CIT 2020--Peak Dialogue| Prof. Gregg W.Stone with Prof.Jian Liu and Prof. Yi Li from China: Renew the dispute! Should stable coronary heart disease be treated with intervention?

The results of the ISCHEMIA trial showed that patients with stable coronary heart disease (SIHD) who had moderate to severe myocardial ischemia benefited from interventional therapy compared with OMT alone. Therefore, at present, there are different views on whether patients with stable coronary heart disease should undergo interventional therapy. How do they choose treatment options in clinical when encounters with such patients? This journal invites one of the ISCHEMIA trial researchers, Professor Gregg Stone from Mount Sinai School of Medicine, Professor Jian Liu from Peking University People's Hospital and Professor Yi Li from the First Affiliated Hospital of Sun Yat-sen University, to conduct in-depth discussions on relevant issues on this study.

 

Prof.Liu: The publication of the results of the ISCHEMIA trial has caused heated debate. What treatment strategies should be adopted for patients with stable coronary heart disease with symptoms? Could you share us your opinion?

Prof.Gregg W.Stone:Thank you very much. The ISCHEMIA trial was a very complex undertaking, and the results of the trial have to be considered very carefully. It is much more complex than to just say the trial was positive or the trial was negative. Overall, when we look at the number of events that occurred at a median 3.2-year follow-up among the 5179 randomized patients with stable coronary artery disease and moderate to severe ischemia, there was no overall major difference in the number of hard MACE (cardiovascular death, myocardial infarction, hospitalization, unstable angina, heart failure or cardiac arrest). However, the curves crossed. Early on, there were slightly more events in the invasive arm (patients undergoing angiography followed by PCI or CABG), mostly because of periprocedural myocardial infarction. But with longer term follow-up, there were actually fewer myocardial infarctions in that group. So the curves crossed at about two years, and at the end of four years, there were actually slightly fewer events in the invasive arm. We would rather have an adverse event later rather than early, so if we look at the overall time for which patients were free of events, it is similar between the two groups, but there was a difference in this trade-off between adverse periprocedural events in the invasive arm, and a better long-term prognosis in patients who were revascularized.

The second major part of this study was quality of life. We measured quality of life with the Seattle Angina Questionnaire. Quality of life was clearly better in patients who went to the cathlab and were revascularized. It is important to note that we actually only enrolled patients with no symptoms or mild symptoms in this trial. There were only 4% of the patients who had class III or class IV angina. Most patients were having either monthly angina or no angina. That was done intentionally to make sure that patients wouldn’t cross over and have revascularization for symptoms. Despite the fact that patients were having so few symptoms at baseline, during follow-up, they clearly felt better - they had a better quality of life with the invasive approach. If we look at the percentage of patients who were angina-free, it was substantially higher in the invasively treated patients during follow-up, all the way through the four years or longer, compared to the conservative approach. However, the final point is that the extent of the benefit in terms of improvement in quality of life really varied according to the symptoms at baseline. The more symptomatic patients were at baseline, the better their quality of life was with the invasive approach. If they were having any angina at baseline, even a couple of times per month, let alone weekly or daily, they felt better with revascularization. If the patients had silent ischemia (no symptoms at baseline) and had just enrolled in the trial (which was one-third of the patients), then you can’t make people having no symptoms feel better in the long-term. They felt similar with an invasive approach compared to a conservative approach. Overall, in my own opinion, I believe this trial was on the positive side for an invasive approach. There tended to be fewer longer-term events with the invasive approach (not statistically significantly different, but nonetheless, fewer events), and the patients who were having any symptoms at baseline clearly felt better. Importantly, the last thing I will say is that there was absolutely no difference in mortality. Despite the fact that we enrolled patients with mostly moderate to severe ischemia, these patients still had a very low mortality rate (around 1.5% per year). Even where the whole anterior wall was ischemic or with even with more extensive ischemia than that, they weren’t dropping dead. The mortality curves were superimposable. So, there was no rush to revascularize these patients. I believe, you can talk to the patients and find out their own preferences. If you have a patient who strongly wishes to avoid any procedures, even an angiogram, then you could consider medical therapy. Presuming they have coronary artery disease, you should do a CT scan first though to rule out left main disease, and that is a very important point. We excluded left main disease in these patients with a blinded CT scan before they were allowed to be enrolled. and almost 10% of patients with moderate to severe ischemia had left main disease. As long as you have undergone a non-invasive CT scan to rule out left main disease, then patients could be managed without an angiogram on medical therapy, and reserved for the cathlab if they had breakthrough symptoms or a myocardial infarction or other adverse events. On the other hand, if you have a patient who is having angina at baseline and who would really like to feel better faster, and don’t want to take medications (due to side effects, for example), then they can go right to the cathlab for angiography and then referral to either PCI or bypass surgery depending on the extent of the disease. Overall, those patients will have a more rapid resolution of their symptoms, and fewer long-term events with that approach.

 

Prof.Liu: Intravascular ultrasound (IVUS), coronary fraction flow reserve (FFR), optical coherence tomography (OCT), etc. have been used in the decision-making of interventional treatment of stable coronary heart disease. Would you please introduce us its guiding value in the evaluation of lesions ?

Prof.Gregg W.Stone:Once you decide you are going to treat the patient by PCI, you have to make sure that you treat the right lesions. We know that FFR, iFR, QFR and other physiological approaches that can be applied in the cathlab are very accurate for determining which lesions are ischemia producing lesions and therefore most likely associated with symptoms. So we should use physiologic lesion assessment on any intermediate stenosis (visually <80% severe) to determine which ones should undergo revascularization, at least with PCI. We also know it is very important that once you know which lesions to treat, you should get an optimal result. Stent implantation needs to be meticulous, and results, even with contemporary stents, vary with the minimal stent area achieved, and making sure all the significant disease is being treated and there is no residual untreated disease left at the edges, or any untreated dissections (at least major dissections, which can be difficult to see on an angiogram). We strongly believe that most cases of PCI, other than the most simple of cases, should undergo guidance with either intravascular ultrasound or optical coherence tomography to ensure an optimal stent implantation result. Finally, there is also some evidence that the prognosis depends on physiology post-procedure. As we have been normalizing the use of iFR or FFR, we are starting to do large scale randomized trials to see if doing that routine measurement of physiology after stenting to look for focal stent issues or distal disease or more diffuse disease or untreated disease, will lead to improved outcomes in those patients.

 

Prof.Liu:  In the ISCHEMIA trial, invasive treatment improved the prognosis of patients with angina than conservative treatment in some extent, but the benefit was limited to 65% of patients who had angina within 1 month before the group. What is your opinion about this?

Prof.Gregg W.Stone:Excellent point, and you are absolutely correct. The benefit in terms of improved quality of life and improved symptom control with regard to becoming angina-free was limited to the patients who were symptomatic on the Seattle Angina Questionnaire, which reflects four weeks prior to treatment. In the ISCHEMIA trial, approximately one-third of the patients (35%) had no symptoms within four weeks. While some of those patients developed symptoms over time, they didn’t have a major difference for whether they developed angina over time or what their quality of life was with the invasive approach versus conservative therapy. There were some slight trends showing they did a little better with the invasive approach, even if they were asymptomatic at baseline in terms of quality of life, but not statistically significant. On the other hand, if patients were having daily or weekly angina, or even just a couple of time a month, then they were likely to have more and more angina over time, and their likelihood of experiencing an substantial quality of life benefit and becoming angina-free was much better using the invasive approach. For example, the number needed to treat (NNT) for symptomatic patients was approximately 3-4. For every 3-4 patients we treated with the invasive approach compared to the conservative approach, we would make one patient angina-free. That is a very low NNT, so it’s a very good therapy.

 

Prof.Li: Looking at the ISCHEMIA trial results, it reminds me of another clinical trial from around 15 years ago, the COURAGE trial, which also involved patients with stable coronary artery disease, and showed that intervention compared to optimal medical therapy cannot improve survival of the patient. ISCHEMIA shows quite similar results. The difference is that the ISCHEMIA trial enrolled the patients with moderate to severe myocardial ischemia. I recall there was a small subgroup study of the MPS subgroup from the CAROTID study that demonstrated that for patients with >10% myocardial ischemia, if the ischemic territory could be decreased by >5%, there is a mortality improvement in these patients. Are there any similar subgroup analyses in the ISCHEMIA trial, because we know that the patients have >10% ischemic territory. After revascularization, to what extent were patients’ ischemia improved? Is there any data from your study on this group of patients?

Prof.Gregg W.Stone:That’s a great question. You are absolutely correct. The results of ISCHEMIA and COURAGE are, in many ways, similar. There were a few differences between COURAGE and ISCHEMIA that are important to understand. Of course, ISCHEMIA was testing a strategy of angiography with PCI or CABG versus medical therapy. In COURAGE, all the enrolled patients were randomized to PCI versus medical therapy after angiography. COURAGE was done in an earlier era when most of the patients treated by PCI received bare metal stents. Here, we used mostly contemporary second-generation drug-eluting stents. And then you mentioned the third big difference, in that ISCHEMIA required moderate to severe ischemia, while moderate to severe ischemia cases were represented by a minority of patients in COURAGE. So when we look at the differences between COURAGE and ISCHEMIA, there was no overall difference in death or myocardial infarction. But we did see in ISCHEMIA that late myocardial infarctions were clearly reduced. That is an important observation because those are the myocardial infarctions that tend to affect mortality, moreso than the procedural myocardial infarctions. We have proven very clearly now with ISCHEMIA that late myocardial infarctions are reduced. Second, the benefits in terms of being angina-free, which were present in COURAGE, were even more notable in ISCHEMIA. In COURAGE, the increase in being angina-free with PCI was lost by three years. In ISCHEMIA, it extended to four years and beyond. That probably reflects the use of good drug-eluting stents in ISCHEMIA compared to bare metal stents in COURAGE, and also that some of the worst patients had surgery in ISCHEMIA, whereas no patients had surgery in COURAGE. Finally, to directly answer your question, we don’t have any post-procedure ischemia testing in the ISCHEMIA trial. However, we are going to importantly be looking at the outcomes of the trial according to whether or not, in the invasive arm, the operator was able to achieve complete revascularization. We are doing a very detailed study of all of the invasive patients according to both anatomical and functional revascularization. We have not yet finished that analysis. We are hoping to present that at TCT this year as a late-breaking trial. That will, at least partially, address your question as to whether we can relieve most of the ischemia with revascularization, and whether that leads to better outcomes. Hopefully, we can present those data at TCT.

 

Prof.Li:  Do you think the ISCHEMIA trial will change future guidelines for the treatment of patients with stable angina?

Prof.Gregg W.Stone:It is hard to say how much it will affect the guidelines. It should affect the guidelines in subtle ways. Basically, ISCHEMIA provides support for both approaches, as there is absolutely no difference in mortality. It provides support for physicians and patients who want to wait and not go for upfront angiography or intervention, as long as they do the CT, as I mentioned, to exclude left main disease. These have to be selected patients with no heart failure and with manageable symptoms at baseline (class 0 to II). On the other hand, there is also a lot in ISCHEMIA to recommend the invasive approach in those patients. Even the patients with mild symptoms and stable disease benefitted in terms of quality of life, Dr Eugene Braunwald and Elliot Antman wrote in their editorial that there is a lot in ISCHEMIA to recommend an early invasive strategy. You don’t need to wait to see if a patient is failing medical therapy (breakthrough symptoms or intolerable side effects to their drugs). Even early on, before trying two or three anti-angina drugs, if the patient is showing moderate symptoms and suspected coronary disease, then you can go straight to angiography and revascularization if appropriate, and that will improve that patient’s quality of life. We will see how the guidelines react to the data. That will probably take several years, but these are the practical implications for caring for your patients.

 

Prof.Li: If the doctor chooses to do a stenting, they can explain to the patient that the stent will help improve symptoms, but there are doctors and patients who don’t like stents, so this gives the option to wait. As an interventional cardiologist, how do we make our decision in the future? How do we explain to our colleagues and our patients the importance of stent implantation?

Prof.Gregg W.Stone:Firstly, ISCHEMIA applies to a very small group of patients. These are patients with stable coronary disease, with no heart failure, nearly normal left ventricular function, who have had a CT angiogram to rule out left main disease. For those cases, doctors should talk to the patient. By placing a stent in those patients, you will not make the patient live longer. We have not found a subset yet in which patients will live longer. You are primarily treating those patients for symptom control, therefore you need to talk to the patient. Those patients who don’t desire a stent can be managed on medication until there are breakthrough symptoms or medication becomes intolerable, and then catheterization and stenting can occur later. On the other hand, those patients who want a more rapid and complete control of symptoms can be offered angiography and revascularization upfront. Again, very importantly, for patients who have acute coronary syndrome, STEMI or non-STEMI, we know that stents save lives and reduce rates of myocardial infarction. You have to strongly encourage those patients, because that is a very different situation. Patients with heart failure, from the STICH trial and other registries, live longer with complete revascularization. So, heart failure patients with extensive coronary disease, and patients with left main coronary disease need revascularization. There, you can strongly tell the patient that the stent may save their life and they should undergo angiography and revascularization.

 

Prof.Liu: Professor Stone, do you have any concluding remarks about the ISCHEMIA trial, and how it can influence daily practice?

Prof.Gregg W.Stone: ISCHEMIA was a very important study because, as the largest and most thorough study of its kind to-date, and the first to use contemporary therapies of good drug-eluting stents, ischemia guidelines and good bypass surgery techniques, it has really refined our knowledge of how to best treat coronary disease. We learned from ISCHEMIA that you will not make patients live longer. If you treat patients without left main disease, with stable symptoms, without heart failure, without acute coronary syndrome, and asymptomatic or with mild symptoms, you will not make them live longer. However, you can make them feel better if they are having even mild symptoms at baseline (as little as one or two episodes of angina per month). They will experience better quality of life with revascularization. If they are having daily or weekly angina episodes, the differences are even more profound. ISCHEMIA offers the strategy of not going to the cathlab versus going to the cathlab to define the coronary anatomy and to them make a revascularization decision with either PCI and bypass surgery depending on how complex the anatomy is. For eligible patients, it is very important to take your patient’s preferences into account. This is not a situation where the physician should beat their chest and say I know what is best for the patient. Unlike, for example, STEMI. We know what is best for the STEMI patient. They should go to the cathlab and get a primary PCI. The patient with left main disease should have either surgery or PCI. But for these types of patients, we have to listen to the patient and respect their wishes in terms of procedures and more rapid symptom relief versus a desire to try medications first. ISCHEMIA has taught us that that is a safe approach.