is indicated, amlodipine is the only CCB that should be used.
Preparations, Dosage, and Administration
Ranolazine [Ranexa] is formulated in extended-release tablets (500 and 1000 mg) that should be swallowed intact, with or without food. Dosing begins at 500 mg twice daily, and it may be increased to a maximum of 1000 mg twice daily. Ranolazine may be used in combination with a nitrate, beta blocker, or amlodipine (a CCB), and other drugs for angina.
TREATMENT MEASURES
Guidelines for Management of Chronic Stable Angina
In 1999, three organizations—the American Heart Association, the American College of Cardiology, and the American College of Physicians–American Society of Internal Medicine—joined forces to produce the first national guidelines on the management of chronic stable angina. The 1999 guidelines were updated in 2002 and again in 2007. Both updates—ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina, and 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients with Chronic Stable Angina—are available free online at circ .ahajournals.org. The discussion that follows reflects recom- mendations in these guidelines.
Treatment of stable angina has two objectives: (1) prevention of MI and death, and (2) reduction of cardiac ischemia and associated anginal pain. Although both goals are desirable, prevention of MI and death is clearly more important. If two treatments are equally effective at decreasing anginal pain but one also decreases the risk of death, then the latter is preferred.
Drugs Used to Prevent Myocardial Infarction and Death
We now have medical treatments that can decrease the risk of MI and death in patients with chronic stable angina. Therapy directed at preventing MI and death is a new paradigm in the management of stable angina, and all practitioners should become familiar with it.
Antiplatelet Drugs. These agents decrease platelet aggrega- tion and thereby decrease the risk of thrombus formation in coronary arteries. The most effective agents are aspirin and clopidogrel. In patients with stable angina, low-dose aspirin produces a 33% decrease in the risk of adverse cardiovascular events. Benefits of clopidogrel seem equal to those of aspirin, although they are not as well documented. The guidelines recommend that all patients with stable angina take 75 to 162 mg of aspirin daily, unless there is a specific reason not to.
Aspirin, clopidogrel, and other antiplatelet drugs are discussed in Chapter 52.
Cholesterol-Lowering Drugs. Elevated cholesterol is a major risk factor for coronary atherosclerosis. Drugs that lower with nifedipine and minimal with verapamil and diltiazem.
Because of their suppressant effects on the heart, verapamil and diltiazem must be used cautiously in patients taking beta blockers and in patients with bradycardia, heart failure, or AV block. These precautions do not apply to nifedipine or other dihydropyridines.
The basic pharmacology of the CCBs is discussed in Chapter 45.
RANOLAZINE
Actions and Therapeutic Use
Ranolazine [Ranexa] represented the first new class of anti- anginal agents to be approved in more than 25 years. In clinical trials, the drug reduced the number of angina episodes per week and increased exercise tolerance. However, these benefits were modest, and were smaller in women than in men. Unlike most other antianginal drugs, ranolazine does not reduce heart rate, blood pressure, or vascular resistance. However, it can prolong the QT interval, and is subject to multiple drug interactions.
Ranolazine works by reducing accumulation of sodium and calcium in myocardial cells, which might help the myocardium use energy more efficiently. However, the exact mechanism of action is unknown. Despite limited efficacy, many drug interactions, and a risk of dysrhythmias (see text that follows), ranolazine is now approved as a first-line drug for angina. It may be combined with nitrates, beta blockers, amlodipine (a CCB), and other drugs used for angina treatment.
Pharmacokinetics
Absorption from the GI tract is highly variable, but not affected by food. Plasma levels peak 2 to 5 hours after dosing. In the liver, ranolazine undergoes rapid and extensive metabolism, mainly by CYP3A4 (the 3A4 isoenzyme of cytochrome P450).
The drug has a plasma half-life of 7 hours and is excreted in the urine (75%) and feces (25%), almost entirely as metabolites.
Adverse Effects
QT Prolongation. Ranolazine can cause a dose-related increase in the QT interval and may thereby increase the risk of torsades de pointes, a serious ventricular dysrhythmia.
Accordingly, the drug is contraindicated for patients with pre-existing QT prolongation and for those taking other drugs that can increase the QT interval. In addition, ranolazine is contraindicated for patients at risk of developing high levels of the drug—namely, patients with hepatic impairment or those taking drugs that inhibit CYP3A4. The issue of drug-induced QT prolongation is discussed in Chapter 7.
Elevation of Blood Pressure. In patients with severe renal impairment, ranolazine can raise blood pressure by about 15 mm Hg. Accordingly, blood pressure should be monitored often in these people.
Other Adverse Effects. The most common adverse effects are constipation, dizziness, nausea, and headache.
Drug Interactions
CYP3A4 Inhibitors. Agents that inhibit CYP3A4 can increase levels of ranolazine and can thereby increase the risk of torsades de pointes. Accordingly, moderate or strong CYP3A4 inhibitors should be avoided. Among these agents are grapefruit
Note that, as we proceed along the drug-selection flow plan, drugs are added to the regimen, resulting in treatment with two or more agents. Combination therapy increases our chances of success because oxygen demand is decreased by multiple mechanisms: Beta blockers reduce heart rate and contractility;
CCBs reduce afterload (by dilating arterioles); and nitrates reduce preload (by dilating veins).
If combined treatment with a beta blocker, CCB, and long- acting nitrate fails to provide relief, coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) may be indicated. Note that these invasive procedures cholesterol can slow the progression of CAD, stabilize ath-
erosclerotic plaques, and even cause plaque regression. Therapies that reduce cholesterol are associated with decreased mortality from coronary heart disease. For example, in patients with established CAD, taking simvastatin can decrease the risk of mortality by 35%. Because of the well-established benefits of cholesterol-lowering therapy, the guidelines recommend that all patients with stable angina receive a cholesterol-lowering drug. The pharmacology of the cholesterol-lowering drugs is discussed in Chapter 50.
Angiotensin-Converting Enzyme (ACE) Inhibitors. There is strong evidence that, in patients with CAD, ACE inhibitors greatly reduce the incidence of adverse outcomes. In the Heart Outcomes Prevention Evaluation (HOPE) trial, for example, ramipril reduced the incidence of stroke, MI, and cardiovascular death. Among one subset of patients—those with diabetes—
benefits were particularly striking. Ramipril decreased the risk of stroke by 33%, MI by 22%, and cardiovascular death by 37%. In addition, ramipril reduced the risk of nephropathy, retinopathy, and other microvascular complications of diabetes.
Because of these well-documented benefits, the guidelines recommend ACE inhibitors for most patients with established CAD, and especially for those with diabetes. The pharmacology of the ACE inhibitors is discussed in Chapter 44.
Antianginal Agents: Drugs Used to Reduce Anginal Pain
The goal of antianginal therapy is to achieve complete (or nearly complete) elimination of anginal pain, along with a return to normal activities. This should be accomplished with a minimum of adverse drug effects.
The basic strategy of antianginal therapy is to provide baseline protection using one or more long-acting drugs (beta blocker, CCB, long-acting nitrate) supplemented with sublingual nitroglycerin when breakthrough pain occurs. A flow plan for drug selection is shown in Fig. 51.3. As indicated, treatment is approached sequentially. Progression from one step to the next is based on patient response. Some patients can be treated with a single long-acting drug, some require two or three, and some require revascularization.
Initial treatment consists of sublingual nitroglycerin plus a long-acting antianginal drug. Beta blockers are the preferred agents for baseline therapy because they can decrease mortality, especially in patients with a prior MI. In addition to providing prophylaxis, beta blockers suppress nitrate-induced reflex tachycardia.
If a beta blocker is inadequate, or if there are contraindica- tions to beta blockade, a long-acting CCB should be added or substituted. Dihydropyridine-type CCBs (e.g., nifedipine) lack cardiosuppressant actions and are safer than beta block- ers for patients with bradycardia, AV block, or heart failure.
When a CCB is to be combined with a beta blocker, a dihy- dropyridine is preferred to verapamil or diltiazem because verapamil and diltiazem will intensify the cardiosuppressant actions of the beta blocker, whereas a dihydropyridine CCB will not.
If a CCB is inadequate, or if there are contraindications to calcium channel blockade, a long-acting nitrate (e.g., trans- dermal nitroglycerin) should be added or substituted. However, because tolerance can develop quickly, these nitrate preparations are less well suited than beta blockers or CCBs for continuous protection.
If serious contraindications
If serious contraindications
Successful treatment?
No Yes
Yes Add a beta blocker
(especially if prior MI) Sublingual nitroglycerin
If serious contraindications
Successful treatment?
No Yes
Add or substitute a calcium channel blocker1
Add a long-acting nitrate Successful treatment?
No
Consider revascularization (CABG or PCI)2
Fig. 51.3 ■ Flow plan for antianginal drug selection in patients with chronic stable angina.
1Avoid short-acting dihydropyridines.
2At any point in this process, based on coronary anatomy, severity of angina symptoms, and patient preference, it is reasonable to consider evaluation for coronary revascularization (PCI or CABG).
Unless a patient is documented to have left main, three-vessel, or two-vessel CAD with significant stenosis of the proximal left anterior descending coronary artery, there is no demonstrated survival advantage associated with CABG or PCI in low-risk patients with chronic stable angina. Accordingly, medical therapy should be attempted in most patients before considering PCI or CABG. (Adapted from Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina].
2002. Available online at circ.ahajournals.org.)
Reduction of Risk Factors
The treatment program should reduce anginal risk factors:
Smokers should quit; sedentary patients should get aerobic exercise; and patients with diabetes, hypertension, or high cholesterol should receive appropriate therapy.
Smoking. Smoking increases the risk of cardiovascular mortality by 50%. Fortunately, smoking cessation greatly decreases cardiovascular risk. Accordingly, all patients who smoke should be strongly encouraged to quit. Smoking cessation is discussed in Chapter 39.
High Cholesterol. As noted, high cholesterol levels increase the risk of adverse cardiovascular events, and therapies that should be considered only after more conservative treatment
has been tried.
How should we treat angina in patients who have a coex- isting condition? The antianginal drugs employed—nitrates, beta blockers, and CCBs—are the same ones used in patients who have angina alone. However, when selecting among these drugs, we must consider the coexisting disorder as well as the angina. For example, as noted earlier, in patients with asthma, CCBs are preferred to beta blockers (because beta blockers promote bronchoconstriction, whereas CCBs do not). Table 51.4 shows more than 20 coexisting conditions and indicates which antianginal agents to use, as well as which ones to avoid.
Coexisting Condition Recommended Treatment (Alternative Treatment) Drugs to Avoid MEDICAL CONDITIONS
Systemic hypertension Beta blockers (long-acting, slow-release CCBs) Migraine or vascular headache Beta blockers (verapamil or diltiazem)
Asthma or COPD with bronchospasm Verapamil or diltiazem Beta blockers
Hyperthyroidism Beta blockers
Raynaud’s disease Long-acting, slow-release CCBs Beta blockers
Type 1 diabetes Beta blockers, particularly if prior MI, or long-acting, slow-release CCBs
Type 2 diabetes Beta blockers or long-acting, slow-release CCBs
Depression Long-acting, slow-release CCBs Beta blockers
Mild peripheral vascular disease Beta blockers or long-acting, slow-release CCBs Severe peripheral vascular disease with
ischemia at rest Long-acting, slow-release CCBs Beta blockers
CARDIAC DYSRHYTHMIAS AND CONDUCTION ABNORMALITIES
Sinus bradycardia Long-acting, slow-release CCBs that do not decrease heart
rate Beta blockers, diltiazem,
verapamil Sinus tachycardia (not due to heart failure) Beta blockers
Supraventricular tachycardia Verapamil, diltiazem, or beta blockers
AV block Long-acting, slow-release CCBs that do not slow AV
conduction Beta blockers, diltiazem,
verapamil Rapid atrial fibrillation (with digoxin) Verapamil, diltiazem, or beta blockers
Ventricular dysrhythmias Beta blockers
LEFT VENTRICULAR DYSFUNCTION Congestive heart failure
Mild (LVEF ≥40%) Beta blockers
Moderate to severe (LVEF <40%) Amlodipine or felodipine (nitrates) Diltiazem, verapamil Left-sided valvular heart disease
Mild aortic stenosis Beta blockers
Aortic insufficiency Long-acting, slow-release dihydropyridine CCBs Mitral regurgitation Long-acting, slow-release dihydropyridine CCBs
Mitral stenosis Beta blockers
Hypertropic cardiomyopathy Beta blockers, verapamil, diltiazem Dihydropyridine CCBs, nitrates TABLE 51.4 ■ Choosing Between Beta Blockers and Calcium Channel Blockers for Treating Angina
in Patients Who Have a Coexisting Condition
Adapted from Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for the Management of Patients with Chronic Stable Angina). 2002. Available online at circ.ahajournals.org/.
AV, Atrioventricular; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction.
Physical Inactivity. Increased physical activity has mul- tiple benefits. In patients with chronic stable angina, exercise increases exercise tolerance and the sense of well-being, and decreases anginal symptoms, cholesterol levels, and objective measures of ischemia. Accordingly, the guidelines recommend that patients perform 30 to 60 minutes of a moderate-intensity activity 3 to 4 times a week. Such activities include walking, jogging, cycling, and other aerobic exercises. Exercise by moderate- to high-risk patients should be medically supervised.