Interview with Eric J. Topol, MD

Eric J. Topol, MD is currently Director of the Scripps Translational Science Institute (STSI) and also serves as Dean of the Scripps School of Medicine and Chief Academic Officer for Scripps Health. He is Professor of Translational Genomics in the Department of Molecular and Experimental Medicine.

Dr. Topol is one of the most respected and oft-quoted cardiologists in the U.S. His name appears on numerous published manuscripts and his experience ranges from his initial training as an interventional cardiology Fellow with angioplasty pioneers Richard Myler and Simon Stertzer to his current cutting edge research and activities in the genomic realm relating to heart disease -- the subject of this interview. While working with Dr. William O'Neill at the University of Michigan, he did pioneering in the use of tPA, at the Cleveland Clinic he served as Chief Academic Officer and Provost and founded the Lerner College of Medicine.

Among his many awards is the Andreas Gruentzig Award from the European Society of Cardiology, named for the inventor of coronary angioplasty. Dr. Topol is also the Editor-in-Chief of the highly-regarded cardiology web site, theheart.org.

Eric J. Topol MD

Q: Over three years ago, we were all at the FDA hearings on stent safety and antiplatelet therapy. You and other panel members agreed that we just didn't have enough data to determine how long antiplatelet therapy should be continued after drug-eluting stents – that we needed more research. So what have we learned since then?
Dr. Topol: Unfortunately, we don't know anything more regarding the appropriate length of dual antiplatelet therapy.

Q: Which is amazing – the FDA panel wound up recommending extending treatment with Plavix and aspirin from six to twelve months. But not really based on much data. However, there are finally some trials underway to get better information. One of these is the SEASIDE trial being done at Scripps.
Dr. Topol: It was Paul Tierstein, David Kandzari and others who initiated the study. But I supported it. It isn't a randomized trial, but it is a test to see whether in the patients with the Endeavor stent, Medtronic’s product, will they be able to be handled with considerably less systematic dual antiplatelet course.

On the DAPT Trial: "The notion that we should treat all patients for X duration is totally crazy. It completely goes against all the evidence that every patient is an individual with a separate biologic story.... I'm amazed that it's going forward."

Q: Right. It’s testing a six month period. And you have designed a genetic substudy within SEASIDE. Is this a specific study just with SEASIDE? Because you have started doing genetic testing at Scripps, genotyping a lot of patients. Could you talk about that whole program and how it interacts with the SEASIDE trial?
Dr. Topol: This is where my background and influence has been felt. There are many studies that have suggested that the cytochrome 2C19 was important as a risk factor, a tripling of risk of death and heart attack. But it was in August, at JAMA, when the genome-wide study that scans all 23,000 genes in the human genome demonstrated that this issue of lack of response of clopidogrel for antiplatelet effect, which occurs in at least 30% of individuals, was tied to one gene in the cytochrome pathway, 2C19, and that this indeed is worth assaying in all patients who are going to be considered for clopidogrel.

So whether it's SEASIDE or whether it's standard practice, we feel that the data are compelling. There's a lot of useful information from knowing if someone is a poor or intermediate metabolizer, because it's associated with considerable increased risk. And, there are other things that can be done to assess that risk. You can do platelet function testing which is a point of care test and you also have many different strategies of double-dose clopidogrel or prasugrel or, in the months ahead, ticagrelor. There's also the issues of how long to use these various therapies, double-dose or the other newer thienopyridines.

So, there's lots of ways to individualize therapy once you know a patient is at increased risk. And then there is also an important point about titrating the risk. Because if an individual patient is frail and elderly you might not want to use a therapy that's tied to much higher bleeding risk. On the other hand, if the coronary anatomy is very vulnerable with, for example, left-main stenting or equivalent or poor left-ventricular function with a single major conduit, then it might be reasonable to consider using the most potent therapy that has been established. So a lot of these things are the integration of genotype data, possibly in some patients, platelet function data, and the clinical and actual angiographic left ventricular function status. All these things are important in each individual patient. It's the epitome of individualized medicine. And it's being applied in SEASIDE as it would be across the board at our center.

Q: So you're doing genotyping of elective stent patients. Is it every third patient?
Dr. Topol: Actually, we're doing every patient. We're even doing patients who are already on clopidogrel. That's up to the treating physician, if they want to test somebody who's already been on it. But all patients who get stented are asked if they are okay to have their genotype assessed and, if they're fine with that -- which most are, not everyone but almost everyone -- we get that done either before the procedure or as soon as possible after the procedure.

Scripps Translational Science Institute

Q: In terms of the testing itself, is it expensive, does insurance pay for it or is this part of the study that the center is doing?
Dr. Topol: It's actually really inexpensive to do a genotype. That can be done for a few dollars. The problem is doing it in a CLIA-supported lab, certified, licensed lab for clinical data, in particular licensed for genotyping, and can do high volume with rapid turnaround and that sort of thing.

Some day this will be done as point of care testing, like platelet function, and hopefully be done in a matter of minutes or even an hour or two. But that's not available today.

So, we linked up with Quest because they're close by, within a 40-minute drive from us here in the San Diego region. They are doing the genotypes for all the loss-of-function alleles, not just the Star 2 allele of cytochrome 2C19, but the other loss-of-function alleles, which are not as frequent but equally as important. That is a way to get the genotyping done for today. Whether that will be the long term plan we don't know, but it was difficult to get our clinical labs geared up to do it locally. Scripps has about 2,000 patients a year that undergo coronary interventions so it's a pretty large volume.

Q: How will this data be worked with? Obviously you’re going to be making clinical decisions for individualized care for patients based on this testing. But how will you be following up the research to see what this means, how this has turned out in terms of outcomes?
Dr. Topol: To be clear, this is not what I consider research, this is clinical care! This is being able to make the call of when it's ready for prime time -- that is taking care of patients. We will be looking at, we have the genotype data for all the patients and we will assess their outcomes, but that's not why we're doing this. This is because we feel, and I strongly feel, that knowing this information today we can't wait. This is a vital thing to have in the care of patients. With all that we know today, the evidence is compelling.

So, yeah…we'll follow-up with more work: what has happened with this new program, have we overall been able to reduce the rates of stent thrombosis and post-procedural infarction deaths by this type of program? But, it isn't a randomized study. It's a clinical practice. It’s a clinical service for patients. It isn't even a study, there's no consent form here, this is not an IRB approved anything.

Q: The only part of the study is where you're doing it in conjunction with the SEASIDE Trial.
Dr. Topol: Right, and there is also, in the GRAVITAS trial that is on-going, nearing completion, we do have a substudy called GIFT where we're getting genomics on all of the patients there. So, we'll gave a lot if data from all of the studies, like SEASIDE and GRAVITAS, where we'll have the link of genomics. The interesting thing for GRAVITAS, that's a trial randomizing double-dose clopidogrel, so we will know whether patients will respond. There are a couple of thousand patients in that, so the patients who have the poor metabolizing, loss of function alleles, we'll see whether in those patients the double-dose works, because no one has ever made that link for clinical outcomes yet. In SEASIDE basically we're just trying to find out, if there are thrombosis events in that study, are they tied to genomic underpinning or are there other explanations. So, that's what we'll learn from that genomic substudy.

Q: Like for example the healing of the stent?
Dr. Topol: Yeah, maybe the stent wasn't put in right in the first place, maybe the duration of antiplatelet therapy does need to be longer, there's lots of uncertainties, of course. But we'll at least be able to know some of that with some additional data that I think is going to be helpful.

Q: The SEASIDE Study is limited to the zotarolimus stent, the Endeavor; why is it just the Endeavor? Isn't the clinical information you’re getting regarding genotyping something that is applicable for all stents?
Dr. Topol: Right, I think that any patient who undergoes a stent today would be best served by knowing their 2C19 status, and there is no way to know that without essentially doing a genotype. And a platelet function test, which is the only other way to get a handle on this is somewhat dynamic, you can test it multiple times and get different answers, the DNA story is obviously as stable and telling as one could ask for in this setting. I think this is useful for all PCIs, we have to figure out ways where this can be done efficiently and inexpensively but that really is not an issue, what we need to do is get all the different entities that can do genotyping and get this thing competitively brought down to what should be a very tiny cost.

This is getting to be more important as we actually get to the point when clopidogrel is generic, which is imminent. Right now it costs between 4 and 5 dollars a day for these drugs, which is incredibly expensive, but when it's generic then this becomes magnified because it's not just about all the other things we were talking about, also there is the issue of being able to use a generic drug compared to much more expensive proprietary drugs -- ticagrelor and prasugrel, which will still be 4 or 5 dollars a day, that's going to be added rationale for knowing the risk of the patient at every level, including the genomic level.

Q: Does this genotyping have any effect for prasugrel and other antiplatelet therapies or aspirin, or is this specifically clopidogrel resistance, the tie that's been made?
Dr. Topol: Yes, it is specifically clopidogrel. There really hasn't been an issue yet demonstrated for any substantive lack of responsiveness for ticagrelor or prasugrel, so those drugs, because they work differently even though they work on the same receptor, the platelet, the way they are metabolized, or in the case of ticagrelor, it's an active drug so it doesn't require any metabolism. Fortunately for those drugs, they don't have this problem of approximately a third or more people having a problem of actually converting it to an active drug. So, for many, getting clopidogrel is not so different than having a placebo. You take the medicine, and it's expensive still today, and, particularly the poor metabolizers that are homozygic for the loss of function, there really isn't much of a way that they can get benefit from the drug.

Q: Why are the other stents not being tested for shorter periods? There is the big trial, which is the DAPT trial which is going to be testing 12 months and 30 months.
Dr. Topol: I don't understand why that trial could possibly be done, to me it's completely lacking acknowledgement that it's not just about the duration of the therapy. This idea of treating all people for some X duration is crazy. What about individualized medicine? What about that we can access the risk at the genomic level, at the platelet function level? I mean it's just crazy for me to think of the amount of resources that are being expended for mega trials like that.

The notion that we should treat all patients for X duration is totally crazy. It completely goes against all the evidence that every patient is an individual with a separate biologic story, and a risk of bleeding. And then there is obviously a big expense. The drug companies would love it to be 30 months or 30 years. But to try to generalize from a trial like that, I'm amazed that it's going forward. Have they started that trial?

Q: I believe they've just agreed on what the ground rules are going to be. About a year ago Spencer King wrote an editorial in JACC Intervention which calls up the same thoughts, which is that the future of treatment in interventional cardiology, or cardiology in general, is really the whole idea of individualizing therapy for patients. Is this the future? Is this where things need to go?
Dr. Topol: Yes, but it's guided with information that cardiologists have never had before, which is key genomic data, understanding pharmaceutical-genomic interactions and applying that. Interventional cardiologists historically have learned a lot of new dance steps. When they needed to learn about radiation they learned about that, when they needed to learn about drug-coated stents they learned about that. I think they will quickly get up to speed on this issue. But that's going to empower physicians, interventional cardiologists, to take much better care of their patients. The notion that the risk of clotting a stent, which all of us have high regard for, what that means and potential fatal consequences, that that could be reduced substantially by knowledge of the patient's genomic data and/or platelet function responsiveness, these are things I think that are going to become common practice. But they don't substitute for the overall assessment of the individual with respect to bleeding risk and with respect to overall stent thrombosis risk - what if it did occur in that particular patient, how big of a problem might it be? And then there are multiple strategies. That's why you can't do a randomized trial here because there's about, I can think of about 20 different things you could put into the mix. Ideally, that's what medicine is about, you know, thinking it through, integrating all the information, discussing with the patient, the patient's family, and then coming up with a plan.

This interview was conducted in November 2009 by Burt Cohen of Angioplasty.Org.