The Editor’s Roundtable: Chronic Stable Angina Pectoris

The Editor’s Roundtable: Chronic Stable Angina Pectoris Vincent E. Friedewald, MDa,*, Spencer B. King III, MDb, Carl J. Pepine, MDc, George W. Vetrovec, MDd, and William C. Roberts, MDe Acknowledgement This CME activity is sponsored by an educational grant from CV Therapeutics, Palo Alto, California. Disclosure Dr. Friedewald has no relevant financial relationships to disclose. Dr. King has no relevant financial relationships to disclose. Dr. Pepine has no relevant financial relationships to disclose. Dr. Vetrovic owns stock in Merck, Whitehouse Station, New Jersey; Pfizer, New York, New York; Medtronics, Minneapolis, Minnesota; Boston Scientific, Natick, Massachusetts; and Johnson & Johnson, New Brunswick, New Jersey; receives consulting fees from Cordis–Johnson & Johnson, Warren, New Jersey; has endpoint committee contracts with Merck, Pfizer, Boston Scientific, and Abbott, Abbott Park, Illinois; has received honoraria for speaking from Pfizer, CV Therapeutics, Palo Alto, California; Eli Lilly, Indianapolis, Indiana; Cordis–Johnson & Johnson, and Stereotaxis, St Louis, Missouri; and has received grants for education or research from Cordis–Johnson & Johnson, Eli Lilly, and The Medicines Company, Parsippany, New Jersey. Dr. Roberts has received honoraria for speaking from Merck, Schering Plough, Kenilworth, New Jersey; Pfizer, AstraZeneca, Wilmington, Delaware; and Novartis, East Hanover, New Jersey. Objectives Upon completion of the activity, the physician should be able to: 1. Explain current concepts of the pathophysiology of chronic angina pectoris.

a

Assistant Editor, American Journal of Cardiology, Clinical Professor, Department of Internal Medicine, The University of Texas Medical School at Houston, Houston, Texas, and Research Professor, University of Notre Dame, Notre Dame, Indiana; bProfessor of Medicine Emeritus, Emory University School of Medicine, Atlanta, Georgia; cChief, Division of Cardiovascular Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida; dDirector, Adult Cardiac Catheterization Laboratory, Medical College of Virginia Campus of Virginia Commonwealth University, and Director, Adult Cardiac Catheterization Laboratory, VA Medical Center, Richmond, Virginia; and eEditor-inChief, American Journal of Cardiology and Baylor University Medical Center Proceedings, Executive Director, Baylor Heart and Vascular Institute, Baylor University Medical Center, and Dean, A. Webb Roberts Center for CME of Baylor Health Care System, Dallas, Texas. Manuscript received and accepted September 5, 2007. This discussion took place at Baylor University Medical Center, Dallas, Texas, on May 16, 2007. *Corresponding author: Tel: 512-264-1611; fax: 512-264-7034. E-mail address: [email protected] (V.E. Friedewald). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.09.001

2. Understand the mechanisms of action of medications for the treatment of angina pectoris. 3. Prescribe antianginal medications according to individual patient needs. 4. Advise patients with chronic stable angina pectoris when coronary artery intervention should be considered. Introduction Chronic stable angina pectoris is a common manifestation of atherosclerotic coronary artery disease, with ⬎400,000 new cases diagnosed annually in the USA.1 Chronic angina affects ⬎2% of the population and ⬎20% of persons ⱖ75 years of age. In this Editor’s Roundtable, the faculty discusses the different forms of angina, the pathophysiology of myocardial ischemia, the medical and surgical therapy of angina, and some unresolved issues about myocardial ischemia. Discussion Dr. Friedewald: What terms are used to describe angina? Dr. Pepine: It is popular in Europe to use the term isolated angina, which applies to the patient with angina who has not had an acute myocardial infarction (AMI) or a coronary arterial revascularization procedure. This is a relatively low-risk clinical syndrome. Refractory angina refers to patients receiving maximum medical therapy, including those who have also had revascularization, who continue to have angina. Persistent angina describes patients who have been revascularized either by percutaneous coronary intervention or by coronary artery bypass grafting (CABG) and, despite patency of all stents and coronary artery vein grafts, continue to have chest pain. Another clinical syndrome is silent myocardial ischemia, which probably occurs in patients with all other forms of angina. The term variant angina was popularized by Prinzmetal,2 but was recognized long before his description. It is hypothesized that variant angina is caused by heightened smooth muscle reactivity, resulting in coronary artery spasm, usually within and around areas of atherosclerosis. Microvascular angina applies to angina in patients in whom there is documented limitation to coronary blood flow at the microvascular level. It seems more frequent in women, but also occurs in men. The true prevalence of this form of angina is unknown because it is difficult to evaluate the patency of distal coronary arteries. There is no early anatomic abnormality, but the coronary artery microvasculature has an abnormal functional response to atherogenic stimuli in non-human animals and in humans in whom risk factors for atherosclerosis are created. There is probably a microvascular component to all atherosclerotic disease, based on non-human animal models in which the microvascular bed is the first portion of www.AJConline.org

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the coronary arteries to become abnormal with experimentally induced cholesterol elevation, hypertension, and diabetes mellitus. Dr. Friedewald: Why do some patients with coronary artery disease (CAD) present initially with angina, some with AMI, and others with cardiac arrest? Dr. Pepine: We do not know why there are different initial presentations of CAD. We do know that women are more likely to present with angina pectoris, and men are more likely to have an AMI as the initial manifestation of CAD. This gender difference has been clear in virtually every population-based study of CAD. Dr. Vetrovec: The impact of angina is huge when you consider all instances of chest pain, which include everyone evaluated in emergency departments for possible angina, most of whom are finally diagnosed with a condition other than angina. Thus, angina is a huge personnel, facility, and monetary resource issue. Dr. Pepine: About 20% of the 5 million chest pain episodes evaluated yearly in the USA are of cardiac origin. Dr. Roberts: How do you define stable versus unstable angina pectoris? Is the first episode of angina automatically presumed unstable? Dr. Pepine: The first episode is, by definition, unstable. Over how long a period of time must angina recur before it becomes regarded as stable? The prevailing concept is that about 2 weeks is the threshold. Why 2 weeks? Perhaps it relates to the time required for partial resolution of the pathologic process that underlies the “unstable” phase of the disease, including plaque disruption, plaque erosion, and plaque rupture associated with thrombus formation. Serial studies show that thrombi disappear from the coronary arteries either by resolution or by incorporation into the lumen by some unproven mechanism. Thus, everyone with chronic stable angina first passes through an unstable period. Dr. King: I challenge the concept that a new episode of angina is necessarily unstable. The underlying pathophysiology might differ between a thrombotic event creating what we term acute coronary syndrome and the first episode of angina caused by increased myocardial oxygen demand due to sufficient coronary obstruction to the supply side of myocardial oxygen requirements. We do not have to assume that a first episode of angina was due to plaque rupture, but that a threshold of obstruction that limited maximum blood flow had been exceeded. Dr. Pepine: I agree, but I have to ask, what is your concept of how coronary atherosclerotic disease progresses? My understanding of the prevailing concept of this disease is that little pieces of plaque rupture account for anginal episodes. Dr. King: If we subscribe to plaque growth as the underlying cause of angina, then there is no such thing as “stable” coronary disease. Dr. Roberts: There are few autopsy studies on patients whose only manifestation of coronary artery disease or myocardial ischemia is angina. Patients with unstable angina who die and come to autopsy usually have an intervening AMI, or they die after a coronary intervention. In my view, the most common cause of plaque rupture is coronary intervention—including CABG—which succeeds by “cracking” plaques. When I was at the National Institutes of

Health, we studied 21 patients who had unstable angina, had subsequent CABG, and died within a week. They had the worst coronary narrowing of any group we studied, including patients with AMI and sudden death. I did not, however, see ruptured plaque other than at the anastomotic site in any case. It is true that patients with unstable angina develop a thrombus, but it is a minute thrombus—a so-called “mural thrombus”—so small that it does not interfere with coronary arterial blood flow. Thus, I do not believe there is morphologic evidence that first episodes of angina are caused by plaque rupture. Dr. King: Because the treatments differ, do you believe that there is clinical value to think in terms of acute versus stable myocardial ischemia? Dr. Roberts: The treatments might differ, but the total quanitity of plaque in the entire coronary arterial tree in patients with stable angina is generally greater than in patients with AMI or sudden death. Dr. Friedewald: Have there been studies of the coronary arteries of persons with stable angina who died incidentally from unrelated causes, such as car accidents? Dr. Roberts: The 2 cases of patients with stable angina who died from unrelated causes that I have seen had extensive coronary arterial narrowing at autopsy. Dr. Friedewald: Many patients in the outpatient setting first present to the physician with stable angina only after having multiple episodes of chest pain. They may have had an episode while jogging or some other activity, and then they tried the same exercise a couple of days later and it recurred. With so many people without health insurance, I would not be surprised if many patients— especially men— delay seeing a physician until after multiple episodes, unless the pain is particularly frightening or severe. Dr. Pepine: My experience in ambulatory practice is that these patients develop their angina during some usual activity for them, such as playing tennis or cleaning up their yard. They had performed that activity many times before and had not been bothered by chest discomfort. Dr. Roberts: It seems that patients with symptomatic myocardial ischemia are better off when they present with angina pectoris as the first manifestation of coronary disease because myocardial function is usually preserved, and they can be helped. In contrast, patients initially presenting with an AMI have lost a large amount of myocardium, and patients who have a cardiac arrest have only a small chance of survival. It is unfortunate that everyone with the new onset of CAD does not present with angina pectoris. Dr. Friedewald: The symptoms of myocardial ischemia are oddly inconsistent from patient to patient. Some people have no chest discomfort, and some have too little pain to seek help. Others have intense discomfort that takes them to an emergency department. Some patients have dyspnea as the only symptom. And women differ from men. Dr. Vetrovic: Dyspnea is an important symptom of myocardial ischemia, especially in older patients and in patients with diabetes mellitus, who are more likely to complain of exercise limitation because of dyspnea rather than chest pain. Dr. Pepine: Although seldom written about today, older cardiology reports point out the significance of what has

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been called blocknea, or angina equivalent, in which patients feel that their breathing is blocked. Dr. Friedewald. What is the course of stable angina? Dr. King: Stable angina has a benign course according to the recent COURAGE (Clinical Outcomes Utilizing Percutaneous Revascularization and Aggressive GuidelineDriven Drug Evaluation) trial,3 in which the mortality was only about 0.5% per year. Dr. Roberts: But that was for only 4 years or so. Dr. Pepine: COURAGE showed that chronic angina pectoris is more an issue of quality of life than mortality. Dr. King: Quality of life is an aspect of CAD we do not pay enough attention to. Rather, our focus is on acute syndromes, interventions, and secondary prevention, but not on angina, which is the symptom that most often bothers people with CAD. Dr. Friedewald: What is the relation of major depression, which terribly affects quality of life, to angina pectoris? Dr. Pepine: Angina is a major predictor of depression, raising the question, “Does the brain know when the heart is ischemic?” I used that question as a title for an editorial I wrote.4 When you create myocardial ischemia in patients with documented CAD by having them exercise or by infusing dobutamine while imaging the brain, the first thing that happens before any anginal symptoms occur is that blood flow in and around the thalamus increases at about the same time as electrocardiographic changes of myocardial ischemia appear. If the myocardial ischemia persists long enough for the patient to experience chest pain, higher centers in the brain closer to the cortex also become active. If a myocardial ischemic episode is aborted before the patient perceives pain, however, these higher brain centers do not light up. The conclusion is that the brain does “know” when the heart is ischemic, although this is not always perceived as chest pain. This is a phenomenon that we do not understand. Dr. Friedewald: This is consistent with the common observation that patients during an exercise test may exhibit ischemic electrocardiographic changes before they have angina. Dr. Vetrovec: In the catheterization laboratory you can blow up a balloon and the first sign of myocardial ischemia is restlessness, not pain. The patient may be asleep and wiggling around on the table. Their hemodynamics— decreased systemic arterial pressure, increased pulmonary capillary wedge pressure, and increased pulmonary arterial pressure—also become abnormal before symptoms occur. Dr. King: The first functional change with acute myocardial ischemia probably involves left ventricular diastolic relaxation. Dr. Friedewald: Are the hemodynamic changes during angina different in men from women? Dr. King: That has not been shown. Dr. Friedewald: What is the significance of “silent” myocardial ischemia? Dr. Pepine: Myocardial ischemia is often not manifested as chest pain. Because myocardial ischemia is the most important index of severity of underlying CAD, we should pay more attention to it, not just whether patients experience chest discomfort.

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Dr. King: There is a lot that we do not understand about angina. There are patients with angina who have no evidence of epicardial CAD. There are also patients whom we believe we have “fixed” with coronary revascularization who continue to have angina through mechanisms of small vessel obstruction. This is a growing population, which was shown in the COURAGE trial. Dr. Vetrovec: The low mortality rate in COURAGE is misleading. The quality of life in patients with continuing angina is decreased because many remain fearful of sudden death and heart attack. Physicians are uncertain what to tell these patients that will alleviate these fears. Thus, there is a relatively high level of disability in patients with chronic angina, even though the mortality rate for these patients is low. Dr. Pepine: I agree. Patients are often quite disabled after receiving intracoronary stents. Dr. Friedewald: Let’s discuss the medical treatment of chronic stable angina. Dr. Pepine: Every patient with chronic angina should receive aspirin, although it does not reduce the frequency of angina. The mechanism of action of aspirin is not fully understood, but it is effective in primary and secondary prevention of atherothrombotic events. In patients with stable angina, it lowers the frequency of sudden cardiac death, AMI, and stroke. Dr. Friedewald: What dose of aspirin do you recommend? Dr. Vetrovec: I recommend 81 mg aspirin per day. Multiple studies suggest that preventive effects persist down to relatively low levels of aspirin, and lower doses have less risk of bleeding complications. Dr. Friedewald: How low? Dr. Vetrovec: There is evidence that 33 mg aspirin has efficacy similar to higher doses. The 33 mg strength, however, is not available. Dr. Pepine: If you ask an audience of physicians, “Do you take aspirin?” and “Do you recommend aspirin to your patients?” almost everyone answers “yes” to both questions. If, however, you ask whether they recommend it to healthy persons with increased risk for CAD, very few answer “yes.” If physicians became more proactive, a huge number of cardiac events would be prevented by giving aspirin in accordance with current guidelines. Dr. King: How do you answer that aspirin was ineffective for primary prevention in The Nurses Health Study? Dr. Pepine: It prevented stroke in the female nurses aged ⬎65 years.5 Dr. Friedewald: Let’s discuss nitrates. Dr. Pepine: Nitrates lessen myocardial ischemia by several mechanisms. They reduce all determinants of myocardial oxygen demand by venodilation. They dilate the large capacitance vessels and reduce venous return, which reduces left ventricular end-diastolic filling pressure and size, thereby decreasing left ventricular wall stress. They also have a small effect in lowering the systolic arterial blood pressure, which decreases left ventricular systolic tension and wall stress. They dilate the major coronary arteries, increasing coronary arterial blood flow. There is evidence, however, that tolerance occurs when used chronically without nitrate-free intervals. This tolerance may be associated

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with the creation of free radicals, which in some experimental models is proatherogenic. Thus, nitrate use should be restricted to labeled uses—including prophylaxis before stressful events—with nitrate-free intervals and intermittent dosing. Dr. King: Does chronic nitrate therapy cause clinically significant endothelial dysfunction? Dr. Pepine: There is evidence that it does.6 All forms of cardiovascular risk, including elevated serum cholesterol and elevated blood pressure, create oxygen stress at the endothelial cell level, leading to cell dysfunction. When such factors are persistent, prolonged, and of sufficient magnitude, the intima thickens, leading to additional lipid and fibrous tissue deposition. Dr. Vetrovec: Nitrates are difficult to use and their effects are unpredictable. During nitrate-free intervals, patients are exposed to myocardial ischemia. I prefer that patients use them only for acute attacks of angina and for specific times or activities when they are more likely to have symptoms. Dr. Pepine: The nitrates are principally tools of the primary care physician, who typically weds patients with CAD to a nitrate bottle or spray and instructs them to take 3 pills if they have chest pain before calling for help. There is no evidence that this common practice is efficacious, yet it is so prevalent that it is impossible to change. I tried to get the American Heart Association to change that statement in their AMI guidelines, but they refused. Dr. Friedewald: What sized coronary arteries dilate in response to nitrate therapy? Dr. Pepine: Maximum dilation is in the large and medium-sized arteries, which is where atherosclerotic stenoses reside. There is some evidence, however, that with a rapid fall in systemic systolic arterial pressure, some constriction at the microvascular level may occur. Nitrates do not dilate the microvasculature, despite the observation that when you fix the intra-arterial pressure in a non-human animal model and inject a nitrate directly into a coronary artery, the entire bed, including the small vessels, relaxes. This does not occur clinically because decreased systolic arterial pressure causes reflex sympathetic activation. Dr. Friedewald: Can coronary arteries with atherosclerotic plaques composed of extensive fibrosis and calcium dilate? Dr. Pepine: The answer is that coronary flow can increase, not necessarily through areas of stenoses, but through collateral vessels. Dr. Friedewald: Is there a steal syndrome with nitrates? Dr. Pepine: No, not with nitrates, but it has been reported with other vasodilators. Dr. King: Atherosclerosis itself is a strong stimulus for vasoconstriction, so there is often increased tone in the coronary arteries, which may be lessened by nitrates. Dr. Friedewald: Let’s move to the ␤ blockers. Do you prescribe them for angina? Dr. Pepine: I believe we are nearing the end of the ␤-blocker era for treating patients with CAD. The nondihydroperidine calcium antagonists, which reduce heart rate and myocardial contractility similar to the effect of ␤ blockers, are the ideal agents to replace them. Dr. King: I am surprised to hear you say that ␤ blockers

are at the end of their career. Our best survival data are related to ␤ blockers. Dr. Pepine: The ␤ blockers were introduced in the late 1960s and early 1970s. We all became convinced that ␤ blockers were superior treatment for post-myocardial infarction prophylaxis, systemic arterial hypertension, and angina pectoris. By the late 1990s, however, it became apparent that ␤ blockers are relatively ineffective antihypertensive agents, and in older patients, they are associated with poor patient compliance. It is almost impossible to adequately lower the systolic blood pressure with ␤ blockers without causing sinus bradycardia, prolonging ventricular diastole, and lowering the arterial diastolic pressure, which is a principal hydraulic determinant of coronary arterial perfusion. In recent years, a number of studies have shown they provoke diabetes mellitus. As a result of all these negative effects they have lost their favor in treating patients with systemic hypertension. What about ␤-blocker prophylaxis for AMI? None of the early studies in the 1970s that showed benefit from ␤ blockers included patients routinely receiving aspirin, no study patients had coronary artery revascularization or reperfusion, and statins were not available. In contrast, the recent COMET (Comparison of Carvedilol and Metoprolol on Clinical Outcomes in Patients with Chronic Heart Failure in the Carvedilol or Metoprolol European Trial) trial,7 which studied 45,000 patients, found that ␤ blockers do not prevent death, AMI, or stroke, but they do increase the risk of cardiogenic shock. Furthermore, ␤ blockers are associated with poorer quality of life. All of this leads many of us to believe that ␤ blockers should not be routine treatment for chronic stable angina, for which there is little evidence of long-term benefit. Beta blockers do, however, reduce mortality in patients with heart failure. They are also useful in the treatment of other select cardiac conditions, such as certain dysrhythmias and hypertrophic cardiomyopathy. Dr. Friedewald: Do you prescribe ␤ blockers for your post-AMI patients? Dr. Pepine: I put my AMI patients who do not have contraindications to ␤ blockers on them for 6 months, and then slowly withdraw them. Patients often feel much better after they are discontinued. Dr. Friedewald: Are ␤ blocker side effects dose-related? Dr. Pepine: Yes, there is a dose relation. The original major post-AMI trials that showed a prophylactic benefit, however, used full ␤-blocking doses—not small doses that are commonly used now. Dr. King: When should you treat a condition with drugs that make patients feel worse, which ␤ blockers often do? I believe the best use of ␤ blockers in chronic angina is to tailor them to specific indications, such as inappropriate tachycardia with exercise. Dr. Vetrovec: The main benefits of ␤ blockers post-AMI are in the first 6 months, but the evidence that ␤ blockers prevent cardiac events after that period is soft. Dr. Friedewald: What about ␤-blocker selectivity? Dr. Pepine: The ␤-blockers are divided into so-called cardioselective and noncardioselective types. Use of cardioselective agents is important in patients with asthma and severe peripheral arterial vascular disease. Their selectivity,

Roundtable Discussion/Chronic Stable Angina Pectoris

however, diminishes as the dose is increased. Betaxolol is the most selective ␤ blocker. Atenolol and metropolol are other popular selective agents. Another characteristic of ␤ blockers is their effect on the central nervous system, including fatigue, depression, and nightmares. These effects require central nervous system entry, which is a function of lipid solubility. Betaxolol has no solubility at all, so it does not enter the central nervous system. Atenolol and metoprolol are slightly lipid soluble, and propranolol is very lipid soluble. Dr. Vetrovec: I always ask patients on medical treatment for angina whether they can do more physically than before they started the drugs. Although patients may experience fewer episodes of angina while taking ␤ blockers, they are often physically unable to do as much as before they were started. Dr. Pepine: Patients with chronic stable angina on ␤ blockers often “gear down” their activities so that they do not experience angina. That cycle leads to a miserable life. Dr. Friedewald: How do you discontinue a ␤ blocker? Dr. Pepine: When terminating a ␤ blocker for any reason—side effects, lack of benefit, poor lifestyle—I always taper it over a fairly long period, a couple months if possible. Dr. Vetrovec: It is very important to taper ␤ blockers, which many physicians do not do, because their sudden termination can precipitate acute cardiac events. Dr. Friedewald: Does anginal frequency sometimes increase during ␤-blocker tapering? Dr. Pepine: Yes, and when it does, it is a reason to perform coronary angiography or a functional test for risk stratification. Dr. Vetrovec: When I taper patients off ␤ blockers, I usually obtain a stress test to see if silent myocardial ischemia is present, even in the absence of angina. Dr. Pepine: I agree with performing a stress test for this purpose, although there are no guideline recommendations for periodic stress testing. Dr. Vetrovec: When I tell patients that they can resume a normal life 6 months after an AMI, I want to be certain that is a safe recommendation. Dr. Roberts: Why wait 6 months? Acute myocardial infarcts heal in 2 months. Dr. King: There are very few patients who do not have post-AMI cardiac catheterization and coronary angiography, which provide functional and anatomical information to help make recommendations to patients. Dr. Friedewald: What is the role of calcium channel blockers in treating patients with chronic angina? Dr. Vetrovec: Calcium channel blockers are very effective for chronic angina. All are available in long-acting forms. They reduce anginal frequency and reverse vasoreactive components of the ischemia. It is useful to select the type of calcium antagonsist prescribed according to other patient requirements. In patients with systemic hypertension, for example— especially older patients— dihydropyridine calcium blockers work very well. In patients with hyperdynamic ventricles, diltiazem and verapamil are better. Dr. Pepine: Every study comparing calcium channel blockers to ␤ blockers shows similar suppression of angina

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and similar prolongation of exercise or delay in emergence of ST-segment shift. But calcium antagonists are better tolerated than ␤ blockers. Dr. King: The treadmill duration on treatment, however, averages only about 30 seconds longer than before treatment. Dr. Pepine: You are correct. There is only a small improvement in exercise duration. Dr. Vetrovec: Interpreting such studies is difficult in that the study drug is always compared with a placebo, and patients on placebo also improve. Another factor is the conditioning effect patients have with repeat exercise testing, causing them to improve due to increasing familiarity with the test. Thus, the real benefit from antianginal drugs is probably greater than demonstrated in the trials, because the control group also appears to improve. Dr. Friedewald: What is the mechanism of action of calcium channel blockers? Dr. Pepine: They act by coronary arterial dilation and prevention of coronary spasm and constriction. Unlike nitrates, they do not cause venous dilation. Diltiazem and verapamil also inhibit sinus node function and depress myocardial contractility. Dr. Friedewald: The mechanisms of action of ␤ blockers and calcium channel blockers are therefore similar? Dr. Pepine: They are similar, and they appear to have additive effects. In my patients who are on only a calcium antagonist or a ␤ blocker and their angina is unsatisfactorily controlled, I then add the other agent. Dr. Friedewald: What calcium blocker do you prescribe? Dr. Vetrovec: I often prescribe amlodipine because many patients have left ventricular dysfunction, for which amlodipine has the best safety data. I rarely prescribe ⬎5 mg/day, however, because the incidence of peripheral edema increases with higher doses. Dr. Pepine: When treating patients with angina without a concomitant ␤ blocker, I use a nondihydoperidine calcium channel blocker— either diltiazem or verapamil—and I prefer the long-acting preparations. Dr. Friedewald: When do you discontinue calcium channel blockers? Dr. Pepine: If the patient has no angina and no hypertension or other reason to take it, I try to discontinue the calcium blocker after stopping a ␤ blocker. I do not believe that there is good evidence that calcium channel blockers improve long-term outcome. Dr. Friedewald: Let’s talk about ranolazine. Dr. Pepine: Ranolazine is an interesting compound. The short-acting form has been available for several years. Many studies have shown that both the short- and long-acting forms of ranolazine suppress angina and prolong exercise duration. Some studies of the long-acting form of the drug have found a small degree of electrocardiographic QT prolongation.8,9 That finding delayed approval of the drug and resulted in strong product labeling that recommended follow-up electrocardiograms and that it should not be used with drugs possessing competitive metabolic pathways. There have not, however, been any reports of proarrhythmic effects of ranolazine. This labeling may prevent some physicians from prescribing the drug. I have prescribed the drug

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for some patients whose primary care physicians discontinued it because of their concerns related to the product label. Dr. King: Another concern is that there is an unexplained 1% increase in syncope in patients receiving ranolazine, but there is no evidence this is due to Torsades. Dr. Vetrovec: The finding of increased syncopal episodes was clustered in patients also receiving nondihydropiridine calcium blockers— especially diltiazem. Dr. Pepine: The ranolazine product label also states it may have less benefit in women, because there were relatively few women in past chronic angina trials. In the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial, however, there was a substantial cohort of women in whom the drug performed better than in men, which I believe dispels that warning. We do not have long-term outcome studies with ranolazine, so we do not know if it improves mortality or morbidity in patients with stable angina. Dr. Friedewald: What is the mechanism of action of ranolazine? Dr. Pepine: The mechanism of action is uncertain. Nonhuman animal data shows that it shifts predominantly freefatty acid metabolism in the myocardium to a glucose pathway, which would be energy-sparing and therefore lessen the potential for myocardial ischemia. In the concentrations ranolazine reaches in the myocardium, however, it is unlikely that mechanism plays an important role. Dr. Vetrovec: That is correct, because ranolazine only affects about 20% of the free-fatty acid metabolism with usual doses. Dr. Pepine: Ranolazine is very active in the late inward sodium channel in myocytes. In cardiomyocytes that are made ischemic, there is either late reopening of these channels or a failure of the channels to close completely, so the drug prevents sodium accumulation in the myocytes. By preventing sodium accumulation, there is less myocardial cellular swelling and less calcium overload. We do not have evidence that mechanism is operative in patients with chronic stable angina, however, because we do not fully understand the pathophysiology of myocardial ischemia and whether the late sodium effect is important. MERLIN-TIMI, a recent trial of ⬎6,000 unstable angina patients, showed suppression of supraventricular arrhythmias including atrial fibrillation and atrial flutter during ambulatory monitoring.10 Thus, ranolazine may have some antiarrhythmic properties, which may be related to its prolongation of the QT interval. Dr. King: We do not know whether its cardiac antiarrhythmic effects have clinical significance. Other drugs with similar effects have not proven to reduce actual arrhythmic events. Dr. Friedewald: Does ranolazine affect the heart rate or blood pressure? Dr. Pepine: There is no effect of ranolazine on resting or exercise blood pressure or heart rate, so there is no effect on the rate–pressure determinants of myocardial oxygen demand, unlike other antianginal agents. Dr. Vetrovec: There also may be a positive effect on left ventricular diastolic function. In myocardial ischemia, left ventricular systolic function is preserved but diastolic dys-

function is the first abnormality to occur and the slowest functional abnormality to recover. Dr. Pepine: Another important consideration in selecting antianginal agents is the increasing number of patients with metabolic syndrome and diabetes mellitus, which is aggravated by ␤ blockers. Calcium antagonists are neutral, and ranolazine is beneficial in diabetes. Dr. Friedewald: Inflammation is a feature of the metabolic syndrome. Is there evidence of an anti-inflammatory effect of ranolazine? Dr. Vetrovec: No, there is not. Dr. Friedewald: Let’s discuss the use of statins in patients with chronic angina. Dr. Vetrovec: Statins are excellent drugs for patients with any form of CAD mainly because of their effect on low-density lipoprotein (LDL) cholesterol. They also have an anti-inflammatory effect, which is important for patients undergoing coronary angioplasty, in which the coronary artery is traumatized and undergoes inflammation secondary to the procedure. Statins also help modulate the risk of contrast-induced nephropathy. For these reasons, every patient having angioplasty should be on a statin. They also appear to improve left ventricular function in ischemic and nonischemic cardiomyopathies. Dr. Pepine: Statins also have significant vascular and microvascular effects. It is well accepted that statins lower arterial blood pressure, which must be through a vascular mechanism. Intracoronary studies have shown that statins prevent or reduce endothelial dysfunction and improve vasodilator function. Dr. Friedewald: What is the target LDL for your patients? Dr. Vetrovec: The target LDL in my patients is ⱕ70 mg/dl. Dr. King: We often make the mistake of trying to treat everyone the same when treating serum lipids. Patients with CAD often have many metabolic abnormalities, so while lowering the LDL may be the most important objective, we must not ignore other risk factors such as decreased levels of high density lipoprotein (HDL) cholesterol. All of the atherosclerosis regression trials have shown that regression requires both LDL lowering and HDL raising. Dr. Friedewald: Do angiotensin receptor blockers (ARBs) and angiotensin coenzyme inhibitors (ACEIs) have antianginal effects? Dr. Pepine: No, they do not, and it is unlikely that they any have anti-ichemic effects, either. Dr. Vetrovec: Many physicians routinely prescribe ACEIs or ARBs in addition to aspirin and statins in patients with angina, but I currently do not. Dr. Friedewald: What is your target blood pressure in patients with chronic angina? Dr. Pepine: All of the risk factor strategies have entered a period in which we talk about “optimal” or “ideal” rather than “normal.” Lowering the diastolic blood pressure to the point of possibly reducing coronary artery perfusion, however—the so-called “J curve” effect—is a concern with this approach. We have found that, among patients with CAD and hypertension, decreasing the diastolic blood pressure to ⬍72 mm Hg is associated with increased cardiac event rates. This could be important in the use of antianginal

Roundtable Discussion/Chronic Stable Angina Pectoris

agents because both ␤ blockers and calcium channel blockers lower the diastolic pressure, but ranolazine does not. Dr. Vetrovec: I believe the J curve is less important in patients who have had coronary artery revascularization. Dr. Pepine: Our data support that. In a cohort of 6,000 patients among 22,000 who had revascularization, the J curve was almost nonexistent. Dr. Friedewald: Is our goal to suppress only anginal symptoms or all episodes of myocardial ischemia, regardless of whether symptoms occur? Dr. Pepine: Myocardial ischemia is our principal target, because it places patients at increased risk for AMI and death. Anginal severity does not accurately reflect the magnitude of myocardial ischemia. For this reason, all patients with angina need to be risk-stratified, and it is especially important to determine whether left main or 3-vessel proximal coronary artery obstruction is present in patients with angina. Dr. Friedewald: What is the role of the stress test in following patients with angina? Dr. Vetrovec: There are 2 main reasons for performing stress tests: first, to confirm the diagnosis of myocardial ischemia, and second, to assess the extent of CAD, which is based on the degree of positivity of the test. The stress test is also useful because it helps in determining the ischemic threshold, so patients can be prescribed a target heart rate that keeps them below that threshold. Dr. Friedewald: Do you perform sequential stress tests? Dr. Vetrovec: That is a muddy issue. The guidelines do not recommend sequential exercise tests. When 1 of my patients has a change in anginal frequency or character, or a change in symptoms, such as having a feeling of dyspnea rather than chest pain, I may order a stress test. Rather than performing yearly stress tests—a practice that has a low yield—I look for changes in the patient’s activity status. It is helpful to hear a patient say, “I used to be able to go up 2 flights of stairs and now I can only walk up a flight and I get very short of breath.” That is a signal that something has changed in the patient. Dr. Friedewald: How does general muscular deconditioning affect people who must limit their exercise due to angina? Dr. Pepine: Improved physical condition extends the duration of exercise to the onset of angina. I often send patients with stable angina to cardiac rehabilitation programs or recommend programs of home conditioning. Dr. Friedewald: Let’s discuss coronary revascularization versus medical treatment of chronic stable angina. Dr. Vetrovec: Neither coronary angioplasty nor CABG has been shown to prolong life except in certain high-risk groups, such as patients with left main coronary artery obstruction or poor LV function. Dr. Pepine: I was not surprised by those findings in COURAGE. Dr. Friedewald: What are your criteria for recommending CABG for patients already receiving medical therapy for chronic stable angina? Dr. Pepine: The primary indication for CABG is in patients with a high risk for acute cardiac events, including patients with left main coronary artery obstruction, multivessel proximal obstruction when the left anterior de-

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scending coronary artery is involved, and systolic heart failure We are confident that patients with the first 2 indications benefit from coronary revascularization, but we are uncertain about its effect on outcomes for patients with heart failure. These high-risk groups, however, constitute only about 15% of patients with chronic stable angina. This leaves a large group of patients with a relatively low mortality and event rate, in which the main indication for CABG is quality of life, which itself varies following revascularization. Dr. Friedewald: The decision about revascularization in such patients is highly individual, with many personal variables entering into each patient’s decision. Dr. Pepine: Yes, it is a very individual choice. For patients who are disabled by other diseases, such as chronic lung disease and dementia, I do not like to offer this choice, because I know that their quality of life is limited by something else and, regardless of the success of the revascularization, quality of life will not be improved. Dr. Vetrovec: Patients prefer to take as few medications as possible, and many will therefore opt for revascularization for that reason alone. Surgery does not eliminate all medications, because there are a certain number of background medications, depending on their overall risk factors, that they are going to be on forever—at a minimum, aspirin and statins. Patients are happier, however, when even only one medication is stopped. We therefore need to prescribe antianginal drugs according to which drug(s) gives the patient the greatest benefit and try to discontinue all others. Another important fact that must be conveyed to patients who are considering CABG is that angina is not always eliminated by revascularization, although it may become easier to control with medications after CABG. COURAGE showed that many patients remain symptomatic following CABG. In the ARTS trial, which compared bare-metal stents with CABG, 60% of the patients having CABG at 1 year post-surgery were asymptomatic, but most of them were on antianginal medications.11 Among the angioplasty patients, 80% were asymptomatic, and most of them were also on medications for angina. Dr. Friedewald: Many patients after CABG no longer have angina but continue to have myocardial ischemia on the stress test. Dr. Pepine: At least 1/3 of post-CABG patients continue to show stress-induced ischemia, which is 1 of the reasons why noninvasive testing has limited use in patients who have had CABG. Most guidelines state that post-CABG patients with persistent symptoms should have repeat angiography. Dr. Friedewald: If they still become ischemic with stress after CABG, to what extent have they really been “improved”? Dr. Pepine: They have been improved in that they may no longer have angina and may have less medication burden. Dr. Vetrovec: Over the past several years medical therapy has steadily improved while revascularization skills have also improved, so answers to questions pertaining to medical treatment versus coronary revascularization for angina are constantly moving targets. Dr. Pepine: There is no question that today’s patients

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The American Journal of Cardiology (www.AJConline.org)

with coronary heart disease are not as sick as comparable patients 30 years ago. This is true for all measurable parameters: coronary angiogram, walking ability, symptom burden, and heart failure classification. Dr. Vetrovec: I believe a large factor in this improvement is that patients now receive coronary angioplasty much earlier than in past years, in which it was used only as a last resort after maximum medical therapy had been exhausted. Dr. Friedewald: What are the most important unanswered questions about chronic angina? Dr. Pepine: We simply need to know more about the disease itself, illustrated by this discussion in which we have spent so much time trying to explain angina. Dr. Vetrovec: We especially need research related to myocardial ischemia. Dr. Friedewald: If there is one question that you could have answered about angina pectoris or myocardial ischemia, what would it be? Dr. Pepine: I would like to know whether angina is caused by obstruction at the microvascular or macrovascular level. We have spent 30 years attacking coronary artery obstruction with CABG and angioplasty, but we still do not know the answer, which might explain why some patients present with angina and others with an AMI or sudden cardiac death. Perhaps AMI is due to microvascular disease, which cannot be collateralized, whereas the chronic angina patient may have a more macrovascular problem, which can be collateralized. Coronary artery disease has a spectrum of underlying mechanisms. On 1 end of the spectrum are patients with atherosclerotic plaque and only minimal obstruction to coronary arterial blood flow. The classic example of that form of CAD is found in the Maasai nomadic tribes in Africa.12 They are carnivores, and they invariably have coronary arterial plaques, but these plaques are almost entirely fibrous tissue located in large coronary arteries, and they do not die of coronary events. At the other end of the spectrum are young patients in western society with familial forms of CAD plus metabolic diseases such as diabetes mellitus. They have horrible fibroproliferative, soft plaque atheromatous disease often with coronary arterial obstruction and acute coronary events at a relatively young age. Dr. Vetrovec: The question I would like answered is how can we improve patient compliance in taking medications? At least 1/2 of the patients prescribed statins are not taking these drugs 6 months later. Dr. Pepine: Aspirin is an even better example of the medicine compliance challenge, because it can be purchased without a prescription for ⬍1 cent per tablet, yet compliance is no better than with taking statins. Dr. Vetrovic: COURAGE, however, showed that high degrees of patient compliance can be achieved with medical therapy. There was ⬎90% compliance in patients taking statins and aspirin. I also believe technology can be used to attain better drug utilization. Dr. Pepine: One more thought for the future is genetically-modified therapy, which may hold the most promise for the treatment of many forms of cardiovascular disease, including chronic angina.

Dr. Friedewald: Thank you. Needs Assessment: The need for this activity for cardiologists and other healthcare specialists in cardiovascular medicine is based on the following premises: 1. Chronic stable angina pectoris is a common manifestation of atherosclerotic coronary artery disease. 2. Many patients with well-controlled chronic angina often have a low quality of life. 3. Patients with chronic angina can be treated with a variety of medical and surgical strategies, alone and in combination. 4. More research is needed in the pathophysiology of angina pectoris. Target Audience: This activity is designed for cardiologists and all other health care specialists caring for patients with acute and chronic coronary heart disease. CME Credit: The A. Webb Roberts Center for Continuing Medical Education of Baylor Health Care System, Dallas, designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s).™ Physicians should only claim credit commensurate with the extent of their participation in the activity. The A. Webb Roberts Center for Continuing Medical Education for Baylor Health Care System, Dallas, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CME Instructions: After reading this article, go online at www.AJConline.org to register, complete a post-test with a minimum score of 80%, complete an evaluation and print a certificate. Combination of Media: Print and Internet Computer Requirements: Windows 2000, Pentium 3 or greater, 512 ram, 80 gigabytes storage Estimated Time to Complete: 1 hour Release Date: December 2007 Termination Date: December 2008 1. Rosamund W, Flegal K, Friday G, Furie K, Go A, Greenland K, Haase N, Ho M, Howard V, Kissela B, et al, for the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: a report from the American Heart Associations Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69 – e171. 2. Prinzmetal M, Kennamer R, Merliss R. A variant form of angina pectoris. Am J Med 1959;27:375–388. 3. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LS, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini J, Weintraub WS, for the COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007:356:1503–1516. 4. Pepine CJ. Does the brain know when the heart is ischemic? Ann Intern Med 1996; 124:1006 –1008. 5. Chan AT, Manson JE, Feskanich D, Stampfer MJ, Colditz GA, Fuchs CS. Long-term aspirin use and mortality in women. Arch Intern Med. 2007;167:562–572. 6. Loscalzo J. Folate and nitrate-induced endothelial dysfunction. Circulation 2001;104:1086 –1088.

Roundtable Discussion/Chronic Stable Angina Pectoris 7. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath PMD, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A, for the COMET Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET). Lancet 2003;362:7–13. 8. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, Pepine CJ, Wang W, Nelson JJ, Hebert DA, Wolff AA, for the MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004;43:1375–1382. 9. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, Skettino SL, Wolff AA. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina

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frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291:309 –316. 10. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, Skene A, McCabe CH, Braunwald E, for the MERLIN-TIMI 36 Trial Investigators. Effects of ranolazine on recurrent cardiovascular events in patients with non–ST-elevation acute coronary syndromes. JAMA 2007;297:1775–1783. 11. Van den Brand MJBM, Rensing BJWM, Morel M-aM, Foley DP, de Valk V, Breeman A, Suryapranata H, Haalebos MMP, Wijns W, Wellens F, Balcon R, Magee P, Ribeiro E, Buffolo E, Unger F, Serruys PW. The effect of completeness of revascularization on event-free survival at one year in the ARTS trial. J Am Coll Cardiol 2002 39: 559 –564. 12. Mann GV, Spoerry A, Gary M, Jarashow D. Atherosclerosis in the Masai. Am J Epidemiol 1972;95:26 –37.