ST Elevation Myocardial Infarction

From the 10th Biennial IAGS Meeting (January 25–31, 2009) South Africa ST Elevation Myocardial Infarction I Speakers: Howard Cohen, Michael Mooney Moderator: William O’Neill Panelists: George Vetrovec, Adam Greenbaum, Tim Fischell INTRODUCTION William O’Neill, MD: We are going to go ahead and shift focus a little bit. I was thinking this morning that one of the great things about this meeting is that sometimes you can get an “ah ha” moment or an insight and I got that yesterday when I was listening to Bonnie (Weiner) speak about messaging. If you take a look at the kind of panoplies of data available for coronary intervention there are probably controversies, which may be a modest word to use, as to whether or not there is actually any role for angioplasty in stable coronary artery disease. We know that it relieves symptoms as there is an abundance of data for that. A recently published article from the cost benefit analysis, quality of life analysis from COURAGE and New England Journal recently suggested that quality of life was improved for the first 2 years and then by year 3 there is no difference in the quality of life between angioplasty and medical therapy for mildly symptomatic or asymptomatic patients. So there is just an enormous amount of controversy about what the actual role is in the treatment of stable coronary disease. Conversely there is no controversy about the use of angioplasty in acute ischemic syndromes and acute infarction and I think at least in the U.S. the dominant reperfusion strategy now is percutaneous intervention for acute infarction. There is overwhelming evidence that there is enormous benefit for PCI in unstable angina. So, what I am thinking is that we really have to play to our strength. The message Bonnie is emphasizing is that angioplasty saves lives but it saves them in acute infarct and acute coronary syndrome and I think that we can try to get that message out a little bit better. So, the next two sessions are going to focus on specific aspects of that message. The area that we are going to be talking about in our first segment on myocardial infarction is the high-risk patient and how to minimize myocyte injuries. Left Ventricular Support and Hemodynamic Support Howard Cohen, MD Lenox Hill Heart & Vascular Institute, New York, New York Thanks Bill. Really again I want to add my thanks to Kirk Garratt and Gary Roubin for organizing the meeting and Tom Mabin thank you for being the local host. Tom is a modest guy. He did not mention this earlier this morning, but I think he and his colleagues when he was at Mayo Clinic really wrote the seminal paper about thrombus being a marker for poor outcomes in acute myocardial infarction. This idea has really held up to this day and we are going to hear more about that in the next session. My role here is to talk about the role of LV unloading or venting and hemodynamic support to enhance outcomes. I am going to stick to what I was told to do and limit my presentation to only five slides. I hope this presentation will provoke you and create some discussion. It is really for me a thrill to be here among some colleagues who have really been the pioneers in acute infarction. Bill O’Neill certainly has set the watermark high in that regard. Furthermore the contributions of Cindy Grines have been fantastic. Bill French, who unfortunately could not be here, spent a good part of his professional career defining acute myocardial infarction outcomes working with the NRMI Registry. Finally, Mike Mooney is making a major contribution in the care of acute MI patients as you are going to hear today. So with that introduction, I want you to remember one thing as I continue: 50% of the final infarct size, at least in the experimental model, is caused by reperfusion injury. What we are trying to do with acute intervention obviously is to restore the patency of the vessel, improve the flow, improve perfusion and function and ultimately enhance survival. I think we do a great job of improving patency and TIMI III flow, but with perfusion and function we do less well, and many times less well than we think we do based on the TIMI III flow. We have improved. Survival after acute MI has definitely improved, but I believe that we can we do even better. These are my disclosures [Dr. Cohen is a consultant to and holds stock options in Cardiac Assist] and they are important in terms of my discussion here. First, it is important to state that acute reperfusion or acute restoration of flow doesn’t necessarily mean that we have improvement in microvascular flow. I have a case description that provides a nice example of this. The patient was a 33-year-old gentleman who presented within 3 hours of his acute MI. He had hyper acute T waves, and he didn’t even have ST elevation. On his angiogram, we could see high grade stenosis in the left anterior descending coronary artery. We performed PCI and stenting and the excellent angiographic result showed TIMI III flow. Next, and this happens all too often, on his MRI we could see great TIMI flow but poor function with late hyper enhancement of the whole anterior wall and apex indicating a lack of viability. So even though we have restored TIMI III flow, the epicardial flow, microvascular flow is severely impaired. Now I am going to move to some basic animal studies and try to provoke you and see if there is a way in which we might improve this scenario and improve long term outcomes for our patients. A model of a pig infarct helps to make my next point. A big difference is evident at the microvascular level when you compare methods of restoring flow. When you look at a histological example, epicardial flow and endocardial flow in the red are reduced to 60% of baseline with an infarct. When a sample is examined in pigs in which a balloon pump or left heart bypass were used it helps illustrate that we have no problem restoring epicardial flow with either a balloon pump or left heart bypass but what happens to endocardial flow or the microvascular perfusion is altogether different. With a balloon pump we don’t do much better than baseline, but with left heart bypass we have a restoration of microvascular flow. One explanation for this is that the reperfusion pressure across the myocardium is increased because mean arterial pressure is increased and left ventricular filling pressure is decreased. A canine infarct model also teaches us a good deal. We’ve looked at two canine infarct studies from the same investigators four years apart, specifically LA-FA (left atrial to femoral artery) bypass and how effective it is in reducing experimental acute infarction. When measuring the area of infarction as a percent of the LV, a marked reduction in the infarct size as a percent of the LV is evident. The area of infarct compared to the area at risk is also markedly decreased. With LA-FA bypass there is unloading of the left ventricle and the tension time index as a measure of oxygen consumption is also markedly decreased. Finally the survival of the animals is markedly improved with LA-FA bypass. If you reperfuse the myocardium in this animal model you reduce infarct size by 47%. If you unload the ventricle surgically by creating a bypass from the LA to the FA you reduce infarct size to 18% of the area at risk. The fourth bar is a percutaneous approach the to LA-FA bypass. What I’d really like to emphasize is unloading of the left ventricle. If you unload the left ventricle you markedly reduce the size compared to reperfusion alone. My next example concerns infarct size in the ovine animal model and the effect of unloading using the Impella device. In general, the more you unload the smaller the infarction. Using this model it is evident that the earlier you provide support, the smaller the infarct. This confirms the same kind of thing that we saw with the dog model. Also It confirms that unloading of the left ventricle improves microvascular flow as shown in the porcine studies also presented to you. So what we have now proposed is the TRIS Trial or the TandemHeart To Reduce Infarct Size. This is expansion of the paradigm of lowest possible door to balloon time or perhaps even a shifting of the paradigm depending on outcomes. We are planning to do a single center safety and feasibility trial in five patients. The plan to do LA-FA bypass prior to reperfusion in five patients with anterior MI in the absence of shock. After each patient we will report to the DSMB and to the IRB as to the immediate outcome. Instead of reperfusing first we are going to place the TandemHeart first and we expect that is going to take 15-30 minutes to do that in the acute setting. Following that we are going to reperfuse the myocardium and we are going to look at infarct size at 30 days measured by MRI. We plan to compare these patients with those who are eligible but who don’t want to participate in the study. So we will look at infarct size, and try to match. Obviously there will be some disparities because this is not a randomized controlled trial. We are going to assess the safety and feasibility of this approach. Kirk Garratt is going to be the PI at our institution and David Holmes is going to be the chair of the DSMB. Our ultimate goal is to decrease infarct size. Infarct size reduction should ultimately lead to improved function and ultimately improved survival. In the current healthcare milieu of trying to do something that is cost effective if you could improve ejection fraction from 35% to 45%, a 10% increase, which I believe is a very significant increase, you may not only improve survival, but you might obviate the necessity for a defibrillator and that would be a very cost effective outcome. ----------------------------------------------- Reducing Time to Revascularization Tim Fischell, M.D. Borgess Medical Center, Kalamazoo, Michigan Disclosure I want to make the disclosure that I am a co-founder of Angel Medical Systems and one of the inventors of this technology. The basic concept of this device gets away from some of the controversial issues related to myocardial salvage. This device is intended to reduce the time from vessel occlusion to revascularization. This is all about time, and I don’t think there is anyone in this room who doesn’t understand the concept of time is muscle, and that if you could somehow get a balloon down the vessel at less than 60 min. after the onset of an infarct, or maybe even hours or days before the full blown (STEMI) infarct actually happens, that the infarct would be smaller, or even prevented completely. We have been working for about 6–7 years on this concept of an implantable ischemia and heart attack detection system that allows real-time, 24/7 intracardiac monitoring of ST segments, using yourself as your own control. It looks encouraging. We have recently completed the phase I trial. I will talk very briefly about that. This device is implanted just like a pacemaker, with an RV apical electrode. It records an intracardiac electrogram and it is looking at your ST segment 24/7. The computer in the device is looking for a change in your ST segment compared to where you were yesterday (Figure 1, Device). It has two different alerts; an “emergency alert,” for potentially life-threatening events, and a “call your doctor alert,” for less life-threatening events. The device buzzes like a cell phone vibrator. If you have an event that looks like a heart attack it will go buzz, buzz, buzz in a recognizable pattern. The next generation downloads to a cellular unit that will go cellular into an Onstar-like network and you will get a call back within in 90 sec. of starting an ST elevation MI. If you have something like a high heart alert or low heart rate or some other less urgent event you will get what is called a “call your physician alert”, which is one brief buzz every eight seconds. We did some preliminary clinical testing of the concept at Borgess Medical Center about 5 years ago. We used a temporary pacemaker, in the RV apex during balloon inflations during PCI. We compared the apical lead electrogram and the surface lead, which is a modified V6 lead, during a balloon inflation in a human LAD. The intracardiac lead was about three times more sensitive than a surface lead and even more than a 12 lead. We found that the RV apical lead was very sensitive to vessel occlusion in all three native beds (LAD, LCX and RCA). We followed this human feasibility study with an animal study, by putting copper stents in a pig’s coronary artery, We then implanted this AngelMed Guardian device in ambulatory animals. We stopped the aspirin and Plavix. As you might imagine, with a copper stent in the coronary and with no antiplatelet medications one sees vessel occlusion from stent thrombosis within 24-48 hours. In the Figure (Figure 2) we see the electrogram after the lead was healed for a couple of days. On the morning after stopping antiplatelet medications the pig had a call your doctor alert for ST depression. About 12 hours later the pig thrombosed the stent and has a massive ST elevation event, and gets an emergency alarm. During the next hour the pig began to have what looked like some reperfusion with some resolution of the ST elevation. We then see R on T events, which appear to trigger VF, followed by flat line and death. So we have ST depression, followed later by ST elevation, probable spontaneous reperfusion, R on T, leading to VF and then death. This is probably a reasonable reproduction of the natural history of what happens in our patients who rupture a plaque and thrombose a major coronary artery. With this device I believe that we will have the opportunity to record these types of events in patients, as we already have in the Phase 1 part of our trial. We have implanted this device in 37 patients in the Phase 1 trial; 17 in Brazil, and 20 in the US. We have had 5 or 6 events that appear to be plaque ruptures with STEMI or aborted infarcts with this device acting as a plaque rupture detector. The next Figure (Figure 3) shows one of the cases from Borgess Medical Center. The patient had chest pain at about two o’clock in the morning. An emergency alert went off. You can see the baseline electrogram, and the electrogram that set off the emergency alert. She called 911 and the paramedics arrived within about 20 minutes. At the time that the paramedics arrived the 12 lead really is pretty unremarkable; at a time that the device has already diagnosed an acute MI and set off an emergency alert. Twenty minutes later the patient arrived at the emergency room. At that time there was substantial ST depression posteriorly, consistent with a true posterior MI, as well as ST elevation inferiorly. This patient had undergone coronary angiography in September 2007, with evidence of a 30-40% lesion in the proximal left circumflex. When she arrived with this acute event 9 months later, she was brought to the cath lab within about 20 min. after ER arrival, and she has a hazy 80-90% obstructive lesion in the proximal portion of the left circumflex. She was treated with a stent and did well, with a minimal infarction. We have had at least four other events where we have actually picked up ST elevation events that then resolved within 5–15 minutes after the emergency alert was triggered by acute ST shift. In one case the patient came in to the hospital, troponin negative, and ECG negative. She was admitted and put on heparin and Plavix and then had three more ST elevation events that were not picked up in 12 lead ECG, but triggered emergency alerts. In this case the patient was then brought to the cath lab and had IVUS evidence of a (new) severe lesion with plaque rupture. Although there has been a lot of important work focusing on “door to balloon” times, we believe that this device may for the first time allow us to address the need of improving the historically difficult issue of “symptom to door time.” This measure has not really improved, despite educational efforts over the last 10 years (still at ~3 hours). What if we could change that +3 hour delay in treatment of STEMI to to a -3 hours; i.e., to get these people in, hours or even a day or two day before they are actually going to have their ST elevation infarct? We might then be able to identify and stent the “culprit” lesion and send them home the next morning a day or two before they would have had a MI, VF and death. That is really the concept. The ALERTS trial has now started in the U.S. It is the pivotal US trial. We are going to have ~35 sites with ~1,000 “high risk” CAD patients. So this is a real device. It is really working, and I believe that this represents a new approach to vulnerable plaque detection and the very early intervention in patients with coronary thrombosis. We hope that this approach may eventually impact the prognosis for high-risk patients. ----------------------------------------------- Check back for a summary of the talk given by Mike Mooney and the discussions that were a part of this session. Metabolic Support to Minimize Myocyte Death: Systemic Hypothermia and Super saturate Oxygen Michael Mooney, MD Discussion