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| | Aspirin Resistance in Thrombosis Management | 
Printer-friendly version | | | | | | | | This ThrombosisClinic.com expert commentary focuses on aspirin resistance in thrombosis management and features Dr Deepak L. Bhatt from the Cleveland Clinic. Dr Bhatt is the Director of the Interventional Cardiovascular Fellowship at the clinic and has published a number of articles in this field, most recently in the Journal of the American College of Cardiology in March 2004. Dr Bhatt is also the Co-chair of the TRACK Thrombosis Resource Initiative and, of course, is internationally known as an expert in this field. Dr Bhatt, thanks for joining us. It’s always a pleasure. | | |  | | | It’s terrific to be here. Thanks for having me. | Back to top 
| | | | | | The title of your latest paper is Aspirin Resistance: More Than Just a Laboratory Curiosity. How so? Do we have a specific definition, for example, that is universally agreed upon? | | | | | | That’s a very fundamental question that you’ve asked and that really gets into a lot of the key issues with aspirin resistance. I think the most common sort of definition for aspirin resistance is the insufficient inhibition of platelet function with standard aspirin dosing, but exactly where the cutoffs are for the degree of platelet inhibition that constitutes aspirin sensitivity is an area of lively debate. | | Back to top
| | | | | | Would you consider aspirin resistance the same thing as interpatient variability? | | | | | I think that there are some things we can say with certainty about aspirin resistance. It can be measured in a number of ways and in a patient who, however you might define it, is categorized as aspirin resistant — that is an insufficient or inadequate response to aspirin in terms of their platelets being inhibited — that sort of patient is at higher risk of subsequent ischemic events (cardiovascular death, myocardial infarction, stroke) than a similar patient who is not categorized as aspirin resistant. So, for sure, the presence of aspirin resistance is a risk factor for future adverse cardiovascular outcomes. So, as a risk marker, aspirin resistance is pretty well validated in my opinion. Now, is it then more than just a marker of risk? That is, is it potentially something that signifies a target for therapy? Well, that’s really the “million dollar question.” It has not been definitively answered. So, right now, we can say that aspirin resistance exists, though its exact prevalence is controversial because that’s dependent on how it’s defined, but it certainly does exist. In patients who are aspirin resistant, again classified by a number of different tests, compared to those who aren’t aspirin resistant, those that are have a substantially higher risk of bad events like heart attacks and strokes. So, that’s really where the consensus on aspirin resistance stops.
Now, you had specifically asked whether aspirin resistance is the same as interpatient variability and that too is a matter of debate. I mean, in the sense that any drug is going to have different effects in different people and maybe even different effects in the same individual over time or in states of illness or wellness. So, there’s a certain degree of interpatient variability with every drug, and is that all that we’re seeing in terms of aspirin resistance? Well, that might explain part of it, but there is probably much more to the aspirin resistance story than just interpatient variability. There is certainly at least some evidence that other medications can contribute to aspirin resistance. There’s good biochemical explanations that agents such as ibuprofen, a common over-the-counter pain reliever, a nonsteroidal anti-inflammatory drug, has the potential to blunt the effect of aspirin on platelet inhibition by binding to the cyclooxygenase enzyme and, through a mechanism known as steric hinderance, keeps aspirin from binding where it would like to exert an antiplatelet effect. So, it does appear that, at least for ibuprofen, it could contribute to aspirin resistance. More recently, in the Journal of the American College of Cardiology, a paper described the potential for naproxen to blunt aspirin’s antiplatelet effect. So, it might be that there are going to be other drugs described of the same class of nonsteroidals or other classes that may keep aspirin from exerting its full antiplatelet effect.
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| | | | | | So, we can say at this point anyway that there appears to be a cause-effect relationship in terms of a correlation with clinical outcomes? | | | | | Yes, aspirin resistance marks a higher risk of adverse outcome, but the key question that clinicians ask in terms of how to use that information to modify therapy is still very much a gray area that future research will have to shed some light upon. But, there are some things that potentially can be done now and 2 of the things I just mentioned (if a patient did have aspirin resistance measured and was found to be aspirin resistant) perhaps stopping these other medications, assuming that that’s clinically feasible, might then turn them into aspirin responders. There are other potential mechanisms of aspirin resistance as well. You know some have hypothesized that there’s a dose effect, that is a patient might be aspirin resistant with 81 mg per day whereas in that same patient you may be able to overcome aspirin resistance with 325 mg per day. This too is a very controversial position. There are some studies to suggest, relatively small studies, to suggest that biochemical aspirin resistance, that is when one is examining platelet inhibition, can be overcome by raising aspirin dose. But I should point out this does go against large sort of associative studies.
If you look at large studies that have used different ranges of aspirin dose, non-randomized studies with respect to the aspirin dosing, but nevertheless large studies, really the bulk of evidence does not support better efficacy but instead suggests potential for more bleeding. And, if one examines the Antiplatelet Trialists’ Collaboration, that large meta-analysis of antiplatelet therapy which included aspirin at a variety of doses, there does not appear to be any benefit in terms of suppressing clinical ischemic events with higher doses of aspirin compared with lower doses of aspirin. So, if you’re looking at populations of patients that have been studied, nothing suggests that a higher dose of aspirin is more efficacious, and some studies suggest that there might be more bleeding. But, on an individual level, is it possible that some patients would benefit from being on a different dose of aspirin than what they’re taking now? Maybe. It’s certainly logical to think so, and it might be that those differences are masked or blunted when we study populations of patients. But, again, this is all a really fertile area for future research, and, right now, I can’t say anything definitive about raising aspirin dose to overcome aspirin resistance because, even though that appears in some studies to overcome biochemical aspirin resistance, no one has yet proved that it makes a difference clinically. So, that would really be the next step to take a patient who is aspirin resistant at 81 mg, take them to 325 mg, show that aspirin resistance has been overcome on an aspirin resistance assay and then follow their clinical outcomes compared with a patient where you didn’t change them to 325 mg. If there was a difference, you know aspirin resistance would have been completely validated to something that is a target for therapy.
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| | | | | | How do we measure aspirin resistance? | | | | | | Well, there are several ways of measuring it. There’s the gold standard light transmission aggregometry that is going to a fancy lab and running all sorts of platelet assays. This is time-consuming, it’s expensive, and it requires a lot of expertise typically from a hematologist or a hemopathologist, and may not be available uniformly at all hospitals. So, that is the historical way of doing it, but that’s more appropriate for research studies and, I should say, small research studies, than it is for daily medical care. There are point-of-care assays available. There is, for example, the Accumetrics VerifyNow™ test, which is a point-of-care aspirin resistance assay. It’s FDA approved for measuring aspirin resistance and just takes about 5 minutes or so. You just put in a couple of drops of blood and it will spit out whether a patient is an aspirin responder or a nonresponder, that is, are they resistant or not, and, in terms of a point-of-care test, I think that’s the best test. There are also ways of measuring aspirin resistance with the urine — urinary thromboxane levels. This involves sending the urine away, so it’s not point of care, and it’s not entirely clear that thromboxane levels in the urine necessarily are reflective entirely of aspirin effect, that is elevated urinary thromboxane levels are bad compared with not having them. A substudy of the HOPE trial demonstrated that, but there are other things potentially that could also affect thromboxane metabolism other than aspirin resistance. So, I think, probably the best test for measuring aspirin resistance is the VerifyNow™ in terms of point-of-care testing for the clinician. | | Back to top
| | | | | | Assuming you have a positive test, what then is the clinical approach that should be used? | | | | | Well, that’s really the most challenging question. There are 2 reasons to identify aspirin resistance, or 3, I suppose. One is just intellectual curiosity and the potential for doing research, and I think that’s a terrific utilization of aspirin resistance measurement right now. The second is as a risk-stratification tool, that is if a patient is aspirin resistant I mentioned a number of studies have shown that’s associated with a worse outcome than if the patient were not aspirin resistant, so as a risk-stratifying tool or a risk marker it has some utility as well. And, in that respect, it’s somewhat like CRP or high-sensitivity C-reactive protein, which is entirely validated as a risk marker, but is it a target of therapy? That’s controversial.
In a patient where aspirin resistance is measured and they are found to be aspirin resistant, there are some simple things to do, like confirm that they are in fact taking their aspirin. As simple as that sounds, as we know, noncompliance with medications is a big issue. So, is the patient in fact compliant and taking their aspirin and, even if they say they are and they come back aspirin resistant, it’s worth asking again, “are you really taking your aspirin” and then are they really taking aspirin if they are taking a medicine? There are patients, of course, who confuse other medications with aspirin — acetaminophen, nonsteroidals. These are things that may seem silly but do come up every now and then. Or, where patients think they are taking aspirin but they’re taking Tylenol instead and in their mind they think that those are the same thing. Other sorts of situations potentially are having to do with absorption; for some reason is a patient not absorbing their aspirin? Is there something going on in that respect? The potential for other drugs blunting aspirin’s antiplatelet effect that we discussed earlier, ibuprofen and naproxen being the 2 where there’s some data to suggest that they may interfere with aspirin’s effect. So, those are some things that can be done right now when a patient is found to be aspirin resistant.
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| | | | | | Can we identify a common cause for aspirin resistance at this stage? | | | | | Well, there are cellular factors that some have hypothesized may contribute to aspirin resistance and some genetic polymorphisms that in small studies have been associated with aspirin resistance, but, I think, it’s actually going to be multifactorial. That is, in a particular patient there may be several causes, and in patients in general there will be multiple causes of aspirin resistance. So, in some it might be that they are taking another drug and in others it might be that they’re not on the right dose or right formulation of aspirin, whereas in others it might be some odd genetic trait that they carry that leads to aspirin resistance. So, I think, there are a number of different pathways to it. I think in part it could also be affected by the patient’s clinical state, that is, I think, a patient who’s got an acute coronary syndrome, for example, and platelets that are already revved up, may be more resistant to antiplatelet therapy. Or perhaps patients who are obese; for example, there’s some data to suggest that obesity and leptin levels may affect platelet response. So, really, multiple different things could contribute to aspirin resistance. Diabetes is another thing. A small study presented at the American College of Cardiology suggests maybe even gender contributes to aspirin resistance, with women having a slightly higher risk of aspirin resistance than men. But, I think, really we’re in the infancy of aspirin resistance and its study, and right now we can say that it’s something that’s interesting, something that will likely be relevant to clinicians in the next couple of years, and something that we can measure right now though we don’t really know what to do with that information.
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| | | | | | Is there a correlation between aspirin resistance and clopidogrel resistance? | | | | | | Well, you know, I mentioned earlier that aspirin resistance and its study was really in its infancy, and, if that’s the case, clopidogrel resistance and its study is barely off the ground. That is, as you could tell, there’s a lot of uncertainty in many statements I made regarding aspirin resistance, and that uncertainty is present to an even greater degree in any discussion on clopidogrel resistance. | | Back to top
| | | | | | Given that the AHA guidelines recommend using both aspirin and clopidogrel for all ACS patients except in cases of known intolerance or, in clopidogrel’s case, when elective CABG is planned, if there is knowledge of resistance should the physician then be doing something different or what is your overall view given that particular guideline? | | | | | | I would first of all respect and follow the guidelines. You know, measurement of aspirin resistance is interesting, as I said, but I don’t know that I would go against the guidelines. For that matter, clopidogrel resistance measurement is also interesting, though there’s not yet any commonly available FDA approved test for that, although in the future there may be. But right now I would base my decisions on what the guidelines recommend and what the clinical trial data support, which is, ultimately, what the guidelines end up endorsing. So, for example, if a patient came in with an acute coronary syndrome as in CURE, I think they ought to be treated with aspirin and clopidogrel as the guidelines support. I think, if a patient received a stent they ought to get aspirin and clopidogrel for at least a year, as the CREDO trial supports, and I wouldn’t modify those recommendations. If somebody happened to test for aspirin or clopidogrel resistance, and the test happened to show that they were resistant, again, I wouldn’t abandon clinical trial data involving thousands of patients based on a test that has been studied with tens or at most hundreds of patients. That just wouldn’t make sense, so I wouldn’t change anything that the guidelines recommend. | | Back to top
| | | | | | So, in other words, you wouldn’t stop either drug. | | | | | No, I wouldn’t stop either drug. I would just, if a patient were aspirin resistant, I would consider all those factors we discussed before (compliance, concomitant medications, etc) but I wouldn’t withdraw aspirin therapy from a patient just because they were aspirin resistant because it’s really quite complex. There are other levels and layers where aspirin or clopidogrel or antiplatelet therapy or any therapy may work other than its primary mechanism. In the example of statins, everybody of course acknowledged their cholesterol-lowering ability, but now most experts in the field would agree that there’s an anti-inflammatory effect. Well, it turns out that antiplatelet therapy in some studies has also been demonstrated to have anti-inflammatory effects. Aspirin, of course, at high doses is definitely an anti-inflammatory. At cardiovascular doses it’s not as clear what its effect on inflammation and inflammatory markers might be. The studies have been mixed, some showing, for example, reductions in inflammatory markers such as CRP, and other studies showing no effect of aspirin on such inflammatory markers. But my point is that even if aspirin is found to not be affecting platelets as potently as it does in most people, that is a patient is aspirin resistant, it’s still possible that some other anti-inflammatory benefit is being realized. So, I wouldn’t change, I wouldn’t withdraw therapy, based on the presence of resistance. On the other hand, if a patient kept coming back in with recurrent ischemic events and they were taking their aspirin and there is no question about it, it wouldn’t be an unreasonable thing to measure aspirin resistance, and if they were aspirin resistant, consider perhaps therapy with clopidogrel or adding it. But again, there’s really no clinical trial data to guide that approach, so I really hesitate to endorse that sort of approach as a blanket approach. But again, in individual patients who are having multiple thrombotic events, multiple episodes of stent thrombosis and situations like that, there I think measurement of resistance may have some value because there may never be clinical trials to guide t he care of such patients because they’re not that common. But, when they come up, they’re very high-risk, so there perhaps, in the absence of data, modifying therapy may be appropriate nevertheless.
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| | | | | | How would genomics impact potentially the dosing and delivery of antiplatelet agents? | | | | | I think this is a great question and I think an area that will likely be of crucial interest in the future. Probably in the next 5, certainly 10, years we’ll have a better understanding of the role that genetics plays in terms of response to a variety of drugs including antiplatelet agents and it may be possible to more precisely tailor an individual’s therapy based on their genetic profile. I do think though, it’s not necessarily going to be as simple as just what their genotype is. I think that’ll just be one factor that affects response to antiplatelet therapy because other things, environmental factors, will also affect the state of the platelets. For example, if the patient is a heavy smoker, that’s going to make them more likely to form a clot. If a patient is obese, as I mentioned before, there’s some evidence to suggest that induces a bit of a hypercoagulable state. Diabetics, again, at higher risk of thrombosis, more likely to have larger platelets, revved up platelets, so greater expression of glycoprotein IIb/IIIa receptor. So, there’s really a lot of different things that aren’t directly in the genome that may predispose a patient to thrombosis. Even though things I mentioned, diabetes, obesity, perhaps even the tendency to get addicted to nicotine, have a potential genomic basis, so it gets very complex, but I don’t know that it’s just going to be a matter of screening the genome and saying you ought to be on this drug for antiplatelets because so many other things go into a patient’s risk for thrombosis. But I do think it could be complimentary to a functional assay, so an assay where you take blood and see if the patient is resistant to aspirin or not and in addition know their genomic profile. I think in the future that could really lead to some very precise targeting of antiplatelet therapy, potentially maximizing efficacy to a degree we’ve never seen before with drugs and hopefully also minimizing cost and bleeding side effects.
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| | | | | | A new investigational antiplatelet drug, prasugrel, is now being studied and is supposedly 10 times more potent on a mg-per-mg basis when compared to clopidogrel. Would you then agree that comparing 10 mg of prasugrel with 75 mg of clopidogrel is the same as comparing 100 mg of clopidogrel with 75 mg of clopidogrel? | | | | | | Well, that’s an interesting question. Prasugrel, as you know, is a new antiplatelet drug, actually a thienopyridine, so it is in the same general class as clopidogrel and ticlopidine, and it’s got some promising preliminary data. There has been a Phase II trial that’s been completed and published, the JUMBO trial, where it was compared with clopidogrel, and it’s a Phase II trial so really it was just designed to look at safety, and it appeared to be a reasonably safe drug. I can’t really say much about efficacy from the Phase II trial but it certainly, in the context of a Phase II trial, appeared to be reasonably efficacious. Whether it compares to clopidogrel, whether it’s inferior, whether it’s superior, I think will be hard to tell or predict just from antiplatelet testing. You’re right, on a mg-per-mg basis it is more potent than clopidogrel, but how will that translate into ischemic event reduction? Might that affect bleeding? It’s very hard to predict. I think the only way to know would be a large Phase III trial and such a large Phase III trial is ongoing. It’s the TRITON trial that is underway that’s looking at about 13,000 ACS, acute coronary syndrome, patients undergoing PCI randomized to prasugrel or to clopidogrel for a year, and that trial should lend a lot of insight into the relative benefits or potential drawbacks of prasugrel versus clopidogrel and I think it’s hard to predict. | | Back to top
| | | | | | Are there any other critical questions that we haven’t previously addressed concerning antiplatelet agent resistance? | | | | | | Sure. I think antiplatelet resistance and its measurement is really much like measurement of novel markers of risk such as hs-CRP and I purposely made that point before and come back to it again so you know it’s the sort of thing that I think is interesting, that practicing clinicians should be aware of, because I do think it’s intellectually interesting and very likely that in the future it will be incorporated into standard risk-stratification algorithms. But having said that, I wouldn’t want to sidetrack clinicians into thinking that they must be measuring these sorts of tests in all patients and then altering therapy, especially that latter point I think is critical. While I think it’s fine to measure and gain information — it never hurts having information — it’s what you do with that information that can be problematic. So, I wouldn’t at this point in time go against anything that’s recommended in the guidelines that you alluded to earlier or anything that clinical trials support based on different tests that are available out there. I think these are tests that you know can be useful in certain circumstances; in the future, I suspect they will be used much more widely, but right now I don’t know that I would take it to the level where I would on a routine basis alter patients’ care based on the results of these tests, not until large randomized clinical trials would validate such an approach. | | Back to top
| | | | | | Dr Bhatt, thanks very much for this extremely thorough review. | | | | | | | Back to top
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