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Diagnostic and therapeutic considerations in silent myocardial ischemia
Diagnostic and Therapeutic Considerations in Silent Myocardial Ischemia JOHN S. SCHROEDER,
MD
disease. Medical therapy, antianginal agents and risk reduction may improve survival. When ischemic involvement is severe, as in 3-vessel disease, interventional surgery may be required, whether or not ischemia is accompanied by angina. Selected clinical practice cases are presented to illustrate these diagnostic and therapeutic considerations, and are followed by group discussion. (Am J Cardiol 1988;61:41F-47F)
Attempts at diagnosis and treatment of silent myocardial ischemia appear to be justified in patients wtth known or suspected coronary artery disease. A positive exercise test result or ambulatory electrocardiographic monitoring showing ST-segment deviation is an appropriate indication for adjustment of anti-ischemic therapy. With the documentation of more severe ischemia, angiography should be considered to determine the extent of coronary artery
T
he physician concerned about silent myocardial ischemia faces a number of unresolved questions. Among the most clinically pressing are: What is the best way to detect silent myocardial ischemia? How often should screening tests be performed for silent myocardial ischcmia? How should patients with silent myocardial ischemia be managed, once diagnosed?
ST depression or ischemia has important prognostic implications. However, should physicians be as aggressive in treating the asymptomatic patient as they are in treating the symptomatic patient who has ST depression on the exercise stress test? If so. what criteria provide a reliable indication of therapeutic efficacy? Is the patient going to be treated until there is
Approach to the Patient with Silent Myocardial Ischemia: Current Considerations Despite advances in current knowledge about silent myocardial ischemia, many questions remain unanswered in the quest to formulate a clinically rational approach to this problem within the realm of existing diagnostic and therapeutic capabilities. For instance, how sensitive and specific is a positive treadmill test for identifying patients with silent myocardial ischemia? Is it really necessary to look any further for silent myocardial ischemia if a patient has a negative treadmill test result, i.e., one that shows no ST-segment changes? If the treadmill test response is positive, can the number of episodes of ST depression be used as a therapeutic marker rather than reliance on a report of symptoms? It is well known that objective evidence of
Group Discussion Dr. Schroeder: Dr. Parmley, how do you use the exercise treadmill test to make management decisions in patients with suspected silent myocardial ischcmia? Dr. Parmley: If the treadmill identifies ischcmictype ST-segment depression in the asymptomatic patient, my next step is to have the patient wear a Holter monitor to see what happens in the work and home environment. If it shows no ischcmia, I feel a little bit more comfortable. If the Holter shows ischemia, I try to associate it with a precipitating stimulus. Dr. Schroeder: So if you have a positive treadmill test, you almost always do a Holter, even in the asymp-
From the Coronary Care Unit, Stanford Ilniversity Medical Center. Stanford University School of h4edicine, Stanford, California. Address for reprints: john S. Schroeder, MD. Cardiology Division, Stanford School of Medicine. 300 Pasteur Drive, Stanford, California 94305. 41F
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tomatic patient. But with a negative treadmill, you might not. Dr. Pepine: Clinical experience has shown that if a patient has a high-level negative treadmill, he is unlikely to have ischemia identified on an ambulatory monitor. A few additional cases can be detected by adding an ambulatory monitor-probably those related to spasm. Dr. Schroeder: But is that really worth the expense of doing Holters on many patients? Dr. Parmley: One of the more important things to keep in mind is what we are trying to do. The goals of management are to prolong life, i.e., reduce mortality, and to reduce the incidence of such cardiac events as myocardial infarction. Very few interventions in coronary artery disease have been shown clearly to do that. So, getting to your first question,’ an asymptomatic patient with a high-exercise negative treadmill has less than a 19’0. chance per year of dying, and less than a 3% chance of developing some coronary event. Frankly, the likelihood of intervening beneficially in that patient is so low, based on current data, that I would not do anything else. The negative treadmill alone puts the patient in such a good risk category that, unless there was some other factor that would affect this patient’s outcome, I would go no further. Dr. Schroeder: What about a 48-year-old patient with a positive treadmill showing 1.5 mm of ST depression without pain at a heart rate of 116 beats/min. Would you do a Holter? Dr. Parmley: We are dealing with about a 75% sensitivity and specificity. Depending on the population, statistically there are more false-positives in patients who have a low risk of having the.disease. If silent myocardial ischemia was suspected, an independent test for ischemia,‘such as a thallium scan, would be appropriate. Some could argue that a radionuclide ventriculogram with exercise or other test might be as effective but, currently, the next step would be to obtain an independent marker of ischemia. Dr. Schroeder: Is there any group, for instance those with known angina, in whom you would use the treadmill test to adjust medications? Dr. Pepine: No, because adjusting medications to change the treadmill response has not been proven to alter prognosis. Dr. Schroeder: Then why bother performing repeat treadmill tests to look for silent ischemia? Dr. Pepine: Once you identify a high-risk treadmill, i.e., 2 mm of ST depression, prolonged recovery, ST shifts at a low work load-nothing can erase it. In my view, even if 5 more treadmills were negative, they would not override the importance of 1 positive test. Dr. Parmley: The issue is whether there is data to prove that treating ST depression has a beneficial effect on either myocardial infarction or mortality. Currently, there is none. We know that ST depression, like arrhythmia and depressed left ventricular function, is an independent marker of poor prognosis and should be measured in the high-risk patient by some tech-
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nique. Therefore, it would certainly seem that if ischemia could be reduced in the same way that we reduce arrhythmias, these patients would live longer. In patients with chronic heart failure, the association be? tween improved ejection fraction and prolonged life is well known. But in the hope of benefiting the patient, I think we could consider treating silent ischemia either medically or, more aggressively, by interventional therapy...including surgery. Again, we are left with the dilemma of recognizing factors that identify high-risk patients, and ischemia is certainly one of them, but we are not sure that treating it has a beneficial effect.
Case 1: The Patient with a Positive Thallium Scan A 73-year-old man who had a positive result on thallium study in 1984 had not been given any antianginal medicine. He had been followed at Stanford Hospital for about 11 years for mixed lymphoma, had an excellent response to therapy, a normal electrocardiographic result and was asymptomatic. During a treadmill test, the patient exercised for 4.7 minutes with no angina, but experienced a decrease in blood pressure.
Group Discussion Dr. Schroeder: Dr. Pepine, what would be your approach to this patient? Dr. Pepine: I would consider this a high-risk treadmill response, with at least 2 markers for ischemia. The patient is also high risk because of such independent variables as age, sex, etc. Therefore, I would proceed immediately to coronary angiography. Dr. Cohn: What about the ST response during exercise? Dr. Schroeder: The patient really had minimal ST displacement; the primary abnormality was a drop in blood pressure. Dr. Cohn: Why did he stop exercising? Dr. Schroeder: Fatigue. Dr. Amsterdam: Could you tell us a little bit more about that blood pressure response? Was there an initial elevation? Were there any symptoms when blood pressure dropped, and was this a true exercise-induced blood pressure drop? Dr. Schroeder: The patient really only got into stage 2 of the Bruce protocol, so there was only 1 additional blood pressure and it was slightly elevated before falling. Dr. Amsterdam: The patient has not had a previous infarct or aortic stenosis? Dr. Schroeder: No, but he did have a positive thallium. Dr. Amsterdam: Right, but that is not what usually gives you a blood pressure ,drop. Dr. Parmley: How positive was the thallium scan? Dr. Schroeder: We don’t know, since it is only referred to in his history as being “positive” 3 years earlier. Or. Parmley: But the details of that must be very important. What we all know from experience is that
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there can be an apical defect in thallium scans. In this age group, that might be a relatively nonspecific high incidence of false positives. Dr. Epstein: I think we ought to ask: On the basis of the data we know in this 7%year-old man, what is the chance of him having a MI or dying of ischemic heart disease over the next 5 years? Dr. Amsterdain: Taking it 1 step further, what is the chance for preventing such a coronary event, say with coronary artery bypass graft (CABG] or percutaneous transluminal coronary angioplasty? Based on the information you presented, I don’t think I would do coronary angiography in a 73-year-old man with a mixed lymphoma who is asymptomatic. Dr. Schroeder: So, despite exercise-induced hypotension and a short exercise time, you feel his expected survival is not sufficiently jeopardized to intervene? Dr. Epstein: Well, I think your information is not specific. Besides the thallium study in 1984, of which we have no details, there is no objective evidence of ischemia; the patient doesn’t have pain or ST-segment depression. I certainly would not go ahead with coronary angiography because of what Dr. Parmley has pointed out. Dr. Schroeder: But aren’t there many people who feel the post-MI treadmill showing poor exercise time is actually a better predictor than ischemia? Dk. Amsterdam: That is a different setting; you know the person has myocardial damage. This could be a deconditioned older man who can’t do very well. He has a VOZ that is over 15, he is 73, he may not be that different from other sedentary 73-year-old men. There is nothing specific on that treadmill, and based on the information shown, I am not convinced about the blood pressure response. If the blood pressure really rose and then fell and the blood pressure was dropping, that would be convincing. What’s up there is suggestive, but it’s not convincing. Dr. Schroeder: The patient’s exercise electrocardiogram showed significant ST depression during stage 2 of the treadmill test, so we proceeded to coronary angiography. The patient had about a 60% left main lesion, and some disease elsewhere. He went on to uneventful coronary bypass surgery in the hope of prolonging life.
Case 2; The Patient Hospitalized to Rule Out Myoeardial Infarction A 59-year-old man was hospitalized to rule out MI. He had a small increase in myocardial enzyme levels, suggesting subendocardial MI or unstable angina. The patient’s condition stabilized in the hospital and he performed a treadmill test about 3 or 4 weeks later, which showed inferior ischemia. Coronary angiography showed very diffuse disease in the left anterior descending artery, an occluded circumflex artery, an occluded mid-right, and mild anterior hypokinesia. The patient was considered to have nonoperative coronary disease. Because of his inoperable state and the diagnosis that ruled out MI, the risk for subsequent cardiovascular event was considered to be extremely
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high. The patient was prescribed maximal doses of diltiazem, 90 mg 3 or 4 times daily, along wi.th small doses of p blockers. Annual follow-up treadmill testing continued to show silent ischemia. The patient, who has been followed for 5 years, averages 1 episode of angina a month, but otherwise is asymptomatic.
Group Discussion Dr. Schroeder: This man has a normal electrocardiogram and an excellent ventricle at rest, but has absolutely terrible coronary disease. His treadmill shows marked ischemia, not only inferiorly, but in some of the other leads. Repeat treadmill showed a normal resting electrocardiogram, but even m,ore dramatic ST depression with no pain at a heart rate of about 90 or 100 beats/min. Should this patient have Holter monitoring, or should he have a thallium scan to evaluate risk and help determine which vessel should be bypassed? Or, should the same regimen, which has worked well for 5 years, be continued? Dr. Pepjne: Rejection for surgery in 1982 doesn’t mean that the patient would necessarily be turned away again in.1987. Dr. Schroeder; Should the coronary ateriogram be repeated? Dr. Pepine: Remember, the quality of these films in 1982 was not as good as it is now, nor were surgical capabilities the same. Contemporary surgeons are more ambitious with endarterectomies and other procedures. Several times, people have been referred to me with that kind of a film in their records, and they turn out to be surgical candidates after all. That would be one thing that I would do; otherwise, there isn’t much more that could be done diagnostically. The patient has been documented to have a lot of ischemia, and has been maximally treated with anti-ischemic medications. So, the major question here is whether or not to perform surgery. Dr. Cohn: Suppose the patient controlled his activities to prevent ischemia out of hospital? Would you feel better about him then? Dr. Schroeder: Not necessarily. The patient is a very active. fellow who plays golf. He gets angry easily. He has a couple of children in their late teens. I think that even if the Ho1te.r didn’t show much, there are certainly going to be times in his life that he’s going to have ischemia whenever he gets a heart rate of 90 or 100. Dr. Cohn: So, actually, that would make you feel worse than if you did the Holter and found out that he had many episodes. Dr. Parmley: This patient throws clubs on the golf course, he’s a high-stress, major-risk individual. Dr. Pepine’s point to reconsider any possibility of revascularization was an important one. I, too, would treat with anti-ischemic agents at doses that provide protection from angina but can be well tolerated. I’m not sure Holter monitoring would be beneficial. The patient is already at maximal medical therapy, and you k:now he has ischemia when he exercises. I think I would tend to stay with that regimen.
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Dr. Epstein: I don’t think CABG is applicable to this patient. We don’t know what his left ventricular ejection fraction is, but he has a normal rest electrocardiogram. So there is a good chance that he has normal left ventricular function. Dr. Amsterdam: If the man limited activity to avoid exercise-induced ischemia, would that make you feel better and would it change his prognosis? It’s a very interesting issue. We like to keep people away from the threshold level of ischemia because intuitively, it sounds prudent. But we don’t have good data that it will change the outlook. The important thing is, the treadmill identifies a risk factor for poor prognosis, not a risk factor if the person exercises at that level. We don’t know that it’s at that work load or at that heart rate that he will get in trouble. So, to be prudent, we might keep the patient below that level of activity. But, the treadmill is just 1 risk factor. Dr. Schroeder: And we know that most people don’t have a myocardial infarction during exercise or even golf. He’s retired and golf is important to him and I’ve not restricted that. Dr. Cohn: To me, simply reviewing the films again is not the answer. There is a good chance that the patient is still not going to be considered operable. What can we do for him then? We need to empirically maximize medical therapy. The patient has to be put on medication titrated to the point of side effects, or we are not doing our job. We cannot assume surgery is going to answer our problems. Dr. Schroeder: And there, I think the Holter might be more helpful. Dr. Pepine: This patient has a real need for Holter monitoring, because we certainly don’t want to make him worse. Blindly adding another calcium blocker to the diltiazem regimen can potentially increase ischemia. So, in this totally asymptomatic man, I would use the Halter to guide therapy. Dr. Kuljersmith: There is absolutely no validation for using either Holter monitoring or the stress test for assessing therapeutic endpoint. In a man with this much coronary disease, there is no way to prevent ischemia, even if you happen to see some reversibility on a 24- or 48-hour Holter. The goal would be to achieve maximum tolerable medical therapy.
Case 3: The Patielit with a Strong Family History of Coronary Artery Disease A 48-year-old bread salesman, who appeared in excellent condition and had no known coronary disease, was referred for evaluation because his brother had coronary disease on a routine treadmill test. The patient had a strong family history of coronary artery disease, smoked, and had markedly abnormal lipids, so was an excellent candidate for treadmill evaluation. Resting heart rate was 60 beats/min, which increased to 135 with a mild fall in blood pressure. The patient rapidly recuperated and exercised about 6 minutes without pain, but had about 3 mm of ST depression in the inferolateral lead.
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Group Discussion Dr. Schroeder: Should this patient have coronary arteriography, or should he have a Holter or thallium scan first? What should be done for this patient to ensure the best chance for a normal life? Dr. Becker: I don’t think a thallium scan is necessary when the exercise test is as strongly positive as this one. Dr. Schroeder: Results of coronary angiography showed 3-vessel disease and multiple lesions in the right coronary artery. The patient has multiple proximal and mid-left anterior descending lesions, as well as some. distal left anterior, descending and obtuse marginal disease. Based on these findings, we considered the patient a candidate for CABG, even though he had absolutely no symptoms and a normal left ventricle. I was quite convinced in 1980 that CABG was going to save the patient’s life. So I had to face this person who had never had any symptoms and recommend CABG, which would disable him from his job for several months. He looked me in the eye and said, “You mean despite the fact that I don’t have any pain, this is serious?” Maybe today he would have been considered for angioplasty. The patient had a routine CABG, which went well. He was discharged on Anturane@ therapy, which was the medicine of the year. Because the patient never had symptoms, the only way I could really follow him was with a yearly treadmill. The first treadmill looked good. The patient had taken my advice about exercising seriously. Consequently, he achieved a high heart rate, with a markedly improved exercise capacity. He continued to be asymptomatic. For the following year, he still had a normal electrocardiogram, with excellent exercise tolerance (he was able to exercise for 13 minutes]. The third year, however, the patient began to show the first signs of ischemia in the lateral leads. Since ischemia had appeared at a high heart rate, the patient was not given anti-ischemic medication. Over the next year or so, the patient continued to have excellent exercise tolerance without the development of hypotension, but the ST depression was becoming more dramatic and more severe. His last treadmill showed marked ST depression in leads II and V5 during exercise stages 4 and 5. Dr. Schroeder: Does this patient need another coronary arteriogram and possible rep~eat surgery? He has never had a symptom. Do you think he is going to believe me if I tell him that? Should I have put him on medication? Dr. Pepine: I don’t agree that these treadmill responses are as serious a prognostic problem as you identified previously. The patient’s blood pressure doesn’t drop. He goes to stage 5, whereas he only exercised for 4.3 minutes the first time. So, from a prognostic standpoint and in terms of markers, the patient looks better. Secondly, from what we know ab,out the conduits that were used in 1980, I wouldn’t be surprised if at least 1, and possibly 2, are functionally occluded. Whether or not disease has progressed or
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not is debatable, but most likely it has. I wouldn’t do anything immediately. I would, however, start mentioning to the patient that he is approaching the limits of therapy for a generally progressive disease, and I’d start preparing him over the next year or 2 for additional intervention. When the stress test again shows him at a high risk, then I would proceed with coronary angiography. Dr. Schroeder: How about a thallium study to detect the degree or extent of myocardium at risk? Dr. Pepine: I probably wouldn’t do that right now. I would be happy with the treadmill. Dr. Parmley: Let me just ask a couple of questions. I assume that you vigorously intervened to reduce risk factors? Dr. Schroeder: I did. The patient does not smoke anymore, and is taking fish oils, with some response in triglycerides, but they remain quite high-around 200 to 300 mg/dl. His cholesterol averages 300 mg/dl. Dr. Parmley: Is he currently being treated with anti-ischemic medication? Dr. Schroeder: No. That’s really one of the questions here. Dr. Parmley: I concur with Dr. Pepine in terms of prognosis. Looking at your data, the patient is at a different point now. It would be reasonable to consider some anti-ischemic medication, if he can tolerate it. I would not do a thallium scan, because I’m not sure how it would further help at this point. Since there is good exercise tolerance, with a reasonably high heart rate and no drop in blood pressure, the patient tends to fall out of the high-risk group. So I would not do a thallium, but I might consider some anti-ischemic therapy. Dr. Schroeder: Should I test the patient again after a course of diltiazem, or is it safe to assume it’s going to protect him? Dr. Parmley: I don’t see any reason to titrate the diltiazem, if that’s what you are asking. Dr. Epstein: Just a point about the post-CABG patient. There are no data on the prognostic value of ST segment deviations in the post-CABG patient; it may or may not be analogous to that in the virginal patient. There are so many differences that I don’t think we can use the treadmill with the same degree of prognostic certainty as we do with a patient who has not had a CABG. A second bypass carries with it an appreciably higher risk than a first bypass procedure. If you decided to do percutaneous transluminal coronary angioplasty, the risk would also be higher. So, I think that the risk/benefit ratio is going to be altered by the greater risk of interventional therapy. I would not, at this point, perform repeat coronary angiography, because it would not reveal anything that would lead me to recommend percutaneous transluminal angioplasty or bypass surgery in this post-CABG patient. Dr. Krucoff: Dr. Epstein, would you agree that the higher heart rate response and the lack of hypotension on the treadmill is a much better prognostic sign that the ST-segment changes?
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Dr. Epstein: Yes, I would agree with that. I’m wondering, however, about the,choice of diltiazem as opposed to a p blocker. Dr. Schroeder: Because the patient is basically healthy, and if he became impotent because of /3 blockade, I would also have created another disease. Diltiazem is very well tolerated. Dr. Kennedy: I absolutely agree with the perspectives of Drs. Pepine and Parmley, but I want to come back to this because as with the arrhythmia issue, we are discovering a phenomenon and instituting therapy with no idea of what the therapy is doing. To institute a calcium channel blocker in the belief that it will decrease ischemia is absolutely correct. But, just as we discovered about proarrhythmic effect, we have no idea now of what the treadmill is going to be. If we start anti-ischemic therapy, let’s look at the results of it. I agree that we must try to modify mortality and Imorbidity. We hope to do that and to stop infarction. 1411of us know that this is a progressive disease. We are all thinking that we have to do coronary angiography at the appropriate time and try to prevent infarction. But we don’t know if therapy creates a proischemic effect. So, we have to examine whether or not therapy had any benefit. Dr. Parmley: I think the proarrhythmic effect of the antiarrhythmic drugs is pretty standard at lo%, or maybe more. A proangina effect of antianginal agents-for instance, reflex tachycardia-is occasionally seen with drugs like nifedipine, but it’s extraordinarily uncommon. So I don’t think a repeat treadmill is necessary to rule out a proangina or proischemia effect, but I do agree with the notion of trying to assess therapeutic efficacy. A repeat treadmill showing that the ST depression was 0.5 mm more or less would not necessarily influence clinical management. Dr. Kennedy: Let’s quantitate this. If the initial dosage of diltiazem has no anti-ischemic effect, I would increase the dose to 90 mg every 8 hours, and then higher. If there was less ST-segment depression in fewer leads, I would try to determine what constitutes anti-ischemic effectiveness. There is tremendous analogy to what we know about arrhythmias: the same variability factors, and the same applications. This is all new knowledge and we can’t skip over it. Dr. Pepine: I agree with your concept. There is no question that we ought to be looking at the potential for risk, but I don’t like the idea of equating ischemia with arrhythmias. First of all, we have good drugs for ischemia, which are very unlikely to increase ischemia. Our drugs for arrhythmias are very poor and can cause a 10% or more incidence of proarrhythmia in patients who need therapy the most. No one feels that a little ischemia is good, but all of us have inconsequential premature ventricular contractions while we are sitting here. So the 2 are not alike. This patient reminds me not so much of a coronary bypass case, but of what we see every day with angioplasty. This patient with multivessel disease had angioplasty last year, and that’s what his treadmill looks like now. So, Dr. Epstein, without all of the compounding influences and
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the reduction in the risk/benefit ratio provided by previous bypass surgery, would you feel differently about how far you would go with this patient, compressing time to months instead of years, and given this exercise test? Dr. Epstein: I would completely agree with the implications. I would treat this patient totally differently from the way I would treat a post-CABG patient. Given the recurrence of profound ST-segment depression, I would repeat the angiogram and I would consider repeating percutaneous transluminal coronary angioplasty. Dr. Amsterdam: I think the treadmill is reliable in this post-CABG patient because, after surgery, he apparently returned to a normal baseline on the treadmill. So the compound variables may not be there. If a negative treadmill later becomes positive, it is highly unlikely to be a false positive. So, a negative treadmill followed by a positive one means ischemia has been reestablished. The patient’s heart rate was tremendous-it looked like it was in the 160s or higher. At what heart rate did it become positive? To me, the heart rate at which the patient initially became ischemic is more important than the number of millimeters of ST depression at maximum. Dr. Schroeder: It looks like 1 mm of ST depression at a heart rate of 111 beats/min and about 2 mm at 128 beats/min. Dr. Amsterdam: That’s low heart rate, so I would take a different viewpoint. I definitely would do a thallium scan to determine the extent of myocardial involvement and provide a much greater perspective than the treadmill. This doesn’t mean I’ll necessarily do an angiogram. Once the thallium is done, I can make my next move. If the person is positive at a low rate and has a drop in blood pressure, this is a bad response. A drop in blood pressure is a very unusual finding. Most high-risk patients are high risk based on ischemia at a low heart rate, without a drop in blood pressure. It’s an extremely unusual finding and is not necessarily a key tip-off. Its predictive accuracy is very good, but its sensitivity is minuscule. Dr. Krucoff: I, too, would take this gentleman back to the catheterization lab for several reasons. First, since the ST changes are in similar leads, we know he is post-CABG, and his anatomy is clearly not the same as was visualized initially. Second, in a post-CABG patient, which is an increasingly common subgroup, there is at least the potential to intervene with angioplasty revascularization in a partially protected scenario. There may be a compromised rather than an occluded graft, and you may be able to work on a native vessel with some distal circulation, despite what’s being done through that graft. Given that there has been such a clear change in this patient’s ischemic activity, waiting until he again becomes high-risk may force a second operation or render the patient intractable to medical therapy. Now may be exactly when you could intervene in a semiprotected environment and help him with angioplasty. Dr. Cohn: Suppose this man presented again with the same exact story, good ejection fraction and so forth, same exercise response, same catheterization
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data, except that it is 1987, and the medical vs surgical longevity for 3-vessel disease with left ventricular function is pretty similar. What would your inclination be now? Dr. Schroeder: I think it would be the same, just because it is my bias that these patients, even though there may not be a difference in mortality, are still at high risk for infarction or other type of cardiac event that may not result in death, but can cause disability. Dr. Epstein: I admit that we don’t have very good longevity data, aside from Erikssen’s study in totally asymptomatic people, so are forced to make clinical decisions with incomplete information. If a person has significant ST-segment depression-and I would do a gated blood pool study to confirm that there is inducible ischemia-in the presence of S-vessel disease, I would consider that patient to be at high risk of death and would recommend revascularization . . . even in the absence of symptoms. Dr. Cohn: If the patient fell into a high-risk group, with profound ST-segment depression and profound ejection fraction on exercise, you would consider this man bypassable in 1987? Dr. Epstein: Absolutely, but I disagree slightly with Dr. Krucoff. If angioplasty is done, 3% to 5% of these patients-even those with l- or 2-vessel disease-run into trouble that necessitates an urgent bypass operation. Dr. Krucoffi Except that he may be in a more protected group. If he has a graft to distal circulation, you work on a native vessel. Dr. Epstein: I’m just saying that it’s a different risk situation. Perhaps I’m intrinsically a little more conservative but have a higher threshold in doing invasive therapeutics in a patient who has already had bypass surgery, because of the higher risk if problems develop. Dr. Hollenberg: What about the recovery phase? Dr. Horwitz: I agree that looking for a drop in blood pressure frequently is unrewarding. I think that you shouldn’t lose sight of the point that Dr. Pepine made. This man has superb exercise capacity. At whatever level he’s beginning to develop ischemia, the most disturbing thing is that there is a change. We should get the maximum amount of information about that change. It would also seem that this patient is an ideal candidate for a Holter monitor. For example, ambulatory electrocardiography showing multiple persistent episodes of silent ischemia signifies the need for aggressive intervention. If there was nothing-no arrhythmia and no ischemia-I think you’d feel a little better about it. I don’t think that this man on a gated is going to suddenly deteriorate at a moderate load...not with the kind of exercise performance he is showing on this test. He’s not a high-risk exercise test. But I think what we are all trying to do is to pick the point at which we may intervene. The patient is beginning to show signs that his initial therapy hasn’t been very good. He is still probably not at an enormous risk. But, the maximum information you can get would be helpful so, since symptoms can’t help you, perhaps a Holter could.
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Dr. Hollenberg: I can’t let this discussion go without commenting on exercise testing. We need a quantifiable, reproducible test. We have ignored many variables in this exercise test, that is, his ST changes occur late so he has late evolutionary changes, and they resolve fairly quickly. These are all hallmarks of mild involvement. We also know that his exercise duration is quite excellent. Sure, the patient gets ST depression at 13 minutes of exercise, but by 2 minutes of recovery, he is almost back to normal. So I think you have to quantify the changes that occur in evolution and resolution, and, in fact, we have a treadmill exercise score that quantifies all of these variables. I have found that a very reproducible, quantifiable exercise test can identify either significant graft occlusion or new lesions in the native vasculature in many patients. So, a quantifiable reproducible exercise test is a very helpful technique to follow post-CABG patients. It also is a very subjective test; the patient stops at variable endpoints according to how he feels that day, and it is very hard to quantify him, unless one uses all these complex features. To still look at this the way we read exercise tests 20 years ago is really a little simplistic, and I think we are shortchanging the information that we do gain with the exercise test.
Case 4: The Postmyocardial Infarction Patient A 69-year-old man had an inferior MI and was treated with intravenous streptokinase. Recovery was uneventful. Because stenosis was not severe, angioplasty or CABG was considered unnecessary. The patient, who had very few risk factors, remained asymptomatic during treatment with diltiazem and aspirin. Several months after MI, repeat treadmill testing showed evidence of lateral wall ischemia, despite good functional capacity and no chest pain. The resting electrocardiogram showed a small inferior MI, and there were small Q waves between leads III and aVF. But during exercise, it appeared that this inferolateral area was still in jeopardy. Recovery at 3 minutes showed significant ST depression. Because the patient was asymptomatic, the dosage of calcium blocker was reduced despite the marked ST depression, The patient returned 6 months later feeling better than ever, still asymptomatic. A repeat treadmill looked about the same, and functional capacity was normal. There was residual evidence of an old inferior MI, with ST depression at stage 3. Exercise was stopped at stage 6 of the Bruce protocol and a heart rate of 150 beats/min. Marked ST depression subsided rapidly.
Group Discussion Dr. Schroeder: Again, the question is what to do for this patient. Dr. Pepine: What was angiographic anatomy after the infarct?
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Dr. Schroeder: The patient had about a 50% midright lesion and a normal left system. So, he was felt not to require angioplasty. Dr. Pepine: This is becoming more common in our postrevascularization patients, where we see much less than 50% narrowing in the revascularized vessel or in the reperfused vessel, with a very abnormal exercise response. I attribute some of this to the abnormal resting electrocardiogram, with those T-wave inversions. However, I don’t think this is the whole picture. I can’t attribute it all to a gross underestimate of the significance of the stenosis from the coronary arteriogram. I don’t know what it means prognostically. I probably would have treated this patient with a Qwave infarction with a fi blocker, and I don’t know that I would have done anything differently, Dr. Schroeder, than you have. Dr. Parmley: This is more than a year postinfarction at this point? Dr. Schroeder: It is now about a year postinfarction. Dr. Parmley: So, the patient has gone through the “high-risk period,” i.e., he hasn’t died in the first 6 weeks, 3 months or 6 months. He has documented coronary artery disease, which was only right coronary artery disease 1 year ago. This is really a difficult case to become overly aggressive with at the moment, with superb exercise tolerance despite the ischemia shown there. In the absence of any other data, I am not sure that I would recatheterize the man at this point. I would probably err on the side of conservatism. Dr. Schroeder: Should I increase his diltiazem, or decrease it? The dosage was decreased because the patient had no pain on the treadmill. However, I am not sure it made much difference. He is on 60 mg 3 times a day. Dr. Parmley: That is a reasonable dose, although not a maximum dose, so I am not sure I would be persuaded necessarily to push at this point. Dr. Krucoff: I would pursue this patient at least with a thallium scan or similar to look at the actual anatomic perfusion defect. If there is none, I think I would use his symptom-free, high functional capacity status to keep withdrawing diltiazem. If, on the other hand, there was a clear-cut defect, I would more strongly consider angiography. Clearly, in 3 or 6 months people can evolve very malignant stenoses in what initially looked insignificant. If the thallium scan revealed a focal defect, I would probably arrange for catheterization.
Participating Investigators Ezra A. Amsterdam, MD, Lewis Becker, MD, Peter F. Cohn, MD, Stephen E. Epstein, MD, Milton Hollenberg, MD, Lawrence D. Horwitz, MD, Harold L. Kennedy, MD, MPH, Mitchell Krucoff, MD, Joel Kupersmith, MD, William W. Parmley, MD, and Carl J. Pepine, MD.
MD
disease. Medical therapy, antianginal agents and risk reduction may improve survival. When ischemic involvement is severe, as in 3-vessel disease, interventional surgery may be required, whether or not ischemia is accompanied by angina. Selected clinical practice cases are presented to illustrate these diagnostic and therapeutic considerations, and are followed by group discussion. (Am J Cardiol 1988;61:41F-47F)
Attempts at diagnosis and treatment of silent myocardial ischemia appear to be justified in patients wtth known or suspected coronary artery disease. A positive exercise test result or ambulatory electrocardiographic monitoring showing ST-segment deviation is an appropriate indication for adjustment of anti-ischemic therapy. With the documentation of more severe ischemia, angiography should be considered to determine the extent of coronary artery
T
he physician concerned about silent myocardial ischemia faces a number of unresolved questions. Among the most clinically pressing are: What is the best way to detect silent myocardial ischemia? How often should screening tests be performed for silent myocardial ischcmia? How should patients with silent myocardial ischemia be managed, once diagnosed?
ST depression or ischemia has important prognostic implications. However, should physicians be as aggressive in treating the asymptomatic patient as they are in treating the symptomatic patient who has ST depression on the exercise stress test? If so. what criteria provide a reliable indication of therapeutic efficacy? Is the patient going to be treated until there is
Approach to the Patient with Silent Myocardial Ischemia: Current Considerations Despite advances in current knowledge about silent myocardial ischemia, many questions remain unanswered in the quest to formulate a clinically rational approach to this problem within the realm of existing diagnostic and therapeutic capabilities. For instance, how sensitive and specific is a positive treadmill test for identifying patients with silent myocardial ischemia? Is it really necessary to look any further for silent myocardial ischemia if a patient has a negative treadmill test result, i.e., one that shows no ST-segment changes? If the treadmill test response is positive, can the number of episodes of ST depression be used as a therapeutic marker rather than reliance on a report of symptoms? It is well known that objective evidence of
Group Discussion Dr. Schroeder: Dr. Parmley, how do you use the exercise treadmill test to make management decisions in patients with suspected silent myocardial ischcmia? Dr. Parmley: If the treadmill identifies ischcmictype ST-segment depression in the asymptomatic patient, my next step is to have the patient wear a Holter monitor to see what happens in the work and home environment. If it shows no ischcmia, I feel a little bit more comfortable. If the Holter shows ischemia, I try to associate it with a precipitating stimulus. Dr. Schroeder: So if you have a positive treadmill test, you almost always do a Holter, even in the asymp-
From the Coronary Care Unit, Stanford Ilniversity Medical Center. Stanford University School of h4edicine, Stanford, California. Address for reprints: john S. Schroeder, MD. Cardiology Division, Stanford School of Medicine. 300 Pasteur Drive, Stanford, California 94305. 41F
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tomatic patient. But with a negative treadmill, you might not. Dr. Pepine: Clinical experience has shown that if a patient has a high-level negative treadmill, he is unlikely to have ischemia identified on an ambulatory monitor. A few additional cases can be detected by adding an ambulatory monitor-probably those related to spasm. Dr. Schroeder: But is that really worth the expense of doing Holters on many patients? Dr. Parmley: One of the more important things to keep in mind is what we are trying to do. The goals of management are to prolong life, i.e., reduce mortality, and to reduce the incidence of such cardiac events as myocardial infarction. Very few interventions in coronary artery disease have been shown clearly to do that. So, getting to your first question,’ an asymptomatic patient with a high-exercise negative treadmill has less than a 19’0. chance per year of dying, and less than a 3% chance of developing some coronary event. Frankly, the likelihood of intervening beneficially in that patient is so low, based on current data, that I would not do anything else. The negative treadmill alone puts the patient in such a good risk category that, unless there was some other factor that would affect this patient’s outcome, I would go no further. Dr. Schroeder: What about a 48-year-old patient with a positive treadmill showing 1.5 mm of ST depression without pain at a heart rate of 116 beats/min. Would you do a Holter? Dr. Parmley: We are dealing with about a 75% sensitivity and specificity. Depending on the population, statistically there are more false-positives in patients who have a low risk of having the.disease. If silent myocardial ischemia was suspected, an independent test for ischemia,‘such as a thallium scan, would be appropriate. Some could argue that a radionuclide ventriculogram with exercise or other test might be as effective but, currently, the next step would be to obtain an independent marker of ischemia. Dr. Schroeder: Is there any group, for instance those with known angina, in whom you would use the treadmill test to adjust medications? Dr. Pepine: No, because adjusting medications to change the treadmill response has not been proven to alter prognosis. Dr. Schroeder: Then why bother performing repeat treadmill tests to look for silent ischemia? Dr. Pepine: Once you identify a high-risk treadmill, i.e., 2 mm of ST depression, prolonged recovery, ST shifts at a low work load-nothing can erase it. In my view, even if 5 more treadmills were negative, they would not override the importance of 1 positive test. Dr. Parmley: The issue is whether there is data to prove that treating ST depression has a beneficial effect on either myocardial infarction or mortality. Currently, there is none. We know that ST depression, like arrhythmia and depressed left ventricular function, is an independent marker of poor prognosis and should be measured in the high-risk patient by some tech-
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nique. Therefore, it would certainly seem that if ischemia could be reduced in the same way that we reduce arrhythmias, these patients would live longer. In patients with chronic heart failure, the association be? tween improved ejection fraction and prolonged life is well known. But in the hope of benefiting the patient, I think we could consider treating silent ischemia either medically or, more aggressively, by interventional therapy...including surgery. Again, we are left with the dilemma of recognizing factors that identify high-risk patients, and ischemia is certainly one of them, but we are not sure that treating it has a beneficial effect.
Case 1: The Patient with a Positive Thallium Scan A 73-year-old man who had a positive result on thallium study in 1984 had not been given any antianginal medicine. He had been followed at Stanford Hospital for about 11 years for mixed lymphoma, had an excellent response to therapy, a normal electrocardiographic result and was asymptomatic. During a treadmill test, the patient exercised for 4.7 minutes with no angina, but experienced a decrease in blood pressure.
Group Discussion Dr. Schroeder: Dr. Pepine, what would be your approach to this patient? Dr. Pepine: I would consider this a high-risk treadmill response, with at least 2 markers for ischemia. The patient is also high risk because of such independent variables as age, sex, etc. Therefore, I would proceed immediately to coronary angiography. Dr. Cohn: What about the ST response during exercise? Dr. Schroeder: The patient really had minimal ST displacement; the primary abnormality was a drop in blood pressure. Dr. Cohn: Why did he stop exercising? Dr. Schroeder: Fatigue. Dr. Amsterdam: Could you tell us a little bit more about that blood pressure response? Was there an initial elevation? Were there any symptoms when blood pressure dropped, and was this a true exercise-induced blood pressure drop? Dr. Schroeder: The patient really only got into stage 2 of the Bruce protocol, so there was only 1 additional blood pressure and it was slightly elevated before falling. Dr. Amsterdam: The patient has not had a previous infarct or aortic stenosis? Dr. Schroeder: No, but he did have a positive thallium. Dr. Amsterdam: Right, but that is not what usually gives you a blood pressure ,drop. Dr. Parmley: How positive was the thallium scan? Dr. Schroeder: We don’t know, since it is only referred to in his history as being “positive” 3 years earlier. Or. Parmley: But the details of that must be very important. What we all know from experience is that
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there can be an apical defect in thallium scans. In this age group, that might be a relatively nonspecific high incidence of false positives. Dr. Epstein: I think we ought to ask: On the basis of the data we know in this 7%year-old man, what is the chance of him having a MI or dying of ischemic heart disease over the next 5 years? Dr. Amsterdain: Taking it 1 step further, what is the chance for preventing such a coronary event, say with coronary artery bypass graft (CABG] or percutaneous transluminal coronary angioplasty? Based on the information you presented, I don’t think I would do coronary angiography in a 73-year-old man with a mixed lymphoma who is asymptomatic. Dr. Schroeder: So, despite exercise-induced hypotension and a short exercise time, you feel his expected survival is not sufficiently jeopardized to intervene? Dr. Epstein: Well, I think your information is not specific. Besides the thallium study in 1984, of which we have no details, there is no objective evidence of ischemia; the patient doesn’t have pain or ST-segment depression. I certainly would not go ahead with coronary angiography because of what Dr. Parmley has pointed out. Dr. Schroeder: But aren’t there many people who feel the post-MI treadmill showing poor exercise time is actually a better predictor than ischemia? Dk. Amsterdam: That is a different setting; you know the person has myocardial damage. This could be a deconditioned older man who can’t do very well. He has a VOZ that is over 15, he is 73, he may not be that different from other sedentary 73-year-old men. There is nothing specific on that treadmill, and based on the information shown, I am not convinced about the blood pressure response. If the blood pressure really rose and then fell and the blood pressure was dropping, that would be convincing. What’s up there is suggestive, but it’s not convincing. Dr. Schroeder: The patient’s exercise electrocardiogram showed significant ST depression during stage 2 of the treadmill test, so we proceeded to coronary angiography. The patient had about a 60% left main lesion, and some disease elsewhere. He went on to uneventful coronary bypass surgery in the hope of prolonging life.
Case 2; The Patient Hospitalized to Rule Out Myoeardial Infarction A 59-year-old man was hospitalized to rule out MI. He had a small increase in myocardial enzyme levels, suggesting subendocardial MI or unstable angina. The patient’s condition stabilized in the hospital and he performed a treadmill test about 3 or 4 weeks later, which showed inferior ischemia. Coronary angiography showed very diffuse disease in the left anterior descending artery, an occluded circumflex artery, an occluded mid-right, and mild anterior hypokinesia. The patient was considered to have nonoperative coronary disease. Because of his inoperable state and the diagnosis that ruled out MI, the risk for subsequent cardiovascular event was considered to be extremely
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high. The patient was prescribed maximal doses of diltiazem, 90 mg 3 or 4 times daily, along wi.th small doses of p blockers. Annual follow-up treadmill testing continued to show silent ischemia. The patient, who has been followed for 5 years, averages 1 episode of angina a month, but otherwise is asymptomatic.
Group Discussion Dr. Schroeder: This man has a normal electrocardiogram and an excellent ventricle at rest, but has absolutely terrible coronary disease. His treadmill shows marked ischemia, not only inferiorly, but in some of the other leads. Repeat treadmill showed a normal resting electrocardiogram, but even m,ore dramatic ST depression with no pain at a heart rate of about 90 or 100 beats/min. Should this patient have Holter monitoring, or should he have a thallium scan to evaluate risk and help determine which vessel should be bypassed? Or, should the same regimen, which has worked well for 5 years, be continued? Dr. Pepjne: Rejection for surgery in 1982 doesn’t mean that the patient would necessarily be turned away again in.1987. Dr. Schroeder; Should the coronary ateriogram be repeated? Dr. Pepine: Remember, the quality of these films in 1982 was not as good as it is now, nor were surgical capabilities the same. Contemporary surgeons are more ambitious with endarterectomies and other procedures. Several times, people have been referred to me with that kind of a film in their records, and they turn out to be surgical candidates after all. That would be one thing that I would do; otherwise, there isn’t much more that could be done diagnostically. The patient has been documented to have a lot of ischemia, and has been maximally treated with anti-ischemic medications. So, the major question here is whether or not to perform surgery. Dr. Cohn: Suppose the patient controlled his activities to prevent ischemia out of hospital? Would you feel better about him then? Dr. Schroeder: Not necessarily. The patient is a very active. fellow who plays golf. He gets angry easily. He has a couple of children in their late teens. I think that even if the Ho1te.r didn’t show much, there are certainly going to be times in his life that he’s going to have ischemia whenever he gets a heart rate of 90 or 100. Dr. Cohn: So, actually, that would make you feel worse than if you did the Holter and found out that he had many episodes. Dr. Parmley: This patient throws clubs on the golf course, he’s a high-stress, major-risk individual. Dr. Pepine’s point to reconsider any possibility of revascularization was an important one. I, too, would treat with anti-ischemic agents at doses that provide protection from angina but can be well tolerated. I’m not sure Holter monitoring would be beneficial. The patient is already at maximal medical therapy, and you k:now he has ischemia when he exercises. I think I would tend to stay with that regimen.
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Dr. Epstein: I don’t think CABG is applicable to this patient. We don’t know what his left ventricular ejection fraction is, but he has a normal rest electrocardiogram. So there is a good chance that he has normal left ventricular function. Dr. Amsterdam: If the man limited activity to avoid exercise-induced ischemia, would that make you feel better and would it change his prognosis? It’s a very interesting issue. We like to keep people away from the threshold level of ischemia because intuitively, it sounds prudent. But we don’t have good data that it will change the outlook. The important thing is, the treadmill identifies a risk factor for poor prognosis, not a risk factor if the person exercises at that level. We don’t know that it’s at that work load or at that heart rate that he will get in trouble. So, to be prudent, we might keep the patient below that level of activity. But, the treadmill is just 1 risk factor. Dr. Schroeder: And we know that most people don’t have a myocardial infarction during exercise or even golf. He’s retired and golf is important to him and I’ve not restricted that. Dr. Cohn: To me, simply reviewing the films again is not the answer. There is a good chance that the patient is still not going to be considered operable. What can we do for him then? We need to empirically maximize medical therapy. The patient has to be put on medication titrated to the point of side effects, or we are not doing our job. We cannot assume surgery is going to answer our problems. Dr. Schroeder: And there, I think the Holter might be more helpful. Dr. Pepine: This patient has a real need for Holter monitoring, because we certainly don’t want to make him worse. Blindly adding another calcium blocker to the diltiazem regimen can potentially increase ischemia. So, in this totally asymptomatic man, I would use the Halter to guide therapy. Dr. Kuljersmith: There is absolutely no validation for using either Holter monitoring or the stress test for assessing therapeutic endpoint. In a man with this much coronary disease, there is no way to prevent ischemia, even if you happen to see some reversibility on a 24- or 48-hour Holter. The goal would be to achieve maximum tolerable medical therapy.
Case 3: The Patielit with a Strong Family History of Coronary Artery Disease A 48-year-old bread salesman, who appeared in excellent condition and had no known coronary disease, was referred for evaluation because his brother had coronary disease on a routine treadmill test. The patient had a strong family history of coronary artery disease, smoked, and had markedly abnormal lipids, so was an excellent candidate for treadmill evaluation. Resting heart rate was 60 beats/min, which increased to 135 with a mild fall in blood pressure. The patient rapidly recuperated and exercised about 6 minutes without pain, but had about 3 mm of ST depression in the inferolateral lead.
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Group Discussion Dr. Schroeder: Should this patient have coronary arteriography, or should he have a Holter or thallium scan first? What should be done for this patient to ensure the best chance for a normal life? Dr. Becker: I don’t think a thallium scan is necessary when the exercise test is as strongly positive as this one. Dr. Schroeder: Results of coronary angiography showed 3-vessel disease and multiple lesions in the right coronary artery. The patient has multiple proximal and mid-left anterior descending lesions, as well as some. distal left anterior, descending and obtuse marginal disease. Based on these findings, we considered the patient a candidate for CABG, even though he had absolutely no symptoms and a normal left ventricle. I was quite convinced in 1980 that CABG was going to save the patient’s life. So I had to face this person who had never had any symptoms and recommend CABG, which would disable him from his job for several months. He looked me in the eye and said, “You mean despite the fact that I don’t have any pain, this is serious?” Maybe today he would have been considered for angioplasty. The patient had a routine CABG, which went well. He was discharged on Anturane@ therapy, which was the medicine of the year. Because the patient never had symptoms, the only way I could really follow him was with a yearly treadmill. The first treadmill looked good. The patient had taken my advice about exercising seriously. Consequently, he achieved a high heart rate, with a markedly improved exercise capacity. He continued to be asymptomatic. For the following year, he still had a normal electrocardiogram, with excellent exercise tolerance (he was able to exercise for 13 minutes]. The third year, however, the patient began to show the first signs of ischemia in the lateral leads. Since ischemia had appeared at a high heart rate, the patient was not given anti-ischemic medication. Over the next year or so, the patient continued to have excellent exercise tolerance without the development of hypotension, but the ST depression was becoming more dramatic and more severe. His last treadmill showed marked ST depression in leads II and V5 during exercise stages 4 and 5. Dr. Schroeder: Does this patient need another coronary arteriogram and possible rep~eat surgery? He has never had a symptom. Do you think he is going to believe me if I tell him that? Should I have put him on medication? Dr. Pepine: I don’t agree that these treadmill responses are as serious a prognostic problem as you identified previously. The patient’s blood pressure doesn’t drop. He goes to stage 5, whereas he only exercised for 4.3 minutes the first time. So, from a prognostic standpoint and in terms of markers, the patient looks better. Secondly, from what we know ab,out the conduits that were used in 1980, I wouldn’t be surprised if at least 1, and possibly 2, are functionally occluded. Whether or not disease has progressed or
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not is debatable, but most likely it has. I wouldn’t do anything immediately. I would, however, start mentioning to the patient that he is approaching the limits of therapy for a generally progressive disease, and I’d start preparing him over the next year or 2 for additional intervention. When the stress test again shows him at a high risk, then I would proceed with coronary angiography. Dr. Schroeder: How about a thallium study to detect the degree or extent of myocardium at risk? Dr. Pepine: I probably wouldn’t do that right now. I would be happy with the treadmill. Dr. Parmley: Let me just ask a couple of questions. I assume that you vigorously intervened to reduce risk factors? Dr. Schroeder: I did. The patient does not smoke anymore, and is taking fish oils, with some response in triglycerides, but they remain quite high-around 200 to 300 mg/dl. His cholesterol averages 300 mg/dl. Dr. Parmley: Is he currently being treated with anti-ischemic medication? Dr. Schroeder: No. That’s really one of the questions here. Dr. Parmley: I concur with Dr. Pepine in terms of prognosis. Looking at your data, the patient is at a different point now. It would be reasonable to consider some anti-ischemic medication, if he can tolerate it. I would not do a thallium scan, because I’m not sure how it would further help at this point. Since there is good exercise tolerance, with a reasonably high heart rate and no drop in blood pressure, the patient tends to fall out of the high-risk group. So I would not do a thallium, but I might consider some anti-ischemic therapy. Dr. Schroeder: Should I test the patient again after a course of diltiazem, or is it safe to assume it’s going to protect him? Dr. Parmley: I don’t see any reason to titrate the diltiazem, if that’s what you are asking. Dr. Epstein: Just a point about the post-CABG patient. There are no data on the prognostic value of ST segment deviations in the post-CABG patient; it may or may not be analogous to that in the virginal patient. There are so many differences that I don’t think we can use the treadmill with the same degree of prognostic certainty as we do with a patient who has not had a CABG. A second bypass carries with it an appreciably higher risk than a first bypass procedure. If you decided to do percutaneous transluminal coronary angioplasty, the risk would also be higher. So, I think that the risk/benefit ratio is going to be altered by the greater risk of interventional therapy. I would not, at this point, perform repeat coronary angiography, because it would not reveal anything that would lead me to recommend percutaneous transluminal angioplasty or bypass surgery in this post-CABG patient. Dr. Krucoff: Dr. Epstein, would you agree that the higher heart rate response and the lack of hypotension on the treadmill is a much better prognostic sign that the ST-segment changes?
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Dr. Epstein: Yes, I would agree with that. I’m wondering, however, about the,choice of diltiazem as opposed to a p blocker. Dr. Schroeder: Because the patient is basically healthy, and if he became impotent because of /3 blockade, I would also have created another disease. Diltiazem is very well tolerated. Dr. Kennedy: I absolutely agree with the perspectives of Drs. Pepine and Parmley, but I want to come back to this because as with the arrhythmia issue, we are discovering a phenomenon and instituting therapy with no idea of what the therapy is doing. To institute a calcium channel blocker in the belief that it will decrease ischemia is absolutely correct. But, just as we discovered about proarrhythmic effect, we have no idea now of what the treadmill is going to be. If we start anti-ischemic therapy, let’s look at the results of it. I agree that we must try to modify mortality and Imorbidity. We hope to do that and to stop infarction. 1411of us know that this is a progressive disease. We are all thinking that we have to do coronary angiography at the appropriate time and try to prevent infarction. But we don’t know if therapy creates a proischemic effect. So, we have to examine whether or not therapy had any benefit. Dr. Parmley: I think the proarrhythmic effect of the antiarrhythmic drugs is pretty standard at lo%, or maybe more. A proangina effect of antianginal agents-for instance, reflex tachycardia-is occasionally seen with drugs like nifedipine, but it’s extraordinarily uncommon. So I don’t think a repeat treadmill is necessary to rule out a proangina or proischemia effect, but I do agree with the notion of trying to assess therapeutic efficacy. A repeat treadmill showing that the ST depression was 0.5 mm more or less would not necessarily influence clinical management. Dr. Kennedy: Let’s quantitate this. If the initial dosage of diltiazem has no anti-ischemic effect, I would increase the dose to 90 mg every 8 hours, and then higher. If there was less ST-segment depression in fewer leads, I would try to determine what constitutes anti-ischemic effectiveness. There is tremendous analogy to what we know about arrhythmias: the same variability factors, and the same applications. This is all new knowledge and we can’t skip over it. Dr. Pepine: I agree with your concept. There is no question that we ought to be looking at the potential for risk, but I don’t like the idea of equating ischemia with arrhythmias. First of all, we have good drugs for ischemia, which are very unlikely to increase ischemia. Our drugs for arrhythmias are very poor and can cause a 10% or more incidence of proarrhythmia in patients who need therapy the most. No one feels that a little ischemia is good, but all of us have inconsequential premature ventricular contractions while we are sitting here. So the 2 are not alike. This patient reminds me not so much of a coronary bypass case, but of what we see every day with angioplasty. This patient with multivessel disease had angioplasty last year, and that’s what his treadmill looks like now. So, Dr. Epstein, without all of the compounding influences and
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the reduction in the risk/benefit ratio provided by previous bypass surgery, would you feel differently about how far you would go with this patient, compressing time to months instead of years, and given this exercise test? Dr. Epstein: I would completely agree with the implications. I would treat this patient totally differently from the way I would treat a post-CABG patient. Given the recurrence of profound ST-segment depression, I would repeat the angiogram and I would consider repeating percutaneous transluminal coronary angioplasty. Dr. Amsterdam: I think the treadmill is reliable in this post-CABG patient because, after surgery, he apparently returned to a normal baseline on the treadmill. So the compound variables may not be there. If a negative treadmill later becomes positive, it is highly unlikely to be a false positive. So, a negative treadmill followed by a positive one means ischemia has been reestablished. The patient’s heart rate was tremendous-it looked like it was in the 160s or higher. At what heart rate did it become positive? To me, the heart rate at which the patient initially became ischemic is more important than the number of millimeters of ST depression at maximum. Dr. Schroeder: It looks like 1 mm of ST depression at a heart rate of 111 beats/min and about 2 mm at 128 beats/min. Dr. Amsterdam: That’s low heart rate, so I would take a different viewpoint. I definitely would do a thallium scan to determine the extent of myocardial involvement and provide a much greater perspective than the treadmill. This doesn’t mean I’ll necessarily do an angiogram. Once the thallium is done, I can make my next move. If the person is positive at a low rate and has a drop in blood pressure, this is a bad response. A drop in blood pressure is a very unusual finding. Most high-risk patients are high risk based on ischemia at a low heart rate, without a drop in blood pressure. It’s an extremely unusual finding and is not necessarily a key tip-off. Its predictive accuracy is very good, but its sensitivity is minuscule. Dr. Krucoff: I, too, would take this gentleman back to the catheterization lab for several reasons. First, since the ST changes are in similar leads, we know he is post-CABG, and his anatomy is clearly not the same as was visualized initially. Second, in a post-CABG patient, which is an increasingly common subgroup, there is at least the potential to intervene with angioplasty revascularization in a partially protected scenario. There may be a compromised rather than an occluded graft, and you may be able to work on a native vessel with some distal circulation, despite what’s being done through that graft. Given that there has been such a clear change in this patient’s ischemic activity, waiting until he again becomes high-risk may force a second operation or render the patient intractable to medical therapy. Now may be exactly when you could intervene in a semiprotected environment and help him with angioplasty. Dr. Cohn: Suppose this man presented again with the same exact story, good ejection fraction and so forth, same exercise response, same catheterization
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data, except that it is 1987, and the medical vs surgical longevity for 3-vessel disease with left ventricular function is pretty similar. What would your inclination be now? Dr. Schroeder: I think it would be the same, just because it is my bias that these patients, even though there may not be a difference in mortality, are still at high risk for infarction or other type of cardiac event that may not result in death, but can cause disability. Dr. Epstein: I admit that we don’t have very good longevity data, aside from Erikssen’s study in totally asymptomatic people, so are forced to make clinical decisions with incomplete information. If a person has significant ST-segment depression-and I would do a gated blood pool study to confirm that there is inducible ischemia-in the presence of S-vessel disease, I would consider that patient to be at high risk of death and would recommend revascularization . . . even in the absence of symptoms. Dr. Cohn: If the patient fell into a high-risk group, with profound ST-segment depression and profound ejection fraction on exercise, you would consider this man bypassable in 1987? Dr. Epstein: Absolutely, but I disagree slightly with Dr. Krucoff. If angioplasty is done, 3% to 5% of these patients-even those with l- or 2-vessel disease-run into trouble that necessitates an urgent bypass operation. Dr. Krucoffi Except that he may be in a more protected group. If he has a graft to distal circulation, you work on a native vessel. Dr. Epstein: I’m just saying that it’s a different risk situation. Perhaps I’m intrinsically a little more conservative but have a higher threshold in doing invasive therapeutics in a patient who has already had bypass surgery, because of the higher risk if problems develop. Dr. Hollenberg: What about the recovery phase? Dr. Horwitz: I agree that looking for a drop in blood pressure frequently is unrewarding. I think that you shouldn’t lose sight of the point that Dr. Pepine made. This man has superb exercise capacity. At whatever level he’s beginning to develop ischemia, the most disturbing thing is that there is a change. We should get the maximum amount of information about that change. It would also seem that this patient is an ideal candidate for a Holter monitor. For example, ambulatory electrocardiography showing multiple persistent episodes of silent ischemia signifies the need for aggressive intervention. If there was nothing-no arrhythmia and no ischemia-I think you’d feel a little better about it. I don’t think that this man on a gated is going to suddenly deteriorate at a moderate load...not with the kind of exercise performance he is showing on this test. He’s not a high-risk exercise test. But I think what we are all trying to do is to pick the point at which we may intervene. The patient is beginning to show signs that his initial therapy hasn’t been very good. He is still probably not at an enormous risk. But, the maximum information you can get would be helpful so, since symptoms can’t help you, perhaps a Holter could.
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Dr. Hollenberg: I can’t let this discussion go without commenting on exercise testing. We need a quantifiable, reproducible test. We have ignored many variables in this exercise test, that is, his ST changes occur late so he has late evolutionary changes, and they resolve fairly quickly. These are all hallmarks of mild involvement. We also know that his exercise duration is quite excellent. Sure, the patient gets ST depression at 13 minutes of exercise, but by 2 minutes of recovery, he is almost back to normal. So I think you have to quantify the changes that occur in evolution and resolution, and, in fact, we have a treadmill exercise score that quantifies all of these variables. I have found that a very reproducible, quantifiable exercise test can identify either significant graft occlusion or new lesions in the native vasculature in many patients. So, a quantifiable reproducible exercise test is a very helpful technique to follow post-CABG patients. It also is a very subjective test; the patient stops at variable endpoints according to how he feels that day, and it is very hard to quantify him, unless one uses all these complex features. To still look at this the way we read exercise tests 20 years ago is really a little simplistic, and I think we are shortchanging the information that we do gain with the exercise test.
Case 4: The Postmyocardial Infarction Patient A 69-year-old man had an inferior MI and was treated with intravenous streptokinase. Recovery was uneventful. Because stenosis was not severe, angioplasty or CABG was considered unnecessary. The patient, who had very few risk factors, remained asymptomatic during treatment with diltiazem and aspirin. Several months after MI, repeat treadmill testing showed evidence of lateral wall ischemia, despite good functional capacity and no chest pain. The resting electrocardiogram showed a small inferior MI, and there were small Q waves between leads III and aVF. But during exercise, it appeared that this inferolateral area was still in jeopardy. Recovery at 3 minutes showed significant ST depression. Because the patient was asymptomatic, the dosage of calcium blocker was reduced despite the marked ST depression, The patient returned 6 months later feeling better than ever, still asymptomatic. A repeat treadmill looked about the same, and functional capacity was normal. There was residual evidence of an old inferior MI, with ST depression at stage 3. Exercise was stopped at stage 6 of the Bruce protocol and a heart rate of 150 beats/min. Marked ST depression subsided rapidly.
Group Discussion Dr. Schroeder: Again, the question is what to do for this patient. Dr. Pepine: What was angiographic anatomy after the infarct?
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
61
47F
Dr. Schroeder: The patient had about a 50% midright lesion and a normal left system. So, he was felt not to require angioplasty. Dr. Pepine: This is becoming more common in our postrevascularization patients, where we see much less than 50% narrowing in the revascularized vessel or in the reperfused vessel, with a very abnormal exercise response. I attribute some of this to the abnormal resting electrocardiogram, with those T-wave inversions. However, I don’t think this is the whole picture. I can’t attribute it all to a gross underestimate of the significance of the stenosis from the coronary arteriogram. I don’t know what it means prognostically. I probably would have treated this patient with a Qwave infarction with a fi blocker, and I don’t know that I would have done anything differently, Dr. Schroeder, than you have. Dr. Parmley: This is more than a year postinfarction at this point? Dr. Schroeder: It is now about a year postinfarction. Dr. Parmley: So, the patient has gone through the “high-risk period,” i.e., he hasn’t died in the first 6 weeks, 3 months or 6 months. He has documented coronary artery disease, which was only right coronary artery disease 1 year ago. This is really a difficult case to become overly aggressive with at the moment, with superb exercise tolerance despite the ischemia shown there. In the absence of any other data, I am not sure that I would recatheterize the man at this point. I would probably err on the side of conservatism. Dr. Schroeder: Should I increase his diltiazem, or decrease it? The dosage was decreased because the patient had no pain on the treadmill. However, I am not sure it made much difference. He is on 60 mg 3 times a day. Dr. Parmley: That is a reasonable dose, although not a maximum dose, so I am not sure I would be persuaded necessarily to push at this point. Dr. Krucoff: I would pursue this patient at least with a thallium scan or similar to look at the actual anatomic perfusion defect. If there is none, I think I would use his symptom-free, high functional capacity status to keep withdrawing diltiazem. If, on the other hand, there was a clear-cut defect, I would more strongly consider angiography. Clearly, in 3 or 6 months people can evolve very malignant stenoses in what initially looked insignificant. If the thallium scan revealed a focal defect, I would probably arrange for catheterization.
Participating Investigators Ezra A. Amsterdam, MD, Lewis Becker, MD, Peter F. Cohn, MD, Stephen E. Epstein, MD, Milton Hollenberg, MD, Lawrence D. Horwitz, MD, Harold L. Kennedy, MD, MPH, Mitchell Krucoff, MD, Joel Kupersmith, MD, William W. Parmley, MD, and Carl J. Pepine, MD.