Chapters Transcript JNC 8 et al.: Is Evidence-Based Medicine the Only Way? – Cardiology Grand Rounds George Bakris, MD, FAHA, FASN, of the The University of Chicago Medicine presents JNC 8 et al.: Is Evidence-Based Medicine the Only Way? SPEAKER 1: Well, as you see the title, I'm going to end up with some interesting perspectives for you. Because I doubt that you've seen this. But I think I've subtitled this, True Confessions of a Guideline Writer. So I'm going to tell you some stuff that you've never seen print, but what's going on behind the scenes. This is my conflict of interest. And compared to some of my colleagues, this pales by comparison. So really, is evidence-based medicine the only way to practice? I mean, we've been doing it without evidence-based for years. So now all of a sudden, we have to do with evidence-based. Is this the only way to go? And is it a minimum standard? Is the evidence providing a minimum standard for what we need to achieve? Or is it actually giving us more? As I said, for the past two centuries, has it been all malpractice? I mean, have the lawyers not capitalized on things? Or I have we relinquished thinking to the epidemiologists, which are going to tell us what to do? So these are things I want to kind of season your thinking with in the beginning. And then we'll go through this. So let's take a look at levels of evidence in, not medicine, but in science. Absolutely at the top of the list is mathematics. You're not going to be mathematics. If we're giving grades, that would be a 1A. Physics is a 1B. And philosophy would be a 2D. So that's kind of cocktail party conversation gossip. But biology, which is probably closest to medicine, is about a 2B, so not real strong. There's something there. But there's a level of uncertainty. Now, I just want to point out to you that in physics, which is much more certain that medicine, there's a thing called the Heisenberg uncertainty principle. So these are guys that live by mathematics. And even they realize there's some uncertainty. But in biology and in medicine, absolutely not. if a guideline said this, we're done. This is the way it is. And I think you can see the stupidity of what I just said. So I think that you need to understand that there are limitations here. So let's take a look at the history of the JNC. If you look at JNC, it started back in the '70s by a grant that was given to the NIH, by a woman who had a stroke and realized her physicians didn't know what the hell to do. And then we have this burgeoning of changes in guidelines with data. And this is all data-driven, based on clinical trials that had come out through the years. And you can see we had no guidelines in the '70s. All of a sudden, when JNC III came out, we had isolated systolic hypertension, because of the SHEP trial. And there were a number of other stages that were evolved. And then ultimately, in JNC VII, we collapsed them into two stages. Why is that? Because the argument was, what are you going to do for somebody with stage three that you're not going to do for somebody with stage two? If they're sicker, you're going to take care of them. It's the same thing. So it was a way to make things simpler. For those of you interested, prehypertension was a term that was mandated by the NIH. Why was it mandated by the NIH? They don't mandate anything, they'll tell you. Because they thought that comments like "borderline," which was reminiscent of personality disorder, or "high normal" didn't resonate with the patient. And the patient was sitting there. Well, OK, if I'm borderline, then I must not be so bad. If I'm high normal-- normal, I'm good. And I'll work on it. So the question was, what term can we come up with that will mandate the patient actually do something, demand the physician do something, to get their pressure better controlled? So we came up with a multiple choice of five terms. We did focus groups of patients in the Midwest and up and down the East Coast. And bottom line-- 99.4% said prehypertension, if they heard it from their physician, would generate them to say, hey, well, what I'm going to do? I don't want to become hypertensive. So that's why it's there. It has no scientific validity whatsoever. And if you've seen analyses by epidemiologists, what they've done is taken old data that was borderline and high normal, collapsed them into one and called it prehypertension. And so the risk isn't any difference. It's just a term. And of course, I will tell you the Europeans made fun of me when I went over there and talked about this. And after I explain to them, they said, oh, yeah, that sounds pretty good. So it's not a scientific term whatsoever. It's a touchy feely term. Now, diastolic blood pressure was a lot more prominent in the early days than systolic. Why? People were dying faster. Systolic blood pressure is a disease of aging. So it's clearly-- and look at this. Look at JNC I. Consider therapy with a diastolic of 105. Consider it. You don't have to do anything. So obviously, things have changed along the way as data grew. So this is data driven. And changes occur. And what you hear today may not be true five years from now. And I hope you understand that. Because in medicine, it's a dynamic field. It's changing. And as new data comes out, there will be new recommendations. It's as simple as that. And it's not that the old ones were wrong. The old ones were based on what we knew at the time. So let's take a look at JNC and its evolution. It's what I just said. There were many studies. And what is the JNC Committee? I don't think people really know what it is. JNC-- this is JNC right here, the Joint National Committee. There's 45 different groups, not just academic groups, but societies, federal agencies, the Salt Institute. It was a whole spectrum of people that had input into these guidelines. It was a very fair process. It was expensive, but it was fair. And now it's gone. It doesn't exist anymore, because the NIH ran out of money. It's very simple. Now, what prompted the changes to go to evidence-based? Well, there's two things-- a dictum from the Institute of Medicine that everything must be evidence-based, because why are you making decisions in the absence of evidence? That can't be right. And also, the American Heart Association, after we did JNC VII, reviewed their guidelines to say, well, what really is evidence-based versus opinion-based? And let's take a look at that. So let's take a look at that. So there were a number of guidelines that were published and updated up to September, 2008. In fact there was a 48% increase. And most of the guidelines were Class II. So they weren't solid guidelines. They were more opinion-based, and the evidence was conflicting. And in fact, of the 16 current guidelines at that time, only 12%-- 12%-- were Level A. 46% were Level C. So the majority were opinion. And in fact, only 9% of the Class I Level A recommendations were there based on really good trials. So is this an indictment of the guidelines? Well, no, it's an indictment of the available evidence to come up with strong facts. So I think there are many people that are criticizing JNC VIII. I know all the players in JNC VIII. And I will tell you they did what they were asked to do. And the problem is not with them. The problem is with what they were mandated to do and the available evidence that was available for them to make statements, and, with all due respect, the ineptitude of NHLBI to administratively get things done. So I will tell you that it cost about $1.5 million to do in JNC VII. And it cost $15 million to do JNC VIII. So you want an epidemiologist? Pay for it. This is our tax money. So that's why they ran out of money. So what's the new system? Well, the new system was to pick a topic area, and important topic areas with new information that are relevant to physicians, convene an expert panel. Then the panel comes up with critical questions. And then from there, this Cochrane-like group does a literature search, finds eligible studies by specific criteria. And then the data are abstracted. They are reviewed in evidence tables. And from that, they are graded based on the level of evidence. And there are specific criteria for this. And from there, the guidelines are written. It's sent off for external review. And then they're disseminated. Now, JNC VII, when we finished it, went out to over 1,000 people for review. JNC VIII went out to 20 people. So I thought that Clyde Yancy and I were the only people in Chicago that got it. And we thought we were privileged, since we were 2 out of 20 in the country that got it. I think the point is everybody thought evidence-based would be better. And then when you actually looked at the quality evidence and what was derived from it, everybody was horrified. So I think, again, the indictment is not with the players. It's with the level of evidence. So how did they grade this? High, moderate, and low-- and I think you can figure out based on the criteria here what would be high. There are very few well-designed randomized clinical trials, because they're quite expensive to do. And nobody's really going to do them unless there's really a vested interest in a critical question that is of importance. And that speaks only for industry and NIH. And so there's a lot of small randomized trials that have a lot of limitations. And so of course the evidence there is not as good. But there are problems. And then that's the evidence quality. And then the strength was strong, moderate, weak, against. So you have a positive statement. Nobody wants to say anything offensive. So everything is positive. But then you have to look at the grade. If you just read the statement, it's irrelevant. Because you could have a positive statement, and then it says evidence against. So again, it's very important to understand how to read JNC. It's very different than the other guidelines. Expert opinion-- so if there really wasn't enough evidence, and they couldn't agree what the evidence grade was, it was expert opinion. And then there were things like no recommendation. So there's an important question. They had no data. So they said no recommendation. Now, they tried to avoid that whenever possible. But nevertheless, that was a possibility. So again, I just want to remind you of the levels of evidence, and what we're talking about here. So what were the questions? Put simply, how low can you go, or should you go, for your blood pressure? When did you start therapy? And how do you get there? Is it still diuretics in the drinking water? Or do we go on and do something else? So what studies did they look at? What were the inclusion criteria? Because they started from the beginning. They didn't take JNC VII and build on it. They started from the beginning. So they only looked at randomized controlled trials. They did not look at systematic reviews. They did not look at meta analysis. Those are off the table. A lot of people think they looked at them. No. Only randomized clinical trials from 1966 to the present. There was a minimum one year follow-up. So if you had less than that, it wasn't good enough. And you had to have at least 100 patients in the study. Otherwise, forget it. And they did that because there were a lot of small studies, and they were pretty well done, and they wanted to look at those as well. So what did they find? They found 56 studies by those criteria that would address how low your blood pressure should be. They found 26 studies as to when to start therapy, what blood pressure. And then they found 66 studies on what drugs should you use to get to where you need to be? That was the database. So they came up with blood pressure levels in terms of how low you can go in the general population, elderly or older individuals, diabetes, and kidney disease. So what are the recommendations? Well, in the general population, 60 years of age or older. Notice it's not 65. It's now 60. You initiate pharmacologic therapy to lower blood pressure at a systolic of greater than 150 over 90 to get it below that. What's the level of evidence. A. Did we need a guideline to tell us, based on what we knew already, that if your blood pressure was above 150 over 90, we needed to treat it? I don't think so. But it's grade A, no question about it. How about this? In the general population, less than 60-- so youngsters-- initiate pharmacological therapy to lower BP if the blood pressure is greater than 140 over 90. Now, you'd think that would be A or B, right? Wrong. E, expert opinion, OK? There's a big controversy in my group about treating people between 140 and 149. Do we have a randomized trial to show this? It wasn't good enough that the Metropolitan Insurance Company thought it was good enough to fund. But now, they are not there. It's a problem. Now, what about in the population non-diabetic kidney disease? Non-diabetic kidney disease with a blood pressure of greater than 140 over 90, would you treat that? There's no nephrologist that would say no. But they have expert opinion saying that you should. They don't believe that the evidence is there. I'll show you in a second some evidence that speaks to that. In the population of diabetic kidney disease, if the blood pressure is above 140 over 90, should you treat it? Expert opinion. In the general non-black population, starting drugs with thiazides, CCBs, ACE,h or ARB-- now we get a B, not bad. Now, with all due respect, our friends in the UK, the NICE guidelines, were saying this in 2009. But please, we've been playing catch up here. By the way, the NICE people, the people at the UK guidelines, knew we were doing this. The process was similar to what they used. They volunteered, because they've already done this. They volunteered to work with us. And we'd have a separate way to do it and what have you. But it would streamline things and move things faster. Absolutely not-- would not hear of it. Please, we want to spend our money. We have it. Leave us alone. So this is why you get what you get. In the non-black population with diabetes-- OK, so you have the general population. Now with diabetes, how about diuretic, CCB, ACE, or ARB? Grade B-- not bad. How about in the general black population? How about a thiazide diuretic or CCB? Evidence is pretty good that you should start with this? How about in the general black population with diabetes, thiazide diuretic or CCB? The evidence is C, not that good, OK? Now, this is only for blood pressure. This is not for outcomes. This is only for controlling blood pressure. In the population 18 to 80 with CKD and hypertension, initial therapy should include an ACE or an ARB to improve kidney outcomes. Grade B. OK. And CKD here is not a GFR of 70. CKD is a GFR below 60, OK? And there's other recommendations. There was going to be a whole section on ABPM and home blood pressures. My good friend Ray Townsend wrote all that. I'm sorry. We don't have any money to do that. So done, not there. So there's a lot more stuff that could be there. But it's not. So time for some true confessions. I am a nephrologist. Let's take a look at the blood pressure goals. We said in JNC VII less than 130 over 80. We knew that we could not defend that. So if you took me to court and said, you're a liar, you cannot defend less than 130 over 80, I would have concede and say, well, you're right, put me in jail. Because we know when we wrote this we couldn't defend it. We were told by the NIH that we better say less than 130 over 80. Because physician inertia would take effect. And we will have rampant kidney disease. Because physicians definitely will not treat to that goal if we say 140 over 90. And we'll have people floating around at 145, 150. That shows you how much faith they had in us. But that's why it was done. So this time, nuh uh. It's off the table. It's evidence-based. We got to say the truth. So you can see here that guidelines changed. And we now have the kidney guidelines, the most recent ones, of which I'm an author on, with less than 140 over 90. And then the ADA guideline is 140 over 80. Now, being fair, 80 is really not evidence-based. It's taken from a failed trial, a prospective failed trial where the diabetes subgroup did better at the lower level of blood pressure. And that's where that 80 comes from, the famous hot trial. Now people are living longer. I really in principle don't have a problem with this. But if you want to be evidence-based, it really isn't evidence-based. So I just want to pull the trump card out, just in case you want to play it, and just to let you know. The other thing is ACEs and ARBs in the drinking water-- not anymore. The only place where ACEs and ARBs have strong evidence, if you want to be evidence-based, is in people with proteinuric kidney disease. So if you've got a GFR of 50, and you've got 300 milligrams of protein in your urine, you'd better be on an ACE or an ARB. If you've got a GFR of 70, which is stage 2, and microalbuminuria, there is no evidence that an ACE or an ARB changes your outcome. Does that mean you shouldn't use it? No, not at all. It just means that if you're using it, thinking you're changing the outcome, you're not. So you need to understand what is being said here. So let's take a look at guidelines for diabetes. Well, there's a bunch of people on board, the NICE, the kidney people, the Latin American Consortium for Diabetes. Everybody says less than 140 over 90. The Europeans, they want to satisfy everybody. They don't want everybody mad at them. So they said 85. Can you defend that? Absolutely not. But it's less than 90. So why not? And then we have the ADA, which I've already told you about. Now, what about in kidney disease? Less than 140 over 90-- where did that come from? Well, there are three randomized trials, all published before JNC VII was written. And here they are-- the MDRD, the AASK, and the REIN-2, all in non-diabetic kidney disease. There is no randomized trial of blood pressure in diabetic kidney disease. But in non-diabetic kidney disease, you have this data. And all of these were negative. And these are real nephropathy. These are people with a gram, two grams, three grams of proteinuria, IJA nephropathy in REIN-2. MDRD was a gemisch of a bunch of stuff, including polycystic disease, some diabetes. AASK was all hypertensive non-diabetic kidney disease in African-Americans. So just so you understand the mix of who's here. So here's the data from REIN-2. You can see clearly no advantage to intensified control. And by the way, these were mean arterial pressures down around 96, which translates to about 130 over 80 in the intensive group. Here is the data from AASK, five years. So when you start trials, you make predictions as to what you think is going to happen. And the calcium blocker arm in this trial I predicted would do badly, based on data that I had already published. So I got that right. I got this dead wrong, as did all 21 PIs. So nobody predicted this. And we went 10 years, thinking well, it wasn't long enough. Uh-uh. Go to New England, 2008. It was long enough. There was no advantage. So lower is not going to get you more. It may protect you from stroke, although we certainly didn't look at that. But it's not going to help you in so far as kidney disease goes. And in fact, you can see in the kidney guidelines, just to compare with JNC, non-diabetic kidney disease normal albuminuria, blood pressure, 140 over 90-- 1B, unlike what the JNC said, which gave it a level here, which would equal about grade 2-- so stronger guidelines. And these are the international guidelines. These are just US. Non-diabetic adults with microalbuminuria and greater than 130 over 80-- how many people, if you saw a patient-- I want a show of hands. How many people in the clinic, if you saw somebody with 100 milligrams of protein in their urine and a blood pressure of 132 over 80, and they had a GFR of 58, how many people would slap these people on an ACE inhibitor and start treating them? Show of hands. SPEAKER 2: [INAUDIBLE]? SPEAKER 1: They're on nothing. They're on nothing. You're seeing-- well, I have bad news for you. 2D-- now, you know what 2D is? 2D is like philosophy. It's a cocktail party. See what happens. Forget about it. There is no data anywhere that shows protection in an outcome. We're talking about outcome studies now. Does it mean it's not going to protect you? No. Just, if you want to be evidence-based, that's the grade you get. All right. So non-diabetic kidney disease with proteinuria greater than 300 milligrams and a blood pressure higher than 130 over 80-- 2C. Now the message there is if you get the blood pressure below 130 over 80, with big time proteinuria, you're not going to really protect the kidney. I just showed you three trials that support the fact that this is a 2C. Those people had big time proteinuria. A non-diabetic diabetic did not get an advantage from a lower blood pressure. You've got to change your concepts. ACE or ARB as first line in people with microalbuminuria-- so forget the blood pressure. They're just coming in. They've got microalbuminuria. Their blood pressure is 132. And they're non-diabetic. They've got a GFR of 58. You got to put them on an ACE or an ARB. How many people would do that? Show of hands. See, you're all good test takers. You already know I'm setting you up. Yeah, 2D. We're back into the realm of philosophy, OK? There's no evidence that supports any benefit there. So here you go, ladies and gentleman. You want a systematic review? Here are all the guidelines that have come out in the last 18 months, with the exception of NICE, that really look at this issue of level of blood pressure, initial drugs, combination therapy, and what have you. And I just want to point out to you a couple of things, that if you look at beta blockers-- I know this is a group of cardiologists-- only the European group said yes, because again, they don't want to offend anybody. But there are no data anywhere supporting beta blockers as first line therapy in the absence of CAD or heart failure, period. End of discussion. I don't care what you tell me. Ain't happening, OK? Nobody else has bought into that. Diuretics-- you need thiazide-like diuretics, not our friend hydrochlorothiazide. Why is it thiazide-like? Because the chemistry is different. So if you want to look at it, you have our kinder, gentler hydrochlorothiazide over here that kind of nudges you a little bit. Then you have indapamide in the middle. You may remember it as Lozol, which is a thiazide-like diuretic. It has a half-life of about 24 hours. Hydrochlorothiazide with metabolites-- about 13 hours. And then you have the gorilla, chlorthalidone, with a 44-hour half-life with metabolites. Now, potency-- indapamide is 10 times more potent than chlorthalidone or hydrochlorothiazide. Why is chlorthalidone not known to the house staff? I mean, I did my own little poll. If you're under 50, nobody's heard of chlorthalidone. Because when I was a house staff in the early '80s, there was a little headline from the Jocelyn-- "diuretics kill diabetics." Now, that was chlorthalidone at 100 milligrams a day. And what was killing it? Not chlorthalidone, hypokalemia, OK? Duh. That was before ACE inhibitors and ARBs. And we were using astronomically high doses. So discover it again for the first time. Friends of mine say, why aren't the drug companies combining chlorthalidone with all these other ACEs and ARBs if it's so good? Well, true confessions-- we lobbied the drug companies big time in the early '90s and mid '90s to do this, because we had the data from SHEP. ALHAT was coming along. They were using chlorthalidone. HDFP was known. And the companies did focus groups. They went out with primary carers and asked them, if we combine it with hydrochlorothiazide versus chlorthalidone-- chlorthalidone? Whoa, forget it. Or what is that? What are we going to do with that? So they decided it was more an uphill battle to educate physicians about chlorthalidone. And so they took the path of least resistance. And that's why you have all these hydrochlorothiazide combinations. So FYI-- not to say that chlorthalidone doesn't have problems, not to say that you don't get into trouble with it, but it's important for you to know that it's not what you-- it's not hydrochlorothiazide. The other points are the targets here are pretty much the same across the board. I didn't talk about the elderly, because it is contentious. If you want to be evidence-based, yes, you should not treat until it's greater than 150 over 90. And you get it below 150 over 90. Does that mean that you stop at 150 over 90? These guidelines are ceilings. They're not floors. It's not like, oh, we're at 148. So we're good. I mean, you'd have to be pretty naive or stupid to believe that. So you really need to get it down to where you should be, which is below 140 over 90, if the patient can tolerate it, all right? That's what the guideline says. So a subgroup o the guideline writing committee took offense to that. One of the reasons why AHA have the guidelines now and NIH isn't doing it anymore is because they were advised by their advisory board that if they put out something saying that the elderly shouldn't be treated until they're above 150, the perception is you're trying to kill us to save money. Forget it. We don't want that. And do you think I'm kidding? It's the truth. So the bottom line is it was a shift over. And then there was a paper in the annals, for those of you who may have missed it, recently, from the subgroup, arguing that really 150 over 90, they disagreed with that. And it really should be less than 140 over 90. So the truth is I was on the guideline committee in 2011 when we published the hypertension guidelines in the elderly for the AHA. We said less than 150 over 80, because you could defend the hell out of that based on the evidence. It went out for public review. I thought we were going to be put in jail. Because how can we say this? And this isn't crazy. So we changed it to say less than 140 over 90, not really evidence-based. But if the patient has symptoms and can't achieve it, 140 to 145 is fine. So guess what? This is not math. This is judgment. Each patient-- these are guidances. They're not edicts. I'm not coming down with the stone tablets and saying, you will obey. It doesn't work that way. I have to speak to the insurance companies next week. They want to hear what's going on. They want the stone tablets. Because it's easier for them. They're going to be told they're idiots. And we'll go from there. You don't think I'll do that? Watch me. So I'm just saying you need to have a prospective here as to what's going on. And by the way, there are really only two guidelines, NICE and JNC VIII. This is an alleged guideline, advertised as such as. The International Society of Hypertension approached-- I mean, the country of Haiti approached Ernesto Schiffrin to come up with a guidance to help poverty patients that can't afford anything treat blood pressure. And it glommed into this pseudo guideline. It really isn't a guideline, per se, not in the true sense. This is a guideline in the traditional sense, like a JNC VII. And this is a feeble attempt of the American Heart and ACC, because they have inherited all the guidelines. Since They weren't going to have a blood pressure guideline, since it was independently done, they get together with the CDC to do this. What is that? OK, I invite you to go to JAMA in April. And look up Alan Go's paper from the Kaiser experience over 10 years on blood pressure control. It's a beautiful paper, as Alan does. And it shows very nicely what they used, what their blood pressure control rates are. It's beautiful. All they did is take get paper, put it around into an algorithm, and boom, you have the AHA ACC CDC guidelines. Be very careful. Caveat emptor when you look at this stuff. OK, I quickly want to go through simplicity with you. And I just want to make the point that refractory hypertension is probably only about 2% of all hypertensives. So you get 75 million people or so with hypertension. It's only about 2% that really have refractory hypertension. And I just want to make some points here. Major issues-- excessive sodium intake, OK? That is by far number one. And tied with that is poor adherence of medication. And I don't think people appreciate-- everybody kind of knows poor adherence. Nobody really appreciates how bad the adherence really is in most people, not everybody. I'm not accusing everybody. And how you measure the blood pressure is also very important. We've had people come into my clinic where substitute nurses are in there one day. They haven't been trained. And we look at this. And this is a patient who's normally well controlled. All of a sudden, it looks like they're hypertensive. We re-check it. They're fine, the antithesis of white coat. But that's because they didn't measure it correctly. So then they get trained. So it's very important. You can't just do this willy-nilly. Not any idiot can do this. It is a bit of an art. I just want to point about salt. This is a paper that is not really appreciated. It's published back in 2005. This is done in the UK. Admittedly, it's in people with CKD, being fair, who are much more salt sensitive than the general population. But having said that, in people who are salt sensitive-- and you're looking here at mean 24 hours urinary sodium-- they controlled the salt intake. And you can see here the number of anti-hypertensive meds that were needed. You can see what the actual sodium output was in milligrams, as opposed to millimoles. And what you find is for about every 200 to 300 milligram increase in sodium, starting at 3,000, you need an additional blood pressure medicine. Now, I will tell you-- and I presented it at the American Heart. And friends of mine were throwing tomatoes at me-- a patient referred to me from a cardiologist-- a good cardiologist who knew exactly what he was doing-- on a great cocktail of medicine, three meds, full does, who I got off all her meds in a period of two months because I simply put her on a low sodium diet. So it is real. Now, the argument came back-- well, how long did she stay on it? Well, the truth is only about four months. Then she came back, begging for more salt. So we compromised. And she's on low dose of one drug and full does of another. And she's doing fine. But that's the point. You've got to work with the patient. And they have to understand what their limitations are. This is a big deal. Now, this is another paper I'm sure you haven't seen. There are now two papers. There's a journal called BMJ HEART, which is one of the spin-offs of BMJ. And I'm not going to show you that paper, because it was just published. But this is a paper that was published in the Journal of Hypertension last year. And these are adherence studies. In outpatient settings-- and this one in particular that I'm showing you this from a resistant hypertension clinic in Germany. Now, that's important, because certain drug behaviors in Germany are different. But you'd think in Germany, you will do this and like it. No, no, it doesn't quite work that way. Look at the data here. They took patients from this clinical who consented. They consented. They filled out questionnaires. They gave urines. They consented to urinalysis of their anti-hypertensive medication, to prove that they were taking it. And they fill out questionnaires, OK? So this is the demographic of the group that you can see here. And it's not anything different than the kinds of patients that you probably would be seeing here, that so-called had resistant hypertension, all right? And what you find is that only 45% were truly adherent with all their medications, 45%. And what you see is the medications they were most adherent with were ARBs-- no big surprise there, because that's been shown in every analysis ever done, because they're well tolerated-- and interestingly, beta blockers. Now, before you get too happy, let me just tell you that in Germany-- that's why I made the point about Germany-- beta blockers are king in Germany. They love beta blockers. I don't know why. But they do, historically. And so they probably thought that there was a reason for that. Plus, a lot of these people did have coronary disease. So maybe they stayed on it for that reason. But the point is, of the 55% that were non-adherent, 30% of that 55% were not taking any of their meds. And what's interesting is they said on their questionnaire that they were taking them. So they were confronted. They said, well, it says here you're taking it. And I have the evidence here. And they're comment was, I don't care what this says. I'm taking them. Blood pressure wasn't controlled. Heart rate was up. But I'm taking them. So what I'm saying is that this happened. And the other paper-- now, the patients there were not told they were going to be screened. It was just done. They collected the urine and did it. And the data there are not that different than the data I just showed your. And that's in a general medical clinic at the University Hospital in London. So my point is that if you're suspicious-- and I've had patients. Because I've asked them straight up. At least my patients I think are pretty honest. Because I've asked some straight up, you're not taking your meds, are you? Well, I'm taking some of them. Oh, I understand that. But you're not taking them all, are you? No. So then you find out it's either cost, or there's a side effect. They like you. So they don't want to hurt. So they weren't going to tell you about it. There's all this psych stuff going on. So you've got to appreciate that and get at it. Because I tell them, listen, your arteries, your brain, your kidney, your heart, they could care less whether you're taking your meds or not. Do you think they care? All they know is the pressure they're seeing second by second. And if it's high, you're being damaged. So you want to damage yourself? Be my guest. Enjoy. So I had this patient who was really retarded. She took all her meds. She looked phenomenal when she came to see me. She was great, 130, 125. She was on five meds. But she took them. One time, the next day, she had an appointment with a friend of mine who's a cardiologist, literally down the hall. I got a stat phone call from the nurse. The patient wasn't even seen, was sent to me to fix her blood pressure. So her pressure is 220 over 100. So I saw her. Now, this is a woman. She's on public aid. But she's got a nice ring. She's well quaffed, got nice clothes. So I said, what's going on? You didn't take your meds today? Well, no. Well, why didn't you take your meds today? I was seeing the cardiologist. What does he care about blood pressure? That was the response. That was the response. So I couldn't make this up. This is a true story. So this is what goes on. And so you have to appreciate this. Now, I want to finish up by making some points. To make it easier for the patient, there are a lot of single pill combinations. And they are generic. And they are reasonably priced. And patients are much more likely to take generic drugs than they are brand drugs, because of the price. But also, they're more likely to take it if you can combine two drugs one. A very quick anecdote-- I had a patient that was sent to me, a lawyer. She told me-- she says, I'm only taking two drugs. I said, well, what if you need more? She goes, well, I don't care. I said, oh, let me guess. Because if you take more drugs, you think you're sick? Yeah. I don't want to be sick. So I'm limiting it to two. Aren't you sick with two? Yeah, but I'm not as sick. So when I finished with her, she was on four drugs. I gave here a combination of Ziac and Lotrel. So I said, with full disclosure, counsel, you're on four drugs. I don't care. I'm on two pills, so I'm good. This is the level of mentality that we have. So let me quickly go through alternatives that are on the horizon, that are not dead, unlike some of you may think, but they're on the horizon. Baroreflex therapy-- alive and well. They now have a single electrode on one side. It's called the Rheos device. There's a clinical trial ongoing. And the data looks very good. Unlike Simplicity, you know exactly what you're doing, because in the OR, when it's implanted, it's like a pacemaker. You can turn it on, turn it off. And you can see the blood pressure response. So this has got some very good data already published-- oh, sorry-- with an update, actually, of this in a paper last year for the long-term follow-up. And it looks like it's very enduring. It's doing quite well, very effective. And now that we've got the surgical procedure streamlined, it may actually have a lot of hope coming down the road. So that's promising. And then we have the Simplicity data, which clearly has a proof of principle. I don't think this data is made up. I know these people personally. And I believe this. Otherwise, Gerry DiBona at the University of Iowa spent his entire career for nothing. And I'm pretty sure that's not true. So there is something here. The question is, what's going on with it? Because when you look at norepinephrine spillover, pre and post renal denervation, there's definitely a reduction. There's definitely an improvement in renal plasma flow. So there's no question something's going on. But what is it? The Simplicity 1 trial was really a pilot trial. That wasn't a randomized controlled trial. No guideline would ever use this study. But here you have three year data with-- by the way, there nobody was controlling dosage of medication, number medications, et cetera. You just had to prove that you were on a bunch of methods to get in. And here you go. So you can see there's a persistence of three years in both systolic and diastolic blood pressure, measured by office readings. And then you have Simplicity 2, which was more randomized. Again, no placebo control, and no real ABPM. That was baseline and afterwards. They did it just for validity, to showed the office readings were there. And again, you can see similar results to what you saw in Simplicity 2. And you can see the ambulatory readings are consistent with this. So based on this, the company wanted-- because it's licensed in Europe. It's licensed in Australia, and actually, a couple of other countries. So the question is, well, what's going on really properly? So we got together and put together a protocol that would satisfy not only the academic community, but the regulatory authorities in terms of getting this approved in the US. And that's Simplicity 3, which many of you have heard about or actually heard the presentation at ACC. But this was a large trial. We were going to recruit 530. We got more. There were actually 88 centers, not 60. The randomization was 2 to 1, because we wanted more people getting the procedure than not. And the primary endpoint was the systolic blood pressure difference in the groups at six months. That's office blood pressure. And there was a pre-specified secondary endpoint, which was ABPM. I will tell you I argued when we designed this to have ABPM be the primary endpoint. The company was very, very antsy about that. And the FDA loved it. So I then had to backtrack and say, well, it wasn't as strong. But that's how it ended up being a pre-specified endpoint. And the follow up is going to be actually five years, not three years. So here's the design. To get in, you had to really prove yourself. And you had to be on full doses, or a fully tolerated dose, of an ACE or an ARB, CCB, and/or diuretic-- not or, and diuretic. And after that, you could be another drugs. You didn't have to be on maximal doses. But you had to show-- and including spiro, by the way. And you had to show that you failed that to make it to the next step. Then we measured home blood pressure. And we actually had pharmacy records to actually look at the drugs, to make sure that we-- that was our way of dealing with compliance. Then we brought you back. And if again the office readings met the criteria, then we did ABPM. If you met the ABPM criteria of greater than 135, then you would go into the cath lab. And that's where you got randomized to either a renal angiogram with nothing or renal angiogram with a procedure. And then you were followed. And again, we get home BPs. And again, we repeated ABPM for the primary implant at six months. And now you're being followed out to five years. If at the end of that six month period, you were randomized to sham group, you had the option to get the actual procedure. And most patients actually opted for it. Because we thought that was ethical. Here are the data. So you can see that ABPMs were around 160. Office readings were around 180. There's no differences between the groups. There were in fact about 25% to 30% African-Americans in the group. And you can see here that there were almost 50% diabetics. And a lot of people had hyperlipidemia. No big surprise here. And you can see the anti-hypertensive medications they were on. So you can see that they were clearly on real medications. These were real resistant hypertensive patients. I might add if you look at this, about 25% were on spiro. So not everybody on spiro gets their resistant hypertension cured. In fact, there's a paper just published in the Journal of the American Society of Hypertension that actually shows the genetics as to why not everybody on spiro has this effect. So there is a subgroup of about 25% of people on spiro that really will not get a blood pressure response because of the aldo response in that genetic subgroup. So nevertheless, this is what it was. And here is the primary efficacy endpoint. And it didn't really make it, as you can see, not even close. We were looking for 5 millimeters. We got 2 and 1/2. Here we were looking for 2 millimeters, and almost got it. But because of the confidence intervals being huge, it was not statistically significant. Now, if you're really interested in this, you can come to New York in May. I'm presenting all the ABPM data as a late breaker at ASH. So you can hear it there. We've submitted it as a rapid communication to JACC. We'll see what happens with that. But at least Val Fuster likes it. So we'll see how it turns out. Somebody said, hey, pressure's weren't high enough. Let's take a look at this. We look at tertiles. And you can see here, obviously the higher your baseline blood pressure, the greater the effect is going to be, not a big surprise. And we see it here. If you look at greater than 184, we're getting a 26 millimeter drop, similar to what you saw in HDN-1 and HDN-2. Oh, by the way, the sham groups getting 20 millimeter. Whoops. You want that placebo? So what are the differences here? How can this be? What happened. OK? So let's take a look at some differences between the trial designs. So HDN-3 had a sham. It had patient blinding. It had blinding of the follow-up assessors. It had blinding of the study management. And it added ABPM as a mandated inclusion criteria. Additionally, it was four times larger, and actually powered for appropriate endpoints. And it was an IDE trial that was conducted with much greater vigor and oversight. So all of those are contributing factor. Plus, if you're in a trial for six months, the placebo group over six months always looks good, especially if you're well being staunched the way we were. These people knew they were going to get hounded about the drugs, what's going on. We were following them. So you can impose to a certain extent, especially if the patient knows you mean business, you can impose adherence rules that the patient does well with. And so I think it's important to understand that I think these people were actually taking their meds. Whoops. Amazing what happens, which by the way is what the FDA was arguing all the time. Now, do they need to take them? Are they going to take them now that we've taken the bull whip away? Well, probably not. So guess what? If you're into public health, you're going to say, well, there's still at risk the way they were before. Absolutely correct. But if you're arguing that I'm going to do procedure because these people don't want to take their meds, I'm just not going to do that. Because that's their problem. So that's the argument that's going on now. Now, the other issue is, were they properly denervated? These people were all proctored. What do we know about the renal artery anatomy of the renal nerves? Well, I got to tell you, not as much as you think. I was shocked. I can tell you, we sent this to New England Journal. The editor, within 48 hours, wrote back and said, this is crazy. This is placebo versus placebo. Did you guys do anything? Is this a joke? What's happening? And I saw that and said, this guy's a real idiot. Even though I talked to him on the phone, and I think he's a great guy, I just thought this was incredible. So I figured, piece of cake, we'll show him the data. Well, then I was humbled a bit. Data is not that easy. And if we were in court, we may have been ruled against. The other issue is that the bundle of the renal nerves, when they started this whole thing, they thought it was all when the artery comes off the aorta. Well, there are renal nerves there. But they're deep in the adventitia. They're not superficial. You want to get them superficial? You gotta go right through the hilum, when they're coming into the kidney. Then they're much more superficial. Were people burning in that area? I don't think so. So was a proper denervation done? That question remains unanswered. It really does. So that's why this is not dead yet. That's why this is not dead. And if you heard Murray Elser, who is kind of the father of this whole thing, he will tell you, you didn't denervate properly. That's why the results were the way they were. No one has a problem with the experimental design. And it's all focused now on what was actually done in the cath lab. So the new guideline process is cumbersome. While it protects us from lawyers and insurance companies, it sets minimum standards of patient care, not maximum, minimum. So if you're not doing what the guidelines say, you get an F. And if you're doing what they say, you may get a C. It's a question of, can you do it even better? You've got to use your judgment. There's no substitution. These are not edicts from stone tablets, as I mentioned earlier. They are suggestions based on evidence, all right? And the topics covered in the JNC VIII were covered in the JNC VII. If you actually look at them, they're not that different. You just have level of evidence. So when you look at any of these things, you can't just look at the statement. You've got to look at the level of evidence. That's the critical point I want to make. So is evidence-based medicine the only way to practice? Absolutely not. And I want to finish with something that is a very, very important document. I think you should read it. I was at the Mayo Clinic Proceedings last year. As an alum, I get it. But I thought it was very good. And I just took experts out of it. So you can look at this. "The overall results of a trial cannot be assumed to apply to any particular individual, not even someone who corresponds to all the entry criteria of the trial." Very important. "Guidelines are key sources of knowledge. Nevertheless, limitations in the extent, quality, generalizability, and transferability of evidence mean that we clinicians must still reason through the best choices." And I can tell you, Doug and I were talking about this. We take some blame for this, because we're not teaching how to think anymore. That's a problem. You've got to know how to think. "Clinical reasoning is the pragmatic, tried and true process of expert clinical problem solving. That does very mechanistic reasoning and clinical experience as well as randomized controlled trials and observational data. Clinicians must continue to value clinical reasoning if the aim is the best clinical care for all the individuals we treat." Thank you very much. Created by Presenters George Bakris, FAHA, MD Professor of Medicine, Director, Comprehensive Hypertension Center View full profile
