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Interactive Learning : HealthCast Transcripts

Episode 17 : How We Learn About Best Treatments

Release Date: May 14, 2007

Dr. David Meyerson: Hi, I'm Dr. David Meyerson, cardiologist at Johns Hopkins and your host for this edition of Vascular Disease Foundation's HealthCast. We are very excited to bring you excellent, easy to understand science to you on all topics relating to heart and blood vessel diseases as a public service. We have been very fortunate to have with us on the line Dr. Alan Hirsch who is Director of Vascular Medicine at the Minneapolis Heart Institute and Professor of Epidemiology and Community Health.

In our last episode, we talked about a very simple test almost like the electrocardiogram for the vascular system and what Dr. Hirsch told us is that the ankle-brachial index means that -- a very simple test,the doctor takes the blood pressure in the arm and he compares it to the blood pressure in the leg and he does it on -- he or she does it on one side and the other and it turns out that if the two pressures are equal, means one -- if you put one number over the other, the ankle-brachial index is one point zero, that's normal. It turns out that believe it or not, if the bottom number, if the pressure to the lower extremities goes down lower than the top number, the point nine, then it indicates that there is likely a seventy percent blockage in the arteries to the legs. Let me rephrase that. If the blood pressure in the legs is substantially lower than the blood pressure in the arms, with that ankle-brachial index being at point nine or less, that indicates a high likelihood of a seventy percent blockage in the arteries that nourish the legs and what he then told us was that if we find disease in the arteries of the legs and we may spend some time on this in this episode, it is a marker that there may be disease that exists in the carotid, those are the arteries that nourish the brain and also the coronary arteries, the arteries that nourish the heart. So again, Alan Hirsch, Dr. Hirsch, thank you so much for being with us. I want to go now and talk about we don't always know exactly what the right therapy is and when we don't exactly know, we have strong suspicions of what the right therapy would be, but we haven't proven it -- I'll give you a for instance. If I walked -- before I -- when I left the house every morning, before I got in the car, if I walked around the fire hydrant three times and then got in the car and I drove to the hospital to work every day and after six months, I never got into a car accident and I never even came close, I could logically assume that walking around the fire hydrant three times, prevents car accidents. Now all of us know that's ludicrous, all of us know that you only have to walk around the fire hydrant twice to prevent car accidents, but you -- the point of the matter with this joke is that you can't use observations to make very strong clinical opinions that generalize to the broad population. So, Dr. Hirsch, there is a study called the CLEVER trial and the CLEVER trial is going to look at whether exercise or whether some sort of intervention with a catheter and a stent or other forms of medical therapy might be better one from the other. Is that right?

Dr. Alan Hirsch: Well right, so with a huge thanks to you. If you were walking around those fire hydrants and you had leg muscle discomfort called claudication and couldn't make it, you would drive to the hospital and ask your physician, "What should I do?" And you'd be potentially offered a range of choices. The CLEVER study evaluates those ranges of choices within a setting whereby both that patient and the rest of the patients around the country will learn which choices really are most associated with benefits, what the risks are, what the costs are. Yes, we want people to participate in clinical trials, assess best strategies of care so we know how to answer the question, "What should I do doc?"

Dr. David Meyerson: So with this study again, they're pitting against each other one group that's going to have a stent put in the arteries that nourish the legs or that lead to the arteries that nourish the legs, one group is going to be on an optimized medical regimen and another group is going to have supervision by an exercise physiologist like our friend Dr. Kerry Stewart to see if exercise makes it better for them long-term. Let me ask you a question. Why is there no surgical arm here?

Dr. Alan Hirsch: Well, there's no surgical arm because in general, although people think of vaso surgery as an effective treatment for leg muscle discomfort from artery blockages, and it is, it is certainly not the first choice and not the most common choice and even the best trained vaso surgeon would say try something else before we take as large a stab at therapy as an operation. So maybe for background David, individuals who might be listening to this PodCast who either have claudication, a primary symptom of P.A.D. or who knows someone, have a friend or a spouse who has claudication, they're probably aware that there are at least four different ways of approaching treatment and they do include supervised exercise, in other words a rehabilitation of the leg muscles by having the individual work with a therapist to strengthen the muscles over between three and four months, or alternatively, at least one very effective medication on the market in the United States and throughout the world called Cilostazol which again, is very effective in improving leg muscle discomfort from claudication --

Dr. David Meyerson: Let me not blow that by too quickly. The medicine that you just mentioned --

Dr. Alan Hirsch: Yeah.

Dr. David Meyerson: -- is spelled C-I-L-O-S-T-A-Z-O-L, Cilostazol --

Dr. Alan Hirsch: Right.

Dr. David Meyerson: -- but most of our patients would probably know it as Pletal, P-L-E-T-A-L. Is that right?

Dr. Alan Hirsch: Right. So a second choice is a pill and this pill is effective in relieving the discomfort in many, many, although not all of the individuals.

Dr. David Meyerson: And you know for American society, we love to do number one through thirteen and take pill number fourteen to make things all better, don't we?

Dr. Alan Hirsch: Well, I'm smiling. And the third choice might be angioplasty and a fourth choice might be surgery, so in designing a trial, designing a research question, we usually want to ask not twelve questions at the same time, but a most important question because there's an awful lot of work and an awful lot of effort to try to collect good quality data. So with first a real thanks to another physician colleague of ours who also works with the Vascular Disease Foundation, a Dr. Tim Murphy, an intervention radiologist and nationally leader really in evaluating methods of best improving vascular symptoms at Brown University. Tim, with my help as well, helped create the CLEVER study entitled Claudication: Exercise Versus Endoluminal Revascularization meaning angioplasty. Now with those two --

Dr. David Meyerson: I'd just like our audience to know that as much thought sometimes go into the eponym, how you name the trial, as well as the clinical research that is underlying that CLEVER name.

Dr. Alan Hirsch: Oh we --

Dr. Kerry Stewart: That's pretty clever actually.

Dr. Alan Hirsch: It's a clever name to allow the clever patient to seek the clever physician to get the best care, so right David, there are three interventions in this trial primarily and not a surgical arm for this leg disease and of the three legs in this trial, I hope you're smiling, --

Dr. David Meyerson: We're --

Dr. Alan Hirsch: -- exercise, medications and angioplasty all are evaluated under circumstances that provide sort of best care. Surgery is not felt to be a first line therapy.

Dr. David Meyerson: Tell us a little bit about Pletal, about the medication that's involved here. What does it do?

Dr. Alan Hirsch: Well, Pletal or Cilostazol is the generic name and this is a medication that is available at the generic equivalent, is a medication that has been in the market for a number of years and it is FDA approved to improve the symptoms of claudication, the symptoms of leg muscle discomfort. The mechanism by which it accomplishes this is to me, actually quite mysterious. When it was developed by our colleagues in Japan and studied in the United States extensively, it was felt it likely dilated the microscopic vessels that serve as alternate pathways for the blood to get past the blockage into the muscles of the leg. It also has some beneficial effects on the cholesterol levels in the body, but regardless of what mechanism directly affects the symptom, people feel better when the drug is used for two to three months at its twice a day dose and not everybody gets better in the same way that not every headache is relieved with Tylenol, but we wished for years and years in vascular medicine that instead of having to always to operate, that it would be great to be able to take a pill to more or less accomplish a biological bypass in a sense to help people walk farther. And that miracle was found by the volunteerism of individuals who are willing to take the time in clinical research over many months to use either this medication when it was a research drug or a placebo and it was well proven when thousands of patient volunteers that this is a known to be effective and safe medication to improve symptoms of claudication in people willing to take it.

Dr. David Meyerson: Now in addition to the three arms or legs in this trial, we teach our patients always one hundred percent of the time, if they are diabetics, they must control their diabetes very well. If they have high cholesterol, we must treat that aggressively and if they are a smoker, they must absolutely stop smoking.

Dr. Alan Hirsch: Yes. But that's not the focus of this study.

Dr. David Meyerson: No, it's not the focus of this study, but again to do the study without – you would not have somebody who is doing those three things at the same time, those people should also be paying attention to those things absolutely and critically. Wouldn't you say?

Dr. Alan Hirsch: Well, perhaps you're raising the overall theme of when a person participates in clinical research, even a study that looks at claudication treatments to feel better, there is a mandate. There is an obligation. There's a system of care placed around the patient to protect them. In the last PodCast, we talked about the ethics of research whereby individuals in a research study generally do as well or better as patients in regular care. In the CLEVER study, every patient has their diabetes controlled, blood pressure, use of anti-platelet medication to prevent heart attack, cholesterol levels very carefully followed so every single patient will essentially achieve an optimal level of background therapy to diminish their risk while they're participating in the trial to feel better.

Dr. David Meyerson: And that is exactly my point that there are very standard things that are not open to research questions, that diabetes must be controlled, that tobacco smoking must be curtailed, that cholesterol, diabetes, tobacco smoke and blood pressure must also be properly controlled and again, when you participate in a research trial, these things will all be looked at and looked at with great care and these are things that whether you are in a research trial or not, you should be exacting this level of care from your own doctor.

Dr. Alan Hirsch: And this is interesting at a time when I think most patients for any particular health problem really are trying very hard to get enough attention from their physician. More than ten minutes, more than fifteen minutes. To have their calls answered. Wouldn't it be great to be in an environment which is created by a clinical research whereby you're actively followed, carefully monitored, spoken to, offered written and verbal information for years. That's really a gift that is offered to individuals who elect to participate.

Dr. David Meyerson: And you know, we should also mention to our patients and to our listeners that when they come in to see the doctor, don't be afraid to come in with things that you've printed off of the internet from reliable sources, don't be afraid to bring a trusted partner or person that may be knowledgeable in the area into the examination with you, don't be afraid to come in with a list of questions and don't be afraid to make certain that the doctor answers those questions.

Dr. Alan Hirsch: Absolutely.

Dr. David Meyerson: So Alan, I'd like to go on now.

Dr. Alan Hirsch: Right.

Dr. David Meyerson: So the CLEVER trial will be an important three-legged study if you will to tell us which of these interventions are best for people. Dr. Kerry Stewart is here in studio and I just want to mention something that there is an exercise arm to this study and there is data to suggest -- different from -- if somebody has coronary artery disease and they are exercising to the point that they get angina or chest pain, we don't tell them to continue exercising. We actually tell them to call their doctor and let's get this fully evaluated. But in the lower extremity, peripheral arterial disease area where somebody has been evaluated, exercise therapy which brings them to a little discomfort and then they rest and then they do it again. That's actually beneficial, isn't it?

Dr. Kerry Stewart: Well, I think you make a very good point that pain actually is a stimulus for the body to adapt in such a way that the pain will eventually go away. The problem is when you have pain in the heart that could lead to an irregular heartbeat and cause someone to collapse and perhaps have a heart attack or die, so when someone has chest pain, they need to stop exercising. But as you say, some mild discomfort with walking is actually the goal.

Dr. David Meyerson: And people if they continue to train that way over months, can do better and better and better?

Dr. Kerry Stewart: They are able to walk further with less pain.

Dr. Alan Hirsch: Now you raise another good point though Kerry that whereas people are known to get better when they have accesses to program, one of the challenges in our nation, huge challenge, a fundamental public health challenge is that we have a proven therapy called exercise with essentially no risk, but it's not really available to the one to three million individuals with claudication, although that brings me back to CLEVER, which obviously I'm interested as a member of the operations committee of this study. How many individual places are there perhaps in this country, Kerry, you believe where a supervised program of exercise intervention is available for someone with claudication?

Dr. Kerry Stewart: Well, as you just kind of alluded to, I think it's pretty scattered. You have to somewhat look a little far and wide to find a program that specifically does peripheral arterial disease rehab, but as you know Alan, we are working on an effort so that cardiac rehabilitation programs which are widely available -- there are thousands of them throughout the country, can be equipped and be able to accept patients with P.A.D. so that if there's not a specific P.A.D. program in a particular community, at least call the hospital or the nearest cardiac rehab program to find out if they accept patients. More and more that is happening.

Dr. David Meyerson: But here's the magic, here's the magic of clinical research. Let's say for argument's sake, the CLEVER trial proves that the exercise arm does as well as the stenting or the medication arm, or let's say for argument's sake that the exercise arm does better with few complications than the other two than that would be the impetus for the medical system, for the government, and for physicians to recognize that this should be offered.

Dr. Alan Hirsch: Well that would be great, but let's come back to the realities of clinical research. So right now if a patient believed as I do that if they have a particular leg artery blockage that there's essentially an equality between the potential benefit of exercise versus an angioplasty versus a pill. If they wanted that range of choices, one place they could go that would offer that range, would be a CLEVER research site. Because every CLEVER sight has gone through a carefully calibrated, certified training program to assure that exercise can be delivered effectively for those people in the trial. In a trial such as CLEVER, people will be asked to be randomly assigned to an exercise program or medical therapy with the medication Cilostazol, or the angioplasty or a combination of angioplasty and exercise, but at least in these sights, two things happen. They're offered therapeutic choice, the actual opportunity to have any one of these or they can participate in the effort to collect the information that would help potentially millions of people have access when the trial's over. But of course, none of this will happen if the public's not aware of the trial or doesn't volunteer or physicians don't support it.

Dr. Stewart Kerry: On the previous PodCast, I had mentioned a www.clinicaltrials.gov which lists the major trials throughout the country and if you go to that website, clinicaltrials.gov and just type in the word CLEVER, that trial immediately pops up, it describes all the details of the trial and as I'm looking right now, it lists at least eight sites that are available throughout the country.

Dr. Alan Hirsch: Eight sites now, there will be twenty as the year passes on and on behalf really of Dr. Murphy of Brown University and the Harvard Clinical Research Center, the University of Minnesota, the twenty sites, we do ask people who live close to one of the CLEVER sites to consider getting information.

Dr. Kerry Stewart: Yeah, right now I see sites in California, Minnesota, New York, North Carolina, Ohio, Pennsylvania, Rhode Island and Washington state.

Dr. David Meyerson: Kerry, give that website once more.

Dr. Kerry Stewart: So it's clinicaltrials.gov and in the box where you can search, just type in the word CLEVER and that trial pops up immediately.

Dr. David Meyerson: That's great. Let me just bring us to another area that our listeners have not heard about on our PodCasts and that's renal artery stenosis. Renal stands for kidneys and the arteries that nourish the kidneys are the renal arteries. Well the kidneys and the adrenal glands together are the source of control of the right amount of fluid and electrolytes in our body and it also controls a great deal of hormones that govern and regulate our blood pressure so that when the kidney arteries become blocked and again, when we're talking about arterial disease and the sixty-year-old house, if we have a problem in the basement, it's not surprising that on the first and second floors there could also be a problem. There are also studies to look at renal artery or kidney artery stenosis. Now the interesting thing is that if you have a blocked kidney artery, you can have high blood pressure, it can cause stroke, it can cause heart failure, it can cause something called flash pulmonary edema where the lungs fill up with fluid abruptly and of course it can cause it can cause kidney and even death, so that again, this is another problem in the vascular tree. The kidney arteries come off of the aorta in an area where atherosclerosis is very common and Dr. Hirsch, there is a study called Carl. What is Carl study?

Dr. Alan Hirsch: Well, again we smiled at the importance of titling things. I know my children's names and I'm proud of it, I'm very proud of the names of the studies that we all are allowed to participate in. Carl stands for Cardiovascular Outcomes for Renal Athroschlerotic Lesions. And Carl is like CLEVER, a study sponsored by the United States National Heart, Lung and Blood Institute and lead by my colleague Chris Cooper and Lance Dorkin [phonetic] and this is a study designed by the best sort of vascular surgeons and ethologist, cardiologists, intervention radiologist to ask the question, if you had a kidney artery blockage, which is actually quite common in this country and this placed you at risk of heart attack and stroke from the high blood pressure that ensues, or if you were at risk of losing kidney function and perhaps requiring dialysis or transplant, what would you choose? Would you choose to have the use of medications be offered that are proven in fact to help the kidney function, lower blood pressure and lower heart attack and stroke rates or to undergo a kidney artery angioplasty and be offered the same medications with the presumption with some information that opening the artery might also help improve the blood pressure outcomes, but you're a physician right now offering you the choice of pills alone or angioplasty and pills, could not rightly answer which is the best choice for most patients because we don't have an adequate knowledge base to offer patients really the guidance that they need to make that fundamental choice that --

Dr. David Meyerson: Alan, let me go a step further which is --

Dr. Alan Hirsch: Please.

Dr. David Meyerson: -- so important and that is that many of our practitioners -- I'm frequently asked to see people with what you might call resistant hypertension. People come in on three and four and sometimes even five medications and the number of times that a lot of the practitioners in the community that will actually look for what we call secondary causes of hypertension, the renal artery stenosis being one of them -- it's just not that common, so I think we probably have to do a better job, not only to the public who have probably never heard of this, but to our providers, our internists and our family practitioners, vascular medicine people and even cardiologists who just don't look for it that often.

Dr. Alan Hirsch: You raise an interesting point. If this had been five or ten years ago, it was much harder to actually know whether a patient with difficult to control hypertension or progressive kidney function problems really had any kidney artery blockage, and what's so wonderful about the world we live in is that this has become relatively easy using very simple techniques of ultrasounds, CT scans or magnetic scans now to take a patient who's at risk of this being caused by an artery blockage and determine in fact, whether that's the case or not. But we're still then left with the question what is the best treatment.

Dr. David Meyerson: Alan, I have to tell you I'm so grateful the time you've spent with us on the three VDF PodCasts that you've done with us. The time flies when you're the guest. The information that you have is so critical and it's so beautifully delivered that both my personal gratitude that of Dr. Kerry Stewart, and the Vascular Disease Foundation for having spent the time to help educate our listeners and hopefully we've educated listeners who are medical professionals as well as people who are consumers of hopefully the best healthcare. Dr. Alan Hirsch, he's the Director of Vascular Medicine Program at the Minneapolis Heart Institute, Professor of Epidemiology and Community Health at the University of Minnesota School of Public Health, he's a past president of the Vascular Disease Foundation. Also in studio with me is my sidekick engineer, producer and friend, Dr. Kerry Stewart who is a Professor of Medicine at Johns Hopkins and Director of Clinical and Research Exercise Physiology and I, as you know am a cardiologist at Johns Hopkins with the VDF Foundation, I'm Dr. David Meyerson, thank you so much for listening. We try our very best to give you the best quality health information we possibly can and we'll continue to do that in the future. Thanks again for listening, till next time.

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