel block-ers (i.e., nifedipine) should not be used in the absence of beta-blocker treatment (class III recommendation, level B evidence).
4. Immediate-release dihydropyridine calcium channel block-ers may be used, if specifically indicated, in patients who are receiving a beta blocker (class II recommendation, level B evidence).
Lipid-Lowering Agents
There is as yet no evidence from a clinical trial that indicates that the use of lipid-lowering agents in hospital confers a benefit for patients with unstable angina/NSTEMI. However, data from a large Swedish registry showed a reduction in mortality in MI patients given statin therapy before discharge.77 In addition, patients given such therapy in the hospital are much more likely to continue it out of hospital, and in-hospital use has therefore been recommended.78,79 The use of a fibrate or niacin in patients with a high-density lipoprotein cholesterol level of less than 40 mg/dl is supported by a class I recommendation and level B evidence. A class IIa recommendation and level B evidence support treatment with statins and diet for patients whose low-density lipoprotein cholesterol is greater than 100 mg/dl; treatment should begin 24 to 96 hours after admission and continue after hospital discharge.
Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors may block inflammatory processes and encourage plaque stability. In the Heart Outcomes Prevention Evaluation (HOPE) trial, use of the ACE inhibitor ramipril was associated with significant reductions in death, MI, or stroke in moderate- to high-risk patients, most of whom had normal left ventricular function.80 The American College of Cardiology/American Heart Association (ACC/AHA) recommends ACE inhibitors for patients with unstable angina/NSTEMI and heart failure; left ventricular systolic dysfunction (ejection fraction less than 40%); hypertension; or diabetes. This class I recommendation is supported by level B evidence.
Mechanical revascularization
Coronary revascularization with percutaneous procedures or CABG is performed to relieve symptoms and improve prognosis [see Early Invasive versus Conservative Strategy, above]. Several factors influence the decision to proceed with coronary revascular-ization, including risk, absence of relevant comorbid conditions, disabling symptoms, viable myocardium at risk, and whether the patient’s coronary anatomy is suitable for the procedure.
Percutaneous Coronary Intervention
Advances in percutaneous coronary intervention techniques and devices have improved safety and long-term vessel patency rates. Several changes in the evolution of coronary stent design, including smaller profile, increased flexibility, small strut diameter, and, the newest development, drug-eluting technology, have improved deliverability and reduced the rate of in-stent resteno-sis. Furthermore, the use of adjunctive antiplatelet and an-tithrombotic therapies, particularly in the setting of acute coronary syndrome, has improved outcomes.
The ACC/AHA guidelines for the use or avoidance of percutaneous coronary intervention in unstable angina/NSTEMI are as follows1:
1. Percutaneous coronary intervention (or CABG) is recommended for patients with single-vessel or two-vessel CAD without significant involvement of the proximal left anterior descending coronary artery (LAD) who have large areas of viable myocardium and high-risk features on noninva-sive testing. This class I recommendation is supported by level B evidence.
2. Percutaneous coronary intervention is recommended for patients who have single-vessel or multivessel CAD, have suitable coronary anatomy, have normal left ventricular function, and do not have diabetes (class 1 recommendation, level A evidence).
3. Percutaneous coronary intervention (or CABG) is recommended for patients who have single-vessel or two-vessel
CAD without significant proximal LAD involvement but who have a moderate area of viable myocardium and ischemia on noninvasive testing (class IIa recommendation, level B evidence).
4. Percutaneous coronary intervention (or CABG) is recommended for patients who have single-vessel disease with significant proximal LAD involvement (class IIa recommendation, level B evidence).
5. Percutaneous coronary intervention (or CABG) is not indicated for patients who have atypical symptoms or have no evidence of ischemia on noninvasive testing or have not received an adequate trial of medical therapy (class III recommendation, level C evidence).
6. Percutaneous coronary intervention (or CABG) is not indicated for patients with significant left main CAD who are suitable candidates for CABG (class III recommendation, level B evidence).
Surgical Revascularization
Surgical revascularization techniques and perioperative outcomes have improved over the years. Particular advances include use of internal mammary artery conduits, off-pump procedures, minithoracotomy, and, the newest development, robot-assisted procedures.
The ACC/AHA guidelines for CABG in patients with unstable angina/NSTEMI are as follows1:
1. CABG is indicated for patients with significant left main CAD. This class I recommendation is supported by level A evidence.
2. CABG is indicated for patients with triple-vessel CAD and abnormal left ventricular function (class 1 recommendation, level A evidence).
3. CABG is indicated for patients who have two-vessel disease with significant proximal LAD disease and abnormal left ventricular function (class 1 recommendation, level A evidence).
4. CABG or percutaneous intervention is indicated for patients who have single-vessel or two-vessel CAD without significant proximal LAD involvement but with large areas of viable myocardium and high-risk features on noninva-sive testing (class 1 recommendation, level B evidence).
Diabetes and Revascularization
Overall, patients with diabetes are more likely to require repeat revascularization after percutaneous intervention, because of increased rates of restenosis; in addition, there is a trend toward higher mortality 1 year after both CABG and percutaneous intervention with stents in diabetic patients.81 In the Bypass An-gioplasty Revascularization Investigation (BARI) trial, diabetic patients with multivessel CAD were found to have better survival rates with CABG than with percutaneous intervention.82 However, analysis of the diabetic subgroup of a randomized trial and registry of percutaneous intervention with bare metal stents versus CABG in unstable angina patients revealed no difference in 3-year survival between the groups.83 Drug-eluting stents display markedly reduced rates of in-stent restenosis, as compared with traditional bare-metal stents, particularly in diabetic patients.84,85
Currently, the available evidence suggests that surgical revas-cularization should be offered to diabetic patients with CAD in three or more vessels, particularly if they have left ventricular dysfunction. However, it is common practice to offer percutaneous intervention as the revascularization strategy for diabetic patients with CAD involving one or two vessels. Trials are needed to compare the most advanced drug-eluting stent technology with the most advanced surgical management to define their roles in diabetic patients with CAD.
Posthospital care
Preparation for the posthospital care of a patient with unstable angina/NSTEMI should begin during the hospitalization, with appropriate education, dietary advice, psychosocial counseling, weight loss advice, exercise prescription, cardiac rehabilitation referral (if appropriate), smoking cessation counseling, and the initiation of drug therapy. Given the importance of aggressive risk modification, the entire medical staff has a responsibility to ensure that all of these therapies and advice are offered, encouraged, and established for the future.
Aspirin therapy should be maintained indefinitely, and clopi-dogrel should be taken for 9 months. For patients who have had an MI or who have left ventricular dysfunction, beta-blocker therapy is recommended indefinitely, in the absence of contraindications. ACE inhibitor treatment is recommended indefinitely for secondary prevention in moderate- to high-risk patients with atherosclerotic disease, diabetes, a low ejection fraction, or other specific indications. Lipid-lowering therapy (e.g., with a statin drug) should be administered if the patient has a low-density lipopro-tein level higher than 100 mg/dl post diet (class I, level B), or a high-density lipoprotein level lower than 40 mg/dl (class IIa, level B).79 Blood pressure should be kept below 140/90 mm Hg unless the patient has renal disease or diabetes, in which case the target is a pressure lower than 130/80 mm Hg.86 All patients should be prescribed sublingual nitroglycerin and instructed in its use; in particular, they should understand the importance of returning to the hospital immediately if symptoms persist despite three doses of nitroglycerin. Finally, follow-up should take place 2 to 6 weeks after discharge in low-risk and revascularized patients, or 1 to 2 weeks after discharge in higher-risk patients.
