La Cardiología Intervencionista que viví en mis 41 años de práctica

I wish to thank the Argentine College of interventional Cardioangiologists (CACI) for giving me the extraordinary opportunity of becoming a founding member of the College and being able to practice this medical specialty for the past 40 years. .

In the following pages I will try to sum up what I think are the most important experiences lived by my colleagues and I since the beginning of this medical specialty including all that has been going on in this changing and fascinating specialty. Back in 1980, I was the Cardiology/Hemodynamics/Cardiovascular Surgery unit chief resident of Sanatorio Güemes, the then called Favaloro Foundation led by directors Dr. Rene G. Favaloro, and Dr. Luis de la Fuente at the time. It was then that we came up with our first tools to perform peripheral angioplasties of both femoral and renal arteries, still without the operative and technical capabilities to start this therapy in the coronary arteries.

Almost three years had gone by since Dr. Andreas Gruntzig had presented the first cases treated in Zurich, Switzerland back in 1977 in a meeting held by the American Heart Association.

Also, by then, in 1979, Dr, Peter Rentrop had already demonstrated the benefits of intracoronary thrombolysis with streptokinase for the reperfusion patients within the first few hours after an acute myocardial infarction.

Interventional cardiology as we know it was taking off.

It was precisely on October 3, 1980—my birthday by the way—that I had my first therapeutic experience using a catheter to treat the ischemic heart disease of a patient with an ST-segment elevation myocardial infarction.

The patient had sustained a 12-hour postoperative period following a side-to-side anastomosis of venous coronary artery bypass grafts to the left anterior descending coronary and diagonal arteries that showed signs of an extensive anterolateral infarction with hemodynamic compromise.

Dr. Favaloro called the cath lab. I talked to him and suggested the possibility of infusing thrombolytic drugs in the potential occlusion site, in other words, use the saphenous vein to perform the coronary artery bypass grafting.

The famous hematologist Dr. Raúl Altman, a collaborator of Dr. Favaloro, had urokinase available because he often used it for specific treatments.

With these elements we selectively catheterized the occluding bypass, proceeded with the 1-hour in-situ infusion of urokinase, and achieved the reperfusion of the diagonal artery and the entire proximal and middle third of the left anterior descending coronary artery resulting in TIMI grade-3 flow followed by complete hemodynamic stabilization.

I gladly remember Dr. Favaloro called me and told me: «Rodriguez this is the best birthday present you’re getting this year».

I presented the case at a South American congress of cardiology, and two years later it was published as a case report in the Journal of the American Heart Association with another case performed by a different member of the Hemodynamics staff unit.

Despite I personally performed this procedure skin to skin—as we say in our day-to-day medical jargon—I was deliberately excluded from the publication without my knowledge and while on one of my numerous trips to the United States during 1981 and 1982.

Back in 1980, Dr Richard Myler, an angioplasty pioneer in the United States, was giving lectures in Sanatorio Güemes as a guest of Dr. Favaloro. The opportunity was ripe for me to join his team, which I did in January 1981 for three months. Years later, Dr. Myler introduced and inducted me as a fellow of the American College of Cardiology.

At that time, I also had the opportunity of visiting Dr. John Simpson from Stanford University who was practicing with a new steerable system of catheters and moveable core metal guidewires to perform coronary angioplasties. Back in Argentina, in April, we started performing the first coronary angioplasties at Sanatorio Güemes.

Angioplasty in Europe and the United States was on the rise with pioneers like Dr. Andreas Gruntzig from Switzerland, and one of the most notorious of all, Dr. Geoffrey Hartzler from Kansas, United States who pioneered the field of myocardial infarction angioplasty. He is one of the greatest ever, there is no doubt about that. Dr. Hartzler was, unfortunately, gone before his time, but in 1982 he introduced the method to perform primary angioplasties without previous thrombolysis (a method called direct angioplasty).

At the time, acute myocardial infarction angioplasty was very controversial with conflicting results. Also, most angioplasties were being performed after the infusion of thrombolytic drugs.

At the end of 1981, one year after having performed the aforementioned intracoronary thrombolysis, I had the opportunity to perform an angioplasty after thrombolysis on a patient with an inferior wall ST-segment elevation myocardial infarction due to right coronary artery occlusion. The first thing I did was coronary artery reperfusion with the intracoronary infusion of urokinase and then perform the balloon angioplasty. The procedure was a success.

The case was published at the beginning of 1982 in the Argentine Journal of Cardiology. To my knowledge, this was the first case of coronary angioplasty after thrombolysis ever performed in Latin America in the acute myocardial infarction setting. Probably, only a German team had performed the same procedure that same year of 1982 publishing the case in Circulation.

During the 1980s our specialty skyrockets in the entire Western world both in the United States and Europe. Also, the late 1980s see the birth of plain old balloon angioplasty (POBA) and new devices like directional coronary atherectomy, rotablation, balloon dilatation catheters, and prolonged infusions, etc. allowing us to develop more complex angioplasties than the one initially performed by Dr. Gruentzig.

It wasn’t until the mid-1980s (1986) that we created our own clinical research working group, the Cardiovascular Research Center (CECI) based on Buenos Aires, Argentina. A research center that still stands today.

At that time, the first limited but very promising experiences with bare metal stents (BMS) to prevent coronary occlusions during balloon angioplasty were beginning to take shape. Names like Dr. Sigwart, Dr. Puel, Dr. Marco, Dr. Serruys, Dr. Roubin, and Dr. Palmaz started to make a difference in all scientific settings of our specialty.

# Decades of 1990/2000/2010. The dramatic ascent of coronary angioplasty as therapeutic procedure for the management of acute and chronic coronary patients.

In my humble opinion, these were the golden decades of our medical specialty.

The first decade of 1990/2000 witnessed a consolidation in the use of bare metal stents (BMS) during angioplasty to treat acute complications and coronary restenosis after POBA to avoid chronic and acute recoil after balloon angioplasty. At the time, this was the leading cause of restenosis after this procedure. The use of BMS was first introduced in the United States by Dr. Roubin and Dr. Palmaz with their balloon-expandable stents. Dr. Gianturco-Roubin’s was the first BMS approved by the FDA in the United States to treat acute complications followed shortly after by Palmaz-Schatz’s stents .

Stents eventually would be used in all clinical conditions including the acute myocardial infarction setting and very complex coronary lesions.

Also, this decade witnesses the publication of the first randomized clinical trials on coronary angioplasty with POBA vs coronary artery bypass graft (CABG) in patients with simple obstructions of multiple vessels, most of them with chronic coronary artery disease, also in diabetic patients. Shortly after these same comparisons would be made with the use of BMS . This is also the time when the first comparative randomized trials on acute myocardial infarctions treated with angioplasty vs thrombolysis are published followed by studies on angioplasty with POBA vs angioplasty with stenting .

During this decade two landmark meta-analyses  confirmed that, in the long run, the angioplasty in patients with multivessel disease has the same survival and infarction-free survival rates compared to CABG excluding diabetic patients. In these analyses the survival rate of young patients showed a clear advantage towards the angioplasty, which is comprehensible, but was confirmed in this meta-analysis  for the first time. The only difference in favor of CABG was the higher rate of new requirements for angioplasty revascularization.

Unfortunately, these findings were published,2008-2009, just when drug-eluting stents (DES) were on the rise, which is why these results were overlooked.

Although the use of bare metal stents minimized the occurrence of acute complications after angioplasty, it also caused in-stent restenosis due to fibrous intimal hyperplasia following the exaggerated scarring caused by new reinterventions of the target vessel within the first 8 to 10 months after stenting (> 20% rate).

The introduction of immunosuppressive drugs within the stent to be released in the arterial endothelium within the first month after stenting caused a significant reduction of this hyperplasia followed by a significant reduction of new revascularizations. Also, this combination prevented acute recoil and fibrous intimal hyperplasia.

This marked the beginning of DES that revolutionized our medical specialty. Actually, to this date, in certain discussion fora—not mine—they still revolutionize our specialty.

Esto es el inicio de los stents liberadores de fármacos (DES) que revolucionaron y aun hoy en algunos foros de discusión, no en el mío propio, siguen revolucionando nuestra especialidad. The names of Antonio Colombo, Eberhard Grube, Martin Leon, Patrick W. Serruys and Greg Stone are largely due to them this technological leap with the introduction of drug-eluting stents (DES). At this point, our colleague Eduardo Sousa and his group in Brazil also played an important role. However, our country was again not absent in this development of deS, and one of the observational studies in its use was carried out in Argentina by Dr Luis de la Fuente and despite the fact that his findings were not endorsed by a long multinational randomized European study, which had to be terminated prematurely due to excess of thrombotic complications of this DES design,  this pilot study was pioneering at the time.

The significant reduction of new revascularizations reported after DES implantation brought expectations that were a little too optimistic regarding the use of stents like this. Rumor had it that «the end of restenosis would also be the end of CABG» following the early findings from the first randomized clinical trials on the use of DES. In the following section we will see how far we still are from these predictions.

This overoptimistic approach was built on reducing completely secondary and non-clinical endpoints to a minimum like minimizing the so-called “late loss” that could never be associated with the occurrence of hard endpoints after angioplasty.

# Decade of 2010/2021. The dramatic ascent of the indication of revascularization to the present day.

At this point I want to be very straightforward, but also very critical, and my opinions should also be taken from this personal point of view.

With the arrival of DES into the routine clinical practice, to this date, several randomized clinical trials including comparison groups have been conducted on angioplasty with DES vs CABG. As a matter of fact, up to 3 studies on unprotected left main coronary artery disease, 1 on multiple vessels and left main coronary artery, and the remaining 4 on multiple vessels including diabetic patients  have been conducted.

From the beginning, all trials but 1 invariably showed more revascularization procedures as a natural companion of the angioplasty, which should not worry us. However, in 7 of these trials, the mortality and/or spontaneous myocardial infarction rates also went up, which is more disturbing and is associated with mortality.

The greater complexity of the patients treated could explain these findings, but it is probably not the only hypothesis. As a matter of fact, several meta-analyses proved that regardless of the anatomical complexity, the rate of hard endpoints like myocardial infarction—and in some studies, mortality—was lower with CABG.

 This change in safety parameters in comparative studies with surgery had already been observed in the long American registry of ASCERT with 190 thousand patients treated with CABG and PCI (78% DES1) during the years 2004 to 2008 in 64 sites in the USA and where in patients >64 years there was a significant reduction in mortality with CABG even in groups of low angiographic and clinical risk (non-diabetic and two-vessel injury). and what a reason why we wrote a review article in 2012, where we already drew attention to these findings. This reference is among the suggested articles to read.

Although it is completely true that DES reduced significantly the rate of new revascularizations, mortality did not change when the old DES and/or even BMS  designs were compared to the new ones.

With the first designs, the use of DES had 4 limitations some of which overlap:

1- Early, late, and very late stent thrombosis.

2- Poor late DES apposition. These 2 overlapped most of the times.

3- Early neo-atherosclerosis immediately after implantation (beyond 1st year).

4- Endothelial dysfunction both in the stent and in the proximal and distal segments of the implant.

Stent thrombosis and poor stent apposition were significantly associated with the polymer, but, to this date, this is not a problem anymore.

However, the 2 remaining ones—early neo-atherosclerosis and endothelial dysfunction—were mainly associated with the local action of the immunosuppressant drug. The former causes spontaneous infarctions not associated with new procedures that we have been invariably seeing in all randomized trials including comparison groups on CABG. Endothelial dysfunction is also associated with cardiac adverse events, but ultimately with non-cardiac adverse events too including a higher incidence rate of solid tumors.

It should not be forgotten that the endothelium is an organ with multiple functions such as: «vasodilation, thrombolysis, platelet disagreggation, antioxidant, antiinflammation, antiproliferation». The loss of its normal function i.e. endothelial dysfunction could produce the opposite effects: «vasocontriction, thrombosis, platelet agreggation, oxidant activity, inflammation and growth factors». At this point it is very important that interventional cardiologists define cost/benefit between suppression of restenosis / endothelial dysfunction and the clinical implications of the last one.

On this topic I recommend reading the manuscripts referenced below by Toya et al. and Abdul-Jawad Altisent et al., within the last references in this chapter.

It is surprising to see several observations associated with non-cardiac mortality in patients treated with angioplasty at the present time who were not in previous observations. Actually, this should be a cause for careful analysis in properly conducted randomized clinical trials and prospective registries. This increased non-cardiac mortality was reported not only in randomized clinical trials on DES and CABG, but also in comparisons of different DES designs. As we already know, large enough randomized clinical trials have the power to homogenize populations at a baseline level, which is why the explanation to this increased mortality should be looked for in other clinical settings. I recommend reading Gaudino’s meta-analysis, the 5 years of EXCEL trial, Pilgrim’s et al 5-year study of an «ultrathin DES», the CREDO-Kyoto registry of angioplasties and CABG all referenced below as well as the abstract of the ISCHEMIA trial published in Circulation in November of last year and the European Heart Journal this year. The publication of the last one was the reason of an Editorial comment of ours that is published in the European Heart Journal Open in February of this year and where in a Table we describe all the studies that reported an increase in non-cardiac death with DES in long-term follow-up, to these we must include the findings of the ISCHEMIA study that is really very worrying.

In my opinion calling non-cardiac mortality an adverse event due to coincidence is reckless, illogical, and eventually hurts our own medical specialty.

Only after a sincere discussion of all these findings with opinion leaders and industry CEOs we will be able to escape this labyrinth we fall into with every new randomized trial on CABG or with every medical therapy that only brings us frustration.

Lately even the introduction of methods of functional diagnosis of coronary lesions such as FFR or iFR to guide PCI have not been successful in demonstrating reduction of post-implantation events of DES both in patients with acute infarction or elective patients. I recommend reading the results published this year of randomized studies in this regard including FUTURE, FAME 3 and that of Puymirat E et al in acute myocardial infarction all referenced below between the suggested readings. The negative results of these studies with FFR show us that quickly interventional cardiologists adopt techniques and new «devices» often generating false expectations due to a hasty overestimation of the benefits.

Although the recently published new clinical guidelines on therapeutics elaborated together with clinical cardiologists are somehow benevolent to our medical specialty, they show that, unlike we thought 15 years ago, despite the arrival of state-of-the-art DES designs, coronary artery bypass grafting is more alive than ever. In fact, both American (USA) and European Societies of Cardiovascular and Thoracic surgery didn’t endorse that guideline.

# Creation of the Cardiovascular Research Center (CECI).

In 1986 together with colleagues and friends we formed an independent working group first in the Anchorena Sanatorium and then moved to the Otamendi Sanatorium from 1993 to the present.

During all these years there are no words to describe the support for all our care and scientific tasks developed in the Otamendi, so my thanks to your past authorities Drs. Jose A. De All for whoever comes to work in this Institution and Dr Jorge Aufiero as well as the current authorities.

During all these years, many cardiologists went through the Service to be trained in the practice of our specialty, many of them today Heads of Service in reference places in our country as well as prominent members of scientific societies that could not list them by the quantity, both in our country and in Latin America. Residents of almost all nationalities of the Spanish- and Portuguese-speaking region passed through the service from Paraguay, Chile, Brazil, Bolivia, Peru, Uruguay, Ecuador, Venezuela, Colombia, Panama and the Dominican Republic who then continued to be connected with us, often carrying out joint research work.

Back in 1988, two years after creating a working group with friends and colleagues, we teamed up again to create an independent department of clinical research. Although it was not created as a CRO (there are several examples of excellent CROs in Argentina), it allowed us to arrange multiple research protocols in our country in an orderly fashion, and one by one at the beginning. Afterwards, we conducted multicenter studies including international clinical trials.

Here is a summary of the most significant clinical trials conducted that I think played a key role in our routine clinical practice:

This whole thing started with the first randomized clinical trial published on coronary angioplasty with POBA vs CABG—the ERACI I trial—published in JACC in 1993 and 1995. Years later with the arrival of BMS, the second version of this study, the ERACI II, was published. Unlike the ERACI I, this multicenter trial was co-authored by the fondly remembered Dr. Liliana Grinfeld. Both manuscripts were published in JACC in 2001 and 2005 including the 1- and 5-year follow-up simultaneously published with Dr. Patrick Serruys’ ARTS study.

Back in 1993, we published an observation suggesting that restenosis after balloon angioplasty was mainly due to acute artery recoil after balloon dilatation. Something completely new that we had never associated. In the animal model of restenosis common knowledge was that the endothelial damage due to the mechanism of the angioplasty triggered vessel restenosis months later. However, this was not the case with human beings in whom atherosclerotic plaque is often eccentric and behaves different from the balloon in such a way that the rate of restenosis was very low in lesions whose diameter did not change 24 hours after balloon angioplasty. This finding was published in several scientific journals: American Journal of Cardiology in 1993 and 1995, Circulation in 1995, and JACC in 1998 and also of academic discussions with world opinion leaders since they spoke of: «.. coronary restenosis a time related phenomenom…» therefore our observations were totally opposite and were the subject of controversy. Time proved us right and Patrick Serruys ended up accepting that acute recoil was a very important phenomenon in the pathophysiology of post POBA restenosis, there he began talking about «stent like results post POBA» in other words optimal post-balloon results without acute recoil.

It was very pleasant 3 years ago to see in the gallery of the PCR Congress exposed as one of the milestones of angioplasty precisely the work of our stent in elastic recoil OCBAS trial that was published in JACC 1998 together with the ERACI I and II studies.

In the same sense, it was also very pleasant to read in the book on the history of cardiovascular interventions and interventional cardiology that one of its greatest pioneers Gary Roubin whose aforementioned book was entitled «The First Balloon-Expandable Coronary Stent an Expedition That Changed Cardiovascular Medicine» published in 2015 included us along with Julio Palmaz and Rene Favaloro as the only Latin Americans in the list of the 93 pioneers of Angioplasty and  Cardiovascular Interventions, this reference is also within the suggested lectures of this chapter.

The use of stent in the acute myocardial infarction setting is appealing but was also very controversial too. Together with the beloved Dr. Gary Roubin our group published a short experience on the use of stent in the ST-segment elevation myocardial infarction setting in the American Journal of Cardiology back in 1996. This experience immediately turned into the first study on the use of stents in the acute myocardial infarction setting accepted for publication. The GRAMI trial—published in the American Journal of Cardiology in 1998—was contemporaneous to Dr. David Antoniucci’s study. Actually, his study was published two months prior to the JACC publication, but ours had already been accepted two months before the Florence study. Therefore, both chronologically and academically we came first. Anecdotes I always like to remember in our family reunions with my great Italian friend.

Already in the new millennium, the CECI Center participated in prospective records and observational studies such as those related to DES thrombosis published in EuroIntervention in February 2007 («Late stent thrombosis the Damocles sword of DES») a month before the promoted article by Camenzid and Wijns in Circulation, the ERACI III record, which was published in JACC in 2006 and in the Eur Heart J in 2007 this last work was one of the reason why this European Journal will increase its «impact factor» according to a personal letter we received from the Editor-in-Chief of that Journal.

The review article on «DES late thrombosis» there were friends who recommended me not to publish it because it could have adverse reactions from the industry that manufactured the DES, despite those tips, the work was sent and then review accepted and published in EuroIntervention. I must also say that I never felt an adverse reaction from the industry for this.

If the doctors of the CACI specialty career wonder how we were able from Argentina to carry out so many studies that were published in the largest English-speaking «Journals» I would tell them that everything is achieved with work and a lot of honesty in the analysis and observation of the facts that one is seeing. You should always be sure of what you are saying, and you should always check the information several times before making a further judgment if this implies original findings outside of what is established and expected. In fact, at the time where these thoughts were writing, April 30 th, 2022, according Research Gate scientific data manuscripts published by us as authors or coauthors deserved 26222 reads,7568 citations and have 3920 points of research interest the largest numbers achieve by any group or individual person in our country in the area of interventional cardiology.

Controversies with our findings happened in several times, with the «elastic recoil», the ERACI studies and with stent in acute myocardial infarction. In these points the collaboration with Igor Palacios, Gary Roubin, John Ambrose, William O’Neill and David Antoniucci were very important. As I said on the occasion of a distinction granted to me by the Legislature of CABA: » the work we did here in Argentina with ideas totally ours and our patients, but nothing would have been the same if our friend from USA or EU didn’t support to us «.

In the ERACI I study, which Favaloro was very angry when we did and spoke ill of the findings including trying to convince the surgeon who had operated on almost all patients not to sign the manuscript once it was approved in the JACC, an Argentine work published in the JACC in 1993 had few precedents in the cardiology of our country,  finally cousin rationality and the surgeon signed the work, Dr Néstor Perez-Balino was a faithful witness of what I am recounting. I had, however, the pleasure that several years later, in May 2000, when the new ERACI II had already been accepted for publication, Favaloro called me by phone to congratulate me personally on this work and with warm memories of the past shared in a very difficult moment of the Foundation and also personal of him  few months before his death.

Over the last 20 years, the Cardiovascular Research Center (CECI) has conducted several multinational and randomized clinical trials on several DES designs and different revascularization strategies in patients with acute myocardial infarction, as well as in chronic patients.

In this way we participate in the abciximab in acute infarction with a carbon metal stent, JESTENT rheolithic thrombectomy in acute infarction, FREEDOM, FREEDOM long term outcome DES vs CABG in diabetic patients, MULTISTRATEGY on DES and abciximab in acute infarction, VALENTINES with Paclitaxel releasing balloon, DEFINITION II treatment of bifurcations with DES including lesions of unprotected trunk and lately MASTER DAPT comparison of antiplatelet strategy with DES,  all of them published several times in NEJM, JAMA, JACC, Circulation, Eur Heart Journal, JACC Intervention and EuroIntervention

Similarly, our database was submitted for analysis and control through several meta-analyses, and eventually, the ERACI and ERACI II clinical trials were submitted for publication (Dr. Pocok in The Lancet, 1995; Dr. Hlatky in The Lancet, 2009 and JACC in 2012; Dr. Daemen in Circulation, 2008, and Dr. Head in The Lancet back in 2018).

Likewise, the database of the EUCATAX trial was submitted to Dr. Valgimigli for the publication of his meta-analysis in The Lancet in 2019, and Circulation in 2021.

Also, based on a prospective registry of multiple vessels, is that the ERACI Score was born as a revascularization strategy in patients with multi-vessel disease and left coronary trunk, which was a joint product of several centers in our country and that tries to reduce the number of DES implanted following anatomical schemes of vessel size and degree of stenosis by angiography,  this Score was validated with both the use of DES and BMS.

Last but not least, the studies on the systemic prevention of restenosis with oral immunosuppressant and anti-inflammatory agents after BMS implantation.

Although in the era of balloon angioplasty this strategy did not had favorable results—as a matter of fact no positive results could come from it because the pathophysiology was not inflammatory—in the era of bare metal stents all the randomized clinical trials conducted by us and European working groups in Germany, Italy, Serbia, and Greece on immunosuppressant drugs like rapamycin and/or prednisone had positive results that were summed up in a meta-analysis published by Dr. Kastrati in 2014. Still this strategy was never part of the routine clinical practice.

At this moment, we are conducting a cost-effective randomized clinical trial between state-of-the-art DES vs BMS plus a 3-month course of colchicine only in the BMS group that is still in the recruiting phase. We can only hope it will be completed in the next months.

Given the conflicting and somehow unexpected long-term results with DES, I still believe all options should be on the table and none should be discarded to achieve a greater mid- and long-term efficacy and safety with our percutaneous revascularization procedures whether coronary angioplasty with DES implantation in bifurcation lesions probably including most of  unprotected left main coronary artery disease, and BMS implantation in more favorable anatomies, and/or a combination of both strategies.

Nothing should be left out if we want our patients to benefit the most, and if we want to improve this medical specialty that has shaped our lives for so long.

In the last Editor Letter we wrote at JAMA at the beginning of 2021 we told the Editor-in-Chief of the Journal that we thought it was important to publish our letter because we felt that: ….»coronary angioplasty is on the cross roads«…

We need to honestly explain and discuss the origin of our failures and redefine the technique, the «devices» and the indications in another way only the current and new generations of interventional cardiologists will have the niches of patients with acute infarction in progress and / or terminal patients with contraindication of CABG or very short life expectance.

Very little for such a rich history!!!

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