controlled trial, drug X suppressed more silent ischemic episodes than placebo, what is the minimum duration of silent ischemia on Holter monitoring

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Earl Holland
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1 107 DISCUSSION - 2 Dr. Moore: Why do you think we have ST depressions without any coronary artery disease? Do you think that these are some patients that actually have ischemia where you cannot easily detect it with radionucleotide studies? Why do we have false negative and positive ST depressions? Dr. Kennedy: Dr. Pitt was defining the syndrome X and I keep saying how can I see 5000 coronary artery disease patients coming through our cath lab and no diagnosis of syndrome X in my cath lab. That is because my patients come in, they have chest pain, or they may have a positive ST segment change on their exercise test or on their Holter or any ECG parameter, but their coronary anatomy is normal. We physicians aren't too sensitized to that. Now what percent of the population that is I expect to be small. It is in abnormality of the capillary bed or of the subendocardial layer and I actually think that also occurs somewhat in hypertrophy, but to my knowledge this has not been studied extensively in LVH. Now that accounts for some of the ST false positives. I also know that autonomic changes may affect flow. That interaction of autonomic change and flow reserve has to be looked at. In addition, having an interest in arrhythmia we are all aware that electrolytes change repolarization and so electrolyte imbalance can also alter that. Those are the things we know about. There are probably a lot of things we don't know as well. Dr. Pitt: On the patient you propose who had a negative radionucleotide test and a positive ECG, I think to my knowledge that is a false positive and probably is due to some repolarization electrolyte changes and I think there is lots of evidence for that. I think a positive exercise ECG and normal anatomy, for the most part do very well and I think that if there isn't some other evidence of ischemia, I really don't think that one can call these people ischemic even though they had ischemic ECG changes and I think they are true false positives. Dr. Moore: Do you think it would be useful in these patients who have ST segment changes with no angina to do signal averaging? This is a technique that has received a lot of recognition recently where you can do signal averaging and look at the presence of low level late potentials. This is a non-invasive, very cheap procedure to do. It does predict patients who are going to have VT. It does a pretty good job of predicting those. How useful do you really think signal averaging and identifying late potentials are? Dr. Kennedy: I have been trying to do that for 6 months. Have you tried to do that in a cath lab. Everything has to be grounded, you have to get the balloons in the right place. This is awkward technically right now and now that we have our signal averaging machines that are isolated form electrical sources, they are more portable. We have been working with 12 lead ECG signal averaging and so from that point of view, I think it may offer promise, but we are in an early stage of that. I am looking at that. Dr. Morganroth: Let's say that I was going to want to study drug X in silent ischemia and I wanted to see if in a placebo

2 108 controlled trial, drug X suppressed more silent ischemic episodes than placebo, what is the minimum duration of silent ischemia on Holter monitoring necessary to enter such a patient into that trial remembering the variability issue? Should that trial use exercise testing in addition to Holter monitoring or is just Holter monitoring alone sufficient? Should one have a radionuclide test to back up what that ST segment depression might mean on Holter monitoring on exercise testing. Let's assume the study population is the asymptomatic post-infarction patient. I know that there is no data to be certain of each of those. Dr. Kennedy: Let's go to the last question first. Let's decide if we are going to accept the fact that in a post-mi patient on Holter, that the ST segment change we see is most likely representative of ischemia. As a matter of fact, on our Holter request form that we now employ, when one does a Holter, they have to establish if there is documented evidence of a myocardial infarction on every Holter request we actually have a copy of the 12 lead ECG now to help us in that diagnosis. Number one, I don't feel in that pre-test likelihood I need a second sequential test. If it was an asymptomatic person I would, but this is a person who you know. Dr. Morganroth: So no radionuclide first? Dr. Kennedy: No. My post-test likelihood that that represents ischemia from the data of my colleagues gives me assurance that most likely it does. Second question, what is the minimal amount of episodes that one needs to require to establish measures of variability? I know Andrew Selwyn presently is investigating that issue. Shlomo Stern submitted a manuscript on variability and these issues are just now being addressed. The early studies that were done by Drs. Selwyn, Deanfield and Stern have looked at when they take a population, examine the electrocardiographic abnormality, they have required a minimal of so many episodes per week. Most of the studies have been a minimal of 5 episodes per week. That does not answer your question. It has not been definitively answered. Dr. Morganroth: I was convinced that the variability data shown for select ischemia was identical to arrhythmias. An 80% or greater suppression in the silent ischemic episodes suggests a therapeutic effect rather than spontaneous variability. Dr. Kennedy: I am a little concerned about that because if they did that study exactly like taking the patients off all their drugs, putting the electrodes in exactly the right place, I am wondering about the selection biases. You have to realize that we have to define that in the variability. Given that, and you and I see all the difficulties there, we are going to do that work and it is going to be defined. If patients do not have exercised induced situations, why put on a Holter? In other words the implication is that potentially inducible ischemia must be there before one sees spontaneous. The implication is that doing an exercise test if it was negative, you would not see spontaneous episodes. I don't know how true that is over all populations. I think that is another question that has to be defined.

3 100 Dr. Morganroth: Don, would you do the exercise test as well as a Holter monitor? Dr. Weiner: My bias is if you do propose a new drug trial, I think the exercise test is a standard method of assessing new drugs, and there may be different mechanisms involved in 5T depression during exercise than during ambulatory monitoring. I think that both procedures are important and I think that both may tell us different things. I think that new drugs should be evaluated to determine whether they lessen both ischemia during exercise testing and during ambulatory monitoring. They mayor may not do both and that would be my approach to do both tests. Dr. Moore: So what you are basically saying is that it is not basically worthwhile. A patient that is going in for his annual physical after 50 years old, they want to do an exercise stress test on you, but if a 12 lead ECG has no indication that you need it, then perhaps you are just wasting that patient's money. Dr. Kennedy: I don't think ambulatory ECG's should be employed as the primary ECG test for silent ischemia at this point. I feel that it should be an exercise test. I have concerns that the exercise test is showing me potentially inducible ischemia, but I am going on some data and it needs to be studied some more, that most commonly, spontaneous occurring events will not occur in the absence of the potentially inducible. I feel that we investigators have to assure and verify this in larger and broader population groups, but I feel that the exercise test should be the primary ECG mode of looking for ischemia. Dr. Cohn: I would like to make a comment that in terms of syndrome X while it is of interest academically, I think we should be aware of the fact that the survival within syndrome X is almost the same as in normal individuals. I don't think it is a topic aside from our academic interest that should concern us too much in this kind of setting. Whatever is wrong with these particular individuals and why they have these electrocardiographic changes, it doesn't seem to affect their life span without obstructive disease to the large coronaries. Dr. Pitt: I think that is certainly true. They have an excellent life span. The only reason for bringing it up is that the true sensitivity of thallium is probably much greater than we think because some of those so-called false positive really have ischemia and the prognosis in the patient who has ischemia and normal coronary arteries is very different than the prognosis in the patient who has ischemia and a significant coronary artery lesion. That doesn't mean that the patient with normal coronary arteries doesn't have ischemia and it doesn't mean that it is not important to know because therapeutically. I think it would still have same meaning that that patient probably should be treated to relieve his symptoms and there is specific treatment to do that rather than someone with just atypical chest pain who doesn't have ischemia. Dr. Cohn: If we are talking about silent syndrome X then the question comes up should you be treating someone who doesn't have symptoms for disease, it doesn't affect them. I think it is sort of a red herring, though I think it is obviously an important issue from a physiologic point of view. The question I had for Don Weiner

4 110 was that with the new data he present to Don is actually very similar to the data that has been presented before showing a similar life expectancy and the people without ischemia and with ischemia, except you subdivide and are now looking at MI's and sudden death. The big difference is that in your three vessel disease group, you show data that suggests for the first time as far as I know that the people who have three vessel disease and silent ischemia significantly do worse than those with three vessel disease and angina, which is a very important finding and your numbers I think are adequate enough to make that in the CASS registry, how do you explain this? Dr. Weiner: I don't know. There was a slight difference but surely not approaching statistical significance of event free rate in patients with silent ischemia versus those with angina and symptomatic ischemia but it appears among patients with three vessel disease that there does seem to be a significant difference, very statistically significant and I really can't explain why, because they are matched for the amount of coronary artery disease. I will have to look to see whether the LV function is equal but I suspect it probably will be between the two groups. Dr. Cohn: This is one of the uses that you could see where the Holter might be useful because it is possible that within this group even though the two groups have three vessel disease and positive exercise tests, it is possible that one group actually has more out of hospital ischemia than the other and this is one of the reasons that the Holter can be used for risk stratification and hopefully will be in the future. Dr. Kennedy: I would make a comment about the technology and what is happening here at the end of I just say to many of the practical people treating patients as well as to pharmaceutical companies assessing things that this silent ischemia, we're like we were when we started with arrhythmia, when all the arrhythmias were all mixed together. We got total ischemia mixed together here and we had to sort out non-sustained V-tach and sustained V-tach, we are having the same situation here. We are sorting out potentially inducible ischemia. We are sorting out spontaneously occurring ischemia and then we are going to arrive upon methods that quantitate it hourly and that is the brink of the threshold we are at right now, this past 3 month period. Major technological advances have come where we are going to be able to quantitate reliably episodes of onset, time frames, minutes of duration, and how that quantity occurs in an hour. Once we get this quantitation with a more precise handle on reliability, then we are going to be able to see which of these parameters of ischemia over a 24 hour day are the most predictive. Physicians make observations. After they make observations on an anecdotal or small basis, then they do limited clinical studies and then we get a data pool and then we develop methods to reliably quantitate it and then we learn to apply the methods correctly in a standardized method and then we do clinical trials. I am very happy about the arrhythmia story because I think it is my guideline to what to do about ischemia here. I feel that we are in a stage right now, particularly in the methodology and the understanding and sorting out these forms of

5 111 ischemia that we are at the right place. We don't want to run too quickly. We have to do this middle part of defining technology and studies and concepts. Dr. Weiner: I would like to make also one comment in the next session there is going to be a discussion about drug trials that I would actually like to know from people involved with the FDA would they start to accept end points of ischemic ST depression without angina as an eligibility criteria for admission into a drug trial. Dr. Lipicky: We do now. Dr. Weiner: In all trials? Dr. Lipicky: Certainly, but why do you think we don't yet. Dr. Weiner: It is my impression having done a lot of drug trials in the past few years that the criteria that we have had to accept were patients who had both angina and ST depression during exercise testing is 5 episodes. Dr. Lipicky: Certainly not from our lips. Dr. Weiner: It is good to know that. Dr. Temple: It must depend upon what you are trying to do with it. For the demonstration that the agent has an anti-ischemic effect, then you probably wouldn't, but if you never showed that angina was improved, you wouldn't have a claim for angina. I mean sooner or later, you have to treat angina, according to our guidelines. Isn't that the way it reads? Dr. Wiener: Are there any drugs that are approved for ischemia but not angina? Dr. Lipicky: No, but that certainly is true that if one wants to make a claim for relief of pain, people have to have angina, and if they want to at the same time demonstrate that there is an anti-ischemic effect in the same test, it would be nice to enroll people who have ST segment depression. I understand. If one wants to document an anti-ischemic effect for documentation of the anti-ischemic effect, there is no necessity to have angina as part of the thing that is being measured, never has. Dr. Temple: That is not what they really want to know. They want to know can you get a pure ischemia claim and the answer is that no one has ever asked us for one for starters and it seems to me that we need to discuss whether that is a meaningful claim. Dr. Lipicky: Let's talk about that if that is the question. The question is can people get into a trial who have only ST segment changes the answer is yes. Dr. Temple: They can get into a trial but what will you get out of the trial. What will you have won if you win? Dr. Lipicky: That wasn't the question asked. Dr. Temple: This is going to come up a fair amount tomorrow, but the current guideline is for angina, so that the people who enter into the major effectiveness trials are people with angina. Up until now at least, perhaps that will change, no one has come forward with a claim, we relieve ischemia only, and I'm not going to tell you what we do about chest pain because chest pain doesn't matter, the only important thing is relieving ischemia. That up until now has not been a claim. There was some discussion this morning whether that should be a claim and that is a fair question, but really that hasn't been addressed. The guideline also says

6 112 that to be an anti-anginal agent, you can't just be an analgesic. You have to treat the angina by relieving its cause which is ischemia so you have to show both and there is no particular reason why you couldn't show one in one study and one in the other, so that is what Ray's answer is, I think about the first part. Dr. Lipicky: But really I guess there is more to it than that. If one is looking at the current attitudinal set that goes into the considerations with respect to an anti-anginal agent the set is that it is for symptomatic care and that therefore there needs to be a symptom that would lead to the claim because it is for the symptomatic care. The attitudinal set is such because it isn't clear that there is a benefit or there is no clear demonstration of benefit from anything other than having the symptom treated. Dr. Moore: Ray, if it improves quality of life, is that enough? Dr. Lipicky: Sure. But now, what it also says is that there has to be an anti-ischemic effect and if one is attempting to demonstrate and anti-ischemic effect, to support the claim of having symptomatic benefits in patients with coronary artery disease, than indeed one can enroll patients with ST segment depression only and the measurement of pain becomes a non-significant end point. Dr. Pepine: I would like to carryon where we left off. The guidelines, at least the guidelines I have been presented, have pain right on top, pain and nitroglycerine pill counts. Now the problem that I see in this whole thing is that industry or the scientific community develops these compounds or devices in animals. Animals don't have pain. They all have anti-ischemic properties and we get a wealth of data and we show that these drugs or devices are tremendous anti-ischemic drugs and then we forget and go to the clinic because we are stuck with anti-anginal issues, and then in the clinic in order to comply with variability issues, in the trade we call it FDA angina. We go and screen 100's of patients to get 10 that comply with your requirements, to have enough, less variability, etc. and then we force those poor patients into walking on a treadmill so that their effort tolerance is improved by your primary measurement as timed onset of angina. Then we take all of that and if it applies in a couple of trials, we have our two positive trials and we say, good, anti-anginal issue, but what do we really do. I mean we relieve pain in a small number of people, we really don't know anything about ischemia because we forgot all that information that was dropped along the way because we didn't have a prime area ischemic indication. So that is where we have to change the thinking. I am not blaming you for it, I am not saying you are responsible for perpetuating it. I am saying, let's look at it from a different point of view, from the ischemic point of view. If you look at it from that point of view, pain will fall by the wayside, pain that is related to ischemia will go away. It will disappear. I think that that is where the focus has to be, on the front end of ischemia, not on the pain. Dr. Temple: The trouble is, it seems to me, how would you define the amount of relief in ischemia for example in a trial for example in which there was no pain end point, that represented a meaningful

7 113 improvement for the patient's anginal syndrome. How would you link those two if you didn't study pain? Dr. Pepine: I could use the definition you use for angina, 50% reduction if I wanted to pull one out of the sky, I could use the definition of eliminating all ischemia. I could say we could only eliminate high risk ischemia. Don Weiner gave you a beautiful list of markers of high risk ischemia and other people have done the same thing. We have a lot of fairly objective end points that are much better than a 50% reduction in angina. Dr. Temple: Are you arguing that these would be perfectly suitable ways of knowing that the drug is anti-anginal or are you saying that we now know that we will improve the survival of these people. Dr. Pepine: I didn't say either one of those two. Dr. Temple: Then why are we doing this? Dr. Pepine: We would know that the drug was anti-ischemia. I say that before you get to first base in ischemic heart disease, you have to have an anti-ischemic agent, like you have to have an anti-hypertensive agent or an antiarrhythmic agent, or you can't go anywhere. We wouldn't have gone anywhere if we had had an anti-headache agent to treat blood pressure and that is what we are doing. We have anti-chest pain agents and in most of those patients we don't know whether or not they have ischemic heart disease. Dr. Temple: The current standards anyway, and this has been emphasized by the re-write of them, is that the treatment of angina is supposed to be with agents that relieve ischemia. So you measure the effect on the anginal syndrome, principally by exercise testing, I should say, not by anginal counts anymore, and simultaneously show that you have improved ischemia. So it is not that the second of those end points is being missed. What is true is at the moment at least, we have not accepted, and have not been asked to accept the claim that didn't come with some evidence that the anginal syndrome, the pain itself was not relieved and we got a very strong message from the advisory committee that for an anginal drug, you need to improve pain. They thought it was an entirely separate question as to whether one might have a drug which was intended to treat ischemia independent whether it had any relationship to angina and the discussion this morning focused to some extent on why you would want to do that exactly. What were you think you were doing when you did that? Would you be improving survival? Would you be relieving the transient periods of abnormal ventricular function that may have some impact or what would you be doing when you did that and how would you lay those effects which you have never measured or known off against the side effects of these drugs which they all have. For what it is worth, it seems to me that when you don't know what your ultimate effect is, when you are not relieving something that is bothering the patient or altering his survival, you don't really know how to deal with questions of small changes in lipids and all those kinds of things. To me the treatment of hypertension indicates some degree of caution. We don't know why most hypertension studies have not shown improvement in the coronary artery disease end points, but it

8 114 seems like one possibility at least is that the effect is rather small and is overcome by some of the abnormal effects on lipids or potassium or who knows what, that some of the anti-hypertensive drugs give you. If you are looking here at changes that you can't measure, haven't really measured yet, it seems to me you are in a very difficult position as to whether you are having a favorable impact on such things as survival which must be the main reason for treating silent and non-symptomatic ischemia.

Section 4 Decision-making

Section 4 Decision-making Decision-making : Decision-making Summary Conversations about treatments Participants were asked to describe the conversation that they had with the clinician about treatment at diagnosis. The most common