Role of Direct Thrombin Inhibitors in ACS (04/2006)
ADOLPH M. HUTTER, JR., MD: Hello. I'm Dolph Hutter. Welcome to the American
me for this discussion is Dr. MAGNUS OHMAN, Professor of Medicine at
James Hoekstra, Chairman of Emergency Medicine at
The topic that we're going to talk about is the role of direct thrombin inhibitors now in acute coronary syndrome. This is the non-ST elevation MI, the unstable angina group, not the ST elevation MI. Before we start, Magnus, could you tell us, what are these drugs? How do they work? What is the difference between the different types of antithrombin agents?
E. MAGNUS OHMAN, MD: Well, direct thrombin inhibitors have been around for a
long time. In fact, as you know, the medical leech has actually got hirudin in it, which is the first hirudin
that was developed, or lepirudin. This was followed
by bivalirudin, which is similar to hirudin or lepirudin. And then
we have the monovalent agents called argatroban. And those are the three available agents in
ADOLPH M. HUTTER, JR., MD: So the first two, including the bivalirudin, is a bivalent. What's the difference between monovalent and bivalent?
E. MAGNUS OHMAN, MD: It's all about how they bind on the thrombin molecule. The bivalent binds to two sites simultaneously, and the monovalent on only the active side. So it's just mechanistic. They have about the same therapeutic effect.
Now, they differ a little bit in their half-life. The shortest half-life is actually bivalirudin, followed by slightly longer with argatroban, and the longest being lepirudin.
ADOLPH M. HUTTER, JR., MD: How about the excretion? Is there a difference there?
E. MAGNUS OHMAN, MD: Yes. The lepirudin is renally excreted. Argatroban, predominantly hepatic, and bivalirudin is a mixture of conversion as well as some Proteolytic, and some renal excretion.
ADOLPH M. HUTTER, JR., MD: So, okay.
E. MAGNUS OHMAN, MD: So they differ a little bit. But what is really key, the only one agent that is actually approved for cardiovascular care, to some extent, is bivalirudin for PCI. The other two are approved for heparin-induced thrombocytopenia, or HIT.
ADOLPH M. HUTTER, JR., MD: So that's probably an advantage for the shorter half-life, I would guess. Is that right?
E. MAGNUS OHMAN, MD: Well, we have no head-to-head comparisons.
ADOLPH M. HUTTER, JR., MD: Okay, all right.
E. MAGNUS OHMAN, MD: Of these two agents, so we really don't know.
ADOLPH M. HUTTER, JR., MD: Good point. Now, what is the advantage of these direct antithrombin agents as opposed to, say, heparin?
E. MAGNUS OHMAN, MD: Well, a number of features. First of all, because they only work on one part, the thrombin molecule, it actually doesn't really involve other components of the coagulation cascade. The other part is, heparin works indirectly. It requires an active step in between. So they're more direct. They're also less affected by other issues, such as protein binding. That is another thing that affects heparin. So they're more specific as an anticoagulant.
ADOLPH M. HUTTER, JR., MD: And they don't cause any immune response, which heparin does. The heparin platelet 4 or factor 4 can cause an immune response in about 3 to 5% of patients going into bypass surgery, and it never occurs with the direct thrombin inhibitors? Is that correct?
E. MAGNUS OHMAN, MD: That's correct.
ADOLPH M. HUTTER, JR., MD: So that's another advantage, but not that big of a problem.
CHARLES V. POLLACK, JR., MD: There is one other, also. The direct thrombin inhibitors can't activate platelets, and heparin actually can activate platelets, which is counterproductive when you're trying to treat ACS.
ADOLPH M. HUTTER, JR., MD: Very good point. Yes, yes.
ADOLPH M. HUTTER, JR., MD: How about ACTs? Do you have to check those with the direct thrombin inhibitors?
CHARLES V. POLLACK, JR., MD: No.
ADOLPH M. HUTTER, JR., MD: Or you just give it by weight, right?
E. MAGNUS OHMAN, MD: Right. And in fact, one of the best things about all the direct thrombin inhibitors, once you dial in the dose, it is a very steady dose, whereas with heparin, as you know, it varies quite a bit.
ADOLPH M. HUTTER, JR., MD: Up and down, yes. And check them. Yes. And many times you're under therapeutic range with these patients. Okay, that's a good summary of the drugs.
Now, Charlie, let me ask you, is there any information we have about the use of these drugs in acute coronary syndrome?
CHARLES V. POLLACK, JR., MD: Well, most recently, the ACUITY study was presented at this ACC meeting (2006). It's the first large study of a direct thrombin inhibitor in a non-ST elevation population. It was compared against heparin or the low molecular weight heparin enoxaparin with or without IIb/IIIa receptor antagonist inhibition. And a very complex study with a lot of results that are still being digested. Jim, I think, was going to talk about some of this.
JAMES HOEKSTRA, MD: Yes.
ADOLPH M. HUTTER, JR., MD: Do you want to go ahead, Jim? Tell us what the results were.
JAMES HOEKSTRA, MD: It's quite interesting. I think we're seeing, because of the results of ACUITY, we're seeing a shift now from what had been the more traditional heparin versus low molecular weight heparin in the cath lab to direct thrombin inhibitors. The reason being, it appears that, based on the results of ACUITY, bivalirudin can be a safe and effective replacement for heparin in ACS, with the biggest advantage being less bleeding.
ADOLPH M. HUTTER, JR., MD: Can you summarize the ACUITY findings for us?
JAMES HOEKSTRA, MD: Yes. The bottom line is that in the ACUITY trial the patients with medium to high-risk ACS were treated with a very catheterization-oriented strategy, a relatively rapid transition to the cath lab.
ADOLPH M. HUTTER, JR., MD: We might say appropriately so, because they were high-risk. I mean, that's why they did those patients.
JAMES HOEKSTRA, MD: And I think there are significant advantages to an invasive strategy, especially in high-risk patients, especially, that seems to be the way things are going in this country more than anything else. But essentially there was a comparison of heparin plus a IIb/IIIa inhibitor to bivalirudin plus a IIb/IIIa inhibitor to bivalirudin alone. And it looked like the bottom line was that in terms of efficacy, death, MI, revascularization, that there was no difference between the heparin IIb/IIIa inhibitor and the bivalirudin, but there was significantly less bleeding in the bivalirudin arm.
ADOLPH M. HUTTER, JR., MD: Now, that was in the bivalirudin alone, right?
JAMES HOEKSTRA, MD: Yes, with…
ADOLPH M. HUTTER, JR., MD: Because in the bivalirudin plus the IIb/IIIa, there was no difference in either bleeding or clinical events with the heparin plus. But the bivalirudin alone was just as good in clinical events, but less bleeding.
JAMES HOEKSTRA, MD: Correct.
ADOLPH M. HUTTER, JR., MD: Significantly less bleeding.
JAMES HOEKSTRA, MD: Correct.
ADOLPH M. HUTTER, JR., MD: Okay.
JAMES HOEKSTRA, MD: Now the bivalirudin alone did have, for instance, a IIb/IIIa bailout in case there were problems. But that was used in a minority of patients.
ADOLPH M. HUTTER, JR., MD: Yes. I think it was only 7% or something like that. Any other studies? What about the SYNERGY trial?
CHARLES V. POLLACK, JR., MD: Well, SYNERGY…
ADOLPH M. HUTTER, JR., MD: Can you tell us about that?
CHARLES V. POLLACK, JR., MD: Yes. SYNERGY came out in July of 2004, so we've had a little longer to digest it, but it's an equally complex trial. The design is actually simpler, but the interpretation has turned out to be rather complex.
It's a simple comparison between unfractionated heparin and enoxaparin, so a low molecular weight heparin, an indirect thrombin inhibitor in patients with high-risk non-ST elevation acute coronary syndrome. Patients had to be elderly, have ST segment changes or an elevated biomarker, two of those three. 10,000 patients, roughly, randomized to receive either enoxaparin or heparin throughout their course, which was intended to include a fairly rapid transition to the cath lab, evidence-based use of other medications such as beta blockers, nitroglycerin, IIb/IIIa's, as the 2002 guidelines would call for.
ADOLPH M. HUTTER, JR., MD: And was a IIb/IIIa involved in the initial part at all, or in the cath lab?
CHARLES V. POLLACK, JR., MD: No, the IIb/IIIa use was at the treating clinician's prerogative.
ADOLPH M. HUTTER, JR., MD: Discretion, okay. Okay.
CHARLES V. POLLACK, JR., MD: Yes. So it might have been started upstream. It might have been started in the cath lab. It might not have been used at all.
ADOLPH M. HUTTER, JR., MD: So it wasn't controlled as it was in the ACUITY trial?
JAMES HOEKSTRA, MD: Right.
ADOLPH M. HUTTER, JR., MD: Okay. What did that study show?
CHARLES V. POLLACK, JR., MD: Well, the primary outcome on the efficacy side was death or MI at 30 days. There were slightly fewer patients who met that adverse outcome on the enoxaparin arm, but statistically there was no difference.
ADOLPH M. HUTTER, JR., MD: Okay.
CHARLES V. POLLACK, JR., MD: The noninferiority criteria were met.
ADOLPH M. HUTTER, JR., MD: Okay.
CHARLES V. POLLACK, JR., MD: There was a trend towards more bleeding on the enoxaparin side, specifically by one measure, but not involving increased need for transfusion.
ADOLPH M. HUTTER, JR., MD: So a little, yes.
CHARLES V. POLLACK, JR., MD: It's a little iffy what the clinical impact of the difference is.
ADOLPH M. HUTTER, JR., MD: And it sounds like the ACUITY trial kind of put that one to rest, because, as you just told us, Jim, much less bleeding in bivalirudin alone.
JAMES HOEKSTRA, MD: Yes. Again, it seems like there's a couple of lessons that are coming along in the last year or two with regard to catheterization lab strategies and ACS, and one lesson is that bleeding is bad. There seems to be a fairly strong link between bleeding, either cath lab related bleeding or in-hospital bleeding, and severe, and bad outcome.
ADOLPH M. HUTTER, JR., MD: Yes. That's a good point. It's not just a minor complication if it's major bleeding.
CHARLES V. POLLACK, JR., MD: So, given that data, the bivalirudin, with its less bleeding in the cath lab, has some significant advantages over either heparin or low molecular weight heparin in ACS.
ADOLPH M. HUTTER, JR., MD: Yes.
JAMES HOEKSTRA, MD: One other lesson that we've gained from this, bleeding is bad. The other thing we've learned is that going to cath quickly is good.
ADOLPH M. HUTTER, JR., MD: Yes. That's another issue, though.
JAMES HOEKSTRA, MD: Yes.
ADOLPH M. HUTTER, JR., MD: Yes, that's another. So, Magnus, how do you look at this now? Our guidelines so far say you can use either low molecular weight heparin or unfractionated heparin. They don't say anything about these agents so far. Do you think the data is good enough that we ought to think about upgrading these guidelines? What's your take on this?
E. MAGNUS OHMAN, MD: My take on it is that we're in a perfect situation. Actually, the AHA guidelines are being rewritten for the non-STEMI right now. And I'm sure that these will be incorporated in the guidelines.
What I see coming out of this, which I think is a fascinating time, because I worked with Charlie and Jim on integrating emergency medicine and cardiology. And now it's going to be even more important, because now we're going to have to figure out jointly who we're going to take to the cath lab early on. In that sort of patient, the bivalirudin strategy, with our without GP IIb, but maybe alone.
ADOLPH M. HUTTER, JR., MD: Well, it sounds like alone so far, if ACUITY's right.
E. MAGNUS OHMAN, MD: Right. Then that would be your preferred strategy. If, on the other hand, you're going to spend some time thinking it over, try to digest what's going to happen with this patient, then low molecular weight heparin, or even fondaparinux, might be a very reasonable, conservative treatment strategy.
ADOLPH M. HUTTER, JR., MD: For acute coronary syndrome.
E. MAGNUS OHMAN, MD: For acute coronary syndrome. So it sort of shifts us into a really new modality of management.
ADOLPH M. HUTTER, JR., MD: Yes. I guess we should just quickly summarize for the audience, there are established criteria for going right to the cath lab for everybody's lab, and that's high-risk, which is ST changes, positive markers, recurrent ischemia or congestive heart failure. So those patients come in. There should be no thinking about it. You ought to get them to the cath lab.
CHARLES V. POLLACK, JR., MD: And that's well understood. It's well documented. The issue for many people who practice emergency medicine, like Jim and I do, is that not every hospital has a cath lab, and that creates all sorts of issues for emergency physicians, who then have to try to provide optimal medical stabilization for patients when they can't get there.
ADOLPH M. HUTTER, JR., MD: That's a very good point. Or early transfer.
ADOLPH M. HUTTER, JR., MD: And that's another question that comes up.
CHARLES V. POLLACK, JR., MD: Which is sometimes feasible, sometimes not.
ADOLPH M. HUTTER, JR., MD: Yes. Let me go back to these drugs. What's the practical use? I mean, they're not approved so far, are they, in the emergency ward?
CHARLES V. POLLACK, JR., MD: For bivalirudin, if the results of ACUITY can be taken to heart, there's utilization possibilities outside of the cath lab in the pre-cath period. That's the way it was studied in ACUITY. However, if you would poll emergency physicians about what is bivalirudin, the vast majority don't have any knowledge of this drug at all, because they have no experience with it.
ADOLPH M. HUTTER, JR., MD: Even if they knew it, could they use it, if it's not FDA-approved for that? Or can they go ahead and use it? What's the rule on that?
CHARLES V. POLLACK, JR., MD: They could use it. I mean, we sometimes use drugs off label, and you do that.
ADOLPH M. HUTTER, JR., MD: Sure. And it's legit. The docs don't have to be afraid, if they know how to use it.
CHARLES V. POLLACK, JR., MD: Well, when you feel there's enough data out there. You know, the FDA approval sometimes lags behind the data accumulation.
ADOLPH M. HUTTER, JR., MD: And that's okay? We can tell our audience that's okay if you know how to use it, right?
JAMES HOEKSTRA, MD: As long as you realize you're using it off label, because everybody needs to be aware of that fact.
ADOLPH M. HUTTER, JR., MD: Okay. Any other issues about this drug or these drugs in this syndrome? It sounds like it's a pretty, you guys all think that it's going to be the antithrombin agent of choice.
E. MAGNUS OHMAN, MD: Well, and I want to emphasize, this is not the first trial. We're actually building on a large experience. We had REPLACE 2, which was purely cath lab, PCI-related experience. It showed almost identical results to ACUITY. And then of course, many years ago there were a few smaller unstable angina trials, and they also had a consistent message. So I think we're looking at a long time of understanding this. So I think the time has come after the ACUITY trial.
ADOLPH M. HUTTER, JR., MD: So it sounds like it's definitely going to change.
E. MAGNUS OHMAN, MD: Yes.
ADOLPH M. HUTTER, JR., MD: Yes, Jim?
JAMES HOEKSTRA, MD: But I also think you need to remember that, you know, even with the ACUITY trial and the prior trials, REPLACE trials, bivalirudin is a cath lab drug. It's been studied in cath lab patients. And if you know a patient's going to cath lab, then it becomes a player and a possibility for its utilization. If you don't know, it really is not quite there yet, and that's where you're looking at other drugs.
ADOLPH M. HUTTER, JR., MD: Now, we learned from another trial, I think it was SYNERGY, that you can't switch from low molecular weight enoxaparin to heparin or vice versa. Is there any data to suggest that that's true with the direct thrombin inhibitors also?
CHARLES V. POLLACK, JR., MD: Well, we're going to need to find out. You're right. That was one of the primary confounding issues, and SYNERGY was this unexpected crossover between enoxaparin and heparin.
There were patients in ACUITY who received an antithrombotic agent prior to being randomized. Some of those patients received either heparin or low molecular weight heparin and then were randomized to bivalirudin. So we'll be doing that analysis to find out.
ADOLPH M. HUTTER, JR., MD: So we'll find out. Okay. Well, gentlemen, this is a great discussion. It sounds like we're on the verge of changing the way we do things in this syndrome, and these direct thrombin inhibitors seem to be a very useful tool.
And thank you for joining us. I'm Dolph Hutter.