New Trials of Antithrombotic Therapy for ACS -- ACC 2006  CME

Introduction

All of us on the interventional side of cardiology were fortunate to have the results of many large new trials presented at the American College of Cardiology (ACC) 55th Annual Scientific Session in Atlanta, Georgia, this year, focusing on assessing different antithrombotic treatments for acute coronary syndromes (ACS). We will want to use many of these results to influence our practice, and they may also be reflected in updates to current guidelines, although it will take time for the guideline committees (and all of us) to fully review the data and their implications. However, we already can see from the results of these trials that there are many different options -- and thus, competing strategies -- that are now available to us, with no single strategy standing out as the "right answer." In this report I want to share some initial observations from these important trials.

Anticoagulant Strategies for Patients With ST-Segment Elevation Myocardial Infarction

Two trials tested different anticoagulant strategies for patients with ST-segment elevation myocardial infarction (STEMI). The first was the ExXTRACT-TIMI 25 (see Trial Glossary for expansions of all trial acronyms), presented by Elliott Antman, MD^[1] and published simultaneously in The New England Journal of Medicine.^[2] The second was the OASIS-6 trial, presented by Salim Yusuf, MD, DPhil^[3] and published in JAMA.^[4] Both trials tested newer anticoagulants:

• ExTRACT-TIMI 25 compared enoxaparin with unfractionated heparin (UFH) in patients treated with thrombolytic therapy; and
  
  
• OASIS-6 compared fondaparinux with either placebo or UFH.

The difference in the control arms of the studies will influence how we use these study findings in our practice.

ExTRACT-TIMI 25

For a complete report of the results of ExTRACT-TIMI 25, see Medscape Cardiology's coverage of ACC 2006 (http://www.medscape.com/viewprogram/5185). In brief, ExTRACT-TIMI 25 was a trial of patients who presented with STEMI and were receiving thrombolytic therapy with TNK, tPA, rPA, or streptokinase at the discretion of the treating physician. All patients were treated with aspirin, and, toward the end of the trial patients could also receive clopidogrel, as evidence of its efficacy became available during the course of the study. In the end, however, only a small number of patients were treated with clopidogrel, which, typically, was administered around the time of coronary stenting; further analyses of those patients are planned.

Following lytic therapy, patients were randomized to either the control arm (UFH) or the treatment arm (enoxaparin). Patients randomized to control received UFH according to ACC/American Heart Association (AHA) guideline dosing, with a weight-adjusted bolus of 60 U/kg, to a maximum of 4000 U, followed by a 12 U/kg/hour infusion with a maximum initial infusion of 1000 U/hr. This was then adjusted in each patient to an APTT of 50 to 70 seconds. Patients in the treatment arm received enoxaparin with a 30-mg IV bolus and a 1-mg/kg subcutaneous dosing every 12 hours. For patients ≥ 75 years of age, a novel strategy was developed, consisting of omission of the IV bolus and 0.75 mg/kg subcutaneously every 12 hours. All patients received the standard adjustment of enoxaparin dosing in cases of renal dysfunction.

The dosing strategies were given for different durations of time. Patients in the control arm received UFH for a minimum of 48 hours, as per the ACC/AHA guidelines, and patients in the treatment group received enoxaparin given through the time of hospital discharge or Day 8, whichever came first; thus, the latter represented a more prolonged treatment strategy. Of note, the treatments were given in a double-dummy fashion, such that knowledge of the duration of treatment could not influence treatment decisions overall (since the investigators were blinded as to patient assignment ).

Overall, the primary endpoint, the composite of death and myocardial infarction (MI) through 30 days, was highly significantly reduced with the strategy of enoxaparin (P < .0001) as compared with UFH. The benefit was an absolute 2% reduction in death/MI MI. In other words, 2 out of every 100 patients did not die or have MI when treated with the enoxaparin strategy. The single endpoint of death was not significantly reduced in the enoxaparin group, although it did trend lower than control. In addition, there was a significant 33% reduction in MI, and a similar reduction in the secondary endpoint of death, MI, or need for urgent revascularization. Conversely, a higher rate of major bleeding was observed with enoxaparin, but there was no difference in intracranial hemorrhage.

Thus, the net clinical benefit of death, MI, or either major bleeding or intracranial hemorrhage (by different definitions) was always highly significantly in favor of the enoxaparin strategy.

Of interest, looking at the Kaplan-Meier curves presented at the ACC, the enoxaparin benefit began to emerge in the first 2 days, when all patients were receiving 1 of the 2 anticoagulants. This suggests that there is a pharmacologic benefit to the low-molecular-weight heparin enoxaparin. The separation of Kaplan-Meier curves favoring enoxaparin grew more prominent over the next 5-8 days, as patients continued treatment during hospitalization with subcutaneous enoxaparin.

The take-home message was that the strategy of enoxaparin worked quite well in preventing death or MI. There was an increase in bleeding, but this was far outweighed by the reduction in MI, with no difference in rates of intracranial hemorrhage. Thus, the net clinical benefit strongly favored enoxaparin. Of importance, the benefit of enoxaparin was shown in comparison to our current ACC/AHA-recommended dosing of UFH, and thus the ExTRACT-TIMI 25 results represent a true advance in how we administer therapy for these patients.

OASIS-6

The OASIS-6 trial had a more complicated design that compared the new factor Xa inhibitor, fondaparinux, to the various current strategies for treating a presentation of STEMI -- ie, primary percutaneous coronary intervention (PCI), medical treatment, or thrombolytic therapy.

The trial also compared fondaparinux to 2 control arms: (1) placebo and (2) UFH. Patients were randomized to control arms according to whether the treating physician felt UFH was indicated. As a result, there was a mix of the 3 treatment strategies in each stratum of the trial (although, essentially, all patients undergoing primary PCI received UFH as their anticoagulant in the control arm).

At 30 days, there was a benefit for fondaparinux compared with either of the control arms, with a reduction in death or MI from 11.2% to 9.7%. Numerically, however, the events differed according to the stratum in which patients were treated. For instance, in patients in whom no UFH was used (fondaparinux vs placebo), the difference at 30 days was decreased from 14% to 11.2%, whereas in those in whom UFH was used, the event rates decreased from 8.7% to 8.3%, not a significant difference. The investigators pointed out, however, that while the P value for the interaction (heparin vs no heparin) was not significant, nevertheless this difference appears to represent a clinical advantage for UFH vs placebo.

Of note, the investigators found that there were 2 trends mitigating against use of fondaparinux in the primary PCI cath-lab setting:

• There was a trend toward a higher rate of death or MI in patients treated with primary PCI plus fondaparinux (5 mg IV) compared with primary PCI patients, who were treated for the most part with UFH. Thus, the OASIS 6 investigators recommended not using the fondaparinux strategy for primary PCI.
  
  
• Similarly, as we had seen in the OASIS-5^[5] trial, several patients in the fondaparinux group developed thrombus on the catheters in the cath lab, whereas among the few hundred patients receiving IV UFH in the cath lab, this problem basically did not occur.

Conclusions From OASIS-6

The rates of severe bleeding with fondaparinux vs the 2 control arms were not significantly different in this trial (1.3% vs 1.0%, respectively). Thus, many of us are looking carefully at the data to understand what was seen. However, given the dramatic benefit compared with placebo, OASIS-6 clearly shows that fondaparinux is active as an anticoagulant with very good clinical outcomes.

The benefit relative to UFH is less clear. Therefore, I would imagine that on the basis of the OASIS-6 results, guideline committees would see fondaparinux as a new alternative for anticoagulant treatment in STEMI patients, treated either with thrombolysis or medical therapy, but not necessarily recommend the drug as superior to another agent, notably UFH. Finally, fondaparinux is clearly not indicated for primary PCI.

Anticoagulant Lessons From ExTRACT-TIMI 25 and OASIS-6

So, how should treatment of STEMI evolve following the presentation of these results at ACC 2006?

First, as with ExTRACT-TIMI 25, when the OASIS-6 investigators looked at the Kaplan-Meier curves, they saw a benefit with more prolonged treatment with fondaparinux that emerged during the in-hospital phase of the study. One conclusion that can be derived from these 2 trials is that there appears to be benefit from continued anticoagulant therapy during the in-hospital phase.

Second, it appears that an anticoagulant is clearly beneficial, even for patients already treated with streptokinase (which was used in many patients in OASIS-6), and thus the notion that you do not need an anticoagulant with streptokinase should be abandoned. In addition, enoxaparin was seen to be superior to UFH among patients receiving streptokinase in ExTRACT-TIMI 25.

Third, of the anticoagulant strategies, there are 3 options at present: the traditional approach of UFH, with weight-adjusted dosing with a maximum initial bolus of 4000 U, or one of these 2 new strategies:

• Fondaparinux, 2.5 mg/day subcutaneously up through hospital discharge; or
  
  
• Enoxaparin with a 30-mg IV bolus and 1 mg/kg subcutaneously every 12 hours with 75% of that dose in no bolus, given to those over the age of 75 years.

Of note, this latter regimen was demonstrated to be superior to UFH. So, while the use of enoxaparin does appear to be associated with more bleeding, it is also the regimen associated with the fewest events, and as a result it may be considered the best option.

Glycoprotein IIb/IIIa Inhibitors

The next pair of trials presented at the ACC meeting -- ISAR-REACT-2^[6,7] and ACUITY[8] -- looked at the use of glycoprotein (GP) IIb/IIIa inhibitors in patients with unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI).

ISAR-REACT 2

This long-anticipated trial studied high-risk UA/NSTEMI patients undergoing PCI, all of whom had been pretreated with clopidogrel 600 mg for at least 2 hours prior to PCI. The patients were then randomized to receive abciximab at the standard dosing vs placebo, and the primary endpoint looked at death, MI, or urgent revascularization through 30 days.

Overall, patients treated with the GP IIb/IIIa inhibitor had a significant 25% reduction in events. When looking at key subgroups, the investigators reported that all of the benefit (and a 30% reduction) was seen among patients who had a positive troponin, with no benefit seen in those who had a negative troponin. Thus, even with pretreatment with high-dose clopidogrel, GP IIb/IIIa inhibition still added significant clinical benefit in the high-risk patients who were troponin positive.

These data from ISAR-REACT 2 can be considered along with the results of the 4 trials that looked at GP IIb/IIIa inhibitors in UA/NSTEMI prior to clopidogrel pretreatment -- namely, the troponin studies of:

• CAPTURE^[9];
  
  
• PRISM^[10];
  
  
• PARAGON-B^[11]; and
  
  
• PRISM-PLUS.^[12]

Each of these trials found a 50% to 70% reduction in events with the GP IIb/IIIa inhibitor among troponin-positive ACS patients. In the ISAR-REACT 2 trial, with pretreatment, the benefit was 30%. Thus, it appears that both drugs have benefit: the clopidogrel pretreatment provides benefit, but in addition, in the high-risk troponin-positive patients, the GP IIb/IIIa inhibitor adds significant benefit as well.

As a result, ISAR-REACT 2 solidifies, in my mind, the need for a GP IIb/IIIa inhibitor among troponin-positive patients undergoing PCI. It also shows, indirectly, that pretreatment with clopidogrel is of benefit, as has been seen recently in a meta-analysis of the PCI-CURE, CREDO, and PCI-CLARITY trials.^[13]

ACUITY

The second trial that presented data on the timing of GP IIb/IIIa inhibition was the ACUITY trial. This was a 2 x 3 factorial design trial that randomized high-risk UA/NSTEMI patients to 1 of 3 arms: in 2 of the 3 arms patients received a GP IIb/IIIa inhibitor, either eptifibatide or tirofiban, in the emergency department, and in the third they received the inhibitor in the cath lab if a PCI was performed. It appeared that treatment was initiated in the trial about 15 hours after presentation, and thus, many patients had received some type of anticoagulant strategy prior to randomization. It was then just another 7 hours until patients underwent their coronary angiography and PCI, and thus the timing differential was relatively modest.

The preliminary data revealed no significant difference in the outcomes of patients who were treated with the upfront strategy of GP IIb/IIIa inhibition in the emergency department compared with those who received it in the cath lab prior to undergoing PCI.

There were some subgroup analyses presented, including duration of timing, but I think many people will await the further data availability and publication to understand better the types of patients who were treated and whether this would clarify whether there was any added benefit with earlier initiation of GP IIb/IIIa inhibition. Thus, this will be an important trial, but many of us are waiting to see further analyses to better understand its place in guiding therapy.

CHARISMA

The final large trial on antithrombotic therapy presented at ACC 2006 was the CHARISMA trial.^[14] CHARISMA compared the long-term use of aspirin alone as antithrombotic treatment vs aspirin plus clopidogrel, with a mean follow-up of about 2.5 years, in over 15,000 patients with stable coronary disease (ie, secondary prevention) and in some high-risk primary prevention patients. Enrollment criteria included known coronary artery disease, peripheral arterial disease, or cerebrovascular disease -- with many patients having had a prior MI or stroke, and others simply having documentation of coronary disease by stress testing or of cerebrovascular disease by imaging. In addition, there were patients included in the trial with multiple risk factors for coronary disease, notably diabetes.

The CHARISMA investigators reported a nonsignificant 7% reduction in death, MI, or stroke with the combination antiplatelet therapy. When they used an expanded endpoint, including rehospitalization for ischemic events, the difference was still only about 7.5%, although this just barely reached significance.

Of interest, these overall results appear to have been influenced by different outcomes in those who were treated for secondary prevention as compared with those being treated for primary prevention. There was no benefit (and an overall trend toward harm) in primary prevention patients, whereas those who had documented coronary, cerebrovascular, or peripheral arterial disease had a statistically significant 12% reduction in events (P = .048). Additional analyses presented later in the meeting found that patients with a prior MI, prior stroke, or documented peripheral arterial disease, similar to those studied in the CAPRIE^[15] trial, had a significant 17% reduction in death, MI, or stroke. It thus appears that the status of the patient does influence the benefit that can be achieved, with the higher-risk patients, as defined by a prior clinical event or documented peripheral arterial disease, benefitting, whereas those enrolled simply with risk factors for coronary disease did not show benefit. Of note, across all the various subgroups, there was an excess of bleeding -- about 1% absolute excess -- for the combination over the 2.5-year period.

Of great interest were the results in the patients with prior stroke. Here, there appeared to be a significant benefit of adding clopidogrel to aspirin, and these results will help guide therapy for these patients. The most recent previous trial data for stroke patients had come out of the MATCH^[16] trial, which studied the addition of aspirin to a background of clopidogrel and failed to show a significant benefit. In CHARISMA, we learned the opposite: that the addition of clopidogrel to a background of aspirin therapy does lead to benefit. Thus, the trial shows that clopidogrel does play an important role in the treatment following ischemic stroke. Further detailed analyses of stroke patients should be very instructive.

In summary, many of us will look forward to additional analyses of the CHARISMA data in order to guide treatment, but the take-home messages from this trial were as follows:

• Patients who simply present with coronary risk factors (primary prevention) should not be treated with a combination of aspirin and clopidogrel.
  
  
• For secondary prevention, it does appear that there is benefit associated with the use of aspirin plus clopidogrel, but it is balanced by the risk of bleeding, and thus we would not aim to start each and every patient who has evidence of vascular disease on the combination of aspirin and clopidogrel.

On the other hand, significant clinical benefit does appear to be present in patients with prior MI or stroke and, thus, further analyses may demonstrate that longer-term treatment in these types of patients could be of significant benefit. The CHARISMA results do not change the treatment recommendations for all of the prior indications, notably in UA/NSTEMI, where patients had a clear benefit when treated for a year, and similarly following PCI, where benefit out through 1 year has been clearly shown. The indications from secondary prevention post event, as studied in CAPRIE, also still hold; and finally, the new benefit recently seen in STEMI also still holds.

The most important group for which therapy should not change is the patients who have undergone stent placement. There was a lot of confusion among patients who saw the news reports about the trial, which focused on lack of benefit (and the trend toward harm) in the primary prevention group. As a result, many patients stopped their clopidogrel (first), and then called their doctors to ask whether that was the right thing to do. (This happened with some of my patients). For patients with stents placed within the past 1-2 years, this is clearly the wrong thing to do; stopping clopidogrel prematurely is a very strong risk factor for developing stent thrombosis, which has a case fatality rate of 30% to 45%.

Fortunately, the ACC, AHA, and the European Society of Cardiology each released follow-up statements and public health warnings advising that patients with stents should not stop their clopidogrel without consulting their doctors. That advice actually holds for all patients -- they should consult their physicians before changing their treatment strategy. Thus, the take-home message from CHARISMA and from the other clopidogrel trials is that the current clopidogrel indications still hold, notably for UA/NSTEMI, PCI, STEMI, peripheral arterial disease, and prior stroke. We will be looking toward further analyses to guide the duration of treatment beyond 1 year in all of these patient groups.

References

1. Antman EM, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin in ST elevation myocardial infarction patients treated with fibrinolysis. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract 422-9.
2. Antman EM, Morrow DA, McCabe CH, et al, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:1477-1488. Abstract
3. Mehta SR, Yusuf S, for the OASIS-6 Investigators. The impact of fondaparinux, a synthetic factor Xa inhibitor, on mortality and reinfarction in patients with acute ST segment elevation myocardial infarction: results of the Michelangelo-Organization To Assess Strategies For Ischemic Syndromes (OASIS)-6 trial. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract 422-7.
4. The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction. The OASIS-6 randomized trial. JAMA. 2006;295:1519-1530. Abstract
5. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464-1476 Abstract
6. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA. 2006;295:1531-1538. Abstract
7. Kastrati A, Mehilli J, Neumann F-J, et al. Prospective, randomized, double blind, placebo controlled trial of glycoprotein IIb/IIIa inhibition with abciximab in patients with acute coronary syndromes undergoing stenting after pretreatment with a high loading dose of clopidogrel. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session, March 11-14, 2006, Atlanta, Georgia. Abstract 411-10.
8. Stone GW, McLaurin BT, Ware JH, et al. Prospective, randomized comparison of heparin plus IIb/IIIa inhibition and bivalirudin with or without IIb/IIIa inhibition in patients with acute coronary syndromes: the ACUITY trial. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract 402-12.
9. Hamm CW, Heeschen C, Goldmann B, et al. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators. N Engl J Med. 1999;340:1623-1629. Abstract
10. Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. Lancet. 1999;354:1757-1762. Abstract
11. Newby LK, Ohman EM, Christenson RH, et al. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin T-positive status: the PARAGON-B troponin T substudy. Circulation. 2001;103:2891-2896. Abstract
12. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med. 1998;338:1488-1497. Abstract
13. Sabatine MS, Cannon CP, Gibson CM, et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) -- Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005;294:1224-1232. Abstract
14. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706-1717. Abstract
15. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet. 1996;348-1329-1339. Abstract
16. Diener HC, Bogousslavsky J, Brass LM, . Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337. Abstract

Trial Glossary

• ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy
  
  
• CAPRIE: Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events
  
  
• CAPTURE: c7E3 F2b Antiplatelet Therapy in Unstable Refractory Angina
  
  
• CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance
  
  
• CREDO: Clopidogrel for the Reduction of Events During Observation
  
  
• ExTRACT-TIMI 25: Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment
  
  
• ISAR-REACT-2: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2
  
  
• MATCH: Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent Transient Ischemic Attacks or Ischemic Stroke
  
  
• OASIS-6: Sixth Organization to Assess Strategies in Acute Ischemic Syndromes
  
  
• PARAGON-B: Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network-B
  
  
• PCI-CLARITY: PCI-Clopidogrel as Adjunctive Reperfusion Therapy
  
  
• PCI-CURE: Percutaneous Coronary Intervention in the Clopidogrel in Unstable angina to prevent Recurrent Events
  
  
• PRISM: Platelet Receptor Inhibition in Ischemic Syndrome Management
  
  
• PRISM-PLUS: Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms