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Expert panel discusses bleeding associated with medications for ACS
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Cardiologists are concerned about bleeding associated with the use of increasingly potent antiplatelet therapy used to prevent ischemia-related events.
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 in November in Orlando, Fla. The panel discussed bleeding associated with medications for acute coronary syndromes.
In part one of this two-part round table, the group considered the optimal antiplatelet strategy, classifications proposed relative to bleeding in and around interventional procedures, the relationship between bleeding and CV outcomes and existing study data. Part two will appear in next month’s issue of Cardiology Today.
Carl J. Pepine, MD: The question on the table is what to do about bleeding related to the treatment of patients undergoing percutaneous coronary intervention for either acute or chronic syndromes? These patients are treated with multiple drugs that interfere with platelet aggregation, what do you think is the optimal antiplatelet strategy? How does this impact ischemic and bleeding events?
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Source: Christie’s
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Stephen Wiviott, MD: Over the last several years, we have recognized the importance of both ischemia and bleeding. In the area of antiplatelet therapy, beginning with aspirin and then extending out to novel compounds with more intense antiplatelet therapy, there have been increases in bleeding associated with the reductions of ischemia. I think it’s not straightforward to answer what the ideal antiplatelet therapy is as a general statement, but with the goal of reducing both important ischemic events while maintaining adequate safety it needs to be tailored for both individual patients and individual situations.
Sunil Rao, MD: I certainly agree with what Steve said, but there are a couple of issues here. No. 1 is why has bleeding all of the sudden become the topic of discussion at these major meetings and around the clinical tables? The second issue is the window during which the bleeding may occur, both acutely as well as chronically. Because of the development of these powerful agents and combination therapies along with the evolution of devices and smaller catheter profiles, the reality is most patients after PCI do extremely well with respect to ischemic events. What has started to bother interventionalists — and complaints we hear from patients — are bleeding complications post-procedure. There’s the acute risk, and then chronically we get a lot of these strategies, like the trial that Steve’s been involved with, that involve therapies that are taken for a year, two years, maybe even longer. So, there is a chronic bleeding risk that becomes manifest. I think the words that Steve used are very appropriate, which is important ischemic event, and I would translate that to important bleeding event because all of these drugs are going to increase bleeding risk. The question is what are the events that are important, both to physicians and to patients, and that may be different actually. What patients complain about may be different from what we think of as important bleeding events.
Roxana Mehran, MD: You both make very important points, but I think the bottom line today is tailored therapy for patients presenting in different clinical scenarios. The days of thinking of bleeding as just a nuisance are over, and it is now clearly established that bleeding is as important as ischemic complications when we treat patients with antiplatelet agents.
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Pepine: Steve, we’re using this term ‘bleeding’ generically, like everybody understands what it is. Can you tell us some of the classifications that have been proposed relative to bleeding in and around interventional procedures?
Wiviott: We have used the TIMI bleeding criteria, developed several years ago in the time of thrombolytic therapy, and in many ways identify the worst bleeding episodes. TIMI major bleeding is bleeding that’s associated with either intracranial hemorrhage or a hemoglobin drop of more than 5 g/dL associated with a clinical syndrome. TIMI minor bleeding, and perhaps minor isn’t exactly the right term in terms of the emotional impact, is a hemoglobin drop of 3 g/dL or more. Below that, we previously termed minimal bleeds, but within that group of bleeding events, it’s a broad array of different things from patients who have enough bleeding that they have to stop their medications, to events that are seemingly trivial such as bruising one’s arm when bumping into a table. Our bleeding definitions have been sort of the tip of the iceberg, and in the lytic era also came the GUSTO bleeding definitions. GUSTO bleeding definitions were more clinically based as opposed to laboratory based. For instance, GUSTO severe bleeding would be things like intracranial hemorrhage or also bleeding resulting in a hemodynamic compromise that required multiple transfusions or other types of interventions. More recently, there has been a move toward more sensitive, more inclusive bleeding definitions. Sunil can correct me if I’m wrong, but the ACUITY definitions have been sort of the standard for these more inclusive definitions, and they contain things even in the more major categories, like large hematomas or even modest-sized skin-related bleeds, in addition to the higher level bleeding. So certainly, as you might expect, with these different approaches you get vastly different estimates of how frequently bleeding occurs and also how likely the value to the patient in terms of quality of life and clinical outcomes differs depending on the severity of the bleeding scale used.
Rao: TIMI and GUSTO certainly served as the foundation, and much of these subsequent bleeding definitions that have been developed build on those. They include elements from those and changed them a little bit; for example, OASIS. What’s happened over time, as Steve said, is that there has been this sort of gradual broadening of what we consider to be a major bleed, for better or for worse. You say we have been able to reconstruct all these definitions. Now, the problem of course is that I’m not sure anyone in clinical practice actually looks at a patient and says, ‘Well, you’ve suffered a GUSTO severe bleed or a GUSTO moderate bleed.’ The challenge becomes, how do you translate that type of safety data into a clinical realm? Perhaps other scales may be important here. There has been a scale developed that has ‘nuisance bleeding’ as part of it. This is not the greatest title because in reality nuisance bleeding is bleeding that happens to somebody else. But it involves these skin ecchymoses and kinds of things that patients complain about. In at least one single-center study, 10% of the patients who suffered a nuisance bleed stopped taking their medication. There seems to be some clinical impact of these more minor or less severe types of bleeding complications that may have relevance in the clinical world, and so we’re expanding this outside the ACS realm, for example, to AF. Steve’s group did a phase-2 trial in AF, where they used a specific bleeding definition called ‘bleeding requiring medical attention.’
Wiviott: Right, this was the ATLAS study, and the bleeding requiring medical attention definition is one that separates TIMI minimal (<3 g Hb) into those that seem to have an immediate clinical impact and those that do not.
Mehran: The trouble we have today is that when we talk about bleeding we have no way of comparing agents across different trials because each trial has used different definitions for major bleeding, and there is no real consensus in which bleeding is important and should be considered major. There is no question that the most widely used definition, TIMI bleeding, is just the tip of the iceberg. There must be an effort to standardize these definitions so we are all on the same page when comparing agents and their effects on bleeding.
Rao: But that’s an important definition because that actually, in the title itself, says that this is an important bleed to the patient. They actually required medical attention for this particular bleeding definition. That may actually be the future of bleeding definitions.
Pepine: Even today we’re starting to realize that patients who bleed don’t have good outcomes. Not from the bleeding, per se, but from the CV outcomes. Do you want to comment on that?
Wiviott: These are complicated relationships. When you’re in a trial or in a clinical setting of comparing endpoints as it relates to bleeding, certainly there are terrible bleeds, like intracranial bleeds. There are bleeds that result in exsanguination, there are bleeds that result in catastrophic events that cause people to die.
Rao: The reality is that these catastrophic bleeds are rare.
Wiviott: Yes, those are quite rare. There are also bleeds that result in stopping medications that have the potential to help patients in terms of reducing ischemic events. For instance, patients with stents who have bleeding events stop their clopidogrel and then have a stent thrombosis. That bleed indirectly led to that ischemic event. There is certainly a relationship between bleeding and adverse outcomes. It’s also the case, though, that people who do bleed are patients who are frailer, older, and at higher risk for other bad things happening to them. This is what makes the relationship between bleeding and ischemic outcomes or death difficult; the same people who are at risk for bleeding are at risk for MI and death, but it may not be a result of the bleeding.
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Rao: Yes, I would actually agree with that. The agent that has the least amount of bleeding is placebo, with the exception of the OASIS 6 trial. Fundamentally, we have to think about why we are treating these patients with these agents. The reason we’re treating them is because we want to reduce ischemic events. Now, doing that while minimizing bleeding risk is ultimately where we want to get to. I completely agree with Steve. A lot of what we’re picking up here are associations which have been consistent over all the studies. Is it really causal? Probably not. In the rare instances in which you have intracranial hemorrhages or perhaps, frankly, fatal bleeding, they are probably causal. So why do we have the association? A large part of it is what Steve said, these are sicker patients in general. But there are other mechanisms that may be involved here. We talked about cessation of medical therapy or lack of adherence to evidence-based therapy in patients who bleed. That’s probably part of it, but the one thing that has been interesting over the last couple of years is that there are certain therapies where an association between a reduction in bleeding risk appears to be also associated with an improvement in survival. I’m choosing my words carefully here because, again, it’s really hard to draw causal inferences. But there are strategies that appear to reduce bleeding risk that may also improve survival. When you have multiple strategies, including using the radial approach, you can reduce bleeding risk by 60%. It seems to me that bleeding reduction should be a goal whether or not it’s associated with improved survival and if you have options to do that, then perhaps that should be the way to go.
Wiviott: One thing worth adding in this area is that, in general, the strategies that have shown reduction in bleeding and improvements in mortality have been neutral with respect to ischemic events. The difficulty comes with most agents where you get a more potent effect on platelets or on anticoagulation, which reduces ischemic events at the expense of bleeding, in which case these balances of trying to minimize bleeding are not so clearly associated with improved survival. It is when you can keep ischemia constant while reducing bleeding or vice versa, improve ischemia without increasing bleeding; that’s the Holy Grail, and we’ve seen that with the antithrombins, but from the antiplatelet standpoint, we haven’t seen that yet. That remains a goal; to alter the balance in one direction without tipping it the other way.
Rao: So what’s your read on the ticagrelor data?
Wiviott: In the PLATO trial, which is what we’re referring to as comparison of ticagrelor, a more potent antiplatelet agent, with a standard-dose clopidogrel in the primary bleeding endpoint, a composite of non-CABG-related bleeding and CABG-related bleeding, there was a neutral effect. When you look at the non-CABG-related bleeding, 95% of the patients in the trial didn’t have CABG. There was the expected 25% to 30% increase in bleeding. In fact, it was exactly the same change in TIMI major bleeding as was observed in the TRITON TIMI 38 trial of prasugrel, which is often pointed to as a drug that is substantially increasing bleeding. Ticagrelor is a reversible agent, so when stopped prior to CABG, the drug effect wears off faster and it would be expected to have less bleeding. In 95% of the people in PLATO, those not undergoing CABG, it did just what you’d expect; it reduced ischemia, increased bleeding and, we haven’t seen this yet, but, unless the survival benefit is wholly contained within that CABG population and something different is happening here with regard to mortality, just that, bleeding isn’t present. That’s actually, in some senses, the best example in my mind of a drug that increases bleeding and improves mortality.
Pepine: Then you have the opposite with dabigatran, where you see better outcomes all across the board, including a reduction in stroke and bleeding. Is that just a case where the comparator is bad?
Rao: It’s interesting isn’t it? We like to beat up on warfarin, but as far as I can tell, this is the first, perhaps viable, competitor to an agent that we all hope to replace someday. There are a couple of issues here. It’s a different patient population, it’s a different setting and it’s a different comparator. We talked a little bit about how we’ve become so focused on bleeding only recently in the world of ACS, but the reality is we’ve known about bleeding with warfarin for a long time. There are validated risk models for bleeding and for stroke with warfarin trials. We’ve actually been able to define something we can’t get defined with antiplatelet therapy, which is, what is that therapeutic window? With the new agent, dabigatran, it certainly does seem to push everything in the right direction. It seems to reduce stroke, reduce bleeding risk. It may have to do with the fact that with warfarin, the therapeutic range fluctuates a little bit more than perhaps a reliable agent, like dabigatran.
Pepine: So let’s talk about some specifics. You have a patient with ACS. You anticipate that the patient is likely to need a stent. What’s your order for that patient?
Rao: I’m very aggressive with early loading with thienopyridine.
Pepine: Before aspirin?
Rao: They get aspirin en route. They get oxygen. About 70% of our patients with ACS get unfractionated heparin and about 30% get low-molecular-weight heparin. That decision is usually left to the ED. But all of them get pretreated with thienopyridine prior to coming to the cath lab. That’s been a relatively recent change. Our use of IIb/IIIa inhibitors has gone substantially down and our median time from presentation to cath for a patient with non-STEMI and ACS is still about 20 to 21 hours. They’ve had a full 24 hours of thienopyridine, dual-antiplatelet therapy on board before coming to the cath lab. Once they’re in the cath lab, the antithrombin choice then becomes the roulette wheel where whoever happens to be doing the intervention will give the antithrombin of choice. Some of us will switch them to bivalirudin. Some will continue the heparin. Some will still use IIb/IIIa in that setting, although most of us don’t. My default approach is the radial approach. The only thing that’s uniform is that the patients are getting loaded with clopidogrel early.
Wiviott: With what dose of clopidogrel?
Rao: That’s a good question. We have adopted a 600-mg loading dose. Not only is that off-label, but as a general strategy does not appear to help the sort of broad population of patients undergoing PCI unless they are getting high-dose aspirin as well.
Mehran: We have an aggressive approach as well. All patients with ACS receive a loading dose of 600 mg of clopidogrel and 325 mg of acetylsalicylic acid regardless of whether they were on chronic therapy at home.
Part two of this round table will appear in next month’s issue.