CLINICAL STUDIES
Overcoming thrombolytic resistance
Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction
Christopher P. Cannon, MDa
a Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
Manuscript received January 4, 1999;
revised manuscript received May 27, 1999,
accepted June 30, 1999.
Reprint requests and correspondence: Dr. Christopher P. Cannon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115
ccannon{at}rics.bwh.harvard.edu
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Abstract
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OBJECTIVES
We sought to review the emerging data and the clinical rationale for combining glycoprotein (GP) IIb/IIIa inhibitors with thrombolytic therapy for acute myocardial infarction (AMI).
BACKGROUND
Although thrombolytic therapy has been a major advance in the treatment of acute ST segment elevation MI, new single-bolus thrombolytic agents have been unable to break the "thrombolytic ceiling" in infarct-related artery (IRA) patency.
METHODS
Recent literature on GPIIb/IIIa inhibitors in acute coronary syndromes was reviewed.
RESULTS
A new approach toward improving current thrombolytic–antithrombotic regimens focuses on "targeted therapy" for each component of the occlusive coronary thrombus: fibrin, thrombin and platelets. For the fibrin component, front-loading and/or bolus dosing of plasminogen activators (PAs) has identified the currently available doses of tissue-type plasminogen activator (t-PA) and recombinant tissue-type plasminogen activator (r-PA). For the thrombin component, several recent trials have shown that lower doses of heparin improve the safety profile of the thrombolytic-antithrombotic regimen. For the platelet component, aspirin has been shown to be effective, but the GPIIb/IIIa inhibitors offer the potential for more effective platelet inhibition and improved clinical efficacy. The benefits of GPIIb/IIIa inhibition in reducing death, MI or urgent revascularization in the setting of percutaneous coronary intervention are well established. Emerging experimental and clinical data now suggest that combining GPIIb/IIIa inhibition with reduced-dose thrombolytic therapy may improve early IRA patency without increasing bleeding risk.
CONCLUSIONS
Given the strong clinical and physiologic rationale, clinical investigation in acute ST segment elevation MI is currently focused on combining the potent GPIIb/IIIa receptor inhibitors with reduced-dose fibrinolytic agents in acute MI, with the goal of overcoming "thrombolytic resistance."
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Abbreviations and Acronyms
| | AMI | = acute myocardial infarction | | GP | = glycoprotein | | GUSTO | = Global Utilization of Streptokinase and TPA for Occluded arteries | | ICH | = intracranial hemorrhage | | IRA | = infarct-related artery | | MI | = myocardial infarction | | PAI-1 | = plasminogen activator inhibitor-1 | | PCI | = percutaneous coronary intervention | | r-PA | = recombinant plasminogen activator | | TIMI | = Thrombolysis In Myocardial Infarction | | TNK-tpa | = TNK–tissue-type plasminogen activator | | t-PA | = tissue-type plasminogen activator | | TxA2 | = thromboxane A2 |
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Although thrombolytic therapy is a mainstay of treatment for acute myocardial infarction (AMI), it has well-documented limitations. With current thrombolytic regimens, patency is restored in 60% to 85% of patients with AMI (1–4), and only 54% to 60% of patients achieve full myocardial reperfusion, angiographically defined as Thrombolysis In Myocardial Infarction trial (TIMI) flow grade 3 in the infarct-related artery (IRA) (1–4). Beyond TIMI flow grade 3, full myocardial perfusion is not present in all patients, leaving only 30% to 45% of patients with truly optimal reperfusion (5,6). In addition, reocclusion or reinfarction, or both, occurs in roughly 30% of patients by three months (7–9), which is associated with increased mortality (10–11). Finally, thrombolytic therapy is associated with increased risk of bleeding complications, including intracranial hemorrhage (ICH), which ranges from 0.5% to 0.9% in major randomized trials (2,3,12,13), but may be higher in clinical practice.
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Thrombolytic resistance
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Rupture or erosion of lipid-rich atherosclerotic plaques exposes the subendothelial plaque components to blood. The ensuing platelet adhesion and activation lead to changes in platelet shape, release of thromboxane A2 (TxA2), plasminogen activator inhibitor-1 (PAI-1), serotonin and other proaggregatory substances. In addition, conformational changes in the glycoprotein (GP) IIb/IIIa receptor occur, making the receptor receptive to ligand binding. Platelet aggregation at the rupture site leads to the buildup of occlusive thrombi that can cause myocardial ischemia, infarction and subsequent complications. This has been confirmed in recent angioscopic studies, showing that a substantial portion of occlusive thrombi (previously thought to consist only of fibrin-rich "red" clot) is made up of platelets (the so-called "white" clot) (14).
The generation of thrombin and activation of platelets at the site of vascular injury frequently limit thrombolytic therapy. This "thrombolytic resistance" may be due to several mechanisms (Fig. 1): 1) incomplete lysis of the clot because plasminogen activators act only on the fibrin portion of thrombi; 2) platelets that elaborate PAI-1, which inhibits the action of the thrombolytic agent, and platelets that release TxA2, which causes vasoconstriction and may limit recanalization of the IRA; 3) exposure of clot-bound thrombin can cleave fibrinogen to fibrin, thereby facilitating rethrombosis; and 4) thrombolytic therapy’s direct platelet-activating effect, leading to increased levels of TxA2 and platelet-activating factor (15). Thus, fibrinolysis promotes platelet activation by creating conditions that actually trigger rethrombosis or reocclusion, or both.
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Figure 1 Thrombolytic resistance. FDP = fibrin/fibrinogen degradation product. (Adapted with permission from Moliterno DJ, Topol EJ. Thromb Haemost 1997;78:214–9.)
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"Targeted therapy" for AMI
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With the understanding of the three major physiologic components of the coronary thrombus—fibrin, thrombin and platelets—therapy is now being targeted at each component of the clot (Fig. 2).
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Figure 2 The three components of coronary thrombus are targets for therapy. Mechanism of action: aspirin—acetylates cyclooxygenase, decreases platelet activation; heparin—reduces clotting formation/propagation; GPIIb/IIIa inhibitors inhibit platelet aggregation; thrombolytic therapy—converts plasminogen to plasmin, which dissolves fibrin in clot. LMWH = low molecular weight heparin; t-PA = tissue-type plasminogen activator; r-PA = reteplase; SK = streptokinase; TNK-tPA = TNK–tissue-type plasminogen activator.
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Thrombolytic therapy with plasminogen activators is better termed "fibrinolytic" therapy, because it generates plasmin, which degrades fibrin to lyse the clot. Initial efforts to improve thrombolysis with higher doses of tissue-type plasminogen activator (t-PA) did not lead to improvement (16). Newer thrombolytic agents, such as lanoteplase (n-PA) (17) and TNK-tPA (TNK–tissue-type plasminogen activator) (18), appear to be similar to t-PA or reteplase (r-PA) when given with aspirin and heparin.
The second component of thrombolytic-antithrombin therapy is heparin. For acute ST segment elevation myocardial infarction (MI), heparin is an important adjunctive agent to maintain patency after t-PA (19–21). The benefit of heparin is believed to be due to decreased reocclusion (22). Heparin has been used in conjunction with all variants of t-PA, including r-PA (4,13), n-PA (17) and TNK-tPA (18). Further support for the use of heparin after t-PA administration comes from the benefit observed in the Global Utilization of Streptokinase and TPA for Occluded arteries (GUSTO-I) (23) and TIMI-4 (3) trials, as compared with the lack of benefit in the International Study of Infarct Survival-3 (ISIS-3) and Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico-2 (GISSI-2) trials, where intravenous heparin was not used with t-PA (24,25). When reduced doses of heparin are used in conjunction with thrombolysis, reduced rates of ICH and major hemorrhage have been observed in four separate trials (18,26–28). Indeed, the update to the American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Management of AMI recommends a new lower dose of heparin: bolus of 60 U/kg (maximum 4,000 U) and an initial infusion of 12 U/kg per h (maximum 1,000 U/h).
Efforts to improve thrombin inhibition by targeting clot-bound thrombin with direct thrombin inhibitors, such as hirudin, were studied (TIMI-9B, GUSTO-IIb), but led to no definitive benefit (26,27). Testing of low molecular weight heparin plus thrombolysis is under way.
The third component of the "targeted therapy" is antiplatelet therapy, currently aspirin. Platelet aggregation is inhibited by aspirin’s ability to permanently acetylate cyclooxygenase, which reduces the formation of TxA2. Aspirin decreases the risk of IRA reocclusion (29) and reinfarction (12) after thrombolysis. More important, aspirin has been shown to reduce mortality by  25%, an additional benefit to that achieved by thrombolytic therapy (12). Aspirin’s dramatic clinical benefits have highlighted the central role of platelet function in thrombus formation and rethrombosis after thrombolytic therapy. Ticlopidine and clopidogrel are adenosine diphosphate receptor antagonists that have benefit as compared with aspirin alone in coronary stenting and secondary prevention, but they have not yet been studied in AMI (30). These findings stimulated the development of agents with a more direct effect on platelet aggregation, such as the GPIIb/IIIa antagonists.
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The promise of antiplatelet therapy with GPIIb/IIIa receptor inhibitors
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The binding of the GPIIb/IIIa receptor with fibrinogen or von Willebrand factor represents the final common pathway of clot formation (Fig. 3). Blockade of these receptors results in profound suppression of platelet aggregation that extends beyond the capabilities of aspirin, ticlopidine or clopidogrel (31).
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Figure 3 Platelet adhesion, activation and aggregation and inhibition by GPIIb/IIIa inhibitors. In this diagram of events associated with platelet adhesion (a), activation (b) and aggregation (c), activated platelets undergo a conformational change in the shape of the GPIIb/IIIa receptors, which makes them receptive to ligand binding. Fibrinogen binds to the platelet GPIIb/IIIa receptors on adjacent platelets, forming bridges between them. As shown in (d), GPIIb/IIIa receptor inhibitors block this fibrinogen-binding receptor and therefore directly prevent platelets from aggregating. AA = arachidonic acid; ADP = adenosine diphosphate; ASA = aspirin; GPIIb/IIIa = glycoprotein IIb/IIIa; TXA2 = thromboxane A2; vWF = von Willebrand factor.
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Abciximab, the Fab fragment of the chimeric antibody to the GPIIb/IIIa receptor (and to a broader group of integrins) is able to block platelet aggregation as well as inhibit thrombin generation by tissue factor, the latter due to blockade of GPIIb/IIIa and alphavbeta3 (32,33). In addition, there are several peptide and pharmacologic GPIIb/IIIa receptor inhibitors (tirofiban, eptifibatide and lamifiban). These agents mimic the arginine-lysine-aspartic acid (RGD) sequence on fibrinogen to inhibit the platelet GPIIb/IIIa receptor (34,35).
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Clinical experience with GPIIb/IIIa receptor inhibitors
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Glycoprotein IIb/IIIa inhibitors have been shown to inhibit platelets, increase resolution of coronary thrombus, improve coronary flow and prevent early recurrent ischemic events (MI, refractory ischemia or urgent revascularization) (34–42).
Percutaneous coronary intervention.
Numerous trials have shown that GPIIb/IIIa receptor blockers are beneficial when used in a wide spectrum of patients undergoing percutaneous coronary intervention (PCI), and these agents have been previously reviewed (38–40). The most recent data in PCI come from the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT) trial, which found that the addition of abciximab led to a >50% reduction in death, MI and urgent revascularization at 30 days, an absolute reduction of 5.5% (41). Furthermore, one-year mortality was reduced by abciximab among patients who received a stent: 1% versus 2.4% for patients with versus without abciximab (p = 0.037) (39). One recent meta-analysis of the 10 large studies showed a 22% reduction in death and MI at 30 days (40), whereas another showed a 30% reduction in mortality with abciximab (p = 0.016) (43). Long-term follow-up is available from one abciximab trial, and it suggests that benefits are sustained up to three years (44).
Unstable angina and non–ST segment elevation MI.
Tirofiban and eptifibatide are the two GPIIb/IIIa inhibitors approved by the Food and Drug Administration for use in patients with unstable angina or non–ST segment elevation MI. Tirofiban plus heparin and aspirin reduced the rate of death, MI or refractory ischemia at seven days by 32% (p = 0.004) as compared with heparin alone (35). Another trial showed a significant reduction (p = 0.04) in the risk of death or MI at 30 days with eptifibatide as compared with placebo (34). Abciximab is approved for use in patients with refractory unstable angina in whom PCI is planned within 24 h. Currently, two large phase III trials are being conducted in this group of patients testing abciximab and lamifiban.
New paradigm for benefit of GPIIb/IIIa inhibitors.
New data from two trials show that the addition of the GPIIb/IIIa inhibitor reduces the amount of coronary thrombus (36,37) and improves coronary flow (37). There is now a paradigm shift in the understanding of the benefit of GPIIb/IIIa inhibitors (Fig. 4): these agents inhibit platelets, increase resolution of coronary thrombus, improve coronary flow, enhance myocardial perfusion (45,46) and prevent early recurrent ischemic events (MI, refractory ischemia or urgent revascularization) (41,42,44–47). Finally, new data suggest that these benefits translate into a late mortality benefit (43).
Adjunct to PCI in ST segment elevation MI.
There is growing experience with the use of GPIIb/IIIa receptor inhibitors in patients with acute ST segment elevation MI who undergo PCI. After promising results in an acute MI subgroup of the Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial (48), there have now been three trials showing that abciximab reduces the rate of death, MI or urgent revascularization by 50% (46,49,50). In the setting of rescue PCI, preliminary data analysis from the GUSTO-III trial showed a reduction in the 30-day mortality rate in a nonrandomized comparison of those who received abciximab versus those who did not (3.7% vs. 9.8%, p = 0.04) (51).
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Combining GPIIb/IIIa inhibitors with thrombolytic therapy
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Combining GPIIb/IIIa inhibitors with thrombolytic therapy for acute ST segment elevation MI to accelerate reperfusion time and reduce the risk of reocclusion is the subject of active investigation (52–58).
Full-dose thrombolysis plus GPIIb/IIIa inhibition.
In the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-8) study, patients received incremental doses of m7E3, a murine monoclonal antibody to the GPIIb/IIIa receptor, after receiving t-PA plus heparin and aspirin. A consistent m7E3 dose-dependent decrease in platelet aggregation was observed and a relationship between receptor occupancy and extent of platelet inhibition was established. A dose that achieved 80% to 90% platelet inhibition was identified. The rate of major hemorrhage was not increased (53).
In the Integrilin to Manage Platelet Aggregation to prevent Coronary Thrombosis (IMPACT) trial (n = 132), patients received simultaneous eptifibatide and t-PA. Patients who received eptifibatide at the highest dosage showed a significantly increased rate of TIMI flow grade 3 in the IRA at 90 min (66% vs. 39% in the placebo group, p = 0.006). No differences were seen in the rates of major or minor bleeding complications, including ICH (54). However, dosages of eptifibatide used were later found to achieve only 50% to 60% platelet inhibition.
A subsequent trial combined full-dose streptokinase with higher dosages of eptifibatide without heparin in patients (n = 181) with AMI (55). TIMI flow grade 3 at 90 min was achieved in 44% to 53% of patients randomized to the three dosage levels of eptifibatide, as compared with 38% of those in the placebo group. An increased incidence of bleeding, most often at the site of arterial puncture, was associated with increasing dosages of continuous infusion eptifibatide. There were no occurrences of ICH; however, a 15% rate of severe bleeding in patients who received the highest dose of eptifibatide led to premature discontinuation of that arm.
The Platelet Aggregation Receptor Antagonist Dose Investigation for reperfusion Gain in Myocardial infarction (PARADIGM) trial compared different lamifiban dosage levels to placebo in patients presenting within 12 h of AMI symptom onset. Patients received aspirin, heparin and either t-PA or streptokinase at standard dosages (56). Lamifiban was associated with improved myocardial reperfusion as measured by early resolution of ST segment elevation. However, no difference in the composite clinical end point was noted. Lamifiban was associated with increased rates of major bleeding.
Reduced-dose thrombolysis plus GPIIb/IIIa inhibition.
The TIMI-14 trial tested the combination of reduced-dose thrombolysis (using t-PA, streptokinase and r-PA) and abciximab. In the first phase, 888 patients with MI with ST segment elevation were randomized within 12 h of symptom onset to one of four reperfusion regimens (each encompassing several dosage levels): front-loaded t-PA alone (control arm), reduced-dose t-PA plus abciximab, reduced-dose streptokinase plus abciximab or abciximab alone. All patients received aspirin and heparin. The initial heparin dose was a 70 U/kg bolus with a 15 U/kg per h infusion in the t-PA control arm and a 60 U/kg bolus with a 7 U/kg per h infusion in the arms that included abciximab.
Abciximab alone produced TIMI flow grade 3 at 90 min in 32% of patients and 90-min patency in 48% of patients, comparable to the rates reported for streptokinase (without GPIIb/IIIa inhibition), as reported in the TIMI-I and GUSTO-I trials (1,16). In TIMI-14, the combination of increasing doses of streptokinase and abciximab produced only modest improvement in early TIMI flow grade 3 (34% to 46%). The 1.5 MU streptokinase regimen plus abciximab was discontinued after four of six patients developed a major hemorrhage, one of whom developed an ICH.
The 50-mg dose of t-PA (15-mg bolus and 35-mg infusion over 60 min) achieved substantial improvement in TIMI grade 3 flow: 77% at 90 min as compared with 62% for t-PA alone (p = 0.01) (Fig. 5) (57). Overall patency at 90 min was achieved in 94% of patients with the combination of abciximab plus t-PA as compared with 78% for t-PA alone. An even greater difference was observed at 60 min when adding GPIIb/IIIa inhibition: the standard t-PA dose achieved only 43% TIMI flow grade 3 at 60 min as compared with 72% for 50 mg of t-PA plus abciximab (p = 0.0009). Overall patency at just 60 min was achieved in 91% of patients with the combination of abciximab and t-PA as compared with 70% for t-PA. Myocardial perfusion as assessed by ST segment resolution was also significantly improved by the combination (45). Major hemorrhage was similar among the t-PA plus abciximab and control groups, 6% in each. In-hospital mortality was similar in all groups, ranging from 3% to 5%. It appears from TIMI-14 that the combination of GPIIb/IIIa inhibition with reduced-dose thrombolytic therapy is a promising new regimen for enhancing both the speed and extent of reperfusion in acute ST segment elevation in MI.
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Figure 5 Results from the Thrombolysis in Myocardial Infarction (TIMI) 14 trial. Comparison of 90-min accelerated tissue-type plasminogen activator (t-PA) with combination therapy using abciximab (abcix) and reduced-dose t-PA (15-mg bolus and 35-mg infusion over 60 min) (t-PA = tissue-type plasminogen activator). (Data from Antman et al. [57].)
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Preliminary results from the r-PA phase of TIMI-14 and from the Strategies for Patency Enhancement in the Emergency Department, a pilot study for GUSTO-IV–AMI, have shown similar promising results using abciximab plus a double bolus of reduced-dose r-PA (5 + 5 U). Preliminary results from the latter trial show that TIMI flow grade 3 at 60 to 90 min was achieved in 63% of patients (58). Additional angiographic trials with other GPIIb/IIIa inhibitors and large phase III trials are underway or being planned. It is hoped these trials will help define a new era of myocardial reperfusion therapy of "true thrombolysis"—that is, lysis and inhibition of the fibrin, thrombin and platelet components of occlusive thrombi.
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Safety issues
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One of the main concerns in considering combination therapy of a potent fibrinolytic agent and a potent antiplatelet agent is bleeding, in particular, ICH (59). The review of three randomized trials shows that GPIIb/IIIa inhibitors produce no increase in ICH (60). Accumulated experience with GPIIb/IIIa receptor inhibitors has shown a very low associated incidence of ICH, from 0.09% to 0.2% (34,35,41,42,44,60–62). Therefore, one potential advantage of combining reduced-dose fibrinolytic therapy plus a GPIIb/IIIa receptor inhibitor and low-dose heparin is a lower risk of ICH than found with current regimens.
Conclusions.
There is a strong rationale, both clinical and physiologic, for combining the potent GPIIb/IIIa receptor inhibitors with fibrinolytic agents in acute ST segment elevation MI: 1) current therapies need enhancement to achieve early reperfusion and decreased risk of reocclusion; 2) fibrinolytic and anticoagulant agents affect only fibrin and thrombin; and 3) GPIIb/IIIa receptor inhibitors have been shown to improve outcomes with a very low rate of ICH in acute coronary syndromes and PCI.
Results observed in dose-ranging trials suggest that combination therapy with reduced-dose fibrinolytic therapy, GPIIb/IIIa inhibitors, aspirin and low-dose heparin appears to be a promising and, in general, safe new strategy to improve true "thrombolysis." Whether the combination also improves clinical outcomes as compared with current standard regimens must be addressed further in large-scale randomized trials. Other issues that await exploration include the relative contributions of other antithrombins with GPIIb/IIIa inhibitors, the cost-effectiveness of adding GPIIb/IIIa inhibitors to thrombolytic therapy and the potential role of GPIIb/IIIa inhibition in facilitating early PCI post-thrombolysis in this era of "super-aggressive" management of acute MI.
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Abstract
Thrombolytic resistance