Our Revolution in Acute Myocardial Infarction
The story of reperfusion in acute myocardial infarction was one of the high points of my career. The thrill of a totally new procedure is like a field of flower buds unfolding: the contents of the buds are unknown but when they open, one has a beautiful new flower. Reperfusion therapy was the new flower in the garden. Through it, myocardial infarction has been conquered, albeit partially, and has opened a new vista in cardiology. Mortality has fallen, infirmity and disability have decreased and life prolonged in patients who suffer from the number one killer in Western society.
A myocardial infarct occurs when one of the arteries (typically the coronary artery) that supplies blood to heart muscle is blocked suddenly. This deprives it of oxygen and the muscle cannot contract, becomes stunned and within two hours it dies. The blockage occurs because cholesterol accumulates in the vessel wall, narrows the lumen, the hillock ruptures, a clot forms and the artery is occluded. This causes disturbances in heart rhythm often with sudden death, or damage to the pump with severe shock and later heart failure. The patient can die, suffer permanent disability or sometimes recover.
This chapter in medicine started in 1954 when Sol Sherry revolutionized the treatment of acute thromboembolic vascular disease by dissolving a causative thrombus (clot) or embolus using the natural, lytic drug, streptokinase. His group treated acute myocardial infarction, pulmonary embolism, thrombophlebitis and peripheral arterial occlusion. But Sherry was uncertain about the effect of lysis in myocardial infarction and stopped his studies. The drug was approved for lysis in other thrombotic states by the FDA in 1977.
Acute myocardial infarction had been treated conventionally by watchful expectancy, usually with three weeks rest in bed. (armchair rest treatment). In 1965 I analyzed its mortality in a general hospital ward at Groote Schuur hospital in Cape Town where we found it to be 34%. Our first revolution was to introduce intensive coronary care with ECG monitoring to control and treat arrhythmias and more personalized care and nursing. In my first coronary intensive care unit, one year later, the mortality dropped dramatically to 14%.
Pathologists have long argued about the pathogenesis (precipitating cause) of myocardial infarction. Was it due to acute thrombotic occlusion of the coronary artery or to sudden coronary spasm which caused long-term ischemia (decreased blood supply) and myocardial necrosis? Peter Rentrop from Göttingen summarized the status in 1977. Autopsy studies in the mid-1960s provided fresh evidence that coronary thrombi were common in acute myocardial infarction and that intimal fissuring of the arterial intima (inner layer) caused both plaque hemorrhage and intraluminal thrombosis. Bill Roberts, the premier pathologist from the NIH, suggested the plaque fissures were artefacts and resulting from sectioning arteries at postmortem, and that coronary thrombosis resulted from a prolonged low output state associated with large infarcts. European investigators continue to explore the possibility of lysis of the thrombus in acute myocardial infarction, although they believed that the lysis time for a coronary thrombus exceeded the time limit of myocardial tolerance from anoxia. They hoped to improve collateral flow (from other coronary arteries) and microcirculation by lysis (dissolving) and opening of the capillaries and venules within and around the infarct zone. The discussion about the pathogenesis of acute myocardial infarction was limited by the inherent selection bias of autopsy studies and the paucity of in vivo and angiographic data.
The great breakthrough came when Marcus de Wood, a surgeon in Spokane, Washington, presented a cohort of patients in 1979 who had undergone coronary artery bypass surgery (to bypass the obstruction) and compared them with a similar group who underwent regular medical therapy. Mortally reduction was dramatic and improved in the patients treated early (hours). Early surgical reperfusion had succeeded.
Rentrop continued his studies of reperfusion in acute myocardial infarction, first using a wire to perforate the thrombus and later controlled dissolution studies with streptokinase. The results were very successful and the clot in the coronary artery was successfully lysed, coronary flow restored and myocardium salvaged. Rentrop then moved to the US and continued his studies in New York. Marc Verstraete from Louvain in Belgium organized working groups in Europe, at first using streptokinase, and used mortality as his endpoint. Initially, the results were indifferent, but gradually improved. Genentech, a new biotech company, cloned tissue plasminogen activator (tPA) which is the natural lytic (dissolving) protein in the blood. It was a superior lytic drug and doubled the reperfusion rates and the clinical results improved further. This aroused excitement in Europe and several centers embarked on large controlled studies.
The new catch phrase in medicine in 1980 was evidence-based medicine. This introduced the second phase of research – randomized double blinded controlled studies - half of the patients were treated with the new drug and the other half received the usual treatment. Peter Sleight from Oxford was the British pioneer (GISSI Trial). Braunwald from Harvard was the other leader and together with Passamani from the NIH set up the first “Thrombolysis in Myocardial Infarction” study. All of their patients with an acute myocardial infarct had an initial coronary arteriogram to demonstrate the narrowing and blockages in the coronary arteries. Then half were given streptokinase and the other half tPA. In patients with occluded arteries the patency rate at 90 minutes was 62% with tPA and 31% with streptokinase. The trailblazing continued:the TIMI studies progressed, and there were large international and national trials in England, Germany, France, Holland and Italy. It now became clear that early treatment within four hours of pain onset, together with adjunctive anticoagulant, antithrombotic therapy and mechanical reperfusion, improved the prognosis.
I heard Rentrop speak for the first time in Oslo in 1979, at a meeting on Timolol, a new beta-blocker drug for high blood pressure, but which was also very effective for glaucoma. He was tall and erect and spoke with a very impressive and forceful voice. He was very convincing and I realized that he had pioneered a new treatment, a real breakthrough in the management of acute myocardial infarction. He had proved that it was possible to lyse the thrombus using a thrombolytic drug. De Wood and his group from Seattle had also just published their paper on the prevalence of total coronary occlusion during the early hours of transmural myocardial infarction in the New England Journal of Medicine: the results were very impressive. It was now clear that 90% of these patients had complete thrombotic occlusion of the culprit artery in the first hour after infarct onset and that there was spontaneous thrombolysis in the following hours.
The obstruction set up a time dependent process of myocardial necrosis in the anoxic zone and this was complete within 4 hours of occlusion.
The pathologists Reimer and Jennings tied off a coronary artery in experimental dogs. They produced convincing microscopic sections of the “wavefront theory” of muscle ischemia, concussion and death, which started soon after the occlusion and which was complete after 4 hours.
Prof. Gabby Isaac, the head of Hematology at Hadassah, was using urokinase to lyse thrombi in the veins of the leg after deep vein thrombosis and thrombi in the pulmonary artery in patients with acute pulmonary embolism. He wanted to give a direct bolus into the pulmonary artery and enlisted our help. The results of direct infusion through a catheter were dramatic, the clot was lysed and disappeared, and the artery reopened. I felt that the time had come to extend its use and infuse the drug directly into the occluded coronary artery which was causing the acute myocardial infarction.
We started intracoronary lysis using urokinase. It was unbelievable to watch the lysis of the clot in the culprit coronary artery during the infusion, relief of the intense chest pain and the return of the ECG to normal. Our first patient was a 73-year-old man who had been admitted to the internal medicine ward with severe unstable angina pectoris. I catheterized him urgently on a Tuesday afternoon and demonstrated severe disease of all three coronary arteries. We felt that he was a good candidate for coronary artery bypass surgery. At 6am on Wednesday morning, he developed acute, severe chest pain with ST segment elevation of the anterior cardiac leads on the ECG and it was clear that he was developing a new myocardial infarction. The surgeons were already using the operating rooms, and the patient’s family asked me if there was any way of unblocking the artery. I had urokinase in the catheterization laboratory and we brought him down for a repeat coronary angiogram. The left anterior descending artery which previously had a 90% obstruction was now completely occluded and there was no flow down the artery. We infused the urokinase and it was amazing to see, how, after 15 minutes, contrast medium trickled down the artery and after another 15 minutes there was rapid flow. The clot had been lysed, and flow restored. The ST segment elevation on the ECG, started to disappear and then suddenly he had ventricular fibrillation and a cardiac arrest. His blood pressure dropped to zero. Jacob, our technician, defibrillated him immediately while Basil Lewis started artificial ventilation. The resuscitation was successful, his blood pressure rose and I could see the heart beating on the x-ray screen. At the same time, Prof. Eliakim, the head of the internal medicine department, appeared at the door of the catheterization laboratory and said ‘Gotsman, how can you snatch the patient from my ward without a formal discussion at the afternoon departmental conference!” He watched the resuscitation and was really quite upset. At that time I did not realize that the ventricular fibrillation was a reperfusion arrhythmia due to oxygenated blood entering the anoxic myocardium. The patient had a fairly small infarct, recovered uneventfully, but later underwent a successful triple vessel coronary artery bypass graft and lived for another 15 years. The thrombolytic reperfusion was dramatic and proved that we could open the artery, restore blood flow and decrease the size of the infarct.
The second patient was no less dramatic. He was a 42-year-old financial director at the local sick fund and came to tell me that I was undertaking too many coronary angiograms and wasting part of his budget. He felt a sudden pain, put his hand on his chest and the pain increased in intensity. I sat him down and gave him a coronary vasodilator. The electrocardiogram showed ST segment elevation in the inferior leads, a sign of an impending myocardial infarction. He had heard of our successful reperfusion and asked me to take him to the catheterization laboratory immediately. He had a single, total occlusion of the right coronary artery and the obstructing thrombus created a picture that looked as if the artery had been amputated. We started an infusion of urokinase and within 15 minutes restoration of flow started. It continued for another 30 minutes, the pain subsided, the ST segment elevation disappeared and he asked for a cigarette. He recovered after a very small infarct (heart muscle death) and was discharged home after a few days. But he continued to smoke and later underwent several balloon dilatations. He is alive and well, some 30 years later.
Teddy Weiss, my senior cardiologist at Mt Scopus Hospital had returned from a post graduate fellowship at Cedars Sinai hospital in Los Angeles in 1984. Willie Ganz, the local proponent of thrombolysis, suggested that we use intravenous streptokinase for lysis and the best method of shortening the time delay from pain onset to lysis was to initiate and administer the treatment at home before transport to the hospital. Teddy undertook the organization of the project. We were joined by Dr. David Applebaum, who was in charge of the Magen David Emergency Ambulance Service. The ambulance was staffed by a trained physician and supplementary experienced ambulance staff and was equipped with ECG monitoring, an ECG recorder and an external defibrillator.
We turned this clinical service into a most exciting and unusual research project and showed that it was possible to start thrombolysis in a pre-hospital setting within one hour of pain onset. The mortality was so low that we needed a more sensitive index of myocardial salvage. We had already studied left ventricular function in detail by left ventricular angiography and we used infarct size to show that the this was a function of time delay, and that death of the heart muscle was complete after 2 hours. Once pain started, the clock started ticking and every minute was critical.
We were conquering acute myocardial infarction and preserving heart muscle and function. Simultaneously, there were similar studies in Rotterdam, Brussels, Paris and the rural areas around Aberdeen, Scotland and Belfast, Northern Ireland. We invited our coworkers to a series of meetings to compare procedures and notes and published a series of monographs.
I became known as the cardiologist who ran around the city with his ECG and syringe opening coronary arteries in acute myocardial infarction.
Basil Lewis and I had learned a great deal from Hal Dodge and Florence Sheehan in Seattle about global and regional left ventricular function of the heart. We had used a computer to analyze the left ventricular angiograms and had defined different patterns of contraction after the obstruction of the different coronary arteries. It was simple to study patients after thrombolysis to determine the extent of myocardial infarction. We produced different models of measuring left ventricular dysfunction and developed 3-dimensional representations. The extent of myocardial necrosis was related to the volume of muscle supplied by the affected artery, the site of the coronary obstruction, the extent of the collateral circulation and, in particular, to the delay from pain onset to reperfusion. The research produced at least 20 major publications and was the pivotal research thrust of the department for the next 10 years.
Sima Welber joined us as a research fellow and completed her MSc degree. David Fine came from the Mayo Clinic but after two years returned to practice in Minneapolis - he had to pay back a large student loan. Teddy Weiss was full of ideas and all the younger staff participated with great enthusiasm.
We had shown that prehospital thrombolysis was very effective. Mortality had fallen to 2.5%.
The most exciting of all the other studies was that undertaken by general practitioners in the rural Grampian region of Scotland, near Aberdeen. The general practitioners were trained to make an initial diagnosis of impending myocardial infarction and provide immediate thrombolysis. Half of the patients were given APSAC (a streptokinase derivative) at home and the other half on admission to hospital. Prehospital initiation of thrombolytic therapy saved one hour (105 versus 240 minutes) and was associated with halving of the three month mortality (from 15.5% to 8%). Beyond the reduction in mortality there were fewer cardiac arrests, fewer Q-wave MI’s, and improved left ventricular function. GP training improved the speed of physician response, clinical assessment and diagnosis, relief of pain and anxiety, correction of autonomic disturbances, and, arrhythmias, and resuscitation. Telephonic transmission of the ECG via the general practitioner to the regional hospital was the most effective approach in rural areas, before the ambulance arrived. It is ideal where the local hospital is a few hours away from the patient.
Other randomized controlled studies such as the EMIP study in France and the West Washington study in Seattle were less decisive because the time delays were much longer.
There was a spate of major international studies that showed the superiority of thrombolysis. We introduced new antithrombotic drugs but now we had to be careful of excessive bleeding.
I travelled abroad extensively discussing our results. The most interesting experience occurred after I had spoken at the Friday morning cardiology meeting in Seattle. The group had studied all the acute infarcts in Seattle. Doug Weaver and Ward Kennedy, who led the randomized controlled studies, had excellent results with mortality reduction in the anterior infarcts but were less successful with inferior infarcts. These infarcts in the inferior wall were usually small, and their time delays too long to make a significant impact.
In Rotterdam the ambulance was also very active. In Belgium they were using general practitioners and in rural Northern Ireland the ambulance was going out into the country. I was invited to develop thrombolytic programs in Spain and Portugal and when the Iron Curtain came down eastern Europe, started to lead the field. The medical metamorphosis was complete. Poland and Hungary were the first countries to implement the treatment. The countries had cardiologists who were as talented as their Western counterparts but had been deprived of the budgets required to make progress. The opening of the intellectual gates, the cross communication of information with the Western countries, and their extreme enthusiasm took them out of the darker ages into a new intellectual sunshine. While it took a generation to eliminate the old communistic bureaucracy, the drug and medical device companies discovered a fertile ground for research and supported new projects and the medical machine of progress took off.
Eric Topol, a young dynamic cardiologist from Ann Arbor, started a series of major multicentered international mega trials (TAMI and GISSI trials). He showed that thrombolytic treatment with tPA was very effective. Eric was a most impressive young man. He would enter the lecture theatre with his little bag and give a most exciting presentation. I went to visit him in Ann Arbor, and found that he was doing 7 to 8 catheterization studies a day, in addition to his clinical load and research studies. He moved to Cleveland Clinic as director of cardiology and then director of the clinic and eventually moved on to San Diego. Braunwald was the father of myocardial salvage and mortality reduction continued with his TIMI studies. He and his group continued to introduce new supplementary thrombolytic regimes to improve the reperfusion and prevent further reocclusion and showed that not only opening the artery and re-establishing flow but also re-establishing the micro circulation was very important. They used mortality as endpoints whereas we used infarct size.
The next innovation was to use immediate coronary angiography to define the coronary anatomy, followed by immediate balloon dilation in order to accelerate opening of the artery more rapidly and completely. This was pioneered by Cindy Grines and Bill O’Neill at the Beaumont Hospital in Royal Oak, Michigan. She was a tall, thin, athletic lady, always on the move and with a very intense work ethic. She would come to the hospital immediately at night and run a 24-hour, seven-day a week service and was prepared to catheterize patients with acute myocardial infarction at any time of the day or week. She started a series of PAMI studies to compare treatment with immediate balloon angioplasty to thrombolysis. She reduced the mortality from 10% percent to 2% and re-infarction within six months from 16 to 8%. There was a gradual acceptance of her new technology, and within five years virtually all the patients with acute infarction were being treated by percutaneous coronary interventions. Stents were introduced, followed by drug, eluting stents, and the long-term results were excellent. Once again, the paradigm had shifted.
We also entered the field of emergency 24-hour angioplasty and because of the new DRG, which reimbursed the hospitals for the extra work and cost - more than the previous payments for angioplasty - the hospital found it profitable to undertake these procedures and we now have two on duty residents and two senior cardiologists on-call. Our mortality also plummeted and within two years the system had been introduced throughout Israel. The patient calls the ambulance, who radios to the on-call hospital, contacting the cath lab immediately. We aim for a door-to-balloon time of under one hour.
Percutaneous Coronary Intervention (PCI) in acute myocardial infarction is quite different from PCI in chronic coronary artery disease. Acute myocardial infarction is an active process in which a coronary artery has been occluded, part of the myocardium has been destroyed and many of the patients come to the catheterization laboratory cold and shocked, with a low cardiac output and poor tissue perfusion. The patient needs acute intensive care to raise the BP, improve the cardiac output and often to use mechanical support such as an intra-aortic balloon pump, or inserting a temporary pacemaker. In many patients the artery must be opened quickly and the artery is filled with fresh thrombus. The balloon dilatations can cause distal embolization as the clot breaks off and fills the distal capillary bed with clot. The operator needs greater experience and more manual dexterity and a sharp eye – brain – finger interaction and the ability to deploy immediate lifesaving procedures. We tried aspiration of the clot through the catheter, but it did not improve outcomes.
A typical example is a 40-year-old man who has blocked his left anterior descending artery and may have disease in his other coronary arteries. He comes into the cath lab with a low blood pressure of 50/30, cold, pale and sweating. He needs immediate intravenous fluids and often also immediate insertion of an intra-aortic balloon to support the circulation. The catheter lab staff are working under extreme pressure and it is essential to open the artery without delay. This may happen at 2am in the morning where everybody has been summoned from their beds and the entire catheter lab machine is shifted into top gear. If the patient develops ventricular fibrillation, he needs resuscitation, defibrillation and intensive drug therapy.
The Cardiac Department at Tel Hashomer Hospital under the leadership of Shimon Bahar and The Israel Cardiac Society started a national registry (ACSIS) and the country-wide mortality has dropped progressively to 4% .
Non–transmural infarction was also upgraded and early interventional procedures undertaken. The workload in our department changed completely and since there were very few patients who developed restenosis, the workload changed and most of the patients are admitted directly from the emergency room.
The department now runs a 24/7 cath lab service. The mortality has dropped dramatically and in more than 70% of the patients we salvage most of the myocardium at risk.
There remain many unresolved issues: training the population to call the emergency services early when chest pain starts, reducing the time delay from pain onset to reperfusion, better methods of preventing myocardial damage, management of large or second infarcts with cardiogenic shock, use of new auxiliary pumps to assist the heart in shocked patients, and management of patients with prolonged cardiac arrest and severe anoxic brain damage. Nonetheless we have excellent new methods for centralized, cloud based monitoring services, to manage high risk ambulatory patients and anticipate the heart attack, internet communication between the ambulance and the receiving hospital cardiac service and more immediate response using neighborhood motorcycle response systems.
I can look back on this complete revolution, from a 34% mortality with a 3-week rest in bed program, to immediate emergency restoration of normal coronary flow within less than two hours of occlusion by a well-trained ambulance service and an efficient coronary catheterization team of trained interventional cardiologists, technicians and nurses.
I am proud of our energy, push, research and enthusiasm and the continued vitality of my dynamic successor, Prof. Chaim Lotan and his active crew.
The sun never sets on cardiology: the lights never dim at night.