When should fibrinolytic therapy be administered in stemi

Adjuvant Therapy

Adjuvant antithrombin and antiplatelet therapies play a critical role in the pharmacologic reperfusion of patients presenting with STEMI. Unfractionated heparin (UFH) has been the traditional antithrombin used, but it has several well-documented pharmacologic and practical limitations. Braunwald, Antman, and others have shown in the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis In Myocardial Infarction 25) trial that a strategy of the low molecular weight heparin (LMWH) enoxaparin (ENOX) was superior to adjunctive therapy using UFH for preventing death or recurrent ischemic events in more than 20,000 patients receiving fibrinolytic therapy for STEMI.[12]

Figure 2.

A number of substudies have been published in 2007, including a Focus Issue of JACC highlighting additional findings from ExTRACT-TIMI 25.

Two papers in the JACC Focus Issue compared outcomes in those who subsequently underwent PCI and those treated concomitantly with clopidogrel. Compared with UFH, ENOX was associated with both delayed onset and reduced recurrence of MI and improved outcomes in those who did undergo PCI (Slide 3).[13] In patients also treated with clopidogrel, ENOX significantly reduced the rate of the composite of death, recurrent MI, myocardial ischemia, or stroke, with only a slight, statistically insignificant increased rate of bleeding (Slide 4).[14] These studies expand our understanding of the benefits of ENOX over UFH in two subgroups of postfibrinolysis patients; suggesting that ENOX is superior in patients likely to undergo PCI as well as in patients treated with clopidogrel.

Figure 3.

Figure 4.

In ExTRACT-TIMI 25, women presented with a profile of higher baseline risk and increased short-term mortality. When data were analyzed by gender, women had similar relative and greater absolute risk reductions than men when treated with ENOX compared with UFH as adjunctive therapy with fibrinolysis.[15]

To determine the relationship between a strategy of ENOX, early ST-segment resolution, and clinical outcomes, investigators evaluated ECGs at baseline and at 180 minutes in 3,208 of the 20,479 patients in ExTRACT-TIMI 25.[16] The data suggest that a strategy of ENOX improves outcomes by preventing reocclusion in patients achieving initial successful reperfusion after fibrinolytic therapy rather than by facilitating initial reperfusion.

Outcomes in STEMI differ between patients in clinical trials and those in routine practice as well as across different regions. ExTRACT-TIMI 25 investigators hypothesized that adjustment for baseline risk would minimize such variations. Trial data were compared with 3,726 patients registered from 109 sites in 25 countries.[17] Patients in the registry had a higher baseline risk than those in the trial; including more extensive prior cardiac histories and more comorbidities. After adjusting for baseline risk, even the gross national income per annum per capita of the country in which the patient presented did not contribute to predicting in-hospital mortality.

Does the choice of thrombolytic agent used affect outcomes with ENOX? Based on the ExTRACT-TIMI 25 data, the benefits of an ENOX strategy over UFH were observed in both streptokinase and fibrin-specific-treated STEMI patients, suggesting ENOX is preferred over UFH regardless of lytic agent.[18]

Finally, Antman, Braunwald, and colleagues recently conducted a meta-analysis of a decade-worth of clinical trial data to determine the effect of age on outcomes following fibrinolysis for STEMI.[19] Compared with younger patients (n = 123,568), elderly patients (n = 24,531) had a three- to four-fold increased risk of mortality and adverse events when treated with fibrinolysis and antithrombin therapy (Slide 5). (Nine of 11 trials defined elderly as ≥75 years, although two studies defined elderly as >65 or ≥70 years.) In this ACCEL interview, Dr. Antman discusses contemporary management of STEMI and an ACC.07 session he chaired entitled "ST Elevation Myocardial Infarction: The First 24 Hours."

Figure 5.

Dr. Smith: I'm Dr. Sidney Smith and with me is Dr. Elliott Antman, director of the Samuel A. Levine Cardiac Unit at Brigham and Women's Hospital and professor of medicine at Harvard Medical School. We're talking about "ST-Segment Elevation Myocardial Infarction: The First 24 Hours."

Elliott, let's start with the first talk in the session you chaired. Robert Wilcox, MD, FRCP, discussed "Fibrinolysis: 2007." Is there still a role for fibrinolysis today?

Dr. Antman: Sid, there has been so much interest in primary PCI for STEMI, but we have to realize that most of our patients who have STEMI in the United States today are still treated with fibrinolysis.

Dr. Smith: Are there more hospitals treating with fibrinolysis than PCI?

Dr. Antman: It's a moving target. The NRMI registry is tracking this, but we don't have data for the last year or so. Rural hospitals in particular are still treating patients with fibrinolysis; so, yes, there remains an important role for this approach in individuals with STEMI.

Dr. Smith: What percentage of patients get reperfusion? How well are we doing overall?

Dr. Antman: We're doing a little better today than we used to when perhaps 30% of patients with STEMI had no reperfusion. That's down to about 20% now, but that's still much higher than we would consider optimal.

Dr. Smith: Have we plateaued in terms of advancing the state-of-the-art of fibrinolysis? Is there anything coming down the pipeline in terms of fibrinolysis or are major developments more likely to be in the use of adjunctive therapies?

Dr. Antman: We have moved from the use of non-fibrin specific agents, like streptokinase, to the relatively fibrin-specific ones we use today. Once we developed the bolus forms of these fibrin-specific agents there hasn't been any other clinical advancement in terms of thrombolytic therapy. That's not to say the bolus agents are necessarily superior to tPA, for example; they were just much more convenient to administer. The real advances are probably in the antithrombotic therapy that we use to support the fibrinolytic strategy.

Dr. Smith: You have been a leader in our understanding of fibrinolysis and one of your key points has been the issue of timing; that is, the window of time in which fibrinolysis is optimal. Can you discuss that for a moment?

Dr. Antman: Time is muscle and that's important whether we're talking about a pharmacologic or a catheter-based reperfusion strategy for STEMI patients. The sooner we get the infarct artery open, the better the patient will do because we're going to salvage myocardium. The longer the clot has matured in the coronary artery, the more difficult it is for a fibrinolytic agent to work.

The optimal window is the first 3 hours after symptom onset. During this 3-hour window, fibrinolytic therapy and primary PCI have about the same efficacy in terms of limiting mortality. As you move progressively beyond the first 3 hours, primary PCI becomes the preferred strategy because of its ability to salvage myocardium much more effectively than fibrinolytic therapy. So, the goal is to get the patient quickly to where pharmacologic reperfusion is available or to create a situation where the patient can be transported rapidly to a primary PCI center. Time is muscle.

Dr. Smith: What other specific time guides should we be aware of?

Dr. Antman: There are other specific windows discussed in the 2004 STEMI guidelines: a door-to-needle time of 30 minutes is optimal, as is a door-to-balloon (D2B) time of 90 minutes. There is always the interesting question: If you're in a hospital where you can't perform primary PCI but you could give a lytic right now, how much time do you have before you lose the benefits of primary PCI? How much time can I afford to transfer a patient?

That's a difficult question to answer. Compared to a fibrin-specific lytic agent, there's roughly a 1-hour grace period for transfer before you start to lose the benefits of primary PCI.[9] Yet, even that is too simple an answer. Recently, an analysis from the NRMI database was published in Circulation that tried to get at this question on a patient-specific level.[11] Patients who presented soon after symptom onset were stratified by whether they were older or younger and by whether they had an anterior or inferior infarction, and there was a range of times recorded.

For a young individual who arrives soon after the onset of symptoms from a large, anterior myocardial infarction, you probably don't have too many minutes for that transfer before you start to lose the benefits of primary PCI. It might be a 50-minute window for transfer time in that situation. On the other hand, for an elderly patient who arrives hours after the onset of symptoms, thrombolytics are going to be a little less effective and if they have a small, inferior myocardial infarction, the breakpoint there might be as much as 120 minutes. Therefore, it must be an individualized decision, patient by patient.

Dr. Smith: Let's talk about facilitated PCI. The young patient you were just describing with a big anterior infarction: would you ship them for PCI? Or would you consider more of a facilitated PCI approach?

Dr. Antman: It's a logical question: Should we prepare a patient for PCI by giving them some pharmacologic regimen that will help open the artery or provide some trickle of antegrade flow so that the primary PCI procedure could be done more safely? In theory, that approach gives you a lower risk of perforating the vessel because it gives you more of a target to shoot for in the infarct artery. That's how the concept of facilitated PCI arose.

Unfortunately, if you look at the data, primary PCI pretty much wins hands down compared to facilitated PCI based on meta-analyses. The most recent study was ASSENT-4 PCI. Some critiques of ASSENT-4, even those by the investigators themselves, pointed out that there wasn't that much difference in time to treatment in the two treatment arms - facilitated PCI versus primary PCI - so, they weren't actually testing a facilitated strategy. Also, there really wasn't the kind of antiplatelet therapy used that we like to see in the group who received facilitated PCI; in other words, this may have hampered the facilitated PCI arm in terms of the outcomes studied. Nevertheless, as I see the literature right now, we shouldn't be looking at giving full-dose lytics in an attempt to do facilitated PCI. Whether or not some other strategy using maybe a partial dose of lytics in combination with antithrombotic therapy is an option remains investigational at this point.

Dr. Smith: What about antithrombotic therapy? Any developments there that were featured in your meeting?

Dr. Antman: Antithrombotic therapy has two components: antiplatelet therapy and anticoagulant therapy. Antiplatelet therapy is built on our foundation antiplatelet agent, aspirin. Plus, we now have solid evidence that the thienopyridine, clopidogrel, is a useful adjunct in patients with STEMI. Of course, that's an agent that would likely be used in nearly all patients undergoing stenting during primary PCI.

However, we also now know from the COMMIT/CCS-2 Clopidogrel study and the CLARITY-TIMI 28 study that clopidogrel should be used in patients who receive pharmacologic reperfusion or who have no reperfusion at all. Clopidogrel appears to be a lifesaving medication in those patients as well. In particular, clopidogrel has real benefit for preventing successfully reperfused arteries from becoming re-occluded.[14]

The anticoagulants include heparin, enoxaparin, fondaparinux, and bivalirudin. We have pretty good data on the first three suggesting that they are useful agents; bivalirudin is still under study in STEMI patients.

Dr. Smith: Where do you stand on the issue of loading dose of clopidogrel? In COMMIT they did not use a loading dose; in CLARITY, they did.

Dr. Antman: It is important to give a loading dose of clopidogrel. In the COMMIT study, patients of any age could be enrolled, including elderly patients, so there was no loading dose given, just a 75 mg per day maintenance dose. In CLARITY-TIMI 28 there was an upper age limit - patients over age 75 were not enrolled - and a 300 mg loading dose was given. As I see the literature, we can give a 300 mg loading dose to younger patients who receive a fibrinolytic, but we don't have good recommendations for using a loading dose in patients who are older.

Dr. Smith: The COMMIT trial was conducted in China in a robust 40,000 or so patients. How do you feel about taking data that's derived entirely from another healthcare system and making assumptions about applying it to the United States or Canada or other healthcare systems? How valid is that? Can we assume that a lack of a loading dose of clopidogrel would work in our healthcare system?

Dr. Antman: We don't know for sure, but from a practical perspective it's virtually impossible to repeat every study with a very large international enrollment. If we demanded that we repeat these international studies in a North American population, we would never really move forward. Therefore, we have to consider what's practical; as a long as the trial was well conducted and the data seem robust, we should be able to extrapolate to our North American patients.

Dr. Smith: We're certainly seeing more progress in medical therapies and, under your leadership with the STEMI guidelines there's been more of an emphasis on prompt reperfusion. Here at ACC.07 there have been presentations on the D2B project and more data on the pharmacologic approaches to reperfusion. So, I guess the future would be very bright if only patients would recognize their symptoms and get to an emergency room.

Dr. Antman: That's a major issue and we still have a lot of work to do to get our patients to understand what their symptoms represent and to get them where they can be treated promptly.

Dr. Smith: Let's hope we'll achieve that goal. Elliott, thanks for joining us today on ACCEL.

Dr. Antman: A pleasure to be here.

Guidelines

Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction - executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:671-719.

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