Which of the following drugs for the treatment of angina is found on a typical crash cart?

Therapeutic Agents to Reduce Angina and Ischemia

The goal of antianginal therapy is to reduce symptoms of cardiac ischemia and to improve quality of life.12,13 β-Blockers, which prevent the binding of catecholamines to the β-adrenergic receptor, lower heart rate and myocardial contractility, thereby reducing myocardial workload, myocardial oxygen demand, and ischemia and anginal symptoms. β-Blockers raise the ischemic threshold and delay or prevent the onset of angina with exercise. β-Blockers also reduce the rate of secondary cardiac events and sudden cardiac death in post-MI patients, but to date there have been no placebo-controlled outcome trials in angina patients. All β-blockers appear to be equally effective in patients with chronic stable angina (Table 62-12). The β-blocker dose should be titrated to a target resting heart rate of 50 to 60 beats per minute as tolerated by the patient.

Calcium-channel blockers (Table 62-13) reduce afterload by their peripheral vasodilatory effects and thus lower myocardial workload and myocardial oxygen demand. Calcium-channel blockers also reduce coronary vascular resistance and inhibit coronary vasospasm by preventing coronary arterial smooth muscle contraction. This favorable reduction in myocardial oxygen demand, coupled with an increase in myocardial oxygen supply, results in a reduction in angina and ischemia. Non-dihydropyridine calcium-channel blockers, such as verapamil and diltiazem, also reduce heart rate. Conversely, dihydropyridine calcium-channel antagonists, such as amlodipine, have greater effect on vascular smooth muscle, are better peripheral and coronary vasodilators, and hence may have advantages for use in the hypertensive patient with angina. In randomized clinical trials, calcium-channel blockers and β-blockers are generally equally effective in relieving angina, improving time to onset of angina, and improving time to ischemic ST depression during exercise. Because calcium-channel blockers have not been shown to reduce death or MI in patients with stable or previously unstable ischemic heart disease, these agents are usually used in patients who cannot tolerate β-blockers or who require additional pharmacotherapy to control their symptoms. When calcium-channel blockers are used withβ-blockers, care must be taken not to cause symptomatic bradycardia with verapamil and diltiazem. When calcium-channel blockers are used alone, diltiazem is often preferred because dihydropyridine calcium-channel blockers can increase the heart rate.

Nitrates (Table 62-14) continue to be widely prescribed for antianginal treatment and are effective when they are administered sublingually, orally, or topically.14 They act as vasodilators by entering vascular smooth muscle, where they are metabolized to nitric oxide, which relaxes vascular smooth muscle, including in coronary arteries. These effects reduce angina by improving coronary blood flow. Nitrates also lower preload because of their venodilatory effects, with a resulting reduction in LV end-diastolic pressure and wall tension, which in turn lowers subendocardial oxygen demand. When nitrates are used in patients with stable angina, they improve exercise tolerance, time to onset of angina, and ST segment depression during treadmill exercise testing. Long-acting nitrates, which are frequently combined with β-blockers and calcium-channel blockers, have additive antianginal and anti-ischemic effects in patients with stable ischemic heart disease. Sublingual nitroglycerin or oral spray can terminate an angina attack and can be used as prophylaxis to prevent exertional angina. Long-acting nitrates administered orally or transdermally are used to prevent angina and to improve exercise tolerance. For avoidance of nitrate tolerance or tachyphylaxis, an 8- to 12-hour nitrate-free interval daily is recommended. Nitroglycerin and nitrates can cause vasodilation-induced headache, a decrease in blood pressure, and, more rarely, severe hypotension with bradycardia due to activation of the vagal Bezold-Jarisch reflex. Because the vasodilation by nitroglycerin is markedlyexaggerated and prolonged in the presence of the phosphodiesterase inhibitors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), these agents and nitrates should not be used concurrently.

Clinical Assessment

In patients with chronic stable angina, episodes of angina are usually initiated at consistent levels of physical stress and promptly disappear with cessation of activity (Table 12-2). Worsening angina provoked by progressively less exertion, over a short period of time, often culminating in pain at rest, is indicative of unstable angina (see Chapter 10).

The likelihood of coronary artery disease as the etiologic factor in the presence of chest pain is increased by the presence of established risk factors. Beyond stigmata of hyperlipidemia (rare) or signs of peripheral atheromatous vascular disease, there usually are no physical signs of angina. However, patients should be examined for signs of other possible causes of anginal chest pain, such as aortic stenosis and hypertrophic obstructive cardiomyopathy.

New Modalities for the Treatment of Chronic Stable Angina Pectoris

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Although a significant amount of progress has been made in the management of CAD with percutaneous coronary intervention (PCI) and CABG, many patients with the condition require additional therapeutic modalities for relief of symptoms and improvement in quality of life. This group of patients includes those with diffuse CAD who are not suitable for revascularization, patients with previous multiple PCIs or CABG limiting the chances for further revascularization, the lack of vascular conduits for CABG, severe left ventricular systolic dysfunction in patients with previous CABG or PCI, and comorbidities that would render the patients at high risk for revascularization.

The following pharmacologic agents have been used for the management of stable angina in combination with the standard protocol of nitrates, beta-blockers, calcium channel blockers, and ranolazine: High-dose statin therapy, trimetazidine, perhexiline, nicorandil, allopurinol, ivabradine, fasudil, and testosterone.

Other, nonpharmacologic modalities that are highly experimental include stem cell therapy, therapeutic angiogenesis, and mechanical therapies like external counterpulsation, spinal cord stimulation, transmyocardial laser revascularization, and coronary sinus reducing device.

In TACT (Trial to Assess Chelation Therapy), Ethylenediaminetetraacetic acid (EDTA) intravenous infusion resulted significant decrease in total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. Thus, chelation therapy was upgraded from Class III (not recommended) to Class IIb in the 2014 SIHD guidelines. Allopurinol, a xanthine oxidase inhibitor, was shown to reduce myocardial oxygen demand per unit of cardiac output in patients with heart failure in a small crossover study of 65 patients given 600 mg of allopurinol daily for 6 wk. Allopurinol increased the median time to ST depression from 232 sec at baseline to 393 sec. Further and larger studies are necessary to recommend allopurinol as an adjunctive therapy for stable angina.

Testosterone improves endothelial dysfunction and may be an effective antiangina agent. However, given the potential side effects, additional trials are necessary to recommend testosterone as an adjunctive drug for chronic angina.

The value of enhanced external counterpulsation(EECP) was assessed with the MUST-EECP trial, which randomly assigned 139 outpatients with angina, documented CAD, and a positive stress test to 35 hr of active EECP. The results indicated the following regarding EECP: (1) Was well tolerated; (2) exercise duration increased in both groups; (3) active EECP patients had a significant increase in time to 1-mm ST-segment depression, while there was no change in the inactive group; (4) more patients undergoing active EECP had a decrease in angina episodes, and fewer had an increase in angina symptoms compared with the active group. These data corroborate similar data from multicenter registries. The American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American Thoracic Society, and Society of Thoracic Surgeons focused update states that EECP may be considered for relief of refractory angina.

19 Which patients with chronic stable angina should be treated with both clopidogrel and a P2Y12 receptor blocker?

The three P2Y12 receptor blockers are clopidogrel, prasugrel, and ticagrelor. In patients with an MI 1 to 3 years prior who are now stable and have tolerated dual antiplatelet therapy (DAPT) without bleeding complications, continuation of DAPT may be reasonable.

Patients with chronic stable angina treated with coronary stent implantation are treated for at least 6 months of DAPT. Continuation of DAPT for more than 6 months may be reasonable. On the other hand, for those at high risk of bleeding, only 3 months of DAPT may be reasonable.

Modest data suggest that DAPT for 1 year after coronary artery bypass grafting (CABG) may increase saphenous vein graft patency rates. Treatment of such patients with DAPT after CABG may be reasonable.

In patients with stable CAD without Hx of MI, percutaneous coronary intervention (PCI) or recent CABG, DAPT is not recommended.

Recommendations on the use and duration of DAPT in patients with chronic stable angina are given in Fig. 15.2.

Patient Follow-Up

The ACCF/AHA guidelines recommend that patients with SIHD have follow-up evaluations at least annually for assessment of symptoms and clinical function, surveillance of complications of SIHD, monitoring of cardiac risk factors, and assessment of the adequacy of and adherence to lifestyle interventions and GDMT (Table 61G.10). Assessment of LVEF is recommended for patients with SIHD and new or worsening HF or evidence of intervening MI. The guidelines urge restraint in the use of routine testing in the follow-up of patients with SIHD if they have not had a change in clinical status (Table 61G.11).

Indications

Chronic Stable Angina – Dihydropyridine calcium channel antagonists reduce myocardial oxygen demand by reducing afterload and increase oxygen supply by dilating coronary arteries. The calcium channel antagonists verapamil and diltiazem also reduce myocardial oxygen demand by slowing heart rate and reducing myocardial contractility. Beta adrenoceptor antagonists (without intrinsic sympathomimetic activity) reduce myocardial oxygen demand by slowing heart rate and reducing myocardial contractility. Third generation beta blockers like carvedilol may offer an advantage because they also block alpha-1adrenergic receptors resulting in vasodilation Galderisi and D'Errico (2008). Low dose organic nitrates induce preferential venodilation to reduce left ventricular end diastolic pressure which reduces resistance to blood flow through endocardial tissue increasing flow in those regions. Higher doses of organic nitrates also dilate arteries which reduces afterload resulting in reduced myocardial oxygen demand. Dilation of large coronary arteries and/or collaterals by the organic nitrates may also increase coronary blood flow and oxygen supply Chaitman (2005) Michel (2006) Hutchison and Shahan (2005).

Ranolazine is a newer drug for the treatment of chronic angina. It inhibits the voltage-gated slowly inactivating sodium current (INa) of the heart action potential. This results in reduced sodium and calcium overload in the heart and improved cardiac function Dobesh and Trujillo (2007) Fraser et al (2006) Scirica (2007).

Variant Angina – Both calcium channel antagonists and organic nitrates can increase oxygen supply in variant angina by inhibiting coronary artery vasospasm. Beta adrenoceptor antagonists are not indicated for variant angina because they may further exacerbate coronary arterial vasospasm Michel (2006) Hutchison and Shahan (2005).

Unstable Angina – Antiplatelet/antihrombotic agents such as aspirin, ticlopidine, clopidogrel, are used to reduce ischemia in unstable angina Aronow (2006). Inhibitors of platelet glycoprotein IIb/IIIa receptors (abciximab, tirofiban, eptifibitide) involved in platelet aggregation have been used to treat unstable angina Michel (2006) Hutchison and Shahan (2005).

Acute Myocardial Infarction – Antiplatelet/antihrombotic agents such as aspirin, ticlopidine, clopidogrel, are used to reduce ischemia in myocardial infarction. Thrombolytics (streptokinase, tissue plasminogen activator (t-PA) and urokinase) which activate the fibrinolytic system have been used to dissolve intravascular clots leading to reperfusion of ischemic myocardium Michel (2006) Hutchison and Shahan (2005).

For angina that does not respond adequately to drug therapy – Percutaneous revascularization (with or without placement of a stent).

For angina that does not respond adequately to drug therapy – Drug-coated stents. These contain an antiimmune or antiproliferative drug. The most common are paclitaxel, sirolimus and heparin. The kinetics of drug release is critical to the success of the stent Tesfamariam (2008).

For angina that does not respond adequately to drug therapy – Coronary bypass surgery.

For angina that does not respond adequately to drug therapy – Metabolic modulators Thadani (2004) These drugs shift some of the energy burden of the heart from fatty acids to glucose, resulting in less oxygen demand. Metabolic modulators include the beta adrenergic receptor blockers, glucose-insulin-potassium, and partial fatty acid oxidation inhibitors such as perhexiline, etomoxir, trimetazidine and ranolazine Jani and Bergmann (2006). Ranolazine likely has more than one mechanism (See above.).

For angina that does not respond adequately to drug therapy – Sinus node rate lowering drugs Thadani (2004).

For angina that does not respond adequately to drug therapy – Spinal cord stimulation. This method uses neuromodulation to reduce ischemic pain and is not often used.

Experimental therapies: A clinical trial is being carried out testing the effect of escitalopram, an antidepressant, in reducing angina. http://www.clinicaltrials.gov/ct2/home. Eplerenone, an aldosterone receptor antagonist, is being tested for a possible beneficial effect in treating angina in women who have microvascular disease. http://www.clinicaltrials.gov/ct2/home. Future drugs may include new antiplatelet drugs Sellers et al (2009).

ANGINA

Angina is classically described as chest discomfort caused by an impaired blood supply (ischemia) to cardiac muscle. This symptom results from an imbalance between myocardial oxygen supply and demand (see Chapter 5). It is a welldocumented finding that a patient's threshold for angina is roughly equivalent to a fixed, clinically measurable product of the heart rate multiplied by the systolic blood pressure. This multiple, referred to as the rate-pressure product, is linearly correlated with myocardial oxygen demand.5 Numerous texts, articles, and scientific papers have been written to describe the reproducibility of a patient's angina at the same rate-pressure product.23,26 Angina that recurs at a fixed rate-pressure product is referred to as chronic stable angina. Two other types of angina have been described—unstable and variant. Variant angina, also called Prinzmetal angina, is caused by vasospasm of a coronary artery. Variant angina can occur anytime and may lead to infarction, but it is not common and is usually treated with vasodilating medications. Unstable angina is angina that occurs at rest or that wakes a patient during the night. This form of angina, also referred to as preinfarction angina, is an ominous symptom of impending myocardial infarction. Chronic stable angina that begins to occur at lower and lower rate-pressure products (i.e., at decreased intensities of exercise) may also be thought of as unstable angina. This section of the text provides the reader with a thorough description of chronic angina and the effects that exercise training may have on this symptom.

Describing chronic stable angina is difficult. Every patient describes this symptom using different words. These descriptions include but are not limited to the following: tightness, burning, pressure, aching, hurting, soreness, difficulty taking a deep breath, squeezing, and “I can't really describe it.” One of the most all-encompassing descriptions is as follows:

Chronic stable angina is any discomfort that occurs above the waist and is reproduced by eating, emotional distress, or exercise and is relieved by rest or nitroglycerin.

Notice that the word pain is not included in this definition. Most patients do not use the word pain when describing their angina. They may use pain when describing the discomfort associated with a myocardial infarction, but they rarely use the word pain when describing the discomfort associated with chronic stable angina. Although this symptom is most often associated with the chest in male patients, in female patients, the anatomic site for this discomfort can vary widely. Examples of the areas most commonly described for both sexes are provided in Fig. 3-16. Note that this symptom is often associated with upper quarter areas, both left and right, and also with the high thoracic area of the spine. Typical distribution patterns for the discomfort are depicted in Fig. 3-16. These variations from classic chest discomfort are more commonly seen in women.

Any clinician working with patients with known heart disease should attempt to determine if they have or have had angina. Once this has been decided, the clinician should refer to that patient's angina using only the word(s) they use to describe their symptoms. In other words, if your patient uses the word tightness, then when you talk to them about their angina, the word tightness should be used. The patient will not respond to or understand your requests to tell about any of their anginal symptoms if you use words that do not describe their angina. This can be critical when one is exercise-training patients or when one is initially getting them up early after myocardial infarction or bypass surgery. Careful examination of patients' descriptions of the pain they had during myocardial infarction can be invaluable. (See the following patient case example.)

In addition to communicating with the patient about his or her angina, it is important for the clinician to help the patient differentiate nonanginal pain from angina. Chest, jaw, and shoulder discomforts occur for a multitude of reasons. In noncardiac patients, these are passed off as insignificant and are certainly not thought of as having anything to do with the heart. The list of causes ranges from any number of musculoskeletal aches and pains to costochondritis, pleurisy, gallbladder dysfunction, cervical impingement, and dental disease. The difference between these causes of discomfort and chronic stable angina is that these discomforts are not reproducible with exercise, eating, or emotional distress, and they are not relieved by nitroglycerin. Many patients who are early post infarction, angioplasty, or bypass surgery do not clearly understand angina, or they deny that they have or have ever had this symptom. It takes careful, diligent interrogation to determine if the patient has ever had this symptom and to ascertain the specific characteristics that are attributed to it by each patient. Differentiation of angina from all other possible causes of chest, jaw, and shoulder discomfort is just as important to the patient as it is to the therapist. Patients who have experienced heart attacks may perceive that any pain is a sign of impending heart attack or death. This can be psychologically debilitating and also may be a cause for unnecessary visits to the emergency room. A clear explanation of the differences between angina and other chest wall discomforts will assist the patient in better defining and living with his or her disease. Once the clinician has definitively determined that the patient has angina, a rating system for determining the level of discomfort may be useful for both the patient and the clinician. The following rating system has been helpful for many clinicians in rating their patients' angina.

Clinical Assessment

In patients with chronic stable angina, episodes of angina are usually initiated at consistent levels of physical stress and promptly disappear with cessation of activity (Box 8-1). Worsening angina provoked by progressively less exertion over a short period of time, often culminating in pain at rest, is indicative of an acute coronary syndrome (ACS; see Chapters 9 and 10Chapter 9Chapter 10).

The likelihood of CHD being the cause is increased by the presence of established risk factors. Beyond stigmata of hyperlipidemia (rare) or signs of peripheral atheromatous vascular disease, no physical signs of angina are usually present. However, patients should be examined for signs of other possible causes of anginal chest pain, such as aortic stenosis and hypertrophic obstructive cardiomyopathy.

Summary

In patients with chronic stable angina, CCBs may be considered for adjunctive treatment but not as monotherapy unless beta blockers and RAAS inhibitors are not tolerated. Early administration of nifedipine in acute myocardial infarction, unless it is specifically indicated in vasospastic angina, is contraindicated. The nondihydropyridines, possibly because of their heart rate–lowering properties, are the only CCBs to show benefit in the post–myocardial infarction population. They also increase the risk for subsequent CHF in post–myocardial infarction patients with reduced ejection fractions and should probably be reserved for patients without heart failure who cannot tolerate a beta blocker or in whom a beta blocker is contraindicated. Amlodipine and felodipine, given their neutral effect on cardiac morbidity and mortality and ease of tolerance, may be considered in the management of hypertension or coronary artery disease (CAD) in patients with heart failure (see Table 11-1).