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Michael A. Weber, M.D. Dr. Weber is Chairman, Department of Medicine at the Brookdale Hospital Medical Center in New York. He also is Professor of Medicine at the State University of New York Health Sciences Center in Brooklyn. Dr. Weber is a Fellow of the Council for High Blood Pressure Research of the American Heart Association, the American College of Cardiology, and the American College of Physicians. He is an editor of the American Journal of Hypertension and several other hypertension journals. His main research interests include the renin-angiotensin system and its relationship to blood pressure regulation and the genesis of hypertension. He is the author of numerous articles and book chapters pertaining to these and related topics and has actively participated in numerous studies of newer cardiovascular therapies. |
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Early observations about adverse effects of high plasma renin levels
What I want to do, of course, is to just wrap up with some clinical thoughts and some clinical data that have been obtained with the ongoing studies with angiotensin II receptor blockers and, of course, most specifically losartan because that is the drug that we've had available the longest and where most of the research has been done.
What I would like to start off with, though, is the same point that John Reid made when he started. To me it is still one of the most exciting things that is happening in cardiovascular medicine--the link, in the simplest sense, between the renin angiotensin system and major clinical events. John showed a slightly different version of the same study by Mickey Alderman [1]. And it's telling us, quite obviously, that when you look at hypertensive people it doesn't matter, for example, whether or not they smoke, if they have high renins as opposed to low renins, they are going to have more myocardial infarctions. And it doesn't matter whether their cholesterol is high or whether it is normal. If their renin is high, they are going to have more myocardial infarctions. And likewise it doesn't matter about their glucose, be it normal or abnormal. High renin predicts more heart attacks. This has been known since 1972. In fact, yesterday was a special day because just across town here, at the Cornell University Medical college, there was a day dedicated to John Laragh. It was a scientific day called "All About Renin", but it was also called "John Laragh Day" to honor John Laragh, who has been at Cornell for many years as a distinguished professor and as director of the division of cardiology. In reminiscing about some of the highlights of his career, and it's very relevant to what we are thinking about today, was this paper. In fact, John Reid also showed data from this paper, the one that Dr. Laragh did with Hans Brunner and Fritz Buhler and Harry Gavras and their other colleagues almost 25 years ago [2]. Having pointed out what we just looked at, namely the link between renin and myocardial infarction and other events, they stated, "The frequency of strokes and heart attacks in these patients" (the high renin patients) "suggests that the renin mechanism may be implicated at least in the pathogenesis of these vascular complications of essential hypertension." As far as I know this was the first time in print in a major journal. The first statement of the hypothesis that in human essential hypertension the renin angiotensin system, quite apart from what it does in terms of blood pressure effects, influences clinical cardiovascular events. It's so interesting now 25 years later to still, in a sense, be talking about the same thing and confirming those exciting early thoughts.
Enzymes other than ACE that convert AI to AII
Now, Victor Dzau pointed out what we all in this room have known for some time and that is that as much as we like ACE inhibitors and certainly in the United States they have emerged probably as the most commonly used treatments now for initiating therapy of hypertension, they don't always effectively block the renin angiotensin system. It is because there are enzymes other than ACE.
We've heard data today about chymases among other enzymes that can convert angiotensin I to angiotensin II therefore, in a sense, bypassing the pharmacologic action of ACE inhibitors. And it is also possible, too, that angiotensin II can be manufactured quite independently of going through angiotensin I. So certainly there is a rationale and a logic to drugs that work by blocking the angiotensin II receptors. We heard a great deal this morning from Thomas Unger and from Victor Dzau explaining a lot of exciting data to do with the AT2 receptor. This is an old slide. It says, "Function unknown." Well, that's a rather simple and probably now totally inaccurate statement, especially when you saw the slide that Thomas had up with a whole long list of possible and very exciting mechanisms that might be mediated over here. But that is perhaps a story for another day. Right now we are thinking more of the AT1 receptor because that is where the action is happening with the development of losartan and other AII receptor antagonists.
High blood pressure is only one aspect of hypertensive disease
I guess if we are going to be clinicians for a moment in a very focused sense, we have to ask the question: What does any drug do that we propose to use in hypertension to the whole picture of hypertension? After all, high blood pressure, as we've heard many times this morning and we'll hear many times about the next few days is only a piece of the hypertension puzzle. We have to think about metabolic problems with lipids, with glucose and insulin abnormalities, changes in the renal function, changes in the structure and function of the heart, changes in what is going on in the arteries. And, of course, these are in some ways very important. If Dick were up here he would obviously be looking at the left ventricle as a pivotal part of where we should be interested in terms of treating hypertension and protecting our patients from major events.
Blood pressure lowering effects of losartan
Well, let's have a look at a couple of these issues. We have blood pressure data [3]. I have shown this slide previously at these meetings last year, and this is just to remind you that no big surprise--losartan lowers blood pressure. This is 24-hour monitoring, 24-hour period from 8 in the morning through to 8 o'clock the next morning. The blue line is a placebo showing that there is, in fact, no effect with placebo with 24-hour monitoring. And when you look at 50 mg once a day, 100 mg once a day, or even 50 twice a day, you get these beautiful, smooth reductions in blood pressure that are sustained for the full 24-hour period. In fact, I know of no other drug class that so effectively has a smooth effect. Even the ACE inhibitors have a relatively big peak effect early in the day and then a relatively more modest trough effect at the end of the dosing interval. This is a unique property of this newer group of drugs. Not unique to losartan, by the way; it is seen with the other AII antagonists also. This is the systolic pressure. Again, highly effective.
Losartan vs. amlodipine
Now we've finally gotten some reasonably good data comparing the losartan with other well-known drugs. I just want to show you one example here. This is a comparison against amlodipine, the long-acting dihydropyridine calcium channel blocker which certainly in the United States is the fastest growing of the calcium channel blockers and probably by now would be considered by most clinicians as the calcium channel blocker of choice in treating hypertension. Certainly it is enjoying wide popularity. And this is a 12-week study in which patients could be randomized either to losartan or to amlodipine and if necessary, low doses of diuretic could be added. It is quite obvious that 12 weeks later the two drugs have virtually identical blood pressure lowering effects.
Early vs. delayed BP effects of losartan
What we can't see from this, and I really don't have time to go through other slides to make the point but this does remind me of it, is that it takes several weeks, I believe, for losartan to maximize its effect and maybe even 12 weeks isn't long enough. And I love to hypothesize that maybe what is happening with losartan is that for the first few weeks, of course, we are seeing the short-acting effect. In other words, it's ability to block the vasoconstrictor actions of angiotensin II. But after several weeks of treatment, we are now recruiting an additional mechanism which is hopefully the ability of losartan to cause some regression of the hypertrophic changes, a thickening of the medial layers and other components of the arterial walls and that the regression of those changes by the losartan is having a further blood pressure lowering effect. I'm hoping to see some 6-month and 12-month studies with this therapy to see if we can really confirm that thinking. But certainly it has performed well when compared with other drugs.
Effects of losartan in African Americans
I wanted to mention from the same database the results in black patients and African Americans. It has been very fashionable to say and it's slightly accurate that the AII antagonists, as with the ACE inhibitors, don't work quite as well in terms of reducing blood pressure in our black patients as in white patients; therefore, maybe we should somewhat hesitate in using them for that population. I think that that is very, very wrong and foolish thinking. As Richard has shown us, as Dick has shown us, what we are really looking for from these drug classes isn't just getting the blood pressure down, it is providing critical renal protection and providing critical cardioprotection. We know from a number of clinical trials that black patients get a great deal of those benefits, even presumably if their blood pressure isn't being reduced quite as much as in other population groups. And here we see, in fact, if you titrate up losartan and add some diuretic and compare it with amlodipine, where there is also an opportunity to add diuretic, 12 weeks into therapy there really isn't much difference between the two groups. And, of course, everyone knows that calcium blockers work very well in black patients. So this, to me, is very encouraging and suggests that whenever we are thinking about renal impairment, whenever we are thinking about the heart or thinking about diabetes, our black patients certainly should get the benefit of these newer treatments.
Losartan in treating severe hypertension
There is also some recent experience now with this therapy in patients with severe hypertension. Usually in the early clinical trials there is a focus on more mild to moderate hypertension. This is a protocol where patients with severe hypertension could be started on 50 a day of losartan and the doses could be increased, and you could add a diuretic if necessary and even add other drug classes as necessary. Over a period that ultimately was about 12 weeks, you can see a progressive and steady reduction in blood pressure finishing up with fairly dramatic reductions in these patients who had severe hypertension at baseline. This is the systolic blood pressure. This is the diastolic blood pressure. You can see that the losartan, especially when mixed with other drugs over a period of time, is highly effective in this group. In fact, the average blood pressure at the end of the study was somewhere around 145 over 97. Considering that most patients started with diastolics that were close to 120, that was really quite a remarkable outcome. In fact, here we have the results. And you can see in the mid-140s over the 90s and starting very close to 120 in this more severe group. So the results are really very powerful and very encouraging. It certainly identifies losartan as an oral therapy that can be considered as one of the first steps in treating people with severe hypertension.
Efects of losartan on insulin resistance and plasma noradrenaline levels
This is kind of a cute study. It is done in a small number of patients, it needs to be confirmed, and we need a lot more studies like this. This is a look at losartan, and as you'll see in the next slide, it is looking at its ability to perhaps do things to glucose metabolism. This is just to show that it lowered the blood pressure in this study. That is not the reason I'm showing it to you. This is the reason I'm showing it to you. These investigators, Dr. Moan and colleagues [4] did the insulin clamp studies, which are now being used as the best way to gauge insulin resistance or insulin sensitivity, however you want to express it. When you look at glucose disposal rates, which is the measure of the insulin clamp studies, you can see that there is a significant increase in the presence of losartan. And this is the sort of thing that has been seen with ACE inhibitors. I don't know if this is better than or the same as ACE inhibitors. Apparently there are even differences among ACE inhibitors. This is an issue that deserves a more rigorous and careful exploration because these are the sort of data that I think are going to be helpful to people when they decide how best to use a new class of drugs. It is also interesting to me that during the clamp studies the investigators noted a modest but significant reduction in plasma norepinephrine or noradrenalin concentrations. They measured adrenalin that did not change. But the noradrenalin did. I think all of us now believe that blocking the renin angiotensin system secondarily has some sympatholytic effect. It does reduce sympathetic nerve traffic, and this certainly would help to support that hypothesis. Now whether it is because of this fall in noradrenalin, we see an improvement in glucose disposal, or whether it is totally unrelated I have no idea. But certainly these are encouraging data with those two important variables each moving in the right direction. This is just the same study confirming throughout the two hours of the insulin clamp study. This is baseline, the solid line; and here you can see after a few weeks of treatment when they repeat the clamp, there is a very nice, sustained reduction in noradrenalin; no change in adrenalin.
Effects of losartan on proteinuria
Now this slide is identical to the one that Dick de Zeeuw showed us a little while ago. Of course, it is from his department--it's his work. I just wanted to put it up even though it is slightly redundant because it is so important to know what is going on in the kidney. It is interesting to me that in the United States hypertension remains the main cause of end-stage renal disease and that end-stage renal disease is a very rapidly growing problem in our communities, especially in black communities...but in all racial and ethnic groups. This is not just a piece of curious science for the academics; this is of great practical importance. Like Dick, I am fascinated by his discovery that when he transitions from 50 mg of losartan to 100 mg of losartan, the blood pressure, which is these yellow dots, remains pretty consistent. And we know that increasing the dose of the drug doesn't really have much more of an effect on the blood pressure, but it does seem to have an additional effect on proteinuria. Now whether that is just a time effect or whether there is some important physiologic mechanism that is being recruited or added to by giving more losartan I can't be certain. But it is a very exciting observation and perhaps opens the door for us to think that losartan and this new class of drugs may have some very special intra-renal properties, perhaps even differentiating them from the ACE inhibitor experience.
Effects of losartan in congestive heart failure
We don't yet have the last word or the definitive data on congestive heart failure. The pivotal studies have been completed and are now being analyzed. I expect we will soon see and hear the results of that work. This is sort of a preliminary study that was published in Circulation a few months ago [5]. I apologize for the poor quality of this slide. I have looked with envy at the beautiful colored slides of my colleagues here in the program. But for those of you who saw the program, you'll notice that I've now moved to the State University of New York in Brooklyn. Out in Brooklyn we are very simple and straight-forward people and we have these rough and ready, black and white slides. But this shows after 12 weeks of treatment of patients with congestive heart failure, these are multiple observations during a 24-hour period during chronic therapy with losartan, we are looking at pulmonary wedge pressure.
Pulmonary capillary wedge pressure (change, mm Hg)
Heart failure patients treated with losartan vs. placebo [5]
The top line here with the little crosses is placebo. Here at the bottom is losartan 50 mg a day. And you can see that there is a beautiful sustained reduction in pulmonary wedge pressure throughout the full 24-hour period during chronic therapy. Likewise when you look at this slide, this is the cardiac index--exactly the same story, exactly the same patients, only of course now the placebo is here and we see the sustained increase in cardiac index in the patients getting losartan 50 a day. So hemodynamically it seems to perform exactly as we would predict. And in a way it is somewhat similar to the ACE inhibitors. Of course what we all want to know is: Are we getting the same symptomatic improvement? Are we getting the same survival benefits that we now have come to expect from the ACE inhibitors? Hopefully those results are just around the corner.
Losartan and patients with ACE-inhibitor induced cough
One could be cynical, and I suspect some of our colleagues in primary care medicine and general practice will be somewhat skeptical or somewhat disinterested, as they tend to be these days, and look upon losartan and its fellow drugs in the angiotensin II receptor blocking class as drugs that are just good for patients who have coughed on ACE inhibitors. Well there is no question that it is good for those patients. This is a study that I think many of you are familiar with--a multicenter trial in which patients who are known to be coughers when taking an ACE inhibitor could then be randomized to receive a diuretic, to receive the ACE inhibitor again or to receive losartan.
And you can see that clearly compared with the ACE inhibitor, hydrochlorothiazide, and losartan have significantly less incidence of cough. This has been verified now by another study. Throughout the whole experience with losartan there has, in fact, been no difference between the drug and placebo in the incidence of cough. So it certainly is a desirable alternative if cough is ever an issue. I hate saying it because I think that is a long way remote from the real good reasons to be thinking about this new drug class.
The ongoing LIFE study
I wanted to put up, as have a couple of my friends on the panel, as a final slide a sort of exhortation to action. This is the (LIFE) Trial that Dick Devereux mentioned [6]. This is our look at a so-called enriched population: Patients with left ventricular hypertrophy, people over the age of 55, people with genuine hypertension. These are people who are likely to have cardiovascular events. It is an opportunity right at the beginning of the life of a drug, which I think is very exciting, to ask the critical question whether compared with a standard of treatment, the beta blocker, atenolol, whether the losartan can reduce the incidence of cardiovascular mortality and morbidity. And, of course, we will be looking at cardiovascular death; we'll be looking at major cardiovascular events, especially myocardial infarction and stroke that are also non-fatal. One of the problems with the study is that we are being a little slow in recruitment, especially in the United States. This is a study that involves a number of Scandinavian centers as well as North American Centers. The Scandinavians are doing a very good job at recruiting. We here are being a little bit on the slow side. I hope those of you who are investigators will really make some effort in finding patients for this study. This is a study of genuine scientific worth. I think once the results come out, and I think those of you who listened carefully to what Dick Devereux was saying will agree it is going to tell us a great deal not just about losartan but about the whole issue of left ventricular hypertrophy and its relationship to cardiovascular prognosis.
Summary
In summary, what we have done this morning, and I'm just delighted at such a wonderful attendance at the first symposium of these ASH meetings, is to really look thoroughly at the role of the renin angiotensin system in the heart, in the artery, in the kidney, its effect on prognosis; we've looked at the receptors; we've looked at the basic mechanisms that govern the way in which angiotensin II has its effects on these critical structures and organs; and we've looked, at least in a preliminary fashion, at some exciting therapeutic data.
Closing remarks
I would like to thank all of my colleagues who have spoken here this morning. I would like to thank our friends at Merck for their support of the scholarly activities here at the American Society of Hypertension. And most of all, I would like to thank all of you for having come and participated and made it such a memorable event. Thank you all very much.
References
1. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 324:1098, 1991.
2. Brunner HR, Laragh JL, Baer L, et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 286:441-449, 1972.
3. Arch Int Med 155:405-411, 1995.
4. J Hum Hypertens 9(85):45, 1995.
5. Crozier et al. Circulation 91:691, 1995.
6. Dahlof B, Devereux RB, de Faire U, Fyhrquist F, Hedner T, et al. for the LIFE Study Group. Losartan intervention for end-point reduction in hypertension (The LIFE Study). Am J Hypertens 1996;9:26A.
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