Antagonists of platelet glycoprotein IIb/IIIa (abciximab, tirofiban, eptifibatide) have now an approved role in reducing the extent of thrombotic complications leading to myocardial damage during percutaneous coronary interventions (PCI). This effect likely here translates into a long-term survival benefit. However, the question of their usefulness in different clinical scenarios (stable or unstable coronary disease, without PCI) has not been fully answered on the basis of considerations of dosing and cost-effectiveness. These agents seem most useful in high-risk patients with unstable coronary syndromes especially in the presence of co-morbidities such as diabetes or renal insufficiency. This article summarizes reasons for the ongoing debate on their efficacy and highlights areas of uncertainty.
Platelet adhesion is triggered by damage to the vessel wall and local exposure of the subendothelial matrix. Coverage of the exposed site by platelets depends on the recognition of adhesive proteins by specific platelet-membrane glycoproteins (GP), most being integrins. 1 The integrin family consists of heterodimeric molecules composed of a series of α and β subunits: α2β1 (GP Ia/IIa), α5β1 (GP Ic/IIa), α6β1, αIIbβ3 (GP IIb/IIIa), αvβ3. The GP IIb/IIIa (αIIbβ3) integrin receptor is the pivotal mediator of platelet aggregation, but has a secondary role also in platelet adhesion; it becomes abundant on the platelet surface, in the active form, when platelets are activated by a variety of agonists (ie, thrombin, ADP, collagen, thromboxane A2, and serotonin). 2 The binding of fibrinogen and other adhesive proteins, such as von Willebrand factor, by means of GP IIb/IIIa receptor on adjacent platelets allows the first formation of a platelet thrombus, and can be effectively attenuated by GP IIb/IIIa antagonists. 3,4
In percutaneous coronary interventions (PCI), the use of GP IIb/IIIa antagonists has been associated with a uniform reduction of ischemic events in several trials. However their use in acute coronary syndromes (ACS) without ST-segment elevation (ie, the combination of unstable angina and non-ST segment elevation acute myocardial infarction (NSTEMI) (otherwise collectively termed “unstable coronary syndromes”)) is a mix of lights and shadows. These uncertainties cause substantial differences in patient treatment according to the type of hospital and geographical location. 5,6 For example, in the Global Registry of Acute Coronary Events (GRACE), which collected data from 95 hospital in 14 countries, contrary to the use of aspirin, which was similar across all hospital types and geographical regions, the use of GP IIb/IIIa inhibitors and of PCI was significantly higher in teaching hospitals compared with non-teaching hospitals (19% vs. 11% and 33% vs. 19%, respectively, P < 0.01 for both comparisons) and was also substantially higher in the United States compared with Europe (32% vs. 14% and 38% vs. 29%, respectively, P < 0.001). 5 During the duration of the registry (July 1999–December 2001), the presentation and publication of major international guidelines was not associated with a measurable change in the pattern of practice. 7
In a spontaneous observational registry of patients hospitalized in the United States, GP IIb/IIIa inhibitors were administered only to a 25% of the 60,770 eligible patients admitted for NSTEMI. 8 Treated patients had lower unadjusted in-hospital mortality compared with untreated patients (3.3% vs. 9.6%, P < 0.0001) and were more likely to undergo PCI (45% vs. 15%, P < 0.0001). The survival benefit conferred by early GP IIb/IIIa inhibition was consistent even after adjustment for patient risk, treatment propensity, and hospital characteristics.
GP IIb/IIIa blockers are however expensive and potentially harmful agents, and the benefit/risk ratio associated with their use needs to be carefully evaluated. We will herein review the evidence for the benefit of such drugs in unstable coronary syndromes with or without PCI, aiming at reaching conclusions about current indications, the solidity of their basis, and areas where further research is needed. This article will deliberately not address the use of these drugs in ST-segment elevation acute myocardial infarction (MI), where controversy still exists on dosages and on the usefulness of combination with other drugs and the different types of revascularization strategies currently possible.
From the Institute of Cardiology and Center of Excellence on Aging, “G. d'Annunzio” University, Chieti, Italy.
Received for publication November 5, 2003; accepted January 5, 2004.
Reprints: Dr. Marco Zimarino, Institute of Cardiology, “G. D'Annunzio” University Chieti, C/o Ospedale S. Camillo de Lellis, Via Forlanini, 50 66100 Chieti, Italy (e-mail: firstname.lastname@example.org).
CHARACTERISTICS OF INTRAVENOUS GLYCOPROTEIN IIb/IIIa ANTAGONISTS
Three agents are currently approved for clinical use: abciximab, eptifibatide, and tirofiban. Abciximab is a derivative of a monoclonal antibody with ≥47,000 days molecular weight and high avidity for the receptor, to which it “binds and sticks”, independent of the fall of plasma concentrations. 3,9 Subsequent to its relatively specific binding to platelets, a very slow recovery of platelet function, requiring days, occurs. 2 In the possible need of a quick recovery of platelet function, platelet transfusion is needed.
Later developed intravenous small-molecules include the cyclic peptide eptifibatide 10 and 2 peptidomimetics, tirofiban 11 and lamifiban. 12 The development of this last compound has been interrupted. All these synthetic compounds have a low molecular weight (<1000 daltons) and are competitive antagonists, inhibiting platelet function as a function of plasma concentration, and therefore only as long as this remains high. 4 The recovery of platelet function upon discontinuation of these molecules is quick, only requiring few hours. In the need of quickly restoring platelet competence, the simple discontinuation of the infusion will rapidly elute the drug from the target platelet binding sites and suffice, for clinical purposes, to halt hemorrhage.
In addition to these differences, abciximab is not totally specific for GP IIb/IIIa, the expression of which is restricted to platelets, but also binds to at least 2 other integrins, including αVβ3 (the so-called “vitronectin receptor”), expressed in endothelial cells and monocytes, and the leukocyte integrin αMβ2 (MAC-1), one of the main ligands for intercellular adhesion molecule-1 (ICAM-1). 13 This may confer abciximab peculiar pharmacological properties, not shared by eptifibatide and tirofiban. 14
BENEFIT OF GLYCOPROTEIN IIb/IIIa INHIBITORS IN PERCUTANEOUS CORONARY INTERVENTIONS
In the setting of PCI, several controlled trials have been performed testing the hypothesis of a benefit of GP IIb/IIIa antagonists. Abciximab has been tested in the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC), 15 the Evaluation in Percutaneous transluminal coronary angioplasty to Improve Long-term Outcome with abciximab Glycoprotein IIb/IIIa blockade (EPILOG), 16 the C7E3 FAB AntiPlatelet Therapy in Unstable REfractory angina trial (CAPTURE), 17 and the Evaluation of IIb/IIIa Platelet Inhibitor for STENTing (EPISTENT) 18 trials; Integrilin has been used in the Integrilin to Manage Platelet Aggregation to Combat coronary Thrombosis-II (IMPACT II) 19 and the Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor using Integrelin Therapy (ESPRIT) 20 trials; tirofiban has been used in the Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis (RESTORE) trial. 21 All such trials have consistently shown that intravenous GP IIb/IIIa inhibitors, used as adjunctive therapy during PCI, exert a protective effect on 30-day ischemic complications, that are reduced from 16 to 56% compared with placebo (Table 1). Of the 16,770 patients enrolled in these large-scale studies, the most compelling support for GP IIb-IIIa and the largest dataset comes from the abciximab trials. 22,23 Benefit extends to all interventional devices and lesion complexities, 24 the most relevant effect being a reduction in nonfatal MI.
EFFECTS ON GP IIb/IIIa ANTAGONISTS ON MYONECROSIS DURING PERCUTANEOUS INTERVENTIONS
The definition of myocardial infarction (MI) has evolved over the past years: with the availability of novel biomarkers, especially creatine kinase (CK)-MB mass and troponin T and I, myocardial necrosis can now be measured with high levels of sensitivity and specificity, regardless of the clinical presentation and associated ECG findings. 25 Elevation of both CK-MB and troponin T are associated with impaired tissue perfusion after PCI. 26 A peri-procedural release of these markers is more common in the presence of diffuse atherosclerosis, thrombus-containing lesions, and with the use of athero-ablative techniques and stenting. 27 Underlying inflammation and friability of the diseased arterial segment likely play a key favoring or triggering role for the embolization of plaque fragments 28; the putative benefit of GP IIb/IIIa antagonists could stem from protection of the microvasculature as well as from reduction in the microembolization. 29 However, mechanisms other than microembolization may be responsible for quantitatively minor myocardial necrosis following PCI: these include spasm, dissection, and transient occlusion of the target artery or of a side branch. The prognostic implications of these once regarded as minor biomarker “leaks” and now classified as real peri-procedural myocardial infarcts likely depend on the absolute size of the infarction, its effect on left ventricular function, and underlying causes.
A CK-MB more than 3 times the upper normal limit has been recently recommended in the ACC/AHA guidelines as the cut-off level for identifying an MI after PCI. 30 The clinical relevance of previously considered “minor” cellular damage can be assessed only studying large populations with a consistent (>3 years) follow-up. When studies with such characteristics are performed, the clinical relevance of “minor” enzyme leaks seems independent from the mechanism leading to peri-procedural myonecrosis. This issue has been enlightened by a recent report of Ellis et al, 24 showing that, among 8409 patients, the detrimental effect of CK-MB release 1÷5 times normal values became evident only 2 years after PCI. Later on, a 2.0% absolute excess mortality stemmed in these patients at a 4-year follow-up (P = 0.024) when compared with patients without evidence of myocardial necrosis. 31
Due to the extensive documentation of the benefit of stent in reducing both acute and long-term adverse events, most current PCI procedure are performed with stent implantation. 32 Aggressive stenting technique, with high pressure inflation and a device/artery ratio ≥1.2, is associated with a reduced need for repeat revascularization, although at the cost of an increased incidence of myocardial necrosis. 33
The translation of a protective effect of GP IIb-IIIa antagonists on myocardial necrosis into a true survival advantage within single studies has been so far documented only in the EPISTENT trial 34: here mortality at 1 year was 2.4% in patients treated with stent and placebo, and 1.0% in patients treated with stent and abciximab (P = 0.037). These results have been corroborated by a recent meta-analysis by Anderson et al, 23 showing an absolute 0.9%/y reduction in mortality in 5154 patients enrolled in various PCI trials (P = 0.031), and a trend toward a survival advantage among 1764 patients treated with stent and abciximab. It has to be noticed however that the mortality reported in the placebo arms of the PCI trials testing the efficacy of GPIIb-IIIa inhibition seems pessimistic: although comparisons of different trials should be performed with caution, the 1-year mortality rate of 0.9% of the 1653 pooled patients enrolled in the STent Anti-thrombotic Regimen Study (STARS) 35 seems comparable to the 1.0% reported in the stent and abciximab arm of the EPISTENT trial. 34
BENEFIT IN SPECIAL SUBSETS
Since cardiovascular complications of diabetes may be due at least in part to heightened platelet activity, there is a rationale for GP IIb/IIIa blockade having enhanced efficacy among patients with diabetes undergoing PCI. 36 In the EPISTENT Diabetic Substudy, abciximab therapy, irrespective of revascularization strategy (stent or balloon angioplasty), resulted in a significant reduction in the 6-month death or MI rate: this combined end point was 12.7% for stent-placebo, 7.8% for balloon angioplasty–abciximab, and 6.2% for the stent-abciximab group (P = 0.029). 37 Collecting data from 6 large-scale GP IIb/IIIa inhibitor trials, platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days, from 6.2 to 4.6% (P = 0.007) among 6458 patients with diabetes and unstable coronary syndromes. 38 Conversely, 23,072 nondiabetic patients showed no survival benefit. The interaction between platelet GP IIb/IIIa inhibition and the diabetic status was statistically significant (P = 0.036).
Patients with chronic kidney disease have several co-morbidities and experience a reduced survival, mostly attributable to cardiovascular disease; in this setting a “therapeutic nihilism” is often caused by the fear of excess drug toxicity. 39 The use of GP IIb-IIIa antagonists in patients with acute coronary syndromes and a calculated creatinine clearance <60 mL/min, has shown a protective effect on in-hospital mortality. 40 There is still controversy however whether GP IIb-IIIa would increase the likelihood of any or only minor bleedings among patients with chronic renal insufficiency.
Lesions containing a thrombus are associated with ischemic complications during PCI and should theoretically derive maximum benefit from aggressive inhibition of thrombus formation. 41 The addition of tirofiban to heparin reduced the thrombus burden at the site of the culprit lesion and improved distal perfusion in patients with ACS enrolled in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable signs and Symptoms (PRISM-PLUS) trial. 42 Similarly, angiographic resolution of intracoronary thrombus has been documented in patients receiving abciximab for 18 to 24 hours. 43
Rotational atherectomy is used for the treatment of complex lesions, as the rotating burr pulverizes inelastic plaque without damaging elastic tissue; platelet activation by rotablation contributes to the “no-flow” phenomenon, that constitutes a serious complication of this technique 44 (Fig. 1). Pre-treatment with abciximab has been hypothesized to reduce consequences of platelet aggregation induced by burr rotation. 45 This hypothesis has been validated clinically by Koch et al, 46 who documented a reduction in the incidence, extent, and severity of myocardial hypoperfusion during rotational atherectomy among patients treated with peri-procedural abciximab.
In contrast, GP IIb/IIIa receptor blockers do not provide any protection against atheroembolization during PCI of saphenous vein graft disease (Fig. 2). In the Saphenous vein graft Angioplasty Free of Emboli Randomized (SAFER) trial, 47 801 patients were randomized to stenting with or without a distal protection device, while a GP IIb/IIIa was used at the operator's discretion in 61% of cases. When compared with controls, the protection device group had a reduced 30-day adverse event rate, that was significant both with GP IIb/IIIa inhibitors (10% vs. 21%, P = 0.003), and without adjunctive therapy (7% vs. 12%, P = 0.051). In this trial, patients who received GP IIb/IIIa inhibitors had a worse outcome, although a pre-selection bias for a larger use in higher risk subsets must be considered. Roffi et al, 48 pooling data from 5 intravenous GP IIb-IIIa inhibitor trials, showed that 627 patients who underwent graft PCI had a doubled 30-day mortality when compared with 13,158 subjects receiving PCI in the native circulation (2.1% vs. 1.0%, P = 0.006). The use of GP IIb-IIIa inhibitors failed to improve the 30-day outcome, and was actually deleterious, with a trend toward a higher incidence of 6-month ischemic events (39.4% vs. 32.7% in controls, P = 0.07).
GP IIb/IIIa ANTAGONISTS IN TREATMENT OF ACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION OUTSIDE OF THE SETTING OF PERCUTANEOUS CORONARY INTERVENTION
The “timing of injury” concurrent with the time of maximal platelet inhibition distinguishes the PCI trials of glycoprotein IIb/IIIa inhibitors from the trials of these drugs in medically treated non-ST elevation ACS: while the precise time and the degree of vessel injury are known for patients undergoing PCI, these factors are far less predictable, and likely playing a variable role, in patients considered at risk for spontaneous coronary events. 22 Indeed, within the non-ST elevation ACS population, a marked heterogeneity in patient acuity and pathogenetic mechanisms is likely to occur. 49
Up to 1998, intravenous small-molecules had been tested in non-ST elevation ACS in 4 large-scale placebo-controlled trials: tirofiban had been used in the Platelet Receptor Inhibition in ischemic Syndrome Management (PRISM) 50 and the PRISM-PLUS trial 51; Integrilin had been used in the Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial 52; and lamifiban in the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-A 53 trials. Compared with standard therapy, the use of tirofiban was associated with a 4.9% absolute reduction (P = 0.03) of the 30-day occurrence of death or MI in the PRISM-PLUS 51 trial. The use of Integrilin (best treatment group) was consistently associated with a 1.5% absolute reduction in the same end point (P = 0.04) in the PURSUIT 52 trial; this effect was magnified whenever a PCI was performed. To distinguish benefit obtained during medical management from that accrued because of PCI, a meta-analysis was conducted pooling data from CAPTURE, 17 PRISM PLUS, 51 and PURSUIT 52 trials: absolute reductions of 1.3% in the composite end point of death or MI preceding PCI (P = 0.001) and 3.1% in the PCI-related events (P = 0.001) were documented 54 (Fig. 3). Although the authors could identify a significant benefit of GP IIb-IIIa both before and after PCI, the interventional strategy varied substantially among the three studies and does not reflect the current “state-of-the-art”. In the CAPTURE, 17 PRISM-PLUS, 51 and PURSUIT 52 trials, stents were used in 10.5, 20.3, and 50.2% of patients; in the CAPTURE trial 17 all patients were to undergo PCI, while in the others the decision to perform PCI was at the discretion of the treating physician. Irrespective of treatment assignment, the overall procedure-related event rates were higher in stented patients (9.3% versus 5.3% in balloon-treated patients, P < 0.001). Moreover, GP IIb/IIIa blockade benefit on the composite end point was no longer evident after 6 months.
Patients with ACS and high-risk characteristics derive incremental benefit from aggressive drug therapy. Through a retrospective analysis of some of these trials we have learned that elevation of cardiac-specific troponins identifies a population with a higher propensity to atheroembolization and at increased risk of events. 43,55,56 The TIMI risk score, calculated as the sum of seven presenting characteristics (age ≥65 years, ≥3 cardiac risk factors, documented coronary disease, recent severe angina, ST segment deviation, elevated cardiac markers, prior aspirin use) 57 was tested in the PRISM-PLUS population: patients with a score ≥4 derived a greater relative risk reduction with tirofiban (p interaction= 0.025). 58 Therefore it was assumed that most benefit from an aggressive therapy such as GP IIb/IIIa antagonists should be observed in this patient population. Cardiologists' perception on this issue was however shattered by the publication of the single largest phase 3 trial of this kind, the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries-IV in Acute Coronary Syndromes (GUSTO-IV ACS) trial. 59 In this trial, more than 7000 patients were recruited worldwide with criteria which should have a priori indicated a high risk for events ie, either troponin positivity or the presence of ST changes (ST depression), both hallmarks, within unstable coronary syndromes, of a worse outcome. 60 PCI was explicitly discouraged and only few (<2%) patients underwent PCI within 48 hours. The trial drug was abciximab (ie, the best-performing drug in the setting of PCI). Contrary to the usual 12-hour duration of abciximab infusion previously used in most trials, 15,16,18 the drug regimens tested included either a 24-hour infusion, similar to the CAPTURE trial, 17 or a 48-hour infusion. The results were unexpected. Abciximab given for 24 hours was superimposable to placebo in the combined end point of death and myocardial infarction at 30 days (8.2% vs. 8.0%, P = NS), while the 48-hour infusion actually had a trend to do worse (9.1%, P = 0.19). When compared with the low mortality obtained with placebo (0.3%), an even worse outcome was reported with 24 and 48 hours infusion in the first 2 days after randomization (0.7%, P = 0.048 and 0.9%, P = 0.007, respectively). Subgroup analysis did not indicate any particular group of patients who could benefit from treatment. Therefore, the most effective intravenous GPIIb/IIIa inhibitor in the setting of PCI was at least non-effective (and possibly deleterious) in a purely medical setting. Various interpretations are possible. Probably there was an insufficient level of IIb/IIIa inhibition throughout the 24 and, even more, the 48 hours infusion; however in the GUSTO IV, the bedside monitoring of platelet function in a subset of patients shows that three fourths of patients had more than 80% inhibition of platelet aggregation at 24 hours. Was the study underpowered because of the lower event rate occurring in the placebo group? It is true that the observed event rate was only 8%, much lower than the expected rate of 11%, but the results were not substantially changed when a lower CK-MB threshold was used to define myocardial infarction. 59 Since the GP IIb/IIIa inhibitor with the largest evidence of benefit in the setting of PCI did nothing, or was possibly harmful, in a purely medical setting, it is not surprising that a wave of skepticism pervaded the cardiological community about the use of any GP IIb/IIIa inhibitor in the scenario of a purely medical treatment of unstable coronary syndromes. Much of the discussion was whether GUSTO-IV ACS is by itself a uniquely negative trial, whether the study drug (abciximab) is the wrong drug in those conditions, or whether all GP IIb/IIIa antagonists are actually not beneficial in this scenario.
Since most trials in non-ST elevation ACS were powered for the detection of at least a 20% risk reduction, but underpowered for more modest—yet clinically relevant—effects, Boersma et al 61 conducted a meta-analysis of all the ACS trials in which early (<48 hours) revascularization was discouraged. Data from 31,402 patients enrolled in the PRISM, 50 PRISM-PLUS, 51 PARAGON-A, 53 PURSUIT, 52 PARAGON-B, 62 and GUSTO-IV ACS 59 trials were analyzed. Despite the inclusion of trials with “negative” results, a significant 1% absolute reduction in the 30-day occurrence of death or myocardial infarction was identified with GP IIb/IIIa inhibitors compared with controls (P = 0.015). Although the aim of identifying “some” significant benefit from trials judged “inconclusive” was reached, several ancillary results were contradictory. Even after pooling data on over 30,000 patients, neither death nor acute myocardial infarction, taken in isolation, were significantly reduced at 30 days. There was no convincing evidence that the presence of ST segment depression on the electrocardiogram (or other features of “high risk of events”) might help identify patients who may derive an advantage with the use of these drugs. Strangely, benefit was more evident among patients without ST modifications and with lower levels of CK-MB.
Among the analyzed safety end points, major bleeding complications were in any case significantly increased by GP IIb/IIIa inhibitors (1.0% absolute increase, P < 0.0001), although intracranial hemorrhage (present in 0.08% of the entire population), was not associated with the use of GP IIb/IIIa inhibitors.
GP IIb/IIIa inhibition exerts a protective effect against myocardial damage during PCI that seems to translate into a survival benefit. The efficacy of these drugs is incontrovertible in patients with a high propensity to atheroembolization (complex PCI) and with conditions that identify an increased risk of events (high-risk acute coronary syndromes, diabetes, and chronic renal dysfunction).
In patients with a low-risk or those patients who are not candidates for prompt revascularization, the benefit seems inconsistent.
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