A. Treatment of Acute Attack
Sublingual nitroglycerin is the drug of choice; it acts in about 1-2 minutes. Nitrates decrease arteriolar and venous tone, reduce preload and afterload, and lower the oxygen demand of the heart. Nitrates may also improve myocardial blood flow by dilating collateral channels and, in the presence of increased vasomotor tone, coronary stenoses. As soon as the attack begins, one fresh tablet is placed under the tongue. This may be repeated at 3- to 5-minute intervals. The dosage (0.3, 0.4, or 0.6 mg) and the number of tablets to be used before seeking further medical attention must be individualized. Nitroglycerin buccal spray is also available as a metered (0.4 mg) delivery system. It has the advantage of being more convenient for patients who have difficulty handling the pills and of being more stable. Nitroglycerin should also be used prophylactically before activities likely to precipitate angina. Pain not responding to three tablets or lasting more than 20 minutes may represent evolving infarction, and the patient should be instructed to seek immediate medical attention.

B. Prevention of Further Attacks
1. Aggravating factors  - Angina may be aggravated by hypertension, left ventricular failure, arrhythmia (usually tachycardias), strenuous activity, cold temperatures, and emotional states. These factors should be identified and treated or avoided where possible.

2. Nitroglycerin  - Nitroglycerin, 0.3-0.6 mg sublingually or 0.4-0.8 mg translingually by spray, should be taken 5 minutes before any activity likely to precipitate angina. Sublingual isosorbide dinitrate (2.5-10 mg) is only slightly longer-acting than sublingual nitroglycerin.

3. Long-acting nitrates  - A number of longer-acting nitrate preparations are available. These include isosorbide dinitrate, 10-40 mg orally three times daily; isosorbide mononitrate, 10-40 mg orally twice daily or 60-120 mg once daily in a sustained-release preparation; oral sustained-release nitroglycerin preparations, 6.25-12.5 mg two to four times daily; nitroglycerin ointment, 6.25-25 mg applied two to four times daily; and transdermal nitroglycerin patches that deliver nitroglycerin at a predetermined rate (usually 5-20 mg/24 h). The main limitation to chronic nitrate therapy is tolerance, which occurs to some degree in most patients. The degree of tolerance can be limited by utilizing a regimen which includes a minimum 8- to 10-hour period per day without nitrates. Isosorbide dinitrate given three times daily, with the last dose after dinner, is the most commonly used approach, but longer-acting isosorbide mononitrate is becoming more popular. Because it is the active metabolite of the dinitrate, isosorbide mononitrate has more consistent bioavailability. Transdermal nitrate preparations should be removed overnight in most patients.

Nitrate therapy is often limited by headache. Other side effects include nausea, light-headedness, and hypotension.

4. Beta-blockers  - Beta-blockers prevent angina by reducing myocardial oxygen requirements during exertion and stress. This is accomplished by reducing the heart rate, myocardial contractility, and, to a lesser extent, blood pressure. The beta-blockers are the only antianginal agents that have been demonstrated to prolong life in patients with coronary disease (post-myocardial infarction). They are at least as effective at relieving angina as alternative agents in studies employing exercise testing, ambulatory monitoring, and symptom assessment. As a result, they should be considered for first-line therapy in most patients with chronic angina.

In the United States, only propranolol, metoprolol, nadolol, and atenolol are approved for angina. Nonetheless, all available beta-blockers appear to be effective for angina, though those with intrinsic sympathomimetic activity, such as pindolol, are less desirable because they may exacerbate angina in some individuals and have not been effective in secondary prevention trials. The pharmacology and side effects of the beta-blockers are discussed here (Table 11-6). The dosages of all these drugs when given for angina are similar. The major contraindications are bronchospastic disease, bradyarrhythmias, and overt heart failure.

5. Calcium channel blocking agents  - Verapamil, diltiazem, and the dihydropyridine group of calcium blockers are chemically and pharmacologically heterogeneous agents that prevent angina by reducing myocardial oxygen requirements and by inducing coronary artery vasodilation. Myocardial oxygen demand is lessened by reducing blood pressure, left ventricular wall stress, and, in the case of verapamil and diltiazem, resting or exercise heart rate. Though these agents are all potent coronary vasodilators, it is unclear whether they improve myocardial blood flow in most patients with stable exertional angina. In those with coronary vasospasm, the calcium channel blockers may be the agents of choice.

Most calcium channel blockers have negative inotropic, chronotropic, and dromotropic properties in vitro, but the reflex sympathetic response may obscure these effects in vivo (except in the presence of beta blockade or severely depressed left ventricular function). Unlike the beta-blockers, calcium channel blockers have not reduced mortality postinfarction and in some cases have increased ischemia and mortality rates. This appears to be the case with some dihydropyridines and with diltiazem and verapamil in patients with clinical heart failure or moderate to severe left ventricular dysfunction. A recent meta-analysis suggested that short-acting nifedipine in moderate to high doses causes an increase in mortality in patients early after myocardial infarction or with unstable angina. It is uncertain whether these findings are relevant to longer-acting dihydropyridines, and data with verapamil and diltiazem suggest that these latter agents are safe in postinfarction patients with preserved left ventricular function. Nevertheless, considering the uncertainties and the lack of demonstrated favorable effect on outcomes, calcium channel blockers should be considered third-line anti-ischemic drugs in the postinfarction patient. Similarly, with the exception of amlodipine, which in the PRAISE trial proved safe in patients with heart failure, these agents should be avoided in patients with congestive heart failure or low ejection fractions.

The pharmacologic effects and side effects of the calcium channel blockers are discussed in here and summarized in Table 11-8. Although all have been shown to be efficacious for angina, not all preparations and agents are approved for this indication. By and large, diltiazem and verapamil are preferable as first-line agents because they produce less reflex tachycardia and because the former, at least, may cause fewer side effects. Nifedipine, nicardipine, and amlodipine are also approved agents for angina. Isradipine, felodipine, and nisoldipine are not approved for angina but probably are as effective as the other dihydropyridines.

6. Alternative and combination therapies  - Patients who do not respond to one class of antianginal medication often respond to another. It may, therefore, be worthwhile to use an alternative agent before progressing to combinations. If the patient remains symptomatic, a beta-blocker and a long-acting nitrate or a beta-blocker and a calcium channel blocker (other than verapamil, where the risk of atrioventricular block or heart failure is higher) are the most appropriate combinations. A few patients will have a further response to a regimen including all three agents.

7. Platelet-inhibiting agents  - Coronary thrombosis is responsible for most episodes of myocardial infarction and many unstable ischemic syndromes. Several studies have demonstrated the benefit of anti-platelet drugs following unstable angina and infarction. Therefore, unless contraindicated, small doses of aspirin (81-325 mg daily or 325 mg every other day) should be prescribed for patients with angina. Clopidogrel is an antiplatelet agent that acts by inhibiting ADP-induced platelet aggregation. Unlike its older congener ticlopidine, clopidogrel does not cause agranulocytosis but may rarely induce thrombotic thrombocytopenic purpura. It can reduce cardiac events in patients with acute coronary syndromes and is an appropriate alternative in aspirin-intolerant patients.

8. Risk reduction  - As discussed above, patients with coronary disease should undergo aggressive risk factor modification. This approach, with a particular focus on lowering LDL cholesterol to = 100 mg/dL, not only prevents future events but may markedly improve symptomatic angina. Indeed, the Atorvastatin Versus Revascularization Treatment (AVERT) trial showed that patients randomized to aggressive lipid-lowering and medical therapy tended to have fewer subsequent ischemic events.

9. Revascularization  - The indications for coronary artery revascularization and the choice of procedure are discussed below.