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Balancing safety, efficacy of new antiplatelet therapies crucial, panelists say
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Cardiologists, while excited by the possibility of using more potent anticoagulants to prevent ischemic events, are nonetheless wary of the increased bleeding associated with the treatments.
Carl J. Pepine, MD, chief medical editor of Cardiology Today, moderated a round table discussion that included Stephen Wiviott, MD, associate physician at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Sunil Rao, MD, assistant professor of medicine at Duke University Medical Center, and
Roxana Mehran, MD, associate professor of medicine at Columbia University Medical Center, during the American Heart Association’s Scientific Sessions 2009 in November in Orlando, Fla. The panel discussed bleeding associated with medications for acute coronary syndromes.
In part two of this two-part round table, the group discussed differences between clopidogrel dosing regimes, patient monitoring, the challenges of using aspirin, the use of proton pump inhibitors and other treatment strategies for different patient populations. Part one appeared in last month’s issue of Cardiology Today.
Pepine: What is the difference in bleeding with the 600-mg vs. 300-mg dose of clopidogrel?
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Source: Christie’s
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Wiviott: In the OASIS 7 trial, they looked at double-dose clopidogrel and in that case they meant 600 mg [loading dose] and 150 mg a day for a week compared to the standard 300-mg loading dose followed by 75 mg a day for a week. If you look at all of the patients who were enrolled in the trial, there was no difference in ischemic events and there was an increase in the primary bleeding endpoint of this trial of about 25%. That was highly statistically significant. Of note, they did not see differences in some of these more severe bleeding scales, like GUSTO severe and TIMI major, but often in short period treatment trials that’s not seen mostly because of power.
Rao: It is kind of interesting, the widespread adoption of this strategy. With an agent we’ve had 10 years of experience with, we’re readily willing to increase the dose, whereas a newer agent, like prasugrel, we tend to be a little bit more cautious about.
Mehran: Interestingly, in the HORIZONS AMI study, there was not a bleeding risk in patients who received the 600-mg loading dose. In fact, the trend was the other way, which was obviously a strange finding.
Pepine: How essential is the antithrombin in this patient that we’ve just talked about, Steve?
Wiviott: Well, what we’ve learned from this set of recent trials is that you need to have some level of antithrombin activity, certainly, and that any trial that has tried to use very low doses in this setting has generally done poorly in terms of PCI-related outcomes, particularly catheter-related thrombosis. Lower levels of antithrombin in the setting of more potent P2Y12 blockade, particularly, have been successful. In some senses, a strategy to balance ischemia and bleeding is a more potent P2Y12 blockade either with higher dose clopidogrel or with one of the novel agents coupled with relatively conservative antithrombin therapy.
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Pepine: Let’s talk for a minute about monitoring. If we’re going to stay in the antiplatelet area, how comfortable are you, Sunil, with some of these ways to monitor platelet activity?
Rao: I’m not comfortable at all with them, actually. I don’t think they’re ready for clinical use yet. Certainly, the studies are ongoing and that’s important. I just don’t think that we have enough clinical outcome information in a prospective randomized way to support the routine use of platelet function monitoring to guide therapy. There’s a very large GRAVITAS trial that’s going on right now that may help us determine whether the platelet monitoring strategy is appropriate to use to increase the dose. The interesting thing about that is it’s not technically platelet function-guided therapy. It’s higher doses in people who don’t have a phenotypic response that you would expect. The reason I say that is that, in my mind, platelet function guided therapy goes two ways. It means that you increase the dose in people who are hyporesponders and then you decrease the dose in people who are hyper-responders. That is not part of the trial. It’s all just increasing the dose. Technically, it’s not guided therapy. I don’t know if you agree. Perhaps I’m a little bit more cynical about routine platelet-function testing.
Wiviott: Yes. No, we are not routinely testing by any stretch.
Mehran: We are actually measuring the platelet function in all patients after PCI and stenting. We use the data in identifying high-risk patients who have <10% platelet inhibition. In these patients, we adopt the use of the newer agent prasugrel instead of clopidogrel.
Pepine: Who are you testing? Second stent thrombosis or third?
Wiviott: We are testing at the discretion of the physician within our hospital. There aren’t specific guidelines within our hospital. Some people would consider testing in situations of very high risk in terms of stent thrombosis, a left main distal bifurcation stent or similar circumstances where a poor response would be potentially catastrophic. The key point here is that what we’re really looking for are patients who have almost no response. Clinically, you’re trying to identify this small proportion of patients who have no antiplatelet effect or very limited antiplatelet effect from clopidogrel. When you get a result that says on one test or another that it’s 35% or 45% or 55%, we don’t have any idea of what that means and whether you wish to be a 55% or 35% or 75% we don’t know. We know you don’t want to be at zero. So in some senses it helps to guide clinical decision-making when it’s very abnormal, but we’re not in the setting now of altering therapy based on shades of gray.
Rao: Are you testing for the genomic abnormalities? Polymorphisms?
Wiviott: We currently don’t have that available at our hospital for routine clinical use. There are a number of groups that are looking toward making point-of-care testing available for genetic polymorphisms. There’s disagreement as to whether you’ve got to carry one or carry two reduced function alleles to put you at risk, but those patients may be at increased risk for thrombosis. It’s also possible that with certain genotypes you may have higher levels of platelet inhibition, ultra-metabolizers of clopidogrel that may be at increased risk for bleeding. It’s tantalizing, but we’re still even farther from genetic profiling, if you will, in order to change therapy, than we are from using functional testing.
Pepine: So what about aspirin? We’ve been using it for years, and now we’re seeing it get tremendous criticism in certain areas. Are you at all considering dropping aspirin, or are you considering changing dosing?
Rao: That’s a good question. This certainly comes up when we talk among ourselves and talk to some of our referring doctors, particularly in long-term [situations]; like someone who’s a year out from a stent and they want to drop the aspirin or someone comes in with a clearly ulcerative source of a gastrointestinal (GI) bleed. Do you stop the clopidogrel or do you stop the aspirin long-term again? I’m not sure that any of that can be supported based on the data. I’m still a big believer in aspirin. The bulk of the data for long-term therapy supports a lower dose of aspirin. The guidelines, as you know, recommend 325 mg early after a stent and then decrease the dose afterward. That’s generally what we’re tending to do in our practice, and then after a month to three months, we drop the dose down to 81 mg.
Pepine: Do you give patients with diabetes the same dose?
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Wiviott: Aspirin is a drug that not only inhibits platelets, but also irritates the gastric lining. So it has the potential to both cause a source of bleeding and then exacerbate it, whereas the thienopyridines do not have direct causality in terms of bleeding. Aspirin is an important component of this bleeding question and many of the particularly troublesome types of bleeds that occur following PCI are GI bleeds. It’s an important issue. I agree with Sunil — I tend to use 325 mg for a month following a stent. After that, one of the things that I do as part of my regular follow-up clinic visits, is look at their aspirin dose and if it’s 325 mg and they’re on chronic therapy, I reduce it. In patients with diabetes, there does seem to be more of a dose response, and I tend to keep that at 162 mg. It seems like you’re getting a similar kind of a benefit than you would with 81 mg in a patient without diabetes. Clinical trials have not been done to compare that, but that’s how I interpret the data.
Pepine: Sunil, my practice is mostly comprised of people older than 70 years, and a lot of elderly women are in this high-risk category for bleeding. This woman comes in a month or two after PCI and she’s pointing out ecchymotic areas on her arms, which are intolerable to her. Men don’t usually complain very much but women can’t tolerate it. So what’s the first management change in such a situation? Now she’s clearly out of the six-month window.
Rao: First what we generally do is take a look at the medication list and make sure she’s not on anything that necessarily isn’t indicated. There are a lot of drugs that patients take that really are not evidence-based. In terms of antiplatelet therapy, if we feel comfortable that the patient is out of the risk window for stent thrombosis, we will actually go ahead and stop the clopidogrel and continue the aspirin, make sure that they’re on a low-dose aspirin, again (81 mg). In terms of length of therapy with respect to coronary stenting, I’m not sure we know that yet. There is a large trial that’s ongoing to try and figure that out. Some of the data actually does suggest that the risk of stent thrombosis is sort of minimized after six months of therapy. So if it’s been six months or a year, I feel very comfortable stopping the clopidogrel. Is it the right thing to do? I don’t know.
Pepine: Steve, what do you do in your practice?
Wiviott: The first step is thinking about these patients at the time that they have their stents. Many patients have AF and an indication for warfarin. We’re doing much better at using bare metal stents in those patients than we were a few years ago. This helps to avoid the need for obligate co-treatment with warfarin and thienopyridine. Assuming this patient doesn’t have a drug-eluting stent, the first thing I would do is reduce the aspirin to the lowest dose available, and if they’re still having intolerable ecchymoses, I would stop the clopidogrel as well.
Pepine: What about the use of proton pump inhibitors (PPI)? So we have aspirin plus clopidogrel, and we have GI issues. Who wants to start?
Rao: It’s become a very interesting area. You know we have a series of observational analyses suggesting an association between the use of PPI, specifically omeprazole, and the reduction in the efficacy of clopidogrel. When you have that type of equipoise, the right thing is to do a randomized trial, and that randomized trial was done using a combination pill of Prilosec or omeprazole plus clopidogrel, but unfortunately the trial stopped well short of their planned enrollment because the company that was marketing the drug and funding the trial went bankrupt. The results of that trial were presented at the Transcatheter Cardiovascular Therapeutics meeting, suggesting that in the 3,600 patients that were randomized, [there was] no significant difference in terms of efficacy. Interestingly, there was a significant reduction in GI bleeding with the addition of omeprazole to clopidogrel, which is an interesting finding and puts us in a little bit of a quandary because those data would certainly suggest that if you want to improve the safety of clopidogrel perhaps you should be actively prescribing the drug now rather than avoiding it. Our approach has been to decide whether the patient really needs a PPI. Patients take PPIs for all kinds of reasons, and if they don’t really need it, we generally stop it. If they do have a history of something that’s perhaps helped by a PPI or acid reduction, we try to give them an H2 blocker, or if the patient insists that they want the PPI, then we just simply switch them to another agent. We haven’t had a high level of anxiety over the interaction that some of the studies would suggest we needed to have.
Pepine: Steve?
Wiviott: I agree. There clearly is a pharmacologic interaction that the antiplatelet effect of clopidogrel is mildly reduced by part-time pump inhibitors, specifically omeprazole. Now whether this is clinically meaningful is up for debate. What we have done in our practice is similar to what Sunil said, and I think that if a patient can take it with their insurance and pocketbook something that is not omeprazole and is a PPI, I feel very comfortable giving that because pantoprazole, particularly, doesn’t seem to have this interaction. If they can’t and they have a good indication for PPI, I don’t change anything and I leave them on both agents. It’s something that we just need to think about as a potential small contributor. When you can fix something small without risk to the patient or cost to the patient, terrific, but otherwise I wouldn’t.
Pepine: Give me your take-home message. We’ll start with Steve.
Wiviott: The take-home message is that antiplatelet therapy is clearly important to reduce ischemic events, but in the background of making those therapeutic decisions, whether it’s antiplatelet therapy or antithrombin therapy, it is important to keep in mind the bleeding risk, both from the clinical outcomes perspective, as well as from the tolerability perspective for the patients, and make sure you warn them about it because they don’t want to be surprised by it.
Rao: Achieving an optimal balance of safety and efficacy is the goal in any therapeutic arena. There is a role for more potent antiplatelet therapy in appropriately selected patients who are at high risk for ischemia and low risk for bleeding. We have to make a much bigger effort to do the things that can protect the patients from bleeding without cost for ischemia, like radial artery catheterization and not overdosing the medicines we currently use. It’s easy to point at the clinical trial results and say we shouldn’t use a novel therapy, but let’s look at our own practices and make sure we’re treating patients as safely as possible.
Mehran: We have made great strides in treating patients with CAD undergoing PCI. The newer antiplatelet agents have shown great promise in reducing ischemic complications. The balance of safety and efficacy is now center stage and all efforts must be made to minimize the bleeding complications while improving the benefit from these more potent agents. This requires great scrutiny in choosing therapies for the right patient in the right setting for the right duration of therapy.