This transcript has been edited for clarity.
Gayatri Acharya, MD: Greetings. I'm Dr Gayatri Acharya, cardiology fellow at Mayo Clinic. Today we will be discussing the baseline characteristics of the ISCHEMIA trial. I'm joined by my colleague, Dr Raymond Gibbons, a senior cardiologist in cardiovascular medicine. Great to have you here.
Raymond Gibbons, MD: Thank you for having me.
Acharya: Would you share the background for the ISCHEMIA trial?
Gibbons: Twenty years ago we routinely sent everyone with an abnormal stress test to the cath lab in the belief that if we could identify enough coronary disease, the patient would benefit from stenting or bypass surgery. Mayo subsequently participated in the BARI 2D and COURAGE trials, which emphasized optimal medical therapy (OMT), and did not find benefit from coronary revascularization in many patients. That began to influence our practice. It also prompted the search, from a scientific standpoint, for how much ischemia was required to benefit from revascularization.
The nuclear substudy of the COURAGE trial, in which we participated, suggested that patients with ischemia of 10% of the left ventricle that improved with revascularization (percutaneous coronary intervention [PCI] + OMT) had better long-term outcomes. That figure was supported by observational data from one academic medical center which found that short-term mortality improved in patients in whom 10%-12.5% of the left ventricle was ischemic. But that same center found that long-term mortality was only improved in patients with at least 15% of the left ventricle that was ischemic; that criteria was based on the summed stress score, which, as you know, includes both the extent and the severity of ischemia, which many people have missed.
Acharya: I imagine that if we're trying to clarify an issue that's been studied previously, we would need many patients. What was the final enrollment of the ISCHEMIA trial?
Gibbons: The uncertainty about the amount of ischemia led the National Heart, Lung, and Blood Institute to support the ISCHEMIA trial. It was a big undertaking by hundreds of centers in many countries. The trial randomly assigned 5179 patients to receive OMT or OMT + PCI. That's a real triumph. It's the largest trial ever carried out in patients with stable coronary artery disease and exceeds the combined enrollment of the BARI 2D and COURAGE trials.
The Good, the Bad, and the Ugly
Gibbons: The patients were screened generally with CT coronary angiography for enrollment in ISCHEMIA, and indeed the CT angiography data show that most of these patients had severe coronary artery disease. That was certainly good news for the trial. However, about 10% of them were enrolled after invasive coronary angiography. The detailed coronary anatomy knowledge that use of that test implies may have excluded patients with the most severe disease in that subset.
The other positive feature of ISCHEMIA was that they anticipated crossovers, which is a known confounder in any procedural trials, so they only enrolled patients with mild angina to try to limit crossovers. Finally, the baseline medical therapy was truly outstanding. The rate of use of statins, aspirin, and antihypertensives exceeded 90% at baseline, which is remarkable. Even when other drugs weren't used that consistently, such as high-intensity statins, the baseline LDL cholesterol was still only 83 mg/dL [2.15 mmol/L] in these patients. All of these are very positive features of the trial.
Acharya: What are the possible areas of concern with the trial?
Gibbons: The baseline data raise several concerns. First, to improve enrollment, the investigators had to enroll patients in countries that were not used to doing stress imaging, and those patients qualified on the basis of their stress ECGs. Unfortunately, their clinical characteristics would suggest that they may be at lower risk. They were younger and less often had a prior history of infarction, coronary stenting, or bypass surgery, so their event rates may be on the low side, limiting the power of the study.
Second, the baseline data showed that not all of the patients actually met the enrollment criteria for the trial. Some participating centers thought that patients had enough ischemia to qualify, but the review of their data by the core laboratory did not find that to be the case, and that was true for almost 15% of the patients who were enrolled. That would further suggest that the overall event rates may be lower than what is necessary to show a benefit from revascularization.
Finally, if one looks carefully at the data, fewer than 1000 patients—only about 18%—actually met the severe nuclear ischemia criteria that were reported in the observational data to benefit from revascularization.
Acharya: Why did the ISCHEMIA trial have difficulty enrolling patients with moderate to severe ischemia?
Gibbons: That's a key question that everyone will be asking. I would offer a couple of explanations. One is that the trial was not well supported in the United States. Fewer than 1000 patients, only about 1 in 6 of the patients enrolled in the trial, were enrolled in our country. That may reflect the recognized difficulty these days of doing clinical trials in the United States or the fact that US interventionists didn't believe that there was equipoise in this trial, even though three review articles,[8,9,10] including one by a leading US interventionist, believed that there was equipoise.
The second issue is more interesting, which is that patients with moderate to severe ischemia are on the decline. Several long-term studies,[11,12,13] including two from Mayo Clinic, have found that patients with truly severely abnormal stress tests are a vanishing breed. So there are simply fewer of these patients available for enrollment in ISCHEMIA.
Acharya: Would you say that's related to better medical optimization of patients? Maybe we're catching patients sooner?
Gibbons: It probably reflects the known data that have been reported by the Centers for Disease Control and Prevention, which show that rates of high blood pressure, high cholesterol, and smoking in the United States have declined over the past 20 years, and that we are doing a better job-certainly not a perfect job-of treating high blood pressure and hyperlipidemia. Those factors have probably contributed to the decline in severely abnormal stress tests. We'll need more studies to actually learn whether those factors have contributed to a true decline in anatomic coronary artery disease.
Acharya: What else should we know? As fellows, it's always nice to hear from the experts what we should know about the trials. What other features of ISCHEMIA should we be aware of as we await more information?
Gibbons: We should realize that this trial is going to set a new standard for the treatment of stable coronary artery disease because of its size, its excellent baseline medical therapy, and all of the other data that they've collected. The endpoint results are anticipated later this year, and I believe that they are going to be an important landmark for us.
However, the trial may not have enough patients with moderate to severe ischemia to answer the original question, and that reflects the decline in numbers of those patients. If the trial is negative when the primary endpoint is published, and particularly if the event rates are low in both groups, I believe that the trial will be criticized on those grounds. I don't think it will represent a failure of ISCHEMIA if that happens; I think it will represent the success of OMT when it is consistently delivered, which it appears to have been in the baseline data shown in this paper.
Acharya: It's excellent to hear from you as an expert in the field and to learn a little more about the ISCHEMIA trial as we await more information. Thank you very much, Dr Gibbons, for these very important insights. And thank you, the audience, for joining us on the heart.org | Medscape Cardiology.
© 2019 Mayo Clinic
Cite this: ISCHEMIA: Do Baseline Data Hint at Triumph for OMT? - Medscape - Apr 22, 2019.