To stent or not to stent? Treating angina after ISCHEMIA—introduction

Thomas F Lüscher, Filippo Crea In 1772, the English physician William Heberden gave a talk at the Royal Society in London on some account of a disorder of the breast as he called it. He described it in a seminal fashion that remains valid today: ‘Those who are afflicted with it, are seized while they are walking (more especially if it be up hill, and soon after eating) with a painful and most disagreeable sensation in the breast, which seems as if it would extinguish life…; but the moment they stand still, all this uneasiness vanishes. …The pain is sometimes situated in the upper part, sometimes in the middle, sometimes at the bottom of the os sterni, and often more inclined to the left than to the right side. It likewise very frequently extends from the breast to the middle of the left arm. The seat of it and sense of strangling and anxiety with which it is attended may make it not improper to be called angina pectoris’.1 Heberden meticulously described a symptom, but he did not understand the disease. Edward Jenner noticed thickened coronary arteries at autopsy of his colleague John Hunter who had died suddenly after an angina attack in 1793,2 but it took decades for a first remedy for angina pectoris and even longer for a true understanding of the underlying disease. Thomas Lauder Brunton was the first to describe the effects of amyl nitrite in angina pectoris in the Lancet in 1867.3 Twelve years later, Thomas Murrell introduced what we still prescribe today: nitroglycerine.4 For the decades to follow, however, no progress occurred until 30 October 1958 when Mason Sones by mistake performed the first coronary angiography in a 26-year-old gentleman with rheumatic heart disease.5 Ever since, it was possible to visualize the narrowings of epicardial coronary arteries that were and still are considered the major cause of angina pectoris. Sir James Whyte Black, Nobel Laureate in 1988, then discovered the beta-blocker propranolol in 1964.6 At the same time, calcium channel blockers such as verapamil, diltiazem and nifedipine were developed.7 These three classes of drugs remain the cornerstones of optimal medical therapy (OMT) of angina pectoris today. More recently, nicorandil, a hybrid of nitrate and a potassium channel opener,8 ranolazine that blocks late inward sodium currents in cardiomyocytes,9 and finally, ivabradine, an If-channel blocker in the sinus node,10 were added to the medical armamentarium but with less evidence of efficacy. In 1967, the Argentinian cardiac surgeon René Favaloro, working at the Cleveland Clinic, used a saphenous vein of the lower limb and sewed it in reverse order to the ascending aorta and distal to the narrowing into a diseased coronary artery—and coronary artery bypass grafting (CABG) was born.11 Indeed, CABG showed a marked improvement of symptoms in patients with coronary artery disease and was ever since increasingly used in such patients. Twenty years later, Andreas Grüntzig, working at the University Hospital Zurich, introduced percutaneous transluminal coronary angioplasty (PTCA) and opened the door for interventional cardiology.12 PTCA, later renamed percutaneous coronary intervention (PCI) with the introduction of stents, became one of the most commonly performed medical procedures around the globe. In spite of all the success of CABG and PCI, debates and doubts on their effectiveness continued. Specifically, the following questions were again and again asked: do revascularization procedures such as CABG and PCI really improve symptoms of angina pectoris? Do these procedures improve outcomes as well, i.e. do they prevent myocardial infarction and premature death? The initial enthusiasm for PCI was dampened by the COURAGE trial,13 showing no benefit of percutaneous revascularization over OMT. However, the trial was criticized as it recruited only a small proportion of patients treated in the participating centres and as bare metal stents had been used. It was argued that, with the new drug-eluting stents, things would be completely different. Then came ORBITA,14 comparing OMT with PCI using drug-eluting stents in a sham-controlled design and was again neutral. This again was criticized as the trial was very small, and although symptoms and exercise tolerance only showed a trend, regional wall motion improved significantly in the stress echocardiograms.15 Thus, this uncertainty called for a large definitive trial. The ISCHEMIA trial presented at the American Heart Association Scientific Sessions in November 2019 and later published in the New England Journal of Medicine16 tried to fulfil this gap. The data are the backbone of a trial, but their interpretation is often not so straight forward. In this article, therefore, the editors of the European Heart Journal present two different, but complementary views by highly respected experts in the field. While Bernard Gersh and Deepak Bhatt in their contribution ‘The Impact of the ISCHEMIA Trial on the Indications for Angiography and Revascularization in Patients with Stable Coronary Artery Disease’ lean more towards an interventional reading of the data, William Boden and Peter Stone present in their contribution ‘Why a Conservative Approach with Optimal Medical Therapy is the Preferred Initial Management Strategy for Chronic Coronary Syndromes’ the more conservative view. Conflict of interest: none declared. Bernard J Gersh, Deepak L Bhatt Corresponding author. Tel: +1 507 284 4441, Fax: +1 507 266 0228, Email: gersh.bernard@mayo.edu The ISCHEMIA trial is a large, multinational trial sponsored by the National Heart, Lung, and Blood Institute, which has recently been published.1 The main trial compares coronary revascularization and optimal medical therapy (OMT) vs. OMT alone in 5179 patients enrolled after stress testing, in addition to two ancillary studies in patients with chronic kidney disease (777 patients)2 and a quality of life sub-study in the main ISCHEMIA trial, which enrolled 4617 patients.3 Crucial to placing the results of this important trial into perspective is a review of where we stood prior to the publication of ISCHEMIA, in regard to the indications for coronary revascularization vs. OMT in patients with chronic stable angina, more recently referred to as chronic coronary syndromes.4 Trials of the indications for revascularization have a long history dating back to the publication of the Veterans Affairs (VA) cooperative study of surgical vs. medical therapy for left main coronary disease.5 Since that time, a considerable body of evidence has been acquired, albeit far from perfect, but notwithstanding, this has been the basis for most of our societal guidelines on the management of stable angina. Nonetheless, it is relevant to highlight the strengths and the limitations of what evidence we have and to clarify the gaps in our knowledge base that were the impetus and, in fact, the rationale for the ISCHEMIA trial. The early trials of coronary bypass surgery vs. medical therapy in patients with stable coronary artery disease had major limitations in terms of their relatively small sample size, lack of use of the internal mammary artery in the majority, and all of these preceded the contemporary era of aggressive secondary prevention, which is the cornerstone of OMT.6 Nonetheless, these trials established the superiority of coronary bypass over medical therapy in the short to intermediate term for the relief of symptoms and in regard to survival; the ‘sicker the patient’, the greater the benefit of were in patients with disease and left in patients with angina and left coronary disease and in patients with left main coronary disease It is to that patients the indications for revascularization with the of are by the of disease and left established by the three trials of bypass surgery vs. medical therapy years were trials of percutaneous transluminal coronary angioplasty (PTCA) vs. medical percutaneous coronary intervention (PCI) with vs. medical by large of PCI For the most part, these trials did not benefit of on and myocardial infarction in stable patients with coronary artery disease. trials the study of vs. medical therapy in patients a benefit on and at years in a treated with bypass in the trial of patients years with angina on medical the a in for coronary at and a towards a in at but these were not the of in the trial of patients with a stress PCI significantly the of cardiac and at a of and in the trial of PCI a in the for early revascularization at and at years was a in late of the trial and two trials of stable patients in which PCI was a in and late In the trial of patients with coronary artery bypass (CABG) surgery was with a in and an of the a benefit with CABG on and but not from PCI in a as by and In terms of angina revascularization is to medical but of angina after PCI has been in the and bare metal In the COURAGE trial at the PCI vs. OMT were The exercise on a of the small trial to a benefit of PCI in stable although was greater relief of angina in a of patients with a and in the PCI The of symptoms In most not prior studies that the and of patients at for and and would be improved by In a large of patients and and years in the from the COURAGE and trials however, in regard to the the of and and and by the benefit of coronary the of revascularization in the of coronary is not up for In patients with chronic stable angina and left is no benefit from coronary revascularization the of The only two were the from the and trials The therefore, was to these data to the at large who have not angiography and the of stress in for is the of revascularization in patients with and to This to the ISCHEMIA trial. ISCHEMIA is the trial of an vs. conservative for patients with stable heart The are as an initial after coronary angiography to coronary did not over a of years for the of for angina, heart cardiac was no in the secondary of these data are with prior trials of revascularization vs. medical therapy in stable patients. were in the In patients with angina on a revascularization in an and improvement in angina and in the quality of This benefit was not in patients angina was not in the was a towards an of in the treated over time, which to the for all important these results but new of the trial a in the in to were and this not The is to this trial into a to understand the gaps in knowledge that have been and to the of these trials than the of which was in and in stress studies and as in of patients stress the was a at of Patients were Society angina was in and the was an coronary the and left main coronary disease on angiography a left of angina symptoms on medical coronary for PCI for as in the design was who in the of the physician is to have left main is are stress underlying this and in the the proportion of patients who were for this is not It is that in the of symptoms on medical angiography and revascularization are to improve the quality of The of disease with left is to improve It is that on and on stress are indications for angiography with a to The ISCHEMIA trial, however, would that the of on alone may not be an for early angiography and that such patients be treated with OMT. Indications for angiography and of the ISCHEMIA trial. left Indications for angiography and of the ISCHEMIA trial. left In patients who have the indications for revascularization are the use of prior established and the of in the in the trial, PCI of of a large and in with of benefit with the longer of The guidelines on coronary revascularization a for patients with a of greater than to of the left The guidelines on chronic coronary that in patients angina symptoms but in large of of more of the left is the is to revascularization on of medical The guidelines on stable angina and the do not the of but angiography in patients and results of of heart The ISCHEMIA trial that it would be to the of alone on as an for coronary angiography in of the guidelines In patients with angina on the results of the ISCHEMIA trial angiography with a to revascularization to improve the quality of In one the results of the ISCHEMIA trial are prior evidence and more data using that a at who would benefit from in the data and and it has long been established that patients in trials do than is that the large studies patients at a of in addition to the of alone and that such patients were from the ISCHEMIA trial. In the ISCHEMIA trial, although the of coronary disease was a this was not the in patients by the of The lack of the vs. conservative was in Nonetheless, the that the was lower in patients with more of is and the patients who were more and considered at were in with a for in this the of is one of which in may not to benefit from The use of a angiography in the ISCHEMIA trial has but of of patients with a stress for had no and left main coronary artery disease was in of patients. It is possible that the use of stress testing, in patients with a lower of coronary in of an in use of to the limitations of published trials of revascularization which the use of stents, improved use of and the artery and medical such as the and trials that a of in and medical are to some but they are the data that we have and to a underlying the and use data in trials and is and although trials that are and have all and studies are to The of the for revascularization to and coronary and and and The ISCHEMIA trial to our data on the management of patients with chronic coronary by a of patients considered at as a lower who be with OMT with the knowledge that an is in relief in with angina. It would be if a trial ISCHEMIA would but the interpretation of the results is more and the of when the data in Conflict of interest: Deepak Bhatt the following of Institute, Society of American Heart Association for Institute, for the trial, by Cleveland for the trial, by Medical Institute, Clinic, of the trial, by American of Trials and for PCI trial by by in Heart Medical and trial trial for the trial, by in Journal of Journal of the American of the and by Medical Society of and The to Heart Medical American of William Peter Stone Corresponding author. Tel: +1 Fax: +1 Email: percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) outcomes in patients with chronic coronary has been a of for more than two While myocardial with PCI, has been the of for patients with coronary it and myocardial infarction in patients with is less trials and that OMT with PCI more angina, the use of and and quality of life to OMT none of these trials have that an initial of OMT PCI and and The recently results of the ISCHEMIA the trial of OMT with myocardial the benefit of revascularization in chronic coronary artery disease patients with and the of optimal management In the early studies that patients with coronary of arteries of and of the left coronary had improved when treated with coronary artery bypass (CABG) surgery to medical therapy and, in that patients who coronary improved when treated with CABG to the early study that patients with on stress had lower when they were treated with a revascularization to medical These to the of guidelines revascularization procedures for benefit for patients with left coronary artery of for a large of of and for with in patients with angina a stress Since which is as the era of contemporary OMT that of the in addition to and to lower with that and have been three that have the of OMT with revascularization in patients with chronic angina and the COURAGE trial showed that in patients with and evidence of angina, who were after coronary angiography to OMT alone to OMT PCI with bare metal stents, was no in the of the two management after a of was a in While PCI was with a in angina to OMT alone this benefit after years of The trial of patients with and was likewise after coronary angiography and into most for revascularization with PCI CABG surgery with patients in then to revascularization OMT. this was no in the OMT revascularization over a was a in the secondary of and in the not the by a in with OMT The was a trial of patients with and who were to PCI vs. medical therapy in patients with showed that the of revascularization was significantly with PCI, but this was by the most of the but to to the design of the trial, COURAGE and was no benefit from PCI vs. OMT on the outcomes of at a of as as at and At was a towards in the PCI but this did not while a of and a in at a of were one with patients who had myocardial of over and was no in a in angina with PCI on the of as with OMT were limitations and of these three trials in that all were only after coronary angiography was which may have introduced a the PCI of the trial by patients who may have most from In none of these a of myocardial as an prior to Thus, was a that patients with in one a greater benefit cardiac with myocardial revascularization were perspective that had been for decades by data in over patients showing that of the left was with a improvement with myocardial This was the for the ISCHEMIA trial, which was to the of prior prior to coronary the of drug-eluting stents, the more use of to revascularization and a to more important that were into the trial. none of these trials were so the of a of PCI on symptoms not be with a design to the small of stable angina patients that PCI vs. on a of OMT in with The of in exercise and secondary were not significantly the at of These results for the very first time, the of a to angina relief with The recently published ISCHEMIA is the effectiveness trial of an vs. conservative management in patients with and limitations of trials patients with at myocardial at patients prior to coronary to and revascularization PCI and drug-eluting stents at interventional who were for their and in and OMT and for in of the The was a for angina, for heart and cardiac while the major secondary were to and symptoms and quality of life as by the coronary angiography was performed prior to to the of left main and the of a were the for the as with the conservative was At the was in the and in the conservative and at the was and was no of on a of the of new more angina, of OMT on and the of left coronary of was no in in the vs. the conservative in was no in the of the two although were more in the in early and more in the conservative in the late were and in angina and quality of life with an in patients who had angina of but more in patients with angina of while was no improvement in patients with less no angina of The most of ISCHEMIA was the of which was to the and which the and some secondary The was on the of for more for after PCI The secondary of was on the alone and the upper from the in more and these may be of the secondary of the at for the was in the and in the conservative a of while the at years was in the and in the conservative that was not significantly were significantly at years in the these were not significantly at and Thus, it is to the of the late in in the While it is that revascularization with CABG lower in the CABG epicardial and it is more to this would be true for PCI, as the of as a of of disease in coronary from the the in be by an in the use of which was significantly in the and the for of the first years of It is that the in was even in to the who did not revascularization of the which that this benefit be to most the late in with the did not into a in at which the interpretation that is a greater of these with of of patients with to revascularization vs. initial conservative which ISCHEMIA and were the that, although was no in the revascularization was with a of and angina but an of In the ISCHEMIA trial study of patients with kidney disease as with the same and was likewise no in vs. conservative for the secondary although the was with a of than the conservative and of of was no with regard to the two small sub-study of patients with in and over as is to these patients who were enrolled but not into ISCHEMIA they had no on This study to outcomes in this important It is that ISCHEMIA is and it be that the may at The results of the ISCHEMIA trial the of coronary and, the for and i.e. a and the even are an rationale for revascularization procedures to prevent in the These trial results the in history study on the of the coronary that the of remain and do not to cause in in an study of patients for of the results of COURAGE therapy at the of the is where the benefit of is and It is with all history that in ISCHEMIA were to the of on in in and in three more was no benefit from revascularization of the in albeit to OMT It is most that the of of arteries with a is a for the of the of all of the coronary arteries of an it is are that may be at to but most of these are not and not for intervention at the alone would at the of and the for a new cardiac Thus, it is to that to cause an may alone as a that not cause angina, may from a of the that cause angina and but is a for since it is by a and small The is to the of the to of they alone are to a While PCI would be to at for CABG would be to bypass more of and be with a of ISCHEMIA be to surgical bypass of greater of is with the of as was in ISCHEMIA showed that was no the two initial management in the of from for angina, heart cardiac ISCHEMIA in the of from cause in these the of OMT for and this remain our most important While revascularization have an important in relief and quality of our be to by that coronary and The ISCHEMIA trial of our prior management for patients with stable The and most important of ISCHEMIA is that if a the of the ISCHEMIA trial and has no angina and an quality of which a of patients with stable then is no for with an initial revascularization of OMT. the results of ISCHEMIA that is to no in to the of an epicardial coronary to the of The remains of for patients who angina OMT that quality of of and management for stable patients is in The first would be by history that the is stable that angina is not the quality of that heart Heart Association is not would be at that of which as in ISCHEMIA, are not The most is the of left main which was present in of patients for is the only that the of left main and are with but with to the small of patients with left main may not be testing, to the and of but it is that such would not be in an of a conservative management and that may be with an of cardiac is with and would management with a conservative would be to the of left For patients who do not these the of management would be to and as to angina and if Management of patients with stable coronary artery disease. coronary coronary heart left main coronary artery left New Heart optimal medical quality of Management of patients with stable coronary artery disease. coronary coronary heart left main coronary artery left New Heart optimal medical quality of It would be important to to of the to Patients who only would with the conservative with at patients who remain quality of life would be considered for with angiography and if on for patients who present with angina that is an would be to coronary artery and, if to coronary revascularization with PCI as In the results and the of the ISCHEMIA trial are to our and of the of patients on the and of myocardial and then revascularization of to that while the ISCHEMIA trial prior that cardiac outcomes are more in the of more coronary the results very that revascularization of not that in terms of and that the and of disease and and the for as the for and, in remain our of management for the stable with myocardial revascularization for symptoms and quality of life to OMT. Conflict of interest: none declared.

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