Cardiovascular Drugs and Therapy 2: 149-153, 1988 © Kluwer Academic Publishers. Printed in the U.S.A.

SUMMARYOFORALPRESENTATIONS

Paul S. Hugenholtz

t is with some trepidation that I am looking forward to what I am going to do in the next 15 or 20 minutes, because to try to summarize an excellent two days and to do justice to each of the speakers will clearly be impossible. I hope the speakers will forgive me if I don't mention all they have said, since I'll emphasize what I thought were the highlights. At the outset, I should give you a brief raison d' ~tre why this meeting took place. The firm that makes this excellent drug, which, once in a while, we hear about, felt that it would be appropriate to discuss coronary artery disease (CAD), myocardial ischemia, and infarction in a much wider connotation. I aimed at getting the local color of Munchen and Rotterdam in the sense that Rudolph and I could invite a number of people who could potentially contribute in these areas. Although there were some delays in the timing, we have achieved the original idea, which was to provide this audience, over a 2-day period, access to people who are leaders in their field and to hear what they had to offer. It was a wise choice to begin with Professor Parratt, who emphasized that thrombocyte aggregation leads to lower transit times, increased distal aggregation, with trapping of thrombocytes as microemboli and microclots around the area that we call the ST segment border zone. Recent experiments clearly show that aspirin can counteract this by reducing the release of thromboxane, which enhances the entire process. The second major experimental point of view was the interrelationship between the endothelial relaxing factor (EDRF) and the whole prostacyclin cycle. The hypothesis that all of us in this room should accept is that endothelial damage with loss of the relaxing factor and with disturbances in prostacyclin production leads to hyperaggregation and hyperactivity of the vessel wall, and then everything else follows. Pharmacological firms ought to work on this thromboxaneprostacyclin balance far more intensively than they do at present. Rudolph gave a masterly overview of the strategies that we must employ if we wish to manage the huge clinical volume of stable and unstable angina pectoris. From all sources in the literature, he felt that there are

a number of things that really have been established. The proven benefit of bypass surgery for main stem and three-vessel diseases, particularly when there was identifiable dysfunction of the left ventricle, demands that all these patients should undergo coronary angiography at least when severe coronary artery disease is suspected. The question that remains is, what do we do with the lesser forms of the disease, and what do we do in terms of proving that we do good? The controlled long-term studies with more than one pharmacological agent were, at this point, not all that convincing. Rudolph gave us very important statistics by stating that ultimately only 25% of the total population that we see as stable or unstable angina would end up with just pharmacological treatment, whereas 41% would sooner or later go to bypass surgery and 36% to PTCA. These percentages are important to keep in mind when evaluating patients in practice or hospital. It is also an important message to those who are in the health care field and/or those who must prepare legislation and provide planning. The message that we've been getting in the past, to treat more people medically or pharmacologically, because that would be so efficient, is now really out-of-date. Then we entered deeper into silent ischemia, and it became quite silent indeed. Rutishauser felt that there was perhaps a reservoir of as many as half a million people in Germany right now walking around with sufficient coronary artery disease that they could soon be afflicted with some kind of complication. And then we were talking about males only between 40 and 69 years. The importance of the message is that silent ischemia is not silent, in the sense that there is a serious malfunction in the heart but the patient doesn't perceive it. He pointed out that there are several degrees of silent ischemia that can lead to more or less permanent damage in myocardial function and, in that sense, he completely agrees with what Cohn told us later in the meeting. Some of the data now collected--Eriksson's from Oslo, Rutishauser's from Geneva, and Deanfield's data--in which the ultimate outcome of these asymptomic episodes was studied, show a high complication and death rate in the subsequent years. The possibilities are:

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1. Pain is not there because it does not lead up to the pain threshold, although ischemia takes place 2. Collaterals play a role with intermittent potency: "Then they're there and then they're not there," and 3. Insufficient perception of pain is an important event, possibly related to endorphins. In our questionnaires and in patient interviews, we don't always ask the right questions. Many patients talk about breathlessness and may have increased stiffness and diastolic dysfunction of the left vent r i c l e - a n equivalent of ischemia. The next speaker, Araujo, gave us a very important clue when we suspect an unstable state in the patient in the hospital and discussed how we might discover it. Perhaps it's a rather expensive way to use a P E T machine, to determine whether or not there is disturbed cellular metabolism. If it's true that the abnormal glucose uptake or the improper use of free fatty acids (being replaced by an increased glucose metabolism) predicts reversible ischemia, we will have a major diagnostic tool. This is to me one of the most nebulous areas in all of cardiology. When is the cell still alive and should you go fight for it and when is it doomed to die anyway, so we could avoid unnecessary interventions? When Schaper gave her talk it was suggested that a combination of antimyoglobin with radioactively labeled agents might be used to provide the localization or the density of live cells in apparently "dead" regions. This, of course, is very important research, which will have to be continued before we can assess its true value. Bassenge gave us a review of the basic mechanisms and principles of pharmacological therapy. He stressed the increased power of combined therapy engaging multiple receptors at the same time by virtue of synergism, lower dosing, and reduced side effects. What was new for me was his comment that nitrates and EDRF compete for the same transfer mechanism employing cyclic GMP. Klaus did clearly state, at the end of the first morning, that the best researched drug in terms of toxicology is molsidomine. Given its lack of toxicity in physiologic doses, we can now take it with the greatest confidence. By the same token, all other drugs in this area should either be required to be tested in the same thorough fashion, or we simply take the risk. We cannot say, at this point, that other drugs that are used even more frequently have been equally well researched. He also stated very clearly that it was his view that most other drugs were reasonably well researched so that, from a toxicological point of view, continued long-term pharmacological therapy for cardiac pa-

tients is not to be feared. Whether we know enough about their physiology, of course, is another question, which remains to be answered. Dirschinger attempted to tell us the difference between the effect of dilating drugs on coronary blood vessels and myocardial blood flow. He gave a very fundamental review of the combination of nitrates and molsidomine with nifedipine--they increased myocardial blood flow, both in normal and post-stenotic regions. Other calcium antagonists, such as diltiazem and verapamil, led to a reduction in blood flow in the particular coronary areas that they were studying. The point for me out of this paper was that one should really think through what one wishes to achieve with a given drug, rather than just try any drug in angina pectoris. Swan was very clear in his misgivings about the use or current abuse throughout the world of beta blockade. He gave us a lot of reasons why we should think twice before we give this group of drugs and left us with the challenging statement that in ischemic states it might be good to use it very early on and that, of course, leads to the questions that we all have, "What is early on?", "How long could we wait?", and "What is the right model to study it in?" He distinctly left me with the impression that if unwanted side effects were to be outweighed by clear benefits, a lot more research would be needed. Borchard opened a series of papers on tolerance development. I would summarize that today nobody doubts that tolerance is a problem with nitrates. However, it can readily be overcome by several tricks, such as the one proposed here in Munchen by temporarily interrupting its administration. Still, a drug that wouldn't have this problem such as, it seems so far, molsidomine does, would really be an improvement. Blasini gave us facts why we, indeed, can now trust that long-term molsidomine will give a continuous effect over months. Aptecar found that the majority of patients studied in Argentina already react to a relatively modest dose of molsidomine and also that there was no clear relation between increasing dosage and greater clinical effects. This is somewhat in discrepancy with other observations, but that could be related to the number of patients studied. Lichtlen presented many data that were consistent with what we all should practice. First, that one must think of the pathophysiology of the patient, then of the main or side effect of the drug intended, then of their combined efficacy, and then only should the final decision be made. As Schmutzler showed many years ago, it is the judicious combination of drugs in a given case that is far better than monotherapy. This is very

Summary and Conclusion

disturbing to the authorities. They think that we are polypharmacists and all other sorts of "half" doctors, but I think it is just simply very good pharmacology to try to manipulate several regulatory mechanisms at the same time at doses that cause less side effects. Regardless of future problems, I would encourage those that prescrible to try not to use a fixed dose in every patient. Try, rather, to titrate and, where needed, to add other drugs to achieve your goal. Do not forget that a patient isn't someone whom you send home with a given amount of drug only to forget about him or her. One must retest a patient repeatedly, either by exercise test of by interview or by Holter tape, to see whether we are still achieving the correct benefit. And also, I think this is the main message from Lichtlen, once you decide to go for pharmacological therapy, it should be effective for the full 24-hour period, because it is the silent episode that may do far more damage than you realize. So, if you decide to do it, do it the complete way. Bertel had interesting data. Although his series was rather small, it indicated that molsidomine could be given a place in the resistant or refractory group of patients with unstable angina prior to the decision to revascularize. If confirmed in other series of patients, that will be an interesting field for molsidomine. I have difficulties in conceiving that a vasodilator really can overcome obstruction. For, once there is major obstruction with thrombus, no dilator will work. Schulz gave a very scholarly perception of what we must consider when a patient is not responding to therapy. Unfortunately, frequent problems still involve inadequate dosing or improper selection or classification of the patient. He also argued, I think a bit too strongly, about the paradoxical effects with the "steal" phenomenon, which, to me, certainly cannot be the main explanation for therapy resistance. Rather, I would think it is misdiagnosis first, inadequate doses second, and "steal" very much at the end, that are the likely explanatory factors for failure to respond to therapy. Then we had a classic paper from Kansas City. Dr. Lewis presented one of the strongest bits of evidence of the last decade in terms of large scale multicenter trials, the VA Study and the study from Canada. He showed quite clearly that we have long-term efficacy against recurrent cardiac events when one prescribed aspirin between 51 hours and 8 days (average values) after an episode of unstable angina. My question remains, can we extrapolate these data for secondary prevention to the case of acute unstable angina when we see that patient for the first time? But this as yet unproven thesis will be looked at now in several trials that are underway, such as the ISIS-H, and we hope

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that the hoped-for early efficacy will be borne out. In my view, the best paper of the whole meeting was that of Cohn. He restated clearly what he had written, and it is clear that silent ischemia has really three types. All of us are now willing to accept this classification system. If there really are no signs beforehand in a totally asymptomatic pat_ient, that is type I. Type II patients had a prior infarct, and then something goes wrong on stress testing or the Holter tape, although they're not aware of it. In Type III there is angina preceding a subsequently documented myocardial ischemic episode. Cohn confirmed the figures from Rutishauser. He gave an estimate that in the USA silent ischemia would involve somewhere around 2% to 4% of the totally asymptomatic population, which works out to roughly between two and three million individuals. Furthermore, he said that 10,000 of some 50,000 sudden deaths that occur annually were coming from this group. So if you go after that, one would have a pretty good yield in terms of reducing sudden death. And what was most important in Cohn's talk was when he was asked, "How does one go for it?" He clearly left instructions not to start looking for "needles in the haystack" but rather to go after the patient whom, for some reason, presents himself with increased risk factors, where the family history is positive, and where there is a reason to go look for it. For the rest, it was the exercise test in type II, and we are talking about an exercise test that involves the total body evaluation, blood pressure response, work load, duration of work, time to onset of symptoms, and then, also, the electrocardiogram. I want to once and for all say this, clearly, the electrocardiographic parameters in the exercise test come at the bottom of the list in terms of prognostic information. And that's where all the confusion originates with the so-called "negative" exercise test. I have seen time and time again people who say, "Look at this negative exercise test, nothing to see on the ECG." And I said, "What was his blood pressure?"--"Well he didn't get much above 90." So you know how close the patient was to cardiac dysfunction with his "negative" test. The two papers by Rentrop and myself on the value of PTCA in unstable states came down to more or less the same thing, except that Rentrop had near 100% success rate, while we don't seem to be getting above 80%. He attacks all vessels, whereas our group goes after the culprit vessel and tries to apply the principle of N i l nocere. I suspect his patients are "sicker." Both felt that this procedure is now established and has really deserved its right to stay in our total armamentarium. It indeed will get into the space that Rudolph has allotted to it, 36% of the total.

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Next, a number of speakers dealt with anti-ischemic effects of drugs. Erbel showed during the angioplasty procedure that calcium antagonists have a protective effect on induced ischemia. His final conclusion was that analysis of ischemic tolerance of the heart during PTCA may be an ideal method for evaluating the efficacy of any antianginal drug, and that clearly might be a nice way of comparing activities if PTCA-induced ischemia is indeed a constant phenomenon, which I doubt, given the potential confusing role of collaterals. Meyer is evaluating a long-term follow-up, and I wish him a lot of luck with molsidomine, which seems currently to show a slight positive effect in these patients as a postoperative or postangioplastic protective agent against restenosis. If that were to come about, I think the firm should be very happy, as we would have a solution for a very vexing problem: the 25% to 30% restenosis rate after angioplasty. Even aspirin hasn't shown that much beneficial effect. Schaper gave one of her usual thorough demonstrations of what we need to think of in our own minds when we are dealing with the patient in acute ischemia. It is a fantastic world when I think of all these mitochondria, clumping together with edema in between and contractures coming in there. Those pictures urged me more than an ST segment depression of "silent" episode to do something about these patients. Dr. Martorana confirmed that there are quite different ischemia models and different facts to be learned from the different animals. We cannot really extrapolate the animal data directly to man, and this is an important thing to remember when one listens to such presentations. Then the topic of the usefulness of vasodilation in acute myocardial infarction came. Bussman gave an overview of his experience, and I was pleased that he felt that captopril by now seems to be getting into the lead position ahead of the nitrates. There are many more reasons why it would be the better agent, and I hope that figures finally will come out that show convincingly that early vasodilators can, by timely unloading the heart, limit infarct size in the classic sense of the concept. The improved survival and maintained ventricular function, may be more than just a shift in enzyme release. Tauchert confirmed that tolerance is also a frequent problem, even in the acute situation with short-term dosing. I have never been aware that it could appear so quickly, but I shall think of it next time when we have a nonresponder to intravenous nitrate. Kjekshus, with cool calm, pulled apart many of the collected studies on early and late beta-blockade in and after infarction. I remember the Rome meeting on metoprolol (the MIAMI trial) as a sort of lion's den, in which some recommended the use of this drug early in all patients,

even though the MIAMI data were hardly convincing. The audience then did not believe the proof to be very strong, and ISIS I (the atenolol study) certainly hasn't helped it. On the other hand, we must keep in mind that these studies have been done, people will quote them often out of context, and I would beg you all when you hear such things to consider what is in the small print of the abstract, such as that only 25% of all the patients whom we see with myocardial infarction could be included in these trials. Only a quarter! And then they looked at patients with a control mortality of around 4%. Now these are the patients that you and I would send home without anything. Therefore it's no surprise that the mortality in these giant trials could be reduced only very modestly and that we still do not know what these drugs will do in higher risk patients with 15% to 25% annual mortality. New to me is the fact that ventricular fibrillation apparently is not even an explanation for whatever effect was observed. The final consideration is that you may have to treat something like 1500 patients--many of whom, as Swan will argue, were partially poisoned by these drugs--in order to save one life or 10 myocardial infarctions--hardly a convincing benefit/risk ratio. Kubler was very much to my liking when he was positive about reperfusion strategies, provided they are properly applied. He stressed the time window (in keeping with Schaper and Martorana) and the need for rapidity of interventions and for the proof that we have to demonstrate real benefit and not just patency rates. We have to prove that the infarct size is indeed limited. We have to prove that the function is maintained and that eventually, as a result of all that, we have a dramatic reduction in the death rate. These data and those of the randomized Netherlands study (533 patients) prove this. He also pointed out the role of the collaterals and all the various things that make it so difficult in the individual situation to judge the outcome. De Feyter summarized the total experience in Rotterdam with the role of PTCA in various ischemic syndromes. As long as we can show in 115 patients treated with the combination, usually PTCA following lysis, but sometimes simultaneously, a 2% mortality rate, I dont' think we should argue long as to whether to give lysis before PTCA or PTCA before lysis or the combination directly. It depends entirely on what you see in the angiogram. As long as the community understands that the patient should be given some lytic agent in an existing referral system and come quickly and directly to a center where the proper anatomic diagnosis can then be made. I think we are doing the proper thing. It even makes very little difference what

Summary and Conclusion

the restenosis rate is, as long as we can prove that the infarction is limited and the death rate is low. The Belgian group of Degr~ provided an overview of the various pharmacological therapies we can offer after myocardial infarction. Slama and coworkers from Paris are involved in such a secondary trial with molsidomine, and the hope is, of course, that molsidomine might eventually be beneficial, but one needs a lot more patients before anything can proven. Lamm repeated what we never will forget, namely that risk factor control remains important. Although I disagree with some of his facts, cutting out smoking remains one of the most effective ways of reducing deaths. This, finally, is breaking through in most of our western European communities. But concerning the regression of the arteriosclerotic lesion, there I have big questions. No good proof exists, although hopefully the German-Netherlands INTACT study will help here. Kreuzer reviewed the whole matter of late cardiac failure. From all this and the presentation by Dr. Caralis and Dr. Cantelli, it appears that we have a whole host of drugs, all of which, I think, on good pathophysiological and physiological principles, should work. And they do work, as Sonnenblick has confirmed in the short term. I ~vish that he would stop thinking we can't study drugs in Europe. These substances, inodilators, the inotropic vasodilators, work in the short but not in the long term in all of our centers. What we

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need is proof of their long-term efficacy. Dr. Hall's masterly and scholarly overview of longterm trials was on a somber tone and, perhaps also, shall we say, a bit pessimistic. I would hope that the bottom line is important and understood by the pharmaceutical industry, that we need compounds that improve the sense of well-being and duration of life and not just cardiovascular measurements! And then we ended on an upbeat note with the excellent results here in Germany of cardiac transplantation. Dr. Hetzer related 111 attempts to float "boats" and, of those, 82 boats were not only placed but were kept afloat. With similar data throughout the rest of western Europe, we are now rapidly getting into the act, and I think the few chosen surgeons do it well. While that must remain an extremely small group for whom transplant is indicated, it can yield very impressive results. I end up by wishing to thank several people. The first group we thank on behalf of all of us here is Dr. Rudolph and his staff--Hall, Dirschinger, Blasini, and others--who worked on the selection of abstracts and making the program, with their secretaries who tried to help us by doing their best. Also, on behalf of Dr. Rudolph, I'd like to express my thanks to Dr. Nitz and the group at Cassella Riedel who, with their staff, have been so instrumental in making our 2 days here extremely agreeable.