COMMENTARY

ISHIB Guidelines -- Roadmap for Therapy and in ACCORD With Recent Findings on Stroke

Henry R. Black, MD; John M. Flack, MD, MPH

Disclosures

May 12, 2010

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Henry R. Black, MD: Hi, I'm Dr. Henry Black. I'm currently President of the American Society of Hypertension. I'm a clinical professor of internal medicine at the New York University School of Medicine and a member of the Center for the Prevention of Cardiovascular Disease.

I'm here today with my friend and colleague, Dr. John Flack, who is a professor of medicine and chairman of the Department of Medicine at Wayne State University in Detroit. John has been the chairman of a writing group for guidelines from the International Society of Hypertension, and they will be presented at our annual meeting today in New York City. John, could you tell us a little bit about ISHIB [International Society of Hypertension in Blacks] for one thing and then why guidelines?

John M. Flack, MD, MPH: Well the International Society of Hypertension in Blacks was founded in the 1980s. Neil Shulman, Elijah Saunders, Dallas Hall, and Jim Reed [were] core individuals who really thought that hypertension in blacks needed more attention and coalesced a group down in Atlanta that took off and became ISHIB. The management of the black hypertensive, although not totally unique, does have some nuances, and we thought that an update of our guidelines [that] we published shortly after 2000 was in order. Some things had changed. We learned more, and a goal of these guidelines was not only to really get people to understand the reason for certain goals and preferences for certain drugs and drug combinations, but to also provide a bit more into how to do it.

Dr. Black: So this will be a very practical guideline?

Dr. Flack: A very practical guideline, and a guideline that gives you a roadmap all the way through for drug therapy.

Dr. Black: What do you think of the major changes from the prior one?

Dr. Flack: Well we've expanded our high-risk group that has a lower blood pressure target and importantly even in the lowest risk primary prevention group we've dropped the goal from 140/90 down to less than 135/85.

Dr. Black: Did the ACCORD [Action to Control Cardiovascular Risk in Diabetes] study have anything to do with what you're doing?

Dr. Flack: The ACCORD study created a lot of debate, but our belief was that, one, the ACCORD study was not negative. We are treating, recommending guidelines for a stroke, nephropathy, and retinopathy-prone population. Stroke was reduced approximately 50%. That's not a hypothesis generation because it's a secondary endpoint. The link between stroke and blood pressure reduction is well established. For us to ignore that would have been disingenuous. The study was also underpowered on its composite primary endpoint, and, even though that endpoint moved in the correct direction by a 12% reduction, the study could have missed as much as a 27% benefit on the composite primary endpoint. From the time the trial was planned to the time it was executed, a lot of patients with diabetes went on statins and antiplatelet therapy, and that reduced the background risk. So it generated debate -- but in people with diabetes. We held firm at less than 130/80. There are other studies, including the ABCD [Appropriate Blood-Pressure Control in Diabetes] norm intensive study, showing that you reduce retinopathy and progressive proteinuria by treating patients with diabetes [who have blood pressure readings] under 140/90 at baseline down to lower levels than 130/80.

So we didn't really buy the argument that there was no evidence; and if we were going to make an error on any side it was going to be on really protecting the patients that we're making recommendations for. Retinopathy is not some theoretical complication. People lose vision. Stroke many times doesn't kill; it actually disables, and the harm that was discussed in the ACCORD study was [something] I deal with on a regular basis: a little more hypokalemia (2% vs 1%); a little more hypotension in the range of 1% or less to lower than that; and also an increase in creatinine, in a bit more in the way of people who had estimated glomerular filtration rates less than 30 mL/min, but also somewhat offset by the fact there was less microalbuminuria. So we thought that the overall balance even in the ACCORD study was one, in favor of treatment, and treatment [certainly] to a [blood pressure] goal of less than 130/80 if not more; and, two, that the harm that was talked about was not inconsequential but was nowhere close to offsetting the benefits that we saw.

Dr. Black: Do you have any thoughts about why blacks are particularly prone to strokes and kidney disease?

Dr. Flack: That's a great question and I think it's not one thing. It's probably a confluence of things that has to do, I suspect, in part with lower intake of dietary potassium, poorly controlled blood pressure over many years -- factors probably like even just regular high sodium intake that's no higher than that in the white population but it's coupled with low potassium intake, inadequate blood pressure control, a lesser use of statins, and there may be other factors that we don't know of that [are] a confluence of factors I know that, in all likelihood, contribute.

Dr. Black: Yes it sounds to me, and I know you've said this before, there's nothing inherently biologic as to why that's happening. It has to do with environment and habits and things like that, or do you disagree?

Dr. Flack: Well, the environment will affect your biology, and I think the question is "Are these biological changes that sometimes you see?" Because we do see stiffer vessels even in the normotensive range, higher central aortic pressures, more retinopathy, and things like that. Is it because of something that you're inherently born with, or are these changes that you can sometimes measure physiologically related to things in your environment? I don't know of any good evidence that it's something you're born with per se, and, if it is, that's nothing we can do anything about, so we really try to focus on factors that we can do something about, and we believe that the things we talked about -- and we did recommend comprehensive lifestyle change for people, blacks with pressures of 115/75 or higher -- we believe that that's probably the best we can do along with really good blood pressure control. And I think one thing that people forget about -- [in] diseases that have a strong genetic component -- is that there's also a heavy environmental interaction with the genetics, and you can go to things like familial hypercholesterolemia and PKU [phenylketonuria] and see that [even] if you do change your environment, you may not be able to lower your LDL [low-density lipoprotein] cholesterol if you cut your fat and cholesterol intake down to 120 [mg/dL], but you can probably get it under 200 [mg/dL] if you eat a real stringent diet. But if you eat a typical diet, it's probably going to be over 300 [mg/dL] or more.

Dr. Black: Now I've been very impressed, and I'm sure you have as well, about how much better control rates are in black men now that we've started to concentrate on it. Are you talking about that in the guideline?

Dr. Flack: Yes we did talk about it, and over the past decade or longer black men made a dramatic increase in their blood pressure control. Still inadequate, but you also have to recognize and even celebrate the progress that was made and try to continue it.

Dr. Black: How do you feel about the ALLHAT study, and how did it impact what you said?

Dr. Flack: Well the ALLHAT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial] [was] a very large study with certain -- an appreciable -- number of black hypertensives that really contrasted 3 contemporary first-line therapies, but the ALLHAT study is problematic -- for all the good it potentially brought us -- in that really treating hypertension is not [with] single-drug therapy. The ALLHAT drug treatment regimens passed the first line and were not set up to ensure good blood pressure control over the long term. It violated several principles that we know to be reasonably set in stone. Probably by the time you get to the third drug, if you haven't used a diuretic most of the time [that] you need to use a diuretic, [then] you're going to really run into problems predicatively in black populations or the older populations and probably just [in] hypertension in general. You're not going to knock the pressure down as much as you need to with just continuing to add drugs -- beta-blockers, sympatholytics, vasodilators -- on top of nondiuretic drugs. Hypertension treatment -- to successfully attain goal blood pressure and maintain it below goal -- requires a really reasonably thought-out multi-drug strategy. ALLHAT was really more of a test of the monotherapy, with secondary therapies that were added on or add-on therapies that did not maximize blood pressure control. And even in the ALLHAT study there was really no difference on the primary endpoint, and, at least on a couple of the drugs, no difference in the secondary endpoint. And the interpretation was that it was a positive study when a component of the secondary endpoint was positive, and that was heart failure. So, I think we've learned a lot from ALLHAT, and certainly considered ALLHAT and discussed ALLHAT, and ALLHAT again has been highly informative, but I believe that some of the interpretations require a grain of salt within, and we need to -- I would say -- apply more rigorous interpretations of clinical trial methodology. When we talk about ALLHAT, that's not always done.

Dr. Black: As a trialist and as an ALLHAT steering committee person I'm getting to the point that I begin to think large mega-trials are over, they've failed us, we don't learn what it is. We set up something 10 years before we actually interpret it. The landscape changes, and I'm happy to see I think that your committee is using judgment and not only trials to decide what to recommend.

Dr. Flack: Well, that's an interesting point, and I think ACCORD is another example of a well-conceived trial, and the landscape changed under it and that's the background theory for diabetes, which literally cut the event rates probably in half, and the care for patients requires not only data from trials and observations you make there, but you also have to interpret trials. You have to realize when the trial you believe you're doing [is] one thing, and then you figure out that you were underpowered for things that no one saw coming. You have to really -- in face of a punitively negative result -- I believe, be less definitive in some of the proclamations I've heard about that trial.

Second, you have to not avoid the obvious, and the connection for blood pressure and stroke is very well known, and that's not any hypothesis generation. There are some very smart people that have tried to tell me that's all, that stroke was hypothesis generating. I'm trying to figure out what hypothesis it is that we don't already -- have not already-- proven in multiple populations. I believe that [as for] mega trials, there is certainly reason to debate some of the necessity for then. I'm not willing to say that we shouldn't do them, but I also say that I fully understand the point you're making and I'm sympathetic to it.

Dr. Black: I think we have to do them smarter -- not not [sic] do them, and we have to frame the questions better, appreciate the things we'll change. And the part about stroke I think is particularly important. I also think the ACCORD stroke data are absolutely persuasive and significant. The interpretation by others, the media especially, is that we don't have to be aggressive with therapy anymore. That is not the case at all. The usual care group got to an average of 133. That's pretty good. Yeah, and I'm not sure that all doctors out there are going to be able to do that without us educating them how.

Dr. Flack: Right.

Dr. Black: There were drugs that are on the shelf, they're not expensive, but what we did provide is feedback, encouragement, carrots and sticks, and I think if we do that [then] it works. I'm looking forward to the guideline. It will be published, I presume, soon.

Dr. Flack: It's in review right now under revision, and we are anticipating publications in the near future.

Dr. Black: Very good. Thank you very much John, and thank you very much for your attention.

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