What Do ISCHEMIA and CIAO Tell Us About CVD?

Pam R. Taub, MD, FACC, FASPC; Harmony R. Reynolds, MD


August 28, 2020

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This transcript has been edited for clarity.

Pam R. Taub, MD, FACC, FASPC: Hi. I'm Pam Taub. I'm a cardiologist and associate professor of medicine, and director of the Cardiac Rehabilitation and Wellness Program at University of California, San Diego. I'm delighted to have Dr Harmony Reynolds join me for a discussion today on women and heart disease. Harmony is a cardiologist and clinical trialist at the New York University Grossman School of Medicine, where she is the director of the Sarah Ross Soter Center for Women's Cardiovascular Research. We are going to be discussing CIAO and ISCHEMIA.

ISCHEMIA and CIAO: Implications for Women

Taub: Harmony, you are one of the investigators of the landmark ISCHEMIA trial that reiterated the importance of medical management. What do you think are some of the implications of ISCHEMIA and CIAO in terms of management of women's cardiovascular disease?

Harmony R. Reynolds, MD: ISCHEMIA and CIAO are very nicely complementary to one another. In ISCHEMIA, we found that there was no difference in outcomes in women and men, which was interesting because there were fewer women in the study than one might have expected just based on the number of women with cardiovascular disease. ISCHEMIA included about 23%, women and that is actually consistent with registry data because we selected for obstructive coronary disease, so, much ischemia. Women who were screened for the ISCHEMIA trial had overall on average a little less ischemia and definitely less coronary disease. More of the women were excluded from randomization after enrollment in ISCHEMIA because they had no obstructive coronary disease and so they could not potentially benefit from randomization. Some of those women were included in the CIAO-ISCHEMIA ancillary study, where we followed them for over a year and did serial testing to understand a little bit about the natural history of women and men with ischemia and no obstructive coronary artery disease. The primary trial results of ISCHEMIA showed no difference between the two randomized treatment arms, and that was true for both women and men. So I think the results are equally applicable to both sexes.

Variability in Symptoms

Taub: CIAO and ISCHEMIA are truly landmark studies that change our approach to management of both men and women with cardiovascular disease, and really highlight the importance of medical management, something that was emphasized by the earlier COURAGE study. One thing you noted in the CIAO study is that there are periods where symptoms tend to be more active in women. What are your hypotheses on how factors such as stress and blood pressure could contribute to these periods of heightened symptoms?

Reynolds: One of the most interesting and surprising things that we found in CIAO was that there was a lot of variability in symptoms. There was also a lot of variability in the amount of ischemia on the stress echocardiogram. In general, the stress echocardiograms were showing moderate or severe ischemia as determined by a core laboratory at the time of enrollment, because that was the enrollment criterion based on ISCHEMIA. And then at follow-up, half of the stress echocardiograms had become normal. It was not a fluke because the same core lab was reading all of these studies, and not only were they blinded to whether it was ISCHEMIA or CIAO (we use the same study number and we know that they were blinded because they read them as ISCHEMIA enrollment studies), but also they were blinded to whether it was a CIAO initial study or a follow-up because the period of enrollment for ISCHEMIA was long enough that it was possible to do that (and again use the same study number).

This is a real change and it's a surprising change for many, including us. When it comes to symptoms, we know about this for typical angina with obstructive coronary disease, but sometimes they are different from day to day, and they are different even over the course of the day and over the course of the season. We're accustomed to that. There are probably many inputs into this: the autonomic nervous system, emotional stress, how much physical activity somebody is doing on a given day, the temperature outside, diastolic left ventricular function, wall stress, oxygen-carrying capacity, and medicine. It's already fairly complicated even for a relatively static process like atherosclerosis causing angina. Maybe some of that variability from day to day in obstructive coronary disease patients with angina is actually due to microvascular disease, because we know that the two can coexist. Focusing on the INOCAs (ischemia with no obstructive coronary artery disease) cohorts — their variability and angina — also makes sense for all of the reasons that I described.

The pathophysiology is probably even more dynamic. Spasm is a cause of INOCA. In the CorMicA study, consecutive patients undergoing cardiac catheterization who were found to have no obstructive disease were sent for invasive testing. Almost 40% had inducible coronary spasm on provocative testing. And spasm is obviously inherently very variable. It's either there or it's not. And so it makes sense that people would have symptoms that are worse at one moment than another. I think that microvascular coronary disease is also present in almost everybody and it was present in almost 70% of patients in CorMicA. That is probably also variable from day to day. We happen to see a change that was trending downward over the year in CIAO, simply because we enrolled people based on their most severe ischemia. Patients tend to present to doctors to get testing when they are feeling their worst. That just makes sense to me clinically. And so there was more room for improvement than there was for worsening. But clearly, there is ebb and flow to this. Why exactly some days are worse than others requires a lot more research.

Is Medical Management Better Than an Invasive Strategy?

Taub: These are just really insightful observations. One thing that I noted about the ISCHEMIA study is that 42% of the patients had diabetes and 10% were using insulin. We're now in a new era where we're really looking at diabetes as a cardiovascular disease, and looking at evidence-based drugs for the management of type 2 diabetes that also have an impact on cardiovascular disease. If there were more emphasis on the management of diabetes with evidence-based drugs such as GLP-1 agonists and SGLT2 inhibitors, do you think that we may have seen that medical management actually won over an invasive strategy?

Reynolds: Medical and invasive treatments are constantly changing over time. We worked hard to use most current evidence. We changed the blood pressure threshold during the trial so that sites were aiming for 130 mm Hg systolic instead of 140 mm Hg and changed the diastolic blood pressure target. We tried to incorporate all of the most recent evidence about drugs, but the timing of the trial is going to limit us in a certain way to which medications and invasive treatments were most prevalent at that time. It's a very interesting question. There was no difference between treatment arms in the median 3.2-year follow-up that we had so far. Maybe extension of follow-up in ISCHEMIA, which we hope will be funded soon by the National Heart, Lung, and Blood Institute (NHLBI), will give us some insight into what you are talking about. We will also be analyzing the relationship between meeting medical therapy treatment goals and outcomes in ISCHEMIA, and that may be revealing in that regard.

Promising Agents for Microvascular Dysfunction

Taub: Microvascular dysfunction, which is very poorly understood and is more prevalent in women, is something that you addressed in the CIAO study. There are some preliminary data suggesting potential benefit of calcium channel blockers. What are other promising agents for microvascular dysfunction?

Reynolds: We certainly need more clinical trials in microvascular dysfunction. One going on is called WARRIOR and it's funded by the Department of Defense. They are testing a strategy of using ACE inhibitors or ARBs, statins, and aspirin against usual care. Those are very promising agents as well. In CIAO, over 1 year, we didn't see a relationship between those particular agents and 1-year change in angina or 1-year change in ischemia. But we were not really powered for that. It's a small study and really more of a mechanistic study. We did find, as you mentioned, a relationship between the use of calcium channel blockers very early on at the time of stress testing and improvement over 1 year in angina frequency. That is something that we should explore further. I certainly would not consider it definitive with our small study.

Taub: All of the work that you have done really highlights how important it is to manage cardiovascular disease. In the era of COVID-19, we are seeing that patients with underlying cardiovascular disease and diabetes have more of a severe impact of COVID-19. Your studies really highlight how we need to treat the underlying diabetes, hypertension, and hyperlipidemia. You were in New York which was the epicenter of COVID-19 a few months ago. Now that seems to be shifting. What are some insights that you have on underlying cardiovascular disease and how it impacts COVID-19?

Reynolds: We are still learning and we're having to learn on the fly. There are some parallels between CIAO and COVID-19 so it's interesting that we are talking about both today. No obstructive coronary disease is found in a relatively high proportion of patients who are undergoing cardiac catheterization when they look like they are having myocardial infarction (MI) with COVID-19. We've been very interested in trying to figure out what is causing cardiovascular damage in COVID-19. Many patients have elevated troponins, and elevated troponin is a risk factor for adverse outcomes, so we wondered what is causing this elevation in troponins. There are scattered reports, including one case in our autopsy series, of very focal myocardial lymphocytic inflammation that does not really look particularly like myocarditis. We did not find any variance in myocytes on electron microscopy. Instead, we found lots of thrombosis. In the heart, there was microvascular thrombosis. There was something that I don't think has been described before, which was venous thrombosis in the heart causing MI with pathologic evidence of MI in one case. You see this big wedge of tail myocardium and that case had thrombosis in the vein. I think thrombosis is a major mediator here. How does that relate to the increased risk among patients with diabetes? I'm not sure; it is definitely something for further study.

Taub: Thank you for all of these wonderful insights, and I hope that some of your research will lead to a better understanding of the mechanisms of the disease and important treatment strategies.

Reynolds: Thanks. It's been a great discussion.

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