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- ↵*Reprint requests and correspondence:
Dr. Daniel I. Simon, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Tower 3, Boston, Massachusetts 02115, USA.
“Since the amount of potentially salvageable myocardium progressively decreases as the period of ischemia is prolonged, time is the most critical variable involved in delaying or preventing ischemic myocardial cell death.” —Reimer and co-workers, 1977 (1)
“Time is on my side, yes it is” —Mick Jagger, Rolling Stones, 12 x 5 album, 1964
Time remains the most daunting obstacle in improving clinical outcomes in the treatment of acute ST-segment elevation myocardial infarction (STEMI). Since the landmark angiographic trial of DeWood et al. (2)demonstrating that STEMI is caused by thrombotic occlusion of the infarct-related artery, pharmacologic and mechanical reperfusion strategies have been focused on salvaging ischemic but viable myocardium and, thereby, preserving left ventricular function. Fibrinolytic therapy saves 39 lives per 1,000 patients treated in the first hour, compared with fewer than 7 lives saved per 1,000 patients treated 13 to 24 h after the onset of chest pain (3). Time-dependent efficacy is also observed for primary percutaneous coronary intervention (PCI) for STEMI, with mortality increasing by 61% as door-to-balloon time advances from 0 to 60 min to >180 min (4).
Primary PCI has been adopted as the preferred initial reperfusion strategy at many institutions on the basis of clinical trial data showing early and rapid infarct-related artery patency with >90% technical success and in-hospital mortality rates <7%. An overview of 23 head-to-head randomized trials (5), which together randomly assigned 7,739 fibrinolytic-eligible patients with STEMI to primary PCI (balloon angioplasty or stenting) or fibrinolytic therapy, showed that primary percutaneous transluminal coronary angioplasty was superior to fibrinolytic therapy at reducing short-term death (7% vs. 9%, p = 0.0002), non-fatal re-infarction (3% vs. 7%, p < 0.0001), stroke (1% vs. 2%, p = 0.0004), and the combined end point of death, non-fatal re-infarction, and stroke (8% vs. 14%, p < 0.0001). The results seen with primary PCI remained better than those with fibrinolytic therapy during long-term follow-up, independent of the type of fibrinolytic agent used and whether or not the patient was transferred for primary PCI. This overview suggests that for every 1,000 patients treated with primary angioplasty rather than fibrinolytic therapy, an additional 20 lives are saved, 43 re-infarctions are prevented, 10 less strokes occur, and 13 intracranial hemorrhages are prevented.
Although primary PCI is a superior method of reperfusion, its routine use in clinical practice (presently ∼20% of STEMI patients in the U.S.) is limited by lack of availability or unavoidable delays in mobilizing the cardiac catheterization laboratory team. Efforts to improve clinical outcome when timely angioplasty is unavailable have centered on “facilitated angioplasty” or the combination of pharmacologic reperfusion (i.e., fibrinolytic agents and glycoprotein [GP] IIb/IIIa receptor inhibitors alone or in combination) with delayed mechanical revascularization.
Potent antiplatelet agents that block platelet GP IIb/IIIa fibrinogen binding, the final common molecular pathway of platelet aggregation, are effective at reducing major adverse cardiovascular events (MACE) in a wide variety of clinical syndromes. Two pharmacologic strategies have been employed in designing inhibitors of GP IIb/IIIa: blockade with a humanized monoclonal antibody Fab fragment (e.g., abciximab) or inhibition with agents that mimic the physiologic arginine-glycine-aspartic acid ligand-binding sequence of fibrinogen (e.g., eptifibatide and tirofiban). Results from angiographic trials examining combination therapy with abciximab or eptifibatide and reduced dose fibrinolytic agent suggest that they enhance slightly coronary artery patency and improve ST-segment resolution with an acceptable safety profile (6,7). The clinical benefit and safety of abciximab plus reduced dose reteplase compared with full-dose reteplase was tested in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries (GUSTO V) trial (8). No reductions in 30-day or one-year mortality were observed with combination therapy that was associated with an excess of bleeding complications in elderly patients. In contrast, GP IIb/IIIa inhibitors are routinely used in patients undergoing primary PCI for STEMI based on a series of randomized trials with abciximab during PCI of the infarct-related artery with balloon angioplasty or stenting (9–12). Potent platelet inhibition with abciximab is associated with substantial reductions (39% to 55%) in death, re-infarction, and the need for urgent revascularization. The benefits of stenting and abciximab are likely complementary in improving myocardial perfusion as shown in Stent versus Thrombolysis for Occluded coronary arteries in Patients with Acute Myocardial Infarction (STOPAMI)-2, which demonstrated superior infarct salvage with stenting plus abciximab compared with alteplase plus abciximab (13).
Emerging experimental and clinical evidence has suggested that initiating GP IIb/IIIa blockade earlier in the course of STEMI therapy may have significant benefits with respect to enhancing the speed and effectiveness of reperfusion. The rationale for this approach, first proposed by Gold et al. in 1997 (14), is that coronary thrombus is composed of platelets and fibrin and that it may be possible to initiate coronary reflow without exogenous plasminogen activators by blocking platelet aggregation while fibrin generation is impeded with heparin. In 13 patients with Thrombolysis In Myocardial Infarction (TIMI) 0/1 flow grade studied during primary angioplasty for STEMI, intravenous abciximab increased average TIMI flow grade from 0.31 ± 0.5 to 1.54 ± 0.8, with 54% of patients reaching TIMI 2 or 3 flow grade. The TIMI 14 trial (7)and Strategies for Patency Enhancement in the Emergency Department (SPEED) (6)have expanded these angiographic analyses in randomized, multicenter trials and reported that treatment with aspirin, heparin, and abciximab is associated with 90-min TIMI 3 flow grade rates of 32% and 27%, respectively, compared with expected TIMI 3 flow grade rate of approximately 8% with aspirin and heparin alone (15).
The ability of GP IIb/IIIa inhibitors to prevent fibrinogen binding to activated platelets suggests that they may also promote dissolution of platelet-rich thrombi. In this issue of the Journal, Goto et al. (16)provide additional support for this approach by showing that these agents promote the disaggregation of platelet thrombi induced by collagen and shear. The addition of GP IIb/IIIa blockers to whole blood under dynamic flow conditions reduced platelet thrombus volume by >75%. Previous in vitro studies indicate that abciximab as well as eptifibatide and tirofiban reverse platelet aggregation and are capable of dispersing aggregates to single cells in a dose-dependent manner (17,18), in part by displacing fibrinogen from activated GP IIb/IIIa receptors and/or by altering fibrin exposure and susceptibility to plasmin-mediated fibrinolysis.
Results of the Tirofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot study (19)suggest that early administration of tirofiban in the emergency room rather than later in the catheterization laboratory improves angiographic outcomes (TIMI flow grade, TIMI frame count, and TIMI flow grade myocardial perfusion). The effects of early GP IIb/IIIa use on 30-day major adverse cardiac events are being actively explored in the TIMI 34/Treat with Integrilin to Improve Angiographic Outcomes (TITAN) trial.
The in vitro observations of Marciniak et al. (17)indicate that complete dispersion of platelet aggregates back to single platelets requires a relatively high concentration of abciximab (6.25 μg/ml), raising the possibility that local administration (i.e., intracoronary) might be more efficacious than intravenous administration in clinical settings. Indeed, a recent study in 403 consecutive patients with STEMI or unstable angina undergoing PCI examined whether intracoronary bolus administration of abciximab is associated with a reduced MACE rate compared with standard intravenous administration (20). At 30 days, MACE was significantly lower in patients receiving intracoronary abciximab (10.2% vs. 20.2%, p < 0.008). A smaller study suggests that the intracoronary administration decreases angiographic thrombus at the culprit lesion and/or in the distal microcirculation (21).
Facilitated angioplasty trials combining GP IIb/IIIa antagonists, low-molecular-weight heparin, bivalirudin, and/or reduced dose fibrinolytic agents with mandated or rescue angioplasty are actively enrolling patients to determine the optimal pharmacologic and mechanical revascularization strategies. Rapid upstream treatment will allow us to heartily join in with Mick Jagger and the Rolling Stones, “Time is on [our] side, yes it is!”
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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