Commentary

I want to move to the risk factors for coronary disease in men and women. Jeff, any differences or similarities—I will tell you my view right off the bat that the risk factors for coronary artery disease other than pregnancy and menopause, which act through the traditional risk factors, are the same in men and women. There are some differences, and in her chapter in Braunwald, Kristin pointed them out nicely with regard to diabetes from the INTERHEART study.⁵ What's your view on the risk factors in women? Do we need preventive cardiology clinics for women and for women with heart disease; or can women come to a good preventive cardiology clinic that men also attend?

Dr. Borer: I think the risk factors are pretty much the same. You know there may be some difference in outcomes associated with them, depending on age, with diabetes being the major issue. I think it has more of an impact on the risk of second MI in women than in men, so you have to be more cognizant of that particular risk factor in women.
But I think the risk factors are the same and the outcomes are qualitatively the same and so managing patients by trying to modulate risk factors could be done in a preventive cardiology unit. I don't think you need a separate one for women because I don't think we have sufficient data to suggest a different strategy for men and for women.

Dr. Amsterdam: Kristin?

Dr. Newby: I fully agree. I think that the risk factors, with the possible exception that diabetes may be a bit more potent in women, are still the same risk factors and we know the same treatments work in both groups. What I think is probably more interesting that came out of INTERHEART is the differential strength (stronger in women) of protective factors in women, such as exercise, eating a diet high in fruits and vegetables, and stress management. I found that to be interesting and potentially more informative than focusing on the proven risk factors.

Dr. Amsterdam: I think INTERHEART was a very good confirmation of what the Framingham Heart Study showed of the traditional risk factors.⁶
Would you agree, Kristin, that there is more stress in general, more psychosocial stress, in women than in men? Women work and take care of the kids—men do better now, but we don't do an equal share, and that seems to be having an impact on women and disease.

Dr. Newby: Yes, I think that's an interesting topic, and I think women's response to stress and the stress that they're dealing with may be different from that of men. I think there’s an interesting analysis that’s been done several times about support systems and how men do better when they have a spouse who’s taking care of them. Women on the other hand who have an MI who have a spouse actually do worse. So I'm not sure what that tells us, but I do think there's either some disproportionate amount of reaction to or ability to cope with stress among women. That is important for us to understand and work through.

Dr. Amsterdam: It's too bad we can't measure that the way we measure other data. Now let’s consider a stable patient who comes to the physician’s office with chest pain; it may be typical or atypical, but it's suspicious enough for the patient to require a careful evaluation.

Jeff, which tests do you use to detect objective evidence of myocardial ischemia and, by that factor, the likelihood of coronary disease? Exercise treadmill test has really been criticized for its value in women because of its repute for false-positive results. Some experts have advised going straight to a stress imaging study rather than a plain treadmill test.

Dr. Borer: Yes, well that's what I do, actually. The fact is that the specificity of every noninvasive test for coronary disease is lower in women than in men. The positive predictive value is less in women than in men, whether it be a radionuclide test, an echocardiography-based test, it's not just the exercise ECG. On the other hand, it seems to me that radionuclide based studies do provide greater accuracy in women than the exercise ECG, and that's what I use.

Dr. Amsterdam: This is good because thus far we’ve had little divergence of opinion and it’s good to have some differences. Thus, I am a strong proponent of the standard treadmill exercise test without imaging if the patient has a normal baseline ECG and the history indicates adequate exercise capacity, which is what the guidelines have advocated since 1998. So in these circumstances, my first test is always a plain treadmill study, and we train our fellows to follow this approach. Kristin, your method?

Dr. Newby: Yes, I think I fall a little bit more to Jeff's side of things. So there are two things I think about: one is if I see someone in the clinic who gives me a very good story for symptoms and they can't exercise and can’t do their usual activities. I either move to treat them with medicines and cardiac rehabilitation or with catheterization if I have a high index of suspicion that I'm dealing with coronary disease. So I think that's the first thing. Then the question is, how do we think about the individuals who aren't clear-cut? We want to rule out the group that has the highest likelihood to have a false positive—the ones with very atypical symptoms, which I know we all see in our clinics—and try to work with them without doing any kind of further workup if at all possible. But if I do a stress test in the clinic and I'm on the fence, I, like Jeff, add imaging.⁷ We tend to use more stress echocardiography than stress nuclear testing, but I don't think there's any evidence that one or the other, if you're adding an imaging study, is of a major advantage given the certain limitations of each study in terms of acquiring the images.

Dr. Amsterdam: I agree. They're very similar. Perhaps nuclear is a little more sensitive but less specific than echocardiography.

So I will say quickly, I think we all know the guidelines of the American Heart Association/American College of Cardiology (AHA/ACC)⁸—that I just referred to. They’re very clear in stating that the first test, even in a stable female patient with a normal ECG who is able to exercise should  be a plain old treadmill test. I'll make a couple of points; one, we have in press a paper on how to improve the positive predictive value of the exercise ECG in women. The more risk factors the patient has, the deeper the ST depression, the longer the persistence of ST depression post-exercise—these factors can increase the positive predictive value up to about 80% in women. These ECG factors and non-ECG factors can help. We have also shown that if the patient, man or woman, has a positive treadmill ECG and can exercise to 10 metabolic equivalents (METs) (Stage III of the Bruce test),^9,10 and then is referred for a stress imaging test, about a 94% likelihood that the stress imaging test will be negative.

So the key point for me is that assessment of the exercise test by ECG criteria alone is really obsolete. The poor positive predictive value and the high rate of false-positives are based solely on the ST segment when we know that the best prognostic indicator is functional capacity. So that's why we always do the treadmill test as the initial assessment unless there's a baseline abnormality or the patient can't exercise.

Do you have any comments on any of that, Jeff?

Dr. Borer: I would like to pick up on two things that Kristin said. She talked about symptoms, and I would say that if a person, and it doesn't matter whether it's a man or a woman, has typical symptoms, when you take a history and you put that person on a treadmill and you reproduce the symptoms and you do an ECG alone, the concordance of the ECG criteria and the symptoms has a very high predictive value. But that presumes that the person is going to get symptoms on the treadmill, and that may not happen.

The other point that Kristin made was that in certain patients with a compelling clinical presentation, she might go right to a catheterization. I would have to say that I don't do that. I guess it depends on how you define “compelling.” If somebody has a history that is consistent with crescendo angina, yes, I would send him or her to catheterization. But absent that, I would not because I believe that the noninvasive testing provides prognostic information even in the presence of true coronary disease.

The problem that I fear in sending someone to catheterization is that, in the absence of prognostically important disease, they'll come away with an angioplasty with no evidence at all that anything will be done to their natural history, only that their symptoms will be relieved and that could probably have been done with medication. So I'm a little more wary about sending people directly to catheterization. There really has to be what I would call a “compelling” history, and it may be the same that Kristin would call “compelling” or it may not.

Dr. Amsterdam: We’re into the art of medicine, and it’s legitimate to differ if we have good reasons to go down different paths. Kristin, your comments on this?

Dr. Newby: When I'm thinking of somebody whose symptoms are compelling enough that I would send them to catheterization, it's the woman who was active, doing her gardening, mowing her yard, whatever last summer, and has over the past several months progressively deteriorated in terms of activity levels. So you already know their functional capacity has declined by what they're telling you through their history. In those individuals, I don't think you gain a lot more information by documenting that on a treadmill.
You're right, maybe you take that person and you try medication or maybe you commit that they have coronary disease, you're going to take care of their angina, get them immediately back to functional capacity. I think those are style points, as you said, the art of medicine. To some extent it's driven by patient preferences and I think that's the thing that sometimes we also forget.

There are patients who, once they know what you're thinking, don't want to deal with multiple steps to get to an answer—they want to know. Maybe that's right, maybe that's wrong, maybe that's part of what's wrong with our healthcare system. We could debate those points for another hour probably, but I think those factors all play into how we manage patients.
Then you think about taking somebody when you're pretty sure you know what the diagnosis is, or maybe you're pretty sure you don't think it's the diagnosis, but you put them on a treadmill or a treadmill with imaging and it's positive, and now you've got them worried. They want to know what's going on, and they may or not may not tolerate medicines.
These are some practical issues in medicine, as well, that we have to think about, and again, as you said, that's the art of medicine.

Dr. Amsterdam: Kristin, can you tell us a little about the Duke treadmill score? Because it's a very good prognostic indicator.

Dr. Newby: Absolutely, and that's very much like the study that you described of Dr. Beller’s; if they could do 10 METs they did well. We look at our treadmill information, often we get it in conjunction with an echocardiogram, but we don't ignore the key physiologic information and functional information from the treadmill for that very reason; there's a high correlation between either METs done or various scores. The Duke treadmill score being one type of score that one can use to estimate risk of dying in the next 5 to 10 years. So it is critically important that we don't ignore the wealth of information that can come from a treadmill test.

Dr. Amsterdam: Jeff, you mentioned chest pain and it reminded me of something important. One of the values of stress testing is whether we can reproduce symptoms that the patient complains of. I notice in our chest pain unit that patients are admitted because of chest pain and they have a normal resting ECG and negative troponins. Our first test in these stable patients is, again, a treadmill test, symptom-limited. They do more activity on that stress test than they do in life but it's very rare that we reproduce chest pain. Even the patients with coronary disease who go to catheterization because of a very positive stress test infrequently have chest pain during treadmill testing. Does your experience differ?

Dr. Borer: No, my experience doesn't differ. When people come out of our chest pain unit they have an imaging study, they don't have a straight treadmill exercise ECG, but that's irrelevant. One thing that is perhaps not irrelevant is that in New York State, in the absence of unstable angina, you now cannot send a patient to catheterization unless you have demonstrated a positive exercise test.

If they have unstable symptoms certainly you can catheterize them, but in a patient who has relatively stable symptomatology, you can't catheterize (and expect to be paid for the procedure) unless you have evidence of ischemia by a noninvasive test. Those are called “appropriate use” criteria that have been set up here in New York, and if you don't follow them, the insurance companies don't pay. So there is sort of a brake here that may not be true in other states.

Dr. Amsterdam: Kristin, do you have such a proscription in North Carolina? What about your experience of chest pain on the treadmill?

Dr. Newby: First of all, we don't have such a proscription here in North Carolina, although I think we’re going to see more and more of that. New York State has historically been a leader in that kind of thinking through and monitoring and implementing criteria like these, and I don't think it's all a bad thing.
In our chest pain unit or in referrals from clinic, I agree that most of the time we don't reproduce symptoms on the treadmill and I find it very reassuring if we do reproduce symptoms and we don't see anything. Again we’re doing imaging, but imaging in conjunction with the ECG, I think, is actually helpful information to have, but in the majority of cases we don't reproduce the symptoms.

Dr. Amsterdam: It’s a really interesting phenomenon, and as Jeff has said, the symptoms on the treadmill are very important.
Let's make a couple of comments on heart failure. There are data that women present more typically with heart failure as an indication of underlying coronary disease and also have more diastolic dysfunction than men in terms of the underlying cause of heart failure. Your experience with this, Jeff?

Dr. Borer: I think that's true but, in fact, the truth also is that most heart failure trials include relatively few women. It was the same point you made earlier. I'm one of the principal investigators of the “Systolic Heart failure treatment with the If inhibitor ivabradine Trial” (SHIFT), the largest heart failure trial that was ever done, which used a heart rate–slowing strategy for therapy. We had a marked paucity of women compared with men, so it's hard to draw conclusions.¹¹ I don't know how many women were excluded because they had diastolic dysfunction. It certainly is my perception and my bias that among those with heart failure, women commonly do have diastolic dysfunction, probably more commonly than men, but I think we lack a lot of information about heart failure.

Let me talk about the area on which I focus most closely, which is valve disease. The manifestations of valve disease are different in women than in men. That was demonstrated most clearly in the Placement of Aortic Transcatheter Valve Trial (PARTNER),¹² which was the first randomized trial of any mechanical therapy for valve disease in patients with aortic stenosis. In fact, approximately 50% of the population in PARTNER comprised women. The average age was the mid-80s, and by that age there are a lot more women around than men. So perhaps that had something to do with the fact that many of those who entered the trial were women.

The extraordinary finding was that women did better with percutaneous valve therapy than men. Not only did they do better than men, the relationship of percutaneous therapy to conventional surgery was better in women than in men. We could speculate on why that is (smaller arteries, harder to do, etc.), and maybe we’d be correct. However, the finding does suggest that there is a difference, at least for that valve disease, in women compared to men.

Another piece of evidence is the affects of treadmill testing in patients with aortic stenosis. Asymptomatic patients with aortic stenosis are marked out as being at relatively high risk for the imminent development of symptoms or worse based on treadmill studies. One of the criteria that seems to separate those at high risk is ST-segment depression, but it’s 1 mm in men and 2 mm in women. We see the valve dysfunction more commonly in women than in men and the manifestations of the disease differ.

Dr. Amsterdam: These are fascinating data. We're doing an investigation in aortic stenosis and the overwhelming number of patients are men, but, in general, I agree with your point that because we’re seeing patients with critical aortic stenosis who are now in their 80s, women comprise a very large component of that group.
Kristin, can you comment on heart failure and whether there is more diastolic dysfunction, more hypertension in women, and so relative to their body size they have more left ventricular hypertrophy?

Dr. Newby: Yes I think that diastolic dysfunction is more common and more severe with aging. There are also the effects of hypertension. Both of those obviously are issues with older women. I do share Jeff's concern not just related to diastolic dysfunction, but related to any heart failure, of the underrepresentation of women in our studies that are designed to help us understand how to manage heart failure from any cause.

Dr. Amsterdam: Jeff; do you 
remember the age cutoff in the 
SHIFT trial?

Dr. Borer: There was no upper age limit. However, the average age was 60 years and 11% were at least 75 years old.

Dr. Newby: And if diastolic dysfunction is more prevalent in the older population than systolic dysfunction, the age of the patients will be a big factor in the etiology of the heart failure.

Dr. Amsterdam: In the past decade there has been a proliferation of publications on women with normal epicardial coronary arteries in whom myocardial ischemia and its complications are caused by (or associated with) coronary microvascular dysfunction (which is also presumed to be the underlying cause of the elusive Syndrome X). What are your comments on this issue?

Dr. Borer: Regarding microvascular dysfunction and Syndrome X, it has been my impression that some people, more often women than men, present with atypical chest pain and even typical angina pectoris in the absence of large-vessel coronary artery disease or any other definable cause, but that the problem of demonstrable microvascular dysfunction in these settings is relatively uncommon. Patients who present in this way may benefit from certain types of vasodilating drugs with relief of symptoms. However, I believe the outcomes for these people are substantially more benign than for those with large coronary artery obstruction. In other words, frank MI or death are relatively infrequently associated with this syndrome. Moreover, although it is plausible to associate such a clinical picture with endothelial dysfunction and small-vessel (arteriolar) hyperreactivity, I think the pathophysiology of the syndrome is not clear. Thus, while Syndrome X may contribute to debility and activity limitation particularly in women, I do not think the syndrome is very clearly understood and do not think it is an important cause of premature death or major morbidity.

Dr. Amsterdam: We're going to have concluding comments from each of you. So briefly, Jeff, are there any comments you'd like to make?

Dr. Borer: I would summarize that the situation with regard to sensitivity about heart disease in women has improved considerably over the past decade or two, but we still have a long way to go to understand the differences between women and men in terms of the manifestations of heart disease and how to manage them.

Dr. Amsterdam: And Kristin.

Dr. Newby: I completely agree with Jeff's summary. The only thing I would add is that of the therapies that we have available, they are all equally effective in men and women, and I think we just need to focus right now as we're trying to understand the underlying differences in pathophysiology and symptoms, among other things, on applying these therapies as appropriately as we can across both sexes.

Dr. Amsterdam: Thank you.

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I want to move to the risk factors for coronary disease in men and women. Jeff, any differences or similarities—I will tell you my view right off the bat that the risk factors for coronary artery disease other than pregnancy and menopause, which act through the traditional risk factors, are the same in men and women. There are some differences, and in her chapter in Braunwald, Kristin pointed them out nicely with regard to diabetes from the INTERHEART study.⁵ What's your view on the risk factors in women? Do we need preventive cardiology clinics for women and for women with heart disease; or can women come to a good preventive cardiology clinic that men also attend?

Dr. Borer: I think the risk factors are pretty much the same. You know there may be some difference in outcomes associated with them, depending on age, with diabetes being the major issue. I think it has more of an impact on the risk of second MI in women than in men, so you have to be more cognizant of that particular risk factor in women.
But I think the risk factors are the same and the outcomes are qualitatively the same and so managing patients by trying to modulate risk factors could be done in a preventive cardiology unit. I don't think you need a separate one for women because I don't think we have sufficient data to suggest a different strategy for men and for women.

Dr. Amsterdam: Kristin?

Dr. Newby: I fully agree. I think that the risk factors, with the possible exception that diabetes may be a bit more potent in women, are still the same risk factors and we know the same treatments work in both groups. What I think is probably more interesting that came out of INTERHEART is the differential strength (stronger in women) of protective factors in women, such as exercise, eating a diet high in fruits and vegetables, and stress management. I found that to be interesting and potentially more informative than focusing on the proven risk factors.

Dr. Amsterdam: I think INTERHEART was a very good confirmation of what the Framingham Heart Study showed of the traditional risk factors.⁶
Would you agree, Kristin, that there is more stress in general, more psychosocial stress, in women than in men? Women work and take care of the kids—men do better now, but we don't do an equal share, and that seems to be having an impact on women and disease.

Dr. Newby: Yes, I think that's an interesting topic, and I think women's response to stress and the stress that they're dealing with may be different from that of men. I think there’s an interesting analysis that’s been done several times about support systems and how men do better when they have a spouse who’s taking care of them. Women on the other hand who have an MI who have a spouse actually do worse. So I'm not sure what that tells us, but I do think there's either some disproportionate amount of reaction to or ability to cope with stress among women. That is important for us to understand and work through.

Dr. Amsterdam: It's too bad we can't measure that the way we measure other data. Now let’s consider a stable patient who comes to the physician’s office with chest pain; it may be typical or atypical, but it's suspicious enough for the patient to require a careful evaluation.

Jeff, which tests do you use to detect objective evidence of myocardial ischemia and, by that factor, the likelihood of coronary disease? Exercise treadmill test has really been criticized for its value in women because of its repute for false-positive results. Some experts have advised going straight to a stress imaging study rather than a plain treadmill test.

Dr. Borer: Yes, well that's what I do, actually. The fact is that the specificity of every noninvasive test for coronary disease is lower in women than in men. The positive predictive value is less in women than in men, whether it be a radionuclide test, an echocardiography-based test, it's not just the exercise ECG. On the other hand, it seems to me that radionuclide based studies do provide greater accuracy in women than the exercise ECG, and that's what I use.

Dr. Amsterdam: This is good because thus far we’ve had little divergence of opinion and it’s good to have some differences. Thus, I am a strong proponent of the standard treadmill exercise test without imaging if the patient has a normal baseline ECG and the history indicates adequate exercise capacity, which is what the guidelines have advocated since 1998. So in these circumstances, my first test is always a plain treadmill study, and we train our fellows to follow this approach. Kristin, your method?

Dr. Newby: Yes, I think I fall a little bit more to Jeff's side of things. So there are two things I think about: one is if I see someone in the clinic who gives me a very good story for symptoms and they can't exercise and can’t do their usual activities. I either move to treat them with medicines and cardiac rehabilitation or with catheterization if I have a high index of suspicion that I'm dealing with coronary disease. So I think that's the first thing. Then the question is, how do we think about the individuals who aren't clear-cut? We want to rule out the group that has the highest likelihood to have a false positive—the ones with very atypical symptoms, which I know we all see in our clinics—and try to work with them without doing any kind of further workup if at all possible. But if I do a stress test in the clinic and I'm on the fence, I, like Jeff, add imaging.⁷ We tend to use more stress echocardiography than stress nuclear testing, but I don't think there's any evidence that one or the other, if you're adding an imaging study, is of a major advantage given the certain limitations of each study in terms of acquiring the images.

Dr. Amsterdam: I agree. They're very similar. Perhaps nuclear is a little more sensitive but less specific than echocardiography.

So I will say quickly, I think we all know the guidelines of the American Heart Association/American College of Cardiology (AHA/ACC)⁸—that I just referred to. They’re very clear in stating that the first test, even in a stable female patient with a normal ECG who is able to exercise should  be a plain old treadmill test. I'll make a couple of points; one, we have in press a paper on how to improve the positive predictive value of the exercise ECG in women. The more risk factors the patient has, the deeper the ST depression, the longer the persistence of ST depression post-exercise—these factors can increase the positive predictive value up to about 80% in women. These ECG factors and non-ECG factors can help. We have also shown that if the patient, man or woman, has a positive treadmill ECG and can exercise to 10 metabolic equivalents (METs) (Stage III of the Bruce test),^9,10 and then is referred for a stress imaging test, about a 94% likelihood that the stress imaging test will be negative.

So the key point for me is that assessment of the exercise test by ECG criteria alone is really obsolete. The poor positive predictive value and the high rate of false-positives are based solely on the ST segment when we know that the best prognostic indicator is functional capacity. So that's why we always do the treadmill test as the initial assessment unless there's a baseline abnormality or the patient can't exercise.

Do you have any comments on any of that, Jeff?

Dr. Borer: I would like to pick up on two things that Kristin said. She talked about symptoms, and I would say that if a person, and it doesn't matter whether it's a man or a woman, has typical symptoms, when you take a history and you put that person on a treadmill and you reproduce the symptoms and you do an ECG alone, the concordance of the ECG criteria and the symptoms has a very high predictive value. But that presumes that the person is going to get symptoms on the treadmill, and that may not happen.

The other point that Kristin made was that in certain patients with a compelling clinical presentation, she might go right to a catheterization. I would have to say that I don't do that. I guess it depends on how you define “compelling.” If somebody has a history that is consistent with crescendo angina, yes, I would send him or her to catheterization. But absent that, I would not because I believe that the noninvasive testing provides prognostic information even in the presence of true coronary disease.

The problem that I fear in sending someone to catheterization is that, in the absence of prognostically important disease, they'll come away with an angioplasty with no evidence at all that anything will be done to their natural history, only that their symptoms will be relieved and that could probably have been done with medication. So I'm a little more wary about sending people directly to catheterization. There really has to be what I would call a “compelling” history, and it may be the same that Kristin would call “compelling” or it may not.

Dr. Amsterdam: We’re into the art of medicine, and it’s legitimate to differ if we have good reasons to go down different paths. Kristin, your comments on this?

Dr. Newby: When I'm thinking of somebody whose symptoms are compelling enough that I would send them to catheterization, it's the woman who was active, doing her gardening, mowing her yard, whatever last summer, and has over the past several months progressively deteriorated in terms of activity levels. So you already know their functional capacity has declined by what they're telling you through their history. In those individuals, I don't think you gain a lot more information by documenting that on a treadmill.
You're right, maybe you take that person and you try medication or maybe you commit that they have coronary disease, you're going to take care of their angina, get them immediately back to functional capacity. I think those are style points, as you said, the art of medicine. To some extent it's driven by patient preferences and I think that's the thing that sometimes we also forget.

There are patients who, once they know what you're thinking, don't want to deal with multiple steps to get to an answer—they want to know. Maybe that's right, maybe that's wrong, maybe that's part of what's wrong with our healthcare system. We could debate those points for another hour probably, but I think those factors all play into how we manage patients.
Then you think about taking somebody when you're pretty sure you know what the diagnosis is, or maybe you're pretty sure you don't think it's the diagnosis, but you put them on a treadmill or a treadmill with imaging and it's positive, and now you've got them worried. They want to know what's going on, and they may or not may not tolerate medicines.
These are some practical issues in medicine, as well, that we have to think about, and again, as you said, that's the art of medicine.

Dr. Amsterdam: Kristin, can you tell us a little about the Duke treadmill score? Because it's a very good prognostic indicator.

Dr. Newby: Absolutely, and that's very much like the study that you described of Dr. Beller’s; if they could do 10 METs they did well. We look at our treadmill information, often we get it in conjunction with an echocardiogram, but we don't ignore the key physiologic information and functional information from the treadmill for that very reason; there's a high correlation between either METs done or various scores. The Duke treadmill score being one type of score that one can use to estimate risk of dying in the next 5 to 10 years. So it is critically important that we don't ignore the wealth of information that can come from a treadmill test.

Dr. Amsterdam: Jeff, you mentioned chest pain and it reminded me of something important. One of the values of stress testing is whether we can reproduce symptoms that the patient complains of. I notice in our chest pain unit that patients are admitted because of chest pain and they have a normal resting ECG and negative troponins. Our first test in these stable patients is, again, a treadmill test, symptom-limited. They do more activity on that stress test than they do in life but it's very rare that we reproduce chest pain. Even the patients with coronary disease who go to catheterization because of a very positive stress test infrequently have chest pain during treadmill testing. Does your experience differ?

Dr. Borer: No, my experience doesn't differ. When people come out of our chest pain unit they have an imaging study, they don't have a straight treadmill exercise ECG, but that's irrelevant. One thing that is perhaps not irrelevant is that in New York State, in the absence of unstable angina, you now cannot send a patient to catheterization unless you have demonstrated a positive exercise test.

If they have unstable symptoms certainly you can catheterize them, but in a patient who has relatively stable symptomatology, you can't catheterize (and expect to be paid for the procedure) unless you have evidence of ischemia by a noninvasive test. Those are called “appropriate use” criteria that have been set up here in New York, and if you don't follow them, the insurance companies don't pay. So there is sort of a brake here that may not be true in other states.

Dr. Amsterdam: Kristin, do you have such a proscription in North Carolina? What about your experience of chest pain on the treadmill?

Dr. Newby: First of all, we don't have such a proscription here in North Carolina, although I think we’re going to see more and more of that. New York State has historically been a leader in that kind of thinking through and monitoring and implementing criteria like these, and I don't think it's all a bad thing.
In our chest pain unit or in referrals from clinic, I agree that most of the time we don't reproduce symptoms on the treadmill and I find it very reassuring if we do reproduce symptoms and we don't see anything. Again we’re doing imaging, but imaging in conjunction with the ECG, I think, is actually helpful information to have, but in the majority of cases we don't reproduce the symptoms.

Dr. Amsterdam: It’s a really interesting phenomenon, and as Jeff has said, the symptoms on the treadmill are very important.
Let's make a couple of comments on heart failure. There are data that women present more typically with heart failure as an indication of underlying coronary disease and also have more diastolic dysfunction than men in terms of the underlying cause of heart failure. Your experience with this, Jeff?

Dr. Borer: I think that's true but, in fact, the truth also is that most heart failure trials include relatively few women. It was the same point you made earlier. I'm one of the principal investigators of the “Systolic Heart failure treatment with the If inhibitor ivabradine Trial” (SHIFT), the largest heart failure trial that was ever done, which used a heart rate–slowing strategy for therapy. We had a marked paucity of women compared with men, so it's hard to draw conclusions.¹¹ I don't know how many women were excluded because they had diastolic dysfunction. It certainly is my perception and my bias that among those with heart failure, women commonly do have diastolic dysfunction, probably more commonly than men, but I think we lack a lot of information about heart failure.

Let me talk about the area on which I focus most closely, which is valve disease. The manifestations of valve disease are different in women than in men. That was demonstrated most clearly in the Placement of Aortic Transcatheter Valve Trial (PARTNER),¹² which was the first randomized trial of any mechanical therapy for valve disease in patients with aortic stenosis. In fact, approximately 50% of the population in PARTNER comprised women. The average age was the mid-80s, and by that age there are a lot more women around than men. So perhaps that had something to do with the fact that many of those who entered the trial were women.

The extraordinary finding was that women did better with percutaneous valve therapy than men. Not only did they do better than men, the relationship of percutaneous therapy to conventional surgery was better in women than in men. We could speculate on why that is (smaller arteries, harder to do, etc.), and maybe we’d be correct. However, the finding does suggest that there is a difference, at least for that valve disease, in women compared to men.

Another piece of evidence is the affects of treadmill testing in patients with aortic stenosis. Asymptomatic patients with aortic stenosis are marked out as being at relatively high risk for the imminent development of symptoms or worse based on treadmill studies. One of the criteria that seems to separate those at high risk is ST-segment depression, but it’s 1 mm in men and 2 mm in women. We see the valve dysfunction more commonly in women than in men and the manifestations of the disease differ.

Dr. Amsterdam: These are fascinating data. We're doing an investigation in aortic stenosis and the overwhelming number of patients are men, but, in general, I agree with your point that because we’re seeing patients with critical aortic stenosis who are now in their 80s, women comprise a very large component of that group.
Kristin, can you comment on heart failure and whether there is more diastolic dysfunction, more hypertension in women, and so relative to their body size they have more left ventricular hypertrophy?

Dr. Newby: Yes I think that diastolic dysfunction is more common and more severe with aging. There are also the effects of hypertension. Both of those obviously are issues with older women. I do share Jeff's concern not just related to diastolic dysfunction, but related to any heart failure, of the underrepresentation of women in our studies that are designed to help us understand how to manage heart failure from any cause.

Dr. Amsterdam: Jeff; do you 
remember the age cutoff in the 
SHIFT trial?

Dr. Borer: There was no upper age limit. However, the average age was 60 years and 11% were at least 75 years old.

Dr. Newby: And if diastolic dysfunction is more prevalent in the older population than systolic dysfunction, the age of the patients will be a big factor in the etiology of the heart failure.

Dr. Amsterdam: In the past decade there has been a proliferation of publications on women with normal epicardial coronary arteries in whom myocardial ischemia and its complications are caused by (or associated with) coronary microvascular dysfunction (which is also presumed to be the underlying cause of the elusive Syndrome X). What are your comments on this issue?

Dr. Borer: Regarding microvascular dysfunction and Syndrome X, it has been my impression that some people, more often women than men, present with atypical chest pain and even typical angina pectoris in the absence of large-vessel coronary artery disease or any other definable cause, but that the problem of demonstrable microvascular dysfunction in these settings is relatively uncommon. Patients who present in this way may benefit from certain types of vasodilating drugs with relief of symptoms. However, I believe the outcomes for these people are substantially more benign than for those with large coronary artery obstruction. In other words, frank MI or death are relatively infrequently associated with this syndrome. Moreover, although it is plausible to associate such a clinical picture with endothelial dysfunction and small-vessel (arteriolar) hyperreactivity, I think the pathophysiology of the syndrome is not clear. Thus, while Syndrome X may contribute to debility and activity limitation particularly in women, I do not think the syndrome is very clearly understood and do not think it is an important cause of premature death or major morbidity.

Dr. Amsterdam: We're going to have concluding comments from each of you. So briefly, Jeff, are there any comments you'd like to make?

Dr. Borer: I would summarize that the situation with regard to sensitivity about heart disease in women has improved considerably over the past decade or two, but we still have a long way to go to understand the differences between women and men in terms of the manifestations of heart disease and how to manage them.

Dr. Amsterdam: And Kristin.

Dr. Newby: I completely agree with Jeff's summary. The only thing I would add is that of the therapies that we have available, they are all equally effective in men and women, and I think we just need to focus right now as we're trying to understand the underlying differences in pathophysiology and symptoms, among other things, on applying these therapies as appropriately as we can across both sexes.

Dr. Amsterdam: Thank you.

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I want to move to the risk factors for coronary disease in men and women. Jeff, any differences or similarities—I will tell you my view right off the bat that the risk factors for coronary artery disease other than pregnancy and menopause, which act through the traditional risk factors, are the same in men and women. There are some differences, and in her chapter in Braunwald, Kristin pointed them out nicely with regard to diabetes from the INTERHEART study.⁵ What's your view on the risk factors in women? Do we need preventive cardiology clinics for women and for women with heart disease; or can women come to a good preventive cardiology clinic that men also attend?

Dr. Borer: I think the risk factors are pretty much the same. You know there may be some difference in outcomes associated with them, depending on age, with diabetes being the major issue. I think it has more of an impact on the risk of second MI in women than in men, so you have to be more cognizant of that particular risk factor in women.
But I think the risk factors are the same and the outcomes are qualitatively the same and so managing patients by trying to modulate risk factors could be done in a preventive cardiology unit. I don't think you need a separate one for women because I don't think we have sufficient data to suggest a different strategy for men and for women.

Dr. Amsterdam: Kristin?

Dr. Newby: I fully agree. I think that the risk factors, with the possible exception that diabetes may be a bit more potent in women, are still the same risk factors and we know the same treatments work in both groups. What I think is probably more interesting that came out of INTERHEART is the differential strength (stronger in women) of protective factors in women, such as exercise, eating a diet high in fruits and vegetables, and stress management. I found that to be interesting and potentially more informative than focusing on the proven risk factors.

Dr. Amsterdam: I think INTERHEART was a very good confirmation of what the Framingham Heart Study showed of the traditional risk factors.⁶
Would you agree, Kristin, that there is more stress in general, more psychosocial stress, in women than in men? Women work and take care of the kids—men do better now, but we don't do an equal share, and that seems to be having an impact on women and disease.

Dr. Newby: Yes, I think that's an interesting topic, and I think women's response to stress and the stress that they're dealing with may be different from that of men. I think there’s an interesting analysis that’s been done several times about support systems and how men do better when they have a spouse who’s taking care of them. Women on the other hand who have an MI who have a spouse actually do worse. So I'm not sure what that tells us, but I do think there's either some disproportionate amount of reaction to or ability to cope with stress among women. That is important for us to understand and work through.

Dr. Amsterdam: It's too bad we can't measure that the way we measure other data. Now let’s consider a stable patient who comes to the physician’s office with chest pain; it may be typical or atypical, but it's suspicious enough for the patient to require a careful evaluation.

Jeff, which tests do you use to detect objective evidence of myocardial ischemia and, by that factor, the likelihood of coronary disease? Exercise treadmill test has really been criticized for its value in women because of its repute for false-positive results. Some experts have advised going straight to a stress imaging study rather than a plain treadmill test.

Dr. Borer: Yes, well that's what I do, actually. The fact is that the specificity of every noninvasive test for coronary disease is lower in women than in men. The positive predictive value is less in women than in men, whether it be a radionuclide test, an echocardiography-based test, it's not just the exercise ECG. On the other hand, it seems to me that radionuclide based studies do provide greater accuracy in women than the exercise ECG, and that's what I use.

Dr. Amsterdam: This is good because thus far we’ve had little divergence of opinion and it’s good to have some differences. Thus, I am a strong proponent of the standard treadmill exercise test without imaging if the patient has a normal baseline ECG and the history indicates adequate exercise capacity, which is what the guidelines have advocated since 1998. So in these circumstances, my first test is always a plain treadmill study, and we train our fellows to follow this approach. Kristin, your method?

Dr. Newby: Yes, I think I fall a little bit more to Jeff's side of things. So there are two things I think about: one is if I see someone in the clinic who gives me a very good story for symptoms and they can't exercise and can’t do their usual activities. I either move to treat them with medicines and cardiac rehabilitation or with catheterization if I have a high index of suspicion that I'm dealing with coronary disease. So I think that's the first thing. Then the question is, how do we think about the individuals who aren't clear-cut? We want to rule out the group that has the highest likelihood to have a false positive—the ones with very atypical symptoms, which I know we all see in our clinics—and try to work with them without doing any kind of further workup if at all possible. But if I do a stress test in the clinic and I'm on the fence, I, like Jeff, add imaging.⁷ We tend to use more stress echocardiography than stress nuclear testing, but I don't think there's any evidence that one or the other, if you're adding an imaging study, is of a major advantage given the certain limitations of each study in terms of acquiring the images.

Dr. Amsterdam: I agree. They're very similar. Perhaps nuclear is a little more sensitive but less specific than echocardiography.

So I will say quickly, I think we all know the guidelines of the American Heart Association/American College of Cardiology (AHA/ACC)⁸—that I just referred to. They’re very clear in stating that the first test, even in a stable female patient with a normal ECG who is able to exercise should  be a plain old treadmill test. I'll make a couple of points; one, we have in press a paper on how to improve the positive predictive value of the exercise ECG in women. The more risk factors the patient has, the deeper the ST depression, the longer the persistence of ST depression post-exercise—these factors can increase the positive predictive value up to about 80% in women. These ECG factors and non-ECG factors can help. We have also shown that if the patient, man or woman, has a positive treadmill ECG and can exercise to 10 metabolic equivalents (METs) (Stage III of the Bruce test),^9,10 and then is referred for a stress imaging test, about a 94% likelihood that the stress imaging test will be negative.

So the key point for me is that assessment of the exercise test by ECG criteria alone is really obsolete. The poor positive predictive value and the high rate of false-positives are based solely on the ST segment when we know that the best prognostic indicator is functional capacity. So that's why we always do the treadmill test as the initial assessment unless there's a baseline abnormality or the patient can't exercise.

Do you have any comments on any of that, Jeff?

Dr. Borer: I would like to pick up on two things that Kristin said. She talked about symptoms, and I would say that if a person, and it doesn't matter whether it's a man or a woman, has typical symptoms, when you take a history and you put that person on a treadmill and you reproduce the symptoms and you do an ECG alone, the concordance of the ECG criteria and the symptoms has a very high predictive value. But that presumes that the person is going to get symptoms on the treadmill, and that may not happen.

The other point that Kristin made was that in certain patients with a compelling clinical presentation, she might go right to a catheterization. I would have to say that I don't do that. I guess it depends on how you define “compelling.” If somebody has a history that is consistent with crescendo angina, yes, I would send him or her to catheterization. But absent that, I would not because I believe that the noninvasive testing provides prognostic information even in the presence of true coronary disease.

The problem that I fear in sending someone to catheterization is that, in the absence of prognostically important disease, they'll come away with an angioplasty with no evidence at all that anything will be done to their natural history, only that their symptoms will be relieved and that could probably have been done with medication. So I'm a little more wary about sending people directly to catheterization. There really has to be what I would call a “compelling” history, and it may be the same that Kristin would call “compelling” or it may not.

Dr. Amsterdam: We’re into the art of medicine, and it’s legitimate to differ if we have good reasons to go down different paths. Kristin, your comments on this?

Dr. Newby: When I'm thinking of somebody whose symptoms are compelling enough that I would send them to catheterization, it's the woman who was active, doing her gardening, mowing her yard, whatever last summer, and has over the past several months progressively deteriorated in terms of activity levels. So you already know their functional capacity has declined by what they're telling you through their history. In those individuals, I don't think you gain a lot more information by documenting that on a treadmill.
You're right, maybe you take that person and you try medication or maybe you commit that they have coronary disease, you're going to take care of their angina, get them immediately back to functional capacity. I think those are style points, as you said, the art of medicine. To some extent it's driven by patient preferences and I think that's the thing that sometimes we also forget.

There are patients who, once they know what you're thinking, don't want to deal with multiple steps to get to an answer—they want to know. Maybe that's right, maybe that's wrong, maybe that's part of what's wrong with our healthcare system. We could debate those points for another hour probably, but I think those factors all play into how we manage patients.
Then you think about taking somebody when you're pretty sure you know what the diagnosis is, or maybe you're pretty sure you don't think it's the diagnosis, but you put them on a treadmill or a treadmill with imaging and it's positive, and now you've got them worried. They want to know what's going on, and they may or not may not tolerate medicines.
These are some practical issues in medicine, as well, that we have to think about, and again, as you said, that's the art of medicine.

Dr. Amsterdam: Kristin, can you tell us a little about the Duke treadmill score? Because it's a very good prognostic indicator.

Dr. Newby: Absolutely, and that's very much like the study that you described of Dr. Beller’s; if they could do 10 METs they did well. We look at our treadmill information, often we get it in conjunction with an echocardiogram, but we don't ignore the key physiologic information and functional information from the treadmill for that very reason; there's a high correlation between either METs done or various scores. The Duke treadmill score being one type of score that one can use to estimate risk of dying in the next 5 to 10 years. So it is critically important that we don't ignore the wealth of information that can come from a treadmill test.

Dr. Amsterdam: Jeff, you mentioned chest pain and it reminded me of something important. One of the values of stress testing is whether we can reproduce symptoms that the patient complains of. I notice in our chest pain unit that patients are admitted because of chest pain and they have a normal resting ECG and negative troponins. Our first test in these stable patients is, again, a treadmill test, symptom-limited. They do more activity on that stress test than they do in life but it's very rare that we reproduce chest pain. Even the patients with coronary disease who go to catheterization because of a very positive stress test infrequently have chest pain during treadmill testing. Does your experience differ?

Dr. Borer: No, my experience doesn't differ. When people come out of our chest pain unit they have an imaging study, they don't have a straight treadmill exercise ECG, but that's irrelevant. One thing that is perhaps not irrelevant is that in New York State, in the absence of unstable angina, you now cannot send a patient to catheterization unless you have demonstrated a positive exercise test.

If they have unstable symptoms certainly you can catheterize them, but in a patient who has relatively stable symptomatology, you can't catheterize (and expect to be paid for the procedure) unless you have evidence of ischemia by a noninvasive test. Those are called “appropriate use” criteria that have been set up here in New York, and if you don't follow them, the insurance companies don't pay. So there is sort of a brake here that may not be true in other states.

Dr. Amsterdam: Kristin, do you have such a proscription in North Carolina? What about your experience of chest pain on the treadmill?

Dr. Newby: First of all, we don't have such a proscription here in North Carolina, although I think we’re going to see more and more of that. New York State has historically been a leader in that kind of thinking through and monitoring and implementing criteria like these, and I don't think it's all a bad thing.
In our chest pain unit or in referrals from clinic, I agree that most of the time we don't reproduce symptoms on the treadmill and I find it very reassuring if we do reproduce symptoms and we don't see anything. Again we’re doing imaging, but imaging in conjunction with the ECG, I think, is actually helpful information to have, but in the majority of cases we don't reproduce the symptoms.

Dr. Amsterdam: It’s a really interesting phenomenon, and as Jeff has said, the symptoms on the treadmill are very important.
Let's make a couple of comments on heart failure. There are data that women present more typically with heart failure as an indication of underlying coronary disease and also have more diastolic dysfunction than men in terms of the underlying cause of heart failure. Your experience with this, Jeff?

Dr. Borer: I think that's true but, in fact, the truth also is that most heart failure trials include relatively few women. It was the same point you made earlier. I'm one of the principal investigators of the “Systolic Heart failure treatment with the If inhibitor ivabradine Trial” (SHIFT), the largest heart failure trial that was ever done, which used a heart rate–slowing strategy for therapy. We had a marked paucity of women compared with men, so it's hard to draw conclusions.¹¹ I don't know how many women were excluded because they had diastolic dysfunction. It certainly is my perception and my bias that among those with heart failure, women commonly do have diastolic dysfunction, probably more commonly than men, but I think we lack a lot of information about heart failure.

Let me talk about the area on which I focus most closely, which is valve disease. The manifestations of valve disease are different in women than in men. That was demonstrated most clearly in the Placement of Aortic Transcatheter Valve Trial (PARTNER),¹² which was the first randomized trial of any mechanical therapy for valve disease in patients with aortic stenosis. In fact, approximately 50% of the population in PARTNER comprised women. The average age was the mid-80s, and by that age there are a lot more women around than men. So perhaps that had something to do with the fact that many of those who entered the trial were women.

The extraordinary finding was that women did better with percutaneous valve therapy than men. Not only did they do better than men, the relationship of percutaneous therapy to conventional surgery was better in women than in men. We could speculate on why that is (smaller arteries, harder to do, etc.), and maybe we’d be correct. However, the finding does suggest that there is a difference, at least for that valve disease, in women compared to men.

Another piece of evidence is the affects of treadmill testing in patients with aortic stenosis. Asymptomatic patients with aortic stenosis are marked out as being at relatively high risk for the imminent development of symptoms or worse based on treadmill studies. One of the criteria that seems to separate those at high risk is ST-segment depression, but it’s 1 mm in men and 2 mm in women. We see the valve dysfunction more commonly in women than in men and the manifestations of the disease differ.

Dr. Amsterdam: These are fascinating data. We're doing an investigation in aortic stenosis and the overwhelming number of patients are men, but, in general, I agree with your point that because we’re seeing patients with critical aortic stenosis who are now in their 80s, women comprise a very large component of that group.
Kristin, can you comment on heart failure and whether there is more diastolic dysfunction, more hypertension in women, and so relative to their body size they have more left ventricular hypertrophy?

Dr. Newby: Yes I think that diastolic dysfunction is more common and more severe with aging. There are also the effects of hypertension. Both of those obviously are issues with older women. I do share Jeff's concern not just related to diastolic dysfunction, but related to any heart failure, of the underrepresentation of women in our studies that are designed to help us understand how to manage heart failure from any cause.

Dr. Amsterdam: Jeff; do you 
remember the age cutoff in the 
SHIFT trial?

Dr. Borer: There was no upper age limit. However, the average age was 60 years and 11% were at least 75 years old.

Dr. Newby: And if diastolic dysfunction is more prevalent in the older population than systolic dysfunction, the age of the patients will be a big factor in the etiology of the heart failure.

Dr. Amsterdam: In the past decade there has been a proliferation of publications on women with normal epicardial coronary arteries in whom myocardial ischemia and its complications are caused by (or associated with) coronary microvascular dysfunction (which is also presumed to be the underlying cause of the elusive Syndrome X). What are your comments on this issue?

Dr. Borer: Regarding microvascular dysfunction and Syndrome X, it has been my impression that some people, more often women than men, present with atypical chest pain and even typical angina pectoris in the absence of large-vessel coronary artery disease or any other definable cause, but that the problem of demonstrable microvascular dysfunction in these settings is relatively uncommon. Patients who present in this way may benefit from certain types of vasodilating drugs with relief of symptoms. However, I believe the outcomes for these people are substantially more benign than for those with large coronary artery obstruction. In other words, frank MI or death are relatively infrequently associated with this syndrome. Moreover, although it is plausible to associate such a clinical picture with endothelial dysfunction and small-vessel (arteriolar) hyperreactivity, I think the pathophysiology of the syndrome is not clear. Thus, while Syndrome X may contribute to debility and activity limitation particularly in women, I do not think the syndrome is very clearly understood and do not think it is an important cause of premature death or major morbidity.

Dr. Amsterdam: We're going to have concluding comments from each of you. So briefly, Jeff, are there any comments you'd like to make?

Dr. Borer: I would summarize that the situation with regard to sensitivity about heart disease in women has improved considerably over the past decade or two, but we still have a long way to go to understand the differences between women and men in terms of the manifestations of heart disease and how to manage them.

Dr. Amsterdam: And Kristin.

Dr. Newby: I completely agree with Jeff's summary. The only thing I would add is that of the therapies that we have available, they are all equally effective in men and women, and I think we just need to focus right now as we're trying to understand the underlying differences in pathophysiology and symptoms, among other things, on applying these therapies as appropriately as we can across both sexes.

Dr. Amsterdam: Thank you.

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Any time a clinician is starting to push to higher diuretic doses with no response or is starting to consider additional therapies, one should be cognizant of the risk of additional electrolyte wasting and worsening renal function and assured that these safety parameters are closely monitored. This is when patient selection for more aggressive diuretic regimens must be carefully considered. In addition, there remain many unanswered questions about appropriate alternative therapies and the role of such in further increasing or perhaps mitigating these risks. Alternative therapies studied to date include low dose dopamine, low dose nesiritide, and other vasoactive agents.

With regard specifically to ototoxicity, this is an adverse effect that is probably very underappreciated and perhaps it’s because clinicians rarely monitor it. Most clinicians are very aware that if you administer a large, single, IV bolus dose of 180 mg of furosemide too rapidly (for example, greater than 4 mg per minute), the risk of ototoxicity is increased, but I’m less certain at what precise dose of a furosemide continuous infusion a clinician should avoid or more assertively monitor for ototoxicity. Perhaps the focus of future research should include assessing the role of these additional or alternative therapies in minimizing toxicities including ototoxicity. Do you have any suggestions, Dr. Mehra?

DR. MEHRA: I think that the data suggest that cochlear toxicity or ototoxicity is related to the peak effects and not the trough effect, so the higher the bolus dosing, the more the chance that one could have cochlear toxicity, particularly if there are other ototoxic agents being administered concomitantly. For example, if someone is receiving a drug like a gentamycin-type analog, for instance, along with a diuretic infusion or a diuretic bolus, I think there’s magnification of that ototoxicity. Frankly that isn’t the overriding concern of most clinicians, and in fact we do not systematically study it, as you’ve pointed out. I often am more concerned in the diuretic resistant patients with the best dosing strategy. I know that, Tien, you have done some work in that regard and I wonder if we could turn the conversation toward discussing what kind of combination diuretic strategies really work in reducing fluid overload.

DR. NG: Clearly another option which is commonly used in practice is the combination of diuretic agents, specifically a loop diuretic added to a thiazide agent, a thiazide which is still effective even in the setting of poor renal perfusion. There are a lot of observational and small studies that have evaluated whether or not the addition of a thiazide, such as metolazone, to a loop diuretic, such as furosemide or bumetanide, augments sodium excretion and urine output. A paper that was published in the Journal of the American College of Cardiology summarized some of these data found a signal for increased urine output.⁶ Our group recently evaluated the addition of metolazone to furosemide, compared to just a continuous infusion of furosemide, and found a statistically significant greater increase in mean hourly urine output with the combination compared to furosemide used by itself.

What was interesting about our data, which are consistent with some of the existing data, is there was actually no signal for worsening renal function in our patients who received the combination, although there was a signal for an increased risk of electrolyte disturbances. So the conclusion of our study, since it was an observational study, was because of potential differences in clinical efficacy and safety, there is a great need for further study in prospective trials of these alternative strategies, such as combining agents, to truly understand whether these therapies are more effective while remaining relatively safe.

DR. RODGERS: These studies have made important contributions to the literature, but as Tien explains, are not optimally designed trials. Thus, there is need for prospective evaluations to address these unanswered questions. When conducting these future prospective studies, it will be important to include endpoints such as 30-day rehospitalization. If these alternative regimens more effectively diurese, then length of hospital stay may even be reduced by a day or two. With that said, I would be concerned that patients might subsequently suffer other adverse consequences such as continued unwanted diuresis and related adverse effects post-discharge. This is an important question to address with agents such as metolazone, given the long half-life and considerable intra- and inter-patient variability in onset of action with this agent. Future prospective trials need to address outcomes, such as length of stay and rehospitalization at 30 days, for these very reasons.

There are many reasons these trials have not been prospectively conducted in the past, and one major rate-limiting factor is the uniqueness of the population of patients with refractory fluid overload. When clinicians are faced with these patients, they often start to inquire about the appropriateness of a right heart catheter and inotropic therapy simply because diuretic refractoriness may be an indicator of low cardiac output. Patient characteristics such as concomitant inotropic therapy was most often an exclusion criteria for the previously discussed trials.

DR. MEHRA: So let me respond to that, Jo Ellen. First of all, I was taught to use a lot of metolazone, and frankly, as I matured clinically, I became less enamored by that drug as I realized how tough a drug it was on the kidneys and on electrolyte balance. There is this notion of what is the appropriate clinical endpoint, and I think you alluded to it. The endpoint needs to be clinically relevant. The endpoint should focus on the patient and not be one where the clinician feels better. Essentially we have been a bit swayed by how much urine output can be evoked and how much fluid can be removed. We have a large number of papers and data emerging that tell us that there may be a significant disconnect between the amount of fluid removal and clinical outcomes. As an example, studies like the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST)⁷ with a vasopressin receptor antagonist showed effectiveness of the drug tolvaptan in improving hyponatremia, and in reducing weight in patients significantly, compared to placebo, but was no better than placebo in influencing 24 month outcomes from a cardiovascular endpoint. So we have to fundamentally ask the question, do any of these strategies actually make a real difference in patients?

The other issue is that we need to do a better job of discriminating among the distinct patient groups that present with diuretic resistance syndrome. So, for example, it would be clinically less useful to start using incremental diuretic strategies and multiple drug regimens in a patient who has a clear low output state causing diuretic resistance. In such a patient, perhaps, a strategy that improves cardiac output with or without the need for mechanical circulatory support might be the appropriate one to overcome diuretic resistance.

In another situation where you have acute pulmonary edema, for instance, in the setting of severe hypertension or acute ischemic syndromes, I think the treatment ought to be very different. In such situations, step number one from a clinical standpoint is to segregate the patients into classifications of why the diuretic resistance has occurred and what is the relationship of that diuretic resistance to pump function. As an example, most of the multiple drug use strategies that work do so in the setting where true renal causes of diuretic resistance have occurred. This is manifested pathologically by the development of tubular hypertrophy, which determines classical diuretic resistance. In those situations, even considering a “renal rest” such as with ultrafiltration for a few days in some series has shown to be of benefit. It is in those situations where using multiple agents may be beneficial from a fluid removal standpoint. You’re right, Jo Ellen, we have to ask ourselves to what end we are actually making patients better. And our definitions of how we make patients better are equally critical.

Tien, do you have some thoughts about that?

DR. NG: Yes, I have to agree. I think an issue has always been, what is the appropriate endpoint for our acute heart failure patients? This has been debated for years and years now, and when you look at the safety signals or the safety endpoints that are currently being used and the efficacy endpoints, we really don’t know whether these are the optimal safety and efficacy endpoints. In one sense we’re using urine output, and as you’ve pointed out there are clearly data showing that urine output isn’t necessarily the greatest indicator of an improved prognosis in these patients. At the same time, looking at serum creatinine changes as a measure of renal function obviously has its limitations as well. With serum creatinine one wouldn’t expect large changes in these relatively short-term trials, as it is a delayed marker of renal injury. So in the future, to look at the renal safety of these agents it will be important to incorporate some novel, more accurate and early markers of acute kidney injury. I think that will help us understand whether or not we are actually doing something beneficial for these patients or whether we are just treating ourselves.

DR. RODGERS: I completely agree, Dr. Ng. I think that many of our future trials are focusing on either the right population or the right endpoint. Some good examples, Dr. Mehra just mentioned ultrafiltration and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial,⁸ which is currently recruiting patients, and this study is specifically enrolling patients who are congested and fluid overloaded, but who have experienced renal insufficiency. The primary endpoint is a combination of weight and renal function changes. I am optimistic that any follow-up studies to CARRESS will assess endpoints such as mortality and rehospitalization. Other trials such as the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial⁹ with the agent relaxin, also are enrolling patients with mild to moderate renal insufficiency. This trial is designed to assess clinically meaningful endpoints such as worsening heart failure associated with longer length of stay, as well as 60-day outcomes. It is great that these trials are addressing how to manage the patients that clinicians most struggle with.

DR. NG: Would either of you like to comment on some of the novel pharmacologic approaches which are currently being evaluated? This includes low dose nesiritide compared to low dose dopamine, the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE) trial,¹⁰ designer natriuretic peptides such as CDNP or CUNP. Thus far agents such as vasopressin antagonists and adenosine receptor antagonists haven’t been associated with positive results from a cardiorenal standpoint; however, I was wondering if you believe these agents may still have a potential role?

DR. RODGERS: The ROSE trial, again alludes to what we previously discussed regarding the addition of other agents in an attempt to minimize toxicity of diuretic therapy. This trial is assessing our ability to effectively manage the fluid overload without causing renal injury. Similar to RELAX,⁹ the ROSE trial is enrolling patients with impaired renal function as defined by a creatinine clearance between 15 and 60 mL/min. As Dr. Ng had suggested, they are utilizing a new marker for renal dysfunction in this trial. Their primary endpoint is change in cystatin C. Cystatin C is an excellent marker of kidney function because it is devoid of some of the limitations or inaccuracies of measuring serum creatinine, specifically it may more readily detect milder forms of renal impairment. Also, it is more reliable in patients with varying muscle mass or protein intake, which is commonly a problem in our heart failure patients who have cachexia due to low cardiac output or fluid overload.

Any time a clinician is starting to push to higher diuretic doses with no response or is starting to consider additional therapies, one should be cognizant of the risk of additional electrolyte wasting and worsening renal function and assured that these safety parameters are closely monitored. This is when patient selection for more aggressive diuretic regimens must be carefully considered. In addition, there remain many unanswered questions about appropriate alternative therapies and the role of such in further increasing or perhaps mitigating these risks. Alternative therapies studied to date include low dose dopamine, low dose nesiritide, and other vasoactive agents.

With regard specifically to ototoxicity, this is an adverse effect that is probably very underappreciated and perhaps it’s because clinicians rarely monitor it. Most clinicians are very aware that if you administer a large, single, IV bolus dose of 180 mg of furosemide too rapidly (for example, greater than 4 mg per minute), the risk of ototoxicity is increased, but I’m less certain at what precise dose of a furosemide continuous infusion a clinician should avoid or more assertively monitor for ototoxicity. Perhaps the focus of future research should include assessing the role of these additional or alternative therapies in minimizing toxicities including ototoxicity. Do you have any suggestions, Dr. Mehra?

DR. MEHRA: I think that the data suggest that cochlear toxicity or ototoxicity is related to the peak effects and not the trough effect, so the higher the bolus dosing, the more the chance that one could have cochlear toxicity, particularly if there are other ototoxic agents being administered concomitantly. For example, if someone is receiving a drug like a gentamycin-type analog, for instance, along with a diuretic infusion or a diuretic bolus, I think there’s magnification of that ototoxicity. Frankly that isn’t the overriding concern of most clinicians, and in fact we do not systematically study it, as you’ve pointed out. I often am more concerned in the diuretic resistant patients with the best dosing strategy. I know that, Tien, you have done some work in that regard and I wonder if we could turn the conversation toward discussing what kind of combination diuretic strategies really work in reducing fluid overload.

DR. NG: Clearly another option which is commonly used in practice is the combination of diuretic agents, specifically a loop diuretic added to a thiazide agent, a thiazide which is still effective even in the setting of poor renal perfusion. There are a lot of observational and small studies that have evaluated whether or not the addition of a thiazide, such as metolazone, to a loop diuretic, such as furosemide or bumetanide, augments sodium excretion and urine output. A paper that was published in the Journal of the American College of Cardiology summarized some of these data found a signal for increased urine output.⁶ Our group recently evaluated the addition of metolazone to furosemide, compared to just a continuous infusion of furosemide, and found a statistically significant greater increase in mean hourly urine output with the combination compared to furosemide used by itself.

What was interesting about our data, which are consistent with some of the existing data, is there was actually no signal for worsening renal function in our patients who received the combination, although there was a signal for an increased risk of electrolyte disturbances. So the conclusion of our study, since it was an observational study, was because of potential differences in clinical efficacy and safety, there is a great need for further study in prospective trials of these alternative strategies, such as combining agents, to truly understand whether these therapies are more effective while remaining relatively safe.

DR. RODGERS: These studies have made important contributions to the literature, but as Tien explains, are not optimally designed trials. Thus, there is need for prospective evaluations to address these unanswered questions. When conducting these future prospective studies, it will be important to include endpoints such as 30-day rehospitalization. If these alternative regimens more effectively diurese, then length of hospital stay may even be reduced by a day or two. With that said, I would be concerned that patients might subsequently suffer other adverse consequences such as continued unwanted diuresis and related adverse effects post-discharge. This is an important question to address with agents such as metolazone, given the long half-life and considerable intra- and inter-patient variability in onset of action with this agent. Future prospective trials need to address outcomes, such as length of stay and rehospitalization at 30 days, for these very reasons.

There are many reasons these trials have not been prospectively conducted in the past, and one major rate-limiting factor is the uniqueness of the population of patients with refractory fluid overload. When clinicians are faced with these patients, they often start to inquire about the appropriateness of a right heart catheter and inotropic therapy simply because diuretic refractoriness may be an indicator of low cardiac output. Patient characteristics such as concomitant inotropic therapy was most often an exclusion criteria for the previously discussed trials.

DR. MEHRA: So let me respond to that, Jo Ellen. First of all, I was taught to use a lot of metolazone, and frankly, as I matured clinically, I became less enamored by that drug as I realized how tough a drug it was on the kidneys and on electrolyte balance. There is this notion of what is the appropriate clinical endpoint, and I think you alluded to it. The endpoint needs to be clinically relevant. The endpoint should focus on the patient and not be one where the clinician feels better. Essentially we have been a bit swayed by how much urine output can be evoked and how much fluid can be removed. We have a large number of papers and data emerging that tell us that there may be a significant disconnect between the amount of fluid removal and clinical outcomes. As an example, studies like the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST)⁷ with a vasopressin receptor antagonist showed effectiveness of the drug tolvaptan in improving hyponatremia, and in reducing weight in patients significantly, compared to placebo, but was no better than placebo in influencing 24 month outcomes from a cardiovascular endpoint. So we have to fundamentally ask the question, do any of these strategies actually make a real difference in patients?

The other issue is that we need to do a better job of discriminating among the distinct patient groups that present with diuretic resistance syndrome. So, for example, it would be clinically less useful to start using incremental diuretic strategies and multiple drug regimens in a patient who has a clear low output state causing diuretic resistance. In such a patient, perhaps, a strategy that improves cardiac output with or without the need for mechanical circulatory support might be the appropriate one to overcome diuretic resistance.

In another situation where you have acute pulmonary edema, for instance, in the setting of severe hypertension or acute ischemic syndromes, I think the treatment ought to be very different. In such situations, step number one from a clinical standpoint is to segregate the patients into classifications of why the diuretic resistance has occurred and what is the relationship of that diuretic resistance to pump function. As an example, most of the multiple drug use strategies that work do so in the setting where true renal causes of diuretic resistance have occurred. This is manifested pathologically by the development of tubular hypertrophy, which determines classical diuretic resistance. In those situations, even considering a “renal rest” such as with ultrafiltration for a few days in some series has shown to be of benefit. It is in those situations where using multiple agents may be beneficial from a fluid removal standpoint. You’re right, Jo Ellen, we have to ask ourselves to what end we are actually making patients better. And our definitions of how we make patients better are equally critical.

Tien, do you have some thoughts about that?

DR. NG: Yes, I have to agree. I think an issue has always been, what is the appropriate endpoint for our acute heart failure patients? This has been debated for years and years now, and when you look at the safety signals or the safety endpoints that are currently being used and the efficacy endpoints, we really don’t know whether these are the optimal safety and efficacy endpoints. In one sense we’re using urine output, and as you’ve pointed out there are clearly data showing that urine output isn’t necessarily the greatest indicator of an improved prognosis in these patients. At the same time, looking at serum creatinine changes as a measure of renal function obviously has its limitations as well. With serum creatinine one wouldn’t expect large changes in these relatively short-term trials, as it is a delayed marker of renal injury. So in the future, to look at the renal safety of these agents it will be important to incorporate some novel, more accurate and early markers of acute kidney injury. I think that will help us understand whether or not we are actually doing something beneficial for these patients or whether we are just treating ourselves.

DR. RODGERS: I completely agree, Dr. Ng. I think that many of our future trials are focusing on either the right population or the right endpoint. Some good examples, Dr. Mehra just mentioned ultrafiltration and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial,⁸ which is currently recruiting patients, and this study is specifically enrolling patients who are congested and fluid overloaded, but who have experienced renal insufficiency. The primary endpoint is a combination of weight and renal function changes. I am optimistic that any follow-up studies to CARRESS will assess endpoints such as mortality and rehospitalization. Other trials such as the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial⁹ with the agent relaxin, also are enrolling patients with mild to moderate renal insufficiency. This trial is designed to assess clinically meaningful endpoints such as worsening heart failure associated with longer length of stay, as well as 60-day outcomes. It is great that these trials are addressing how to manage the patients that clinicians most struggle with.

DR. NG: Would either of you like to comment on some of the novel pharmacologic approaches which are currently being evaluated? This includes low dose nesiritide compared to low dose dopamine, the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE) trial,¹⁰ designer natriuretic peptides such as CDNP or CUNP. Thus far agents such as vasopressin antagonists and adenosine receptor antagonists haven’t been associated with positive results from a cardiorenal standpoint; however, I was wondering if you believe these agents may still have a potential role?

DR. RODGERS: The ROSE trial, again alludes to what we previously discussed regarding the addition of other agents in an attempt to minimize toxicity of diuretic therapy. This trial is assessing our ability to effectively manage the fluid overload without causing renal injury. Similar to RELAX,⁹ the ROSE trial is enrolling patients with impaired renal function as defined by a creatinine clearance between 15 and 60 mL/min. As Dr. Ng had suggested, they are utilizing a new marker for renal dysfunction in this trial. Their primary endpoint is change in cystatin C. Cystatin C is an excellent marker of kidney function because it is devoid of some of the limitations or inaccuracies of measuring serum creatinine, specifically it may more readily detect milder forms of renal impairment. Also, it is more reliable in patients with varying muscle mass or protein intake, which is commonly a problem in our heart failure patients who have cachexia due to low cardiac output or fluid overload.

Any time a clinician is starting to push to higher diuretic doses with no response or is starting to consider additional therapies, one should be cognizant of the risk of additional electrolyte wasting and worsening renal function and assured that these safety parameters are closely monitored. This is when patient selection for more aggressive diuretic regimens must be carefully considered. In addition, there remain many unanswered questions about appropriate alternative therapies and the role of such in further increasing or perhaps mitigating these risks. Alternative therapies studied to date include low dose dopamine, low dose nesiritide, and other vasoactive agents.

With regard specifically to ototoxicity, this is an adverse effect that is probably very underappreciated and perhaps it’s because clinicians rarely monitor it. Most clinicians are very aware that if you administer a large, single, IV bolus dose of 180 mg of furosemide too rapidly (for example, greater than 4 mg per minute), the risk of ototoxicity is increased, but I’m less certain at what precise dose of a furosemide continuous infusion a clinician should avoid or more assertively monitor for ototoxicity. Perhaps the focus of future research should include assessing the role of these additional or alternative therapies in minimizing toxicities including ototoxicity. Do you have any suggestions, Dr. Mehra?

DR. MEHRA: I think that the data suggest that cochlear toxicity or ototoxicity is related to the peak effects and not the trough effect, so the higher the bolus dosing, the more the chance that one could have cochlear toxicity, particularly if there are other ototoxic agents being administered concomitantly. For example, if someone is receiving a drug like a gentamycin-type analog, for instance, along with a diuretic infusion or a diuretic bolus, I think there’s magnification of that ototoxicity. Frankly that isn’t the overriding concern of most clinicians, and in fact we do not systematically study it, as you’ve pointed out. I often am more concerned in the diuretic resistant patients with the best dosing strategy. I know that, Tien, you have done some work in that regard and I wonder if we could turn the conversation toward discussing what kind of combination diuretic strategies really work in reducing fluid overload.

DR. NG: Clearly another option which is commonly used in practice is the combination of diuretic agents, specifically a loop diuretic added to a thiazide agent, a thiazide which is still effective even in the setting of poor renal perfusion. There are a lot of observational and small studies that have evaluated whether or not the addition of a thiazide, such as metolazone, to a loop diuretic, such as furosemide or bumetanide, augments sodium excretion and urine output. A paper that was published in the Journal of the American College of Cardiology summarized some of these data found a signal for increased urine output.⁶ Our group recently evaluated the addition of metolazone to furosemide, compared to just a continuous infusion of furosemide, and found a statistically significant greater increase in mean hourly urine output with the combination compared to furosemide used by itself.

What was interesting about our data, which are consistent with some of the existing data, is there was actually no signal for worsening renal function in our patients who received the combination, although there was a signal for an increased risk of electrolyte disturbances. So the conclusion of our study, since it was an observational study, was because of potential differences in clinical efficacy and safety, there is a great need for further study in prospective trials of these alternative strategies, such as combining agents, to truly understand whether these therapies are more effective while remaining relatively safe.

DR. RODGERS: These studies have made important contributions to the literature, but as Tien explains, are not optimally designed trials. Thus, there is need for prospective evaluations to address these unanswered questions. When conducting these future prospective studies, it will be important to include endpoints such as 30-day rehospitalization. If these alternative regimens more effectively diurese, then length of hospital stay may even be reduced by a day or two. With that said, I would be concerned that patients might subsequently suffer other adverse consequences such as continued unwanted diuresis and related adverse effects post-discharge. This is an important question to address with agents such as metolazone, given the long half-life and considerable intra- and inter-patient variability in onset of action with this agent. Future prospective trials need to address outcomes, such as length of stay and rehospitalization at 30 days, for these very reasons.

There are many reasons these trials have not been prospectively conducted in the past, and one major rate-limiting factor is the uniqueness of the population of patients with refractory fluid overload. When clinicians are faced with these patients, they often start to inquire about the appropriateness of a right heart catheter and inotropic therapy simply because diuretic refractoriness may be an indicator of low cardiac output. Patient characteristics such as concomitant inotropic therapy was most often an exclusion criteria for the previously discussed trials.

DR. MEHRA: So let me respond to that, Jo Ellen. First of all, I was taught to use a lot of metolazone, and frankly, as I matured clinically, I became less enamored by that drug as I realized how tough a drug it was on the kidneys and on electrolyte balance. There is this notion of what is the appropriate clinical endpoint, and I think you alluded to it. The endpoint needs to be clinically relevant. The endpoint should focus on the patient and not be one where the clinician feels better. Essentially we have been a bit swayed by how much urine output can be evoked and how much fluid can be removed. We have a large number of papers and data emerging that tell us that there may be a significant disconnect between the amount of fluid removal and clinical outcomes. As an example, studies like the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST)⁷ with a vasopressin receptor antagonist showed effectiveness of the drug tolvaptan in improving hyponatremia, and in reducing weight in patients significantly, compared to placebo, but was no better than placebo in influencing 24 month outcomes from a cardiovascular endpoint. So we have to fundamentally ask the question, do any of these strategies actually make a real difference in patients?

The other issue is that we need to do a better job of discriminating among the distinct patient groups that present with diuretic resistance syndrome. So, for example, it would be clinically less useful to start using incremental diuretic strategies and multiple drug regimens in a patient who has a clear low output state causing diuretic resistance. In such a patient, perhaps, a strategy that improves cardiac output with or without the need for mechanical circulatory support might be the appropriate one to overcome diuretic resistance.

In another situation where you have acute pulmonary edema, for instance, in the setting of severe hypertension or acute ischemic syndromes, I think the treatment ought to be very different. In such situations, step number one from a clinical standpoint is to segregate the patients into classifications of why the diuretic resistance has occurred and what is the relationship of that diuretic resistance to pump function. As an example, most of the multiple drug use strategies that work do so in the setting where true renal causes of diuretic resistance have occurred. This is manifested pathologically by the development of tubular hypertrophy, which determines classical diuretic resistance. In those situations, even considering a “renal rest” such as with ultrafiltration for a few days in some series has shown to be of benefit. It is in those situations where using multiple agents may be beneficial from a fluid removal standpoint. You’re right, Jo Ellen, we have to ask ourselves to what end we are actually making patients better. And our definitions of how we make patients better are equally critical.

Tien, do you have some thoughts about that?

DR. NG: Yes, I have to agree. I think an issue has always been, what is the appropriate endpoint for our acute heart failure patients? This has been debated for years and years now, and when you look at the safety signals or the safety endpoints that are currently being used and the efficacy endpoints, we really don’t know whether these are the optimal safety and efficacy endpoints. In one sense we’re using urine output, and as you’ve pointed out there are clearly data showing that urine output isn’t necessarily the greatest indicator of an improved prognosis in these patients. At the same time, looking at serum creatinine changes as a measure of renal function obviously has its limitations as well. With serum creatinine one wouldn’t expect large changes in these relatively short-term trials, as it is a delayed marker of renal injury. So in the future, to look at the renal safety of these agents it will be important to incorporate some novel, more accurate and early markers of acute kidney injury. I think that will help us understand whether or not we are actually doing something beneficial for these patients or whether we are just treating ourselves.

DR. RODGERS: I completely agree, Dr. Ng. I think that many of our future trials are focusing on either the right population or the right endpoint. Some good examples, Dr. Mehra just mentioned ultrafiltration and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial,⁸ which is currently recruiting patients, and this study is specifically enrolling patients who are congested and fluid overloaded, but who have experienced renal insufficiency. The primary endpoint is a combination of weight and renal function changes. I am optimistic that any follow-up studies to CARRESS will assess endpoints such as mortality and rehospitalization. Other trials such as the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial⁹ with the agent relaxin, also are enrolling patients with mild to moderate renal insufficiency. This trial is designed to assess clinically meaningful endpoints such as worsening heart failure associated with longer length of stay, as well as 60-day outcomes. It is great that these trials are addressing how to manage the patients that clinicians most struggle with.

DR. NG: Would either of you like to comment on some of the novel pharmacologic approaches which are currently being evaluated? This includes low dose nesiritide compared to low dose dopamine, the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE) trial,¹⁰ designer natriuretic peptides such as CDNP or CUNP. Thus far agents such as vasopressin antagonists and adenosine receptor antagonists haven’t been associated with positive results from a cardiorenal standpoint; however, I was wondering if you believe these agents may still have a potential role?

DR. RODGERS: The ROSE trial, again alludes to what we previously discussed regarding the addition of other agents in an attempt to minimize toxicity of diuretic therapy. This trial is assessing our ability to effectively manage the fluid overload without causing renal injury. Similar to RELAX,⁹ the ROSE trial is enrolling patients with impaired renal function as defined by a creatinine clearance between 15 and 60 mL/min. As Dr. Ng had suggested, they are utilizing a new marker for renal dysfunction in this trial. Their primary endpoint is change in cystatin C. Cystatin C is an excellent marker of kidney function because it is devoid of some of the limitations or inaccuracies of measuring serum creatinine, specifically it may more readily detect milder forms of renal impairment. Also, it is more reliable in patients with varying muscle mass or protein intake, which is commonly a problem in our heart failure patients who have cachexia due to low cardiac output or fluid overload.