George Bakris And Rajiv Agarwal Discussion.docx

George Bakris, MD: I'm Dr. George Bakris, Professor of Medicine at the University of Chicago Medical Center. I'm here today with Dr. Rajiv Agarwal, who is a Professor of Medicine at Indiana University. And we're going to talk to you today about blood pressure in hemodialysis patients. Rajiv, this is really an area that is virgin in a sense. Hypertension management in dialysis patients, if you look at any guideline around the world, there is nothing that talks about this because there are no data. So you've pioneered some of the original data. So first of all, let's start with basics. How would you say hypertension is defined as in terms of the numbers? And when do you measure it? Do you measure it on dialysis days, nondialysis days, 24-hour ambulatory blood pressure monitoring (ABPM)? Give us some definitions and guidance here. Rajiv Agarwal, MD: George, thanks a lot for inviting me. I think that's a very important question. How do we define hypertension in dialysis patients? And I have struggled with this question for the past 15 years or so, and I don't know if I have all the answers. But the way I would say that it should be defined is by measuring a lot of blood pressures while the patient is at home. If you're doing a research study, I would suggest that you do an interdialytic ABPM, which would mean 44 hours between 2 dialyses, and average that. And if the blood pressure exceeds 135/85 mm Hg, which is the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) definition of hypertension by ABPM, that patient is certainly hypertensive. What we have found is that using an ABPM in more than 300 patients followed for many years, that the blood pressure threshold that is associated with the lowest mortality is not 135/85 mm Hg. In fact, it's a lot lower than that. It's closer to 120/80 mm Hg. If you're not doing a research study, you probably want to be monitoring blood pressure at home. Not every patient on dialysis wants to measure ambulatory blood pressure. It's very cumbersome. It's expensive. It requires resources. Home blood pressure is a good way to monitor blood pressure. It doesn't need to be monitored every day, but I would recommend monitoring it approximately 4 days a week. The way I do it is to measure it in the morning and before going to bed for 4 days after a mid-week dialysis. If the patient is on Monday, Wednesday, and Friday dialysis, I would measure it on Thursday, Friday, Saturday, and Sunday morning and evening in duplicate and average those blood pressures. If the blood pressures exceed 140/90 mm Hg, then that patient is hypertensive. Blood pressures during dialysis are very important, but [mostly] to maintain hemodynamic stability of the dialysis session, not so much for diagnosing hypertension. Our guidelines are mostly based on predialysis and postdialysis blood pressure, but I think that ought to change to having home blood pressure as more the diagnostic way to define hypertension in these complicated patients. Dr. Bakris: You mentioned something that's actually very important -- hemodynamic stability during the interdialytic period. Why is that important? I mean it's well known that [the blood pressure in] people on dialysis can get very low. They can also go high at the end. What's the importance of maintaining hemodynamic stability as far as ultimately controlling the blood pressure?

Dr. Agarwal: That's a very good question. The interdialytic hypotension and interdialytic hypertension are not that far apart. In a patient who experiences hypotensive episodes during dialysis, it probably means that the patient is at his or her dry weight. If the patient is quite steady during dialysis, never experiences cramps, always comes off feeling pretty good, that patient may actually have hypertension during dialysis and also between dialysis. In fact, there's this entity of intradialytic hypertension, [in which] the blood pressure goes up during dialysis. We have studied this in patients who participated in the Dry-Weight Reduction in Hypertensive Hemodialysis Patients (DRIP) trial; if the blood pressure went up during dialysis, those patients were more likely to have interdialytic hypertension. So in other words, if you have intradialytic hypertension, you're also more likely to have interdialytic hypertension. And those people are likely to be volume overloaded. Continue Reading The way to address that situation is to reduce their dry weight gently, approximately 0.2-0.3 kg every session below their target dry weight and continue to do so until their blood pressure comes to a more normal level. So the focus on intradialytic blood pressure is also important. We actually have to look at all the blood pressures. Dr. Bakris: So I want to spend some time talking about antihypertensive medications in these patients, their use and lack of use. But I'm going to give you a multiple choice [question] now. If I have patient X and they have hypertension by your criteria, the best management for this patient would be A, maximally dialyze them to their dry weight; B, give them a calcium blocker; C, give them a beta-blocker; or D, give them a combination of antihypertensive agents, whatever works to get their blood pressure down. Dr. Agarwal: A good question and a complicated question; it depends on what the blood pressure is. But first, my answer would be A, to maximally dialyze that patient to achieve a target dry weight to enable blood pressure control. That doesn't happen in all the patients and many patients end up requiring antihypertensive drugs. And your choice C was a betablocker. I love that class of drugs. And I personally have used atenolol because it's renally removed and becomes an extremely long-acting drug in dialysis patients. It's not metabolized by the human body. So it's excreted unchanged in the urine, hence, basically dialyzed off during dialysis. So I have used this drug 3 times a week after dialysis and it works pretty well. It also reduces sudden cardiac death or it's been associated with the reduction in sudden cardiac death. And there are a couple of trials looking at carvedilol in patients on dialysis who also have heart failure that have shown an improvement in patient outcomes such as mortality and heart failure. Dr. Bakris: So then, given this information, explain to me why in every analysis that's ever been done in the past decade the use of beta-blockers, the use of angiotensin-converting enzyme inhibitors, the use of calcium antagonists is less than 50% in most dialysis patients, and, in the case of beta-blockers, it's probably 10%-15%. Why are nephrologists specifically not using those agents since they actually do have data, admittedly post hoc; but they do have data showing mortality benefit? Dr. Agarwal: I think that the complacence might be because these are data from databases, observational studies. But at least we have some data with carvedilol and outcomes in dialysis patients. Similarly, there are many studies with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors in dialysis patients, which also show a benefit in outcomes.

In fact, if you combine all of these studies, which have used antihypertensive drugs to control blood pressure, or actually just used them without regard to blood pressure, they have shown an improvement in all-cause mortality. I have done a metaanalysis[1] and Heerspink published a metaanalysis in the Lancet almost simultaneously, which showed the same benefit of using antihypertensive drugs on all-cause mortality.[2] But none of these studies were powered to look at these effects independently. None of these studies were targeting a specific blood pressure level. So it's still open to question about whether what should be the target blood pressure that the patient should achieve. And how should we measure it? These are complicated questions. I think we have just scratched the surface. I believe that more research is needed to inform the care of these complicated groups of patients. Dr. Bakris: So that's very good. A final issue, what's your thought or your comment? Many patients are told not to take any blood pressure medicine on the morning of their dialysis. Do you agree or disagree with that? Dr. Agarwal: I disagree with that. I think most of these medications are long-acting. Dr. Bakris: Right. Dr. Agarwal: And you know that missing a single dose of an angiotensin-converting enzyme inhibitor, for instance, doesn't do much to the blood pressure. However, if you are using hydralazine just before coming on dialysis, yes, I think I should avoid that. Dr. Bakris: True. Dr. Agarwal: Or if you are using a sublingual nifedipine, which nobody should use, it should be avoided. Dr. Bakris: Correct. Dr. Agarwal: But short of that, I think the practice of withholding an antihypertensive before dialysis is without evidence. Dr. Bakris: Yup, very good. I fully agree. So thank you, Rajiv. It's been a real pleasure. And thank you very much for joining us. And we hope you got something out of this, and that you have a good day.