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Journal of the American College of Cardiology © 2000 by the American College of Cardiology Published by Elsevier Science Inc. Vol. 35, No. 5, 2000 ISSN 0735-1097/00/$20.00 PII S0735-1097(00)00554-4 REVIEW ARTICLE Platelet Glycoprotein IIb/IIIa Receptor Blockade in Coronary Artery Disease A. Michael Lincoff, MD, FACC,* Robert M. Califf, MD, FACC,† Eric J. Topol, MD, FACC* Cleveland, Ohio and Durham, North Carolina New strategies for profound inhibition of platelet activity at the injured coronary plaque focus on blockade of the platelet surface membrane glycoprotein IIb/IIIa receptor, which binds circulating fibrinogen or von Willebrand factor and crosslinks platelets as the final common pathway to platelet aggregation. Intravenous agents directed against this receptor include the chimeric monoclonal antibody fragment abciximab, the peptide inhibitor eptifibatide and nonpeptide mimetics tirofiban and lamifiban. Over 33,000 patients have been evaluated in 11 large-scale, placebo-controlled trials of these agents. During percutaneous coronary intervention, an absolute reduction of 1.5% to 6.5% in the 30-day risk of death, myocardial infarction or repeat urgent revascularization has been observed, with some variability in treatment effect among the agents tested (abciximab, eptifibatide and tirofiban). Treatment effect is achieved early with every modality of revascularization and is maintained over the long-term (up to three years). Increased bleeding risk may be minimized by reduction and weight-adjustment of concomitant heparin dosing. In the acute coronary syndromes without ST segment elevation, absolute 1.5% to 3.2% reductions in 30-day rates of death or myocardial (re-) infarction have been achieved with two to four day courses of eptifibatide or tirofiban. Clinical benefit accrues during the period of drug infusion and is durable. Treatment effect may be enhanced among patients undergoing early coronary revascularization, with evidence of stabilization before intervention and suppression of postprocedural ischemic events. Thus, blockade of the platelet glycoprotein IIb/IIIa receptor reduces ischemic complications when used as an adjunct to percutaneous coronary intervention or the management of acute ischemic syndromes. (J Am Coll Cardiol 2000;35:1103–15) © 2000 by the American College of Cardiology Plaque fissure is a key initiating component in the pathogenesis of unstable angina (1,2) and the ischemic complications of percutaneous coronary revascularization (3,4). The central role of platelet activity in these settings is highlighted by consistent clinical benefit derived from aspirin therapy (5–10). Newer strategies for more profound platelet inhibition at the injured coronary plaque focus on the integrin glycoprotein IIb/IIIa receptor (alphaIIbbeta3) on the platelet surface membrane, which binds circulating fibrinogen or von Willebrand factor and cross-link platelets as the final common pathway to platelet aggregation (11). Pharmacologic compounds directed against glycoprotein IIb/IIIa block this receptor, prevent binding of adhesion molecules and potently inhibit platelet aggregation (12). Three intravenous IIb/IIIa receptor antagonists are ap- From the *Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio and the †Duke Clinical Research Institute, Duke University, Durham, North Carolina. The authors have received research grant support for clinical trials in this field sponsored by Centocor, Inc. (Malvern, Pennsylvania), Eli Lilly and Company (Indianapolis, Indiana), COR Therapeutics (South San Francisco, California), Schering-Plough (Kenilworth, New Jersey), Hoffmann LaRoche (Basel, Switzerland) and Merck (White House Station, New Jersey). Manuscript received July 1, 1999; revised manuscript received November 9, 1999, accepted January 5, 2000. proved for clinical use, and this class of therapy has, thus, entered the pharmacologic armamentarium of physicians providing care to a broad spectrum of patients with cardiovascular disease. This review is a systematic overview of the efficacy and safety of the intravenous IIb/IIIa receptor antagonists in the approved clinical settings of percutaneous coronary revascularization and unstable ischemic syndromes, providing practical guidelines based upon randomized trial data for patient selection, choice of agent and clinical use. THE AGENTS Four intravenous glycoprotein IIb/IIIa antagonists have undergone large-scale trial evaluation in the settings of percutaneous coronary revascularization or unstable ischemic syndromes (Table 1). Abciximab (c7E3 Fab, ReoPro, Centocor, Malvern, Pennsylvania) is a human-murine chimeric monoclonal antibody fragment that binds with high affinity for and a slow dissociation rate from the glycoprotein IIb/IIIa receptor (13,14). Abciximab is cleared rapidly from the plasma (15) but is detectable bound to circulating platelets for at least 21 days (16). Abciximab is not specific for the platelet glycoprotein IIb/IIIa receptor; this agent has 1104 Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade JACC Vol. 35, No. 5, 2000 April 2000:1103–15 equal affinity for the vitronectin receptor (alphavbeta3), which plays a role in cell adhesion, migration and proliferation. Eptifibatide (Integrilin, COR Therapeutics, South San Francisco, California), a cyclic heptapeptide based upon the Lys-Gly-Asp (KGD) amino acid sequence, tirofiban (Aggrastat, Merck, White House Station, New Jersey), a tyrosine-derivative nonpeptide mimetic and lamifiban (Ro 44-9883, Hoffman-La Roche, Basel, Switzerland), another nonpeptide mimetic, are highly-specific competitive inhibitors of the glycoprotein IIb/IIIa complex with rapidly reversible pharmacodynamics and short (2 to 2.5 h) plasma half-lives (17–19). Abciximab has been available for clinical use since 1995; eptifibatide and tirofiban were approved in 1998. Platelet aggregation is inhibited by these agents in a dose-related manner, with nearly complete abolition of platelet thrombosis at levels of receptor occupancy ⬎80% (14). After discontinuation of abciximab, platelet aggregation returns toward baseline over the subsequent 12 to 36 h (14); normalization of platelet function occurs much more quickly (over 30 min to 4 h) after discontinuation of the reversible inhibitors (17,18). Abbreviations and Acronyms CAPTURE ⫽ C7E3 AntiPlatelet Therapy in Unstable REfractory angina EPIC ⫽ Evaluation of c7E3 for Prevention of Ischemic Complications EPILOG ⫽ Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade EPISTENT ⫽ Evaluation of Platelet Inhibition in STENTing HACA ⫽ human antichimeric antibody IMPACT II ⫽ Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II MI ⫽ myocardial infarction PARAGON ⫽ Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome events in the Global Organization Network PRISM ⫽ Platelet Receptor Inhibition in Ischemic Syndrome Management PRISM PLUS ⫽ Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs PURSUIT ⫽ Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy RAPPORT ⫽ ReoPro And Primary PTCA Organization and Randomized Trial RESTORE ⫽ Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis TRIALS OF PERCUTANEOUS CORONARY REVASCULARIZATION The role of periprocedural glycoprotein IIb/IIIa inhibition in the setting of percutaneous coronary revascularization was established by seven randomized, placebo-controlled trials enrolling, in total, over 15,000 patients (Table 2) Table 1. Intravenous Glycoprotein IIb/IIIa Receptor Antagonists Brand name Structure Molecular weight (kD) Plasma half-life Excretion Approved indications* Approved dose* Abciximab Eptifibatide Tirofiban Lamifiban ReoPro Antibody Fab fragment 47.6 10–30 min Unknown PCI Integrilin Cyclic heptapeptide 0.832 ⬃2.5 h ⬃50% renal ACS (unstable angina and non-Q wave MI) PCI Aggrastat Nonpeptide 0.495 ⬃2 h 39–69% renal ACS (unstable angina and non-Q wave MI) — Nonpeptide 0.468 ⬃2 h 90% renal Not approved For ACS: 180 g/kg bolus, 2.0 g/kg-min infusion ⫻ 72–96 h (PURSUIT dose) †For PCI: 135 g/kg bolus, 0.5 g/kg-min infusion for 20–24 h (IMPACT II dose) For ACS: 0.4 g/kg-min ⫻ 30 min, then 0.1 g/ kg-min ⫻ 48–108 h Not approved Refractory unstable angina when PCI is planned within 24 h For PCI: 0.25 mg/kg bolus, 0.125 g/kgmin (max 10 g/min) infusion ⫻ 12 h †For unstable angina: 0.25 mg/kg bolus, 10 g/min infusion ⫻ 18–24 h before PCI, continued 1 h after PCI ACS ⫽ acute coronary syndromes; IMPACT II ⫽ Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II; kD ⫽ kilodalton; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention; PURSUIT ⫽ Platelet IIa/IIIb in Unstable angina: Receptor Supression Using Integrilin Therapy. *Approved indications and approved dose according to label of United States Food and Drug Administration (FDA); †FDA approved dose for indication, but may not be optimal (see text). For abciximab in unstable angina, an infusion of 12 h after PCI is recommended. For eptifibatide during PCI, the PURSUIT dose of 180 g/kg bolus and 2.0 g/kg-min infusion is recommended. Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade JACC Vol. 35, No. 5, 2000 April 2000:1103–15 1105 Table 2. Randomized Interventional Trials—Patient Populations Agent Tested Trial Number of Patients Enrollment Period abciximab EPIC 2,099 11/91–11/92 abciximab EPILOG 2,792 2/95–12/95 abciximab EPISTENT 2,399 7/96–9/97 eptifibatide tirofiban IMPACT II RESTORE 4,010 2,139 11/93–11/94 1/95–12/95 abciximab CAPTURE 1,265 5/93–12/95 abciximab RAPPORT 483 11/95–2/97 Entry Criteria High risk PTCA or DCA: Acute MI — within 12 h (direct or rescue PTCA) Recent MI — within prior 7 days Unstable angina — within 24 h of chest pain (rest or postinfarction angina with ischemic ECG changes) Clinical-morphologic criteria (ACC/AHA lesion score B2 or C, ACC/AHA score B1 with DM or with women of age ⬎65) Urgent or elective PTCA, DCA, TEC or laser: Excluding unstable angina or acute MI (EPIC criteria) within prior 24 h, elective stents, rotational atherectomy Coronary intervention suitable for PTCA or elective stent: Excluding acute MI within 24 h, rotational atherectomy All clinical indications, all approved interventions High risk PTCA or DCA: Acute MI — within 72 h (Q wave or non-Q wave) Unstable angina — within 72 h (chest pain at rest or on minimal effort with ECG changes, hemodynamic changes or angiographic thrombus) Refractory unstable angina: Unstable angina — within 48 h (chest pain with ECG changes) despite IV heparin and nitroglycerin Primary PTCA for acute ST elevation MI — within 12 h ACC/AHA ⫽ American College of Cardiology/American Heart Association modified lesion complexity score (58); DCA ⫽ directional coronary atherectomy; DM ⫽ diabetes mellitus; ECG ⫽ electrocardiographic; MI ⫽ myocardial infarction; PTCA ⫽ coronary balloon angioplasty; TEC ⫽ transluminal extraction catheter atherectomy. For Trial Acronyms see “Abbreviations and Acronyms.” (20 –26). The efficacy of abciximab in reducing ischemic complications among patients at high risk, a broad spectrum of patients undergoing elective or urgent revascularization and patients suitable for stent implantation was assessed in Evaluation of c7E3 for Prevention of Ischemic Complications (EPIC) (20), Evaluation in PTCA to Improve Longterm Outcome with abciximab GP IIb/IIIa blockade (EPILOG) (21) and Evaluation of Platelet Inhibition in STENTing (EPISTENT) (22), respectively. C7E3 AntiPlatelet Therapy in Unstable REfractory angina (CAPTURE) tested abciximab as treatment before and during angioplasty among patients with refractory unstable angina (25), while ReoPro And Primary PTCA Organization and Randomized Trial (RAPPORT) focused on angioplasty as primary reperfusion therapy for acute myocardial infarction (MI) (26). Eptifibatide was evaluated among all patients undergoing coronary intervention in Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT II) (23). Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis (RESTORE) assessed tirofiban during revascularization for acute ischemic syndromes (24,27). Trial designs. All trials were blinded throughout longterm follow-up. End points were adjudicated by review of primary data by independent blinded clinical events committees, although the level of adjudication varied among the trials. Myocardial infarction was identified by new Q waves or creatine kinase-MB elevations ⱖ3 times the control. Aside from CAPTURE, all trials evaluated a strategy whereby study drug (glycoprotein IIb/IIIa inhibitor or placebo) was administered as a bolus immediately before coronary intervention, followed by infusions of varying durations. The durations of study drug infusion were based, in part, upon pharmacodynamic differences among the agents: 24-h or 36-h infusions of the competitive inhibitors eptifibatide and tirofiban were chosen for the IMPACT II and RESTORE trials, respectively, whereas the slowly reversible abciximab was evaluated with a 12-h infusion. In CAPTURE, study drug was administered for 20 to 24 h before angioplasty and 1 h thereafter. All patients received aspirin. In EPISTENT, patients received ticlopidine for four weeks after stenting, according to contemporary interventional practice (28,29). As described below, excess hemorrhagic risk was observed with abciximab in EPIC, apparently linked to the level of intraprocedural heparin dosing as well as the practice of leaving vascular access sheaths in place with ongoing heparin infusion for the entire 12-h study drug infusion period. A pilot study showed that the blood loss associated with abciximab might be attenuated by weight-adjustment and reduction of heparin doses and by early vascular sheath removal (30). Based upon these findings, the EPILOG trial explicitly tested low-dose versus standard-dose weight- 1106 Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade JACC Vol. 35, No. 5, 2000 April 2000:1103–15 Figure 1. Composite 30-day end point (death, myocardial infarction or urgent repeat revascularization) event rates for the seven glycoprotein IIb/IIIa interventional trials. This was not the prespecified primary end point of RESTORE or RAPPORT. RESTORE trial end points listed here are for the published post-hoc analysis including only urgent repeat revascularization. RESTORE trial end points listed here differ from those of the other trials in that only patients with successful crossing of the lesion with the guidewire were included in the efficacy analysis of RESTORE, whereas all randomized patients were included in the other studies. RAPPORT trial end points listed here are for secondary end point of death, myocardial infarction or urgent repeat target vessel revascularization. *EPISTENT trial groups compared with reference group of Placebo ⫹ Stent; thus, the “placebo control” for the Abciximab ⫹ PTCA group underwent stenting rather than PTCA. B ⫽ bolus; B ⫹ I ⫽ bolus plus infusion; CAPTURE ⫽ C7E3 AntiPlatelet Therapy in Unstable REfractory angina; EPIC ⫽ Evaluation of c7E3 for Prevention of Ischemic Complications; EPILOG ⫽ Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade; EPISTENT ⫽ Evaluation of Platelet Inhibition in STENTing; IMPACT ⫽ Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis; LDH ⫽ low-dose, weight-adjusted heparin; MI ⫽ myocardial infarction; PTCA ⫽ percutaneous transluminal coronary angioplasty; RAPPORT ⫽ ReoPro And Primary PTCA Organization and Randomized Trial; RESTORE ⫽ Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis; SDH ⫽ standard-dose, weight-adjusted heparin; 135/.5 and 135/.75 ⫽ eptifibatide doses: 135 g/kg bolus, followed by infusions of 0.5 or 0.75 g/kg-min. adjusted heparin regimens with abciximab, and the other trials incorporated some form of protocol-directed limitation or weight-adjustment of heparin dosing. Trials after EPIC and CAPTURE recommended that no heparin infusion be administered after the procedure and that vascular sheaths be removed early (usually during study drug infusion). Efficacy. Event rates for the composite 30-day end point of death, MI or urgent repeat revascularization are summarized in Figure 1. In the EPIC (20), EPILOG (21) and EPISTENT trials (22), abciximab therapy was associated with absolute 4.5 to 6.5% reductions in the 30-day composite end point. The magnitude of treatment effect was independent of the modality of revascularization (balloon angioplasty, directional atherectomy or stenting) (22,31). In the specific disease states assessed in CAPTURE (refractory unstable angina) and RAPPORT (acute MI), therapy with abciximab conferred a similar reduction in ischemic end points (absolute 4.6% to 5.4% risk reduction) (25,26). In CAPTURE, clinical benefit from abciximab began to accrue during the pretreatment phase before angioplasty (preprocedural MI rate reduced from 2.1% to 0.6%; p ⫽ 0.029) (25). The IMPACT II and RESTORE trials provided evidence that eptifibatide and tirofiban, respectively, also diminish periprocedural ischemic events, but the magnitude of treatment effect with these agents (absolute 1.5% to 2.5% risk reductions) was less than in the abciximab trials and did not reach conventional levels of statistical significance (23,24). Ischemic events were reduced considerably by eptifibatide or tirofiban at 24 to 48 h, but attenuation of clinical benefit occurred over the subsequent 30 days. Across the interventional trials, the treatment effect of glycoprotein IIb/IIIa blockade was similar for each of the components (death, MI or urgent revascularization) of the 30-day composite end point. Moreover, clinical benefit was generally consistent among all subgroups of patients, although apparently enhanced in certain settings. In particular, the composite end point rate was decreased from 13.1% JACC Vol. 35, No. 5, 2000 April 2000:1103–15 Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade 1107 Figure 2. Composite six-month end point of death or myocardial (re-) infarction event rates for the glycoprotein IIb/IIIa interventional trials. *EPISTENT trial groups compared with reference group of Placebo ⫹ Stent. Abbreviations as in Figure 1. to 3.8% (p ⫽ 0.004) with abciximab (absolute 9.3% risk reduction) among those patients in EPIC with unstable angina and ischemic electrocardiographic changes (32). Rates of death or MI at six months are summarized in Figure 2. The suppression of acute ischemic events achieved within 30 days by glycoprotein IIb/IIIa blockade was maintained without attenuation over the long term (21,23,25–27,33–36). Evidence of long-term suppression of mortality by GP IIb/IIIa blockade has been derived from the three trials that reported results of follow-up at one year or longer: EPIC, EPILOG and EPISTENT. Nonsignificant trends were observed among the overall trial populations in EPIC (8.6% vs. 6.8% at three years, p ⫽ 0.20) and EPILOG (2.6% vs. 1.7% at one year, p ⫽ 0.07) (34,35) although mortality at three years in EPIC was significantly reduced by abciximab from 12.7% to 5.1% (p ⫽ 0.01) among the 555 highest risk patients enrolled with unstable angina or acute MI (34). In the EPISTENT trial, mortality at one year was significantly reduced by 60% with the combination of abciximab with stenting relative to either therapy alone: 1% in the stent plus abciximab group compared with 2.4% in the stent plus placebo group (p ⫽ 0.04) and 2.1% in the balloon angioplasty plus abciximab group (37). In EPIC, therapy with abciximab was associated with a reduction in target vessel revascularization procedures at six months, from 22.3% to 16.5% (p ⫽ 0.007), a finding that led to speculation that this agent may reduce restenosis (33). A significant decrease in the need for late target vessel revascularization procedures was not observed with glyco- protein IIb/IIIa blockade in the subsequent EPILOG trial, however, nor in any of the other balloon angioplasty trials. Yet among patients undergoing elective stenting in EPISTENT, treatment with abciximab was associated with reduction in six-month target vessel revascularization rates from 10.6% to 8.7% (p ⫽ 0.22) and a significant halving of this end point among the prespecified subgroup of patients with diabetes mellitus (16.6% to 8.1%, p ⫽ 0.021) (36). Thus, in the setting of stenting, wherein the processes of recoil and remodeling are not operative and neointimal hyperplasia is the predominant mechanism of luminal renarrowing, abciximab may reduce restenosis, particularly among diabetic patients, who are known to be at elevated risk for this late complication (38). Hemorrhagic risk. The major limitation of abciximab therapy in the first interventional trial, EPIC, was a substantially increased risk of bleeding (Fig. 3) (20). During subsequent trials, in which heparin dosing was limited and vascular sheaths removed early, bleeding rates were diminished in all treatment groups, and no significant increase in hemorrhagic risk was associated with glycoprotein IIb/IIIa therapy. A trend toward lower rates of bleeding in the abciximab groups compared with placebo was observed when the low-dose, weight-adjusted heparin regimen was used (in EPILOG and EPISTENT). The high rates of bleeding in RAPPORT and CAPTURE were likely related to long vascular access sheath dwell times. Rates of intracranial hemorrhage were not increased by glycoprotein IIb/IIIa blockade (39). 1108 Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade JACC Vol. 35, No. 5, 2000 April 2000:1103–15 Figure 3. Rates of in-hospital Thrombolysis in Myocardial Infarction (TIMI) major bleeding in the glycoprotein IIb/IIIa interventional trials. *EPISTENT trial groups compared with reference group of Placebo ⫹ Stent. Major bleeding defined as intracranial hemorrhage or a fall in hemoglobin by ⱖ5 mg/dl (57). Abbreviations as in Figure 1. TRIALS OF UNSTABLE ISCHEMIC SYNDROMES The role of intravenous glycoprotein IIb/IIIa antagonists in the setting of unstable ischemic syndromes, independent of the use of coronary revascularization, was tested among over 18,000 patients in four placebo-controlled trials (40 – 43). These trials focused on patients with unstable symptoms without persistent ST segment elevations, a proportion of whom would subsequently be determined on the basis of cardiac enzyme elevations to have suffered MI. Patients with persistent ST segment elevations suitable for reperfusion therapy were not eligible for enrollment. These studies assessed the competitive reversible inhibitors: eptifibatide in Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) (40), tirofiban in Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs (PRISM PLUS) and Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) (41,42) and lamifiban in Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome events in the Global Organization Network (PARAGON) (43). Trial designs. Entry criteria were comparable, although a lower risk patient population was included in PRISM (Table 3). There were substantial differences among the trials with regard to treatment strategy. Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy was a broad “mega-trial,” assessing eptifibatide superimposed upon the spectrum of different practice patterns throughout the world. Thus, the protocol did not specify pharmacologic therapies aside from the study agent and did not mandate a particular strategy of coronary angiography and revascularization. In contrast, a 48-h study drug pretreatment period was specified in PRISM PLUS, after which catheterization and revascularization were encouraged to be performed while study drug therapy was ongoing. PARAGON and PRISM focused on patients for whom a conservative strategy of medical therapy was planned, and angiography and revascularization during study drug infusion were discouraged. All patients received aspirin. Approaches to heparinization varied. In PURSUIT, treatment with intravenous or subcutaneous heparin was encouraged during study drug infusion. PRISM PLUS and PARAGON explicitly tested the interaction between heparin and glycoprotein IIb/IIIa inhibition, with patients in the active study drug arms (tirofiban or lamifiban) randomized to either heparin or no heparin. PRISM tested the strategy of glycoprotein IIb/IIIa blockade by tirofiban compared with heparinization in lower risk patients. Efficacy. Event rates for the composite and individual end points at various time points are presented in Table 4; the trials are compared on the basis of the 30-day composite of death or MI in Figure 4. As with the interventional trials, ischemic event rates were generally reduced by glycoprotein IIb/IIIa blockade among patients with unstable ischemic syndromes. In PURSUIT, treatment with eptifibatide was associated with absolute 1.2 to 1.5% reductions in the incidence of death or MI at 96 h, seven days, 30 days and six months Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade JACC Vol. 35, No. 5, 2000 April 2000:1103–15 1109 Table 3. Randomized Acute Ischemic Syndrome Trials—Patient Populations Agent Tested Trial Number of Patients Enrollment Period 10,948 11/95–1/97 Eptifibatide PURSUIT Tirofiban PRISM PLUS 1,915 11/94–9/96 Tirofiban PRISM 3,232 3/94–10/96 Lamifiban PARAGON 2,282 8/95–5/96 Entry Criteria CP at rest within 24 h and either: ECG changes (ST depression, T inversion or transient ST elevation) or CK-MB elevation CP at rest or minimal exertion within 12 h and either: ECG changes (ST depression, T inversion or transient ST elevation) or CKMB elevation CP at rest or minimal exertion within 24 h and: ECG changes (ST depression, T inversion or transient ST elevation) or CKMB elevation or history of coronary disease or positive stress test CP at rest within 12 h, and: ECG changes (ST depression, T inversion or transient ST elevation) Angiography and Revascularization Discretion of attending physician Deferred for first 48 h, then performed during study drug infusion Discouraged Discouraged CK-MB ⫽ creatine kinase MB isoenzyme fraction; CP ⫽ chest pain (or ischemic symptoms); ECG ⫽ electrocardiographic. For Trial Acronyms see “Abbreviations and Acronyms.” (40,44). The observed treatment effect varied considerably among the four predefined geographic regions involved in the trial, with the greatest benefit observed in North America (30-day end point reduced from 15.0% to 11.7%). Similarly, although the reduction in ischemic events was equivalent among men and women in North America, no treatment effect was observed for women in other regions of the world. Such geographic variations in outcome have been observed in other international randomized trials (45) and may have been related to substantial differences in patient baseline characteristics and treatment strategies (including the use of heparin and the performance and timing of coronary revascularization). Therapy with tirofiban plus heparin in PRISM PLUS resulted in a significant and durable reduction in ischemic end points as compared with heparin alone (41). The composite end point of death, MI or refractory ischemia was diminished at seven days, with preservation of the absolute treatment effect to 30 days. Death and MI rates were reduced at 30 days (although the p ⫽ 0.03 did not reach the prespecified level of p ⫽ 0.025 for a three group trial) and at six months (absolute 3.0%–3.2% risk reduction). Tirofiban alone (without heparin) was found at the first interim analysis to be associated with an apparent increased risk of death by seven days, leading to early discontinuation of this group and precluding formal comparison of heparin versus no heparin arms. In PRISM, a significant reduction in the composite end point of death, MI or refractory ischemia was observed at the end of study drug infusion (48 h) among patients receiving tirofiban rather than heparin (42). There was a nonsignificant trend toward suppression of this end point, as well as the composite of death or MI, by 30 days. The results of PARAGON differed somewhat from the pattern of efficacy seen in the other three trials (43). By 30 days, there was no significant effect of lamifiban at either dose, with or without heparin, on the incidence of death or MI compared with placebo. Event rates diverged after 30 days, however, and, by six months, there was a significant treatment effect of low-dose lamifiban (⫾ heparin). No influence of heparin on clinical outcome could be discerned. The interaction between glycoprotein IIb/IIIa blockade and coronary revascularization was not tested in a randomized fashion in these trials. In PURSUIT and PRISM PLUS, however, a substantial number of patients underwent percutaneous revascularization during study drug infusion, although selection for these procedures was a postrandomization event and may have been influenced by the occurrence of ischemic end points. Nevertheless, the consistent finding in these two trials, as in CAPTURE, was that glycoprotein IIb/IIIa blockade was effective in stabilizing patients before the performance of coronary intervention and in reducing ischemic events after revascularization. In PURSUIT, 1,228 patients underwent percutaneous revascularization within the first 72 h (40). Eptifibatide therapy in these patients was associated with a reduction in the risk of MI before revascularization (5.5% vs. 1.7%, p ⬍ 0.001) as well as a significant reduction in the composite end point of death or MI by 30 days (16.7% vs. 11.6%, 5.1% absolute risk reduction, p ⫽ 0.01). Without coronary intervention, the treatment effect was somewhat less (30 day end point rates of 15.6% vs. 14.5% in placebo and eptifibatide groups, respectively, p ⫽ NS). During the first 48 h in PRISM PLUS (while angiography and revascularization were discouraged), death or MI rates were reduced from 2.6% to 0.9% by tirofiban in the overall 1,570 patient cohort (p ⫽ 0.01); among the 475 patients undergoing intervention thereafter on study drug, 30-day rates of death or MI were RI RI RI RI 7.6 — 0.9 7.1 10.1 — 1.5 9.3 14.2 — 3.5 12.6 17.8 — 6.4 14.7 9.1 — 1.2 8.3 11.6 — 2.0 10.4 15.7 — 3.7 13.5 19.0 — 6.2 15.7 Eptifibatide ⴙ Heparin (n ⴝ 4,722) 15.3 32.1 7.0 10.5 11.9 22.3 4.5 9.2 8.3 17.9 1.9 7.0 2.6 7.8 0.3 2.6 Placebo ⴙ Heparin (n ⴝ 797) 12.3 27.7 6.9 8.3 8.7 18.5 3.6 6.6 4.9 12.9 1.9 3.9 0.9 5.7 0.1 0.9 Tirofiban ⴙ Heparin (n ⴝ 773) PRISM PLUS* — — — — 7.1 17.1 3.6 4.3 4.2 11.2 1.6 3.1 1.4 5.6 0.4 1.4 Heparin (n ⴝ 1,616) — — — — 5.8 15.9 2.3 4.1 3.3 10.3 1.0 2.6 0.9 3.8 0.2 0.9 Tirofiban (n ⴝ 1,616) PRISM 17.9 — 6.6 14.3 11.7 — 2.9 10.6 6.6 — 1.3 9.1 3.7 — 0.5 3.3 Placebo ⴙ Heparin (n ⴝ 758) 13.7 — 5.2 10.8 10.6 — 3.0 9.4 6.8 — 1.1 7.9 3.5 — 0.3 3.5 Lamifiban Low-Dose (ⴞ Heparin) (n ⴝ 755) PARAGON 16.4 — 6.8 12.9 12.0 — 3.6 10.9 7.0 — 1.7 9.5 2.6 — 0.4 2.5 Lamifiban High Dose (ⴞ Heparin) (n ⴝ 769) Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade *Efficacy data are not provided for the low-dose eptifibatide group of PURSUIT and the tirofiban plus placebo group of PRISM PLUS treatment arms, which were discontinued before completion of the trials, to avoid inappropriate comparisons of patients who were not contemporaneously enrolled. 48 –96 h end point: assessed in PURSUIT at 96 h, assessed in PRISM PLUS, PRISM and PARAGON at 48 h. Heparin use in PURSUIT was encouraged, but not mandated, and was administered to 89.9% and 89.7% of patients randomized to placebo and eptifibatide, respectively. MI ⫽ myocardial infarction; RI ⫽ refractory ischemia. For Trial Acronyms see “Abbreviations and Acronyms.” 48–96 h Death or MI Death, MI or Death MI 7 Days Death or MI Death, MI or Death MI 30 Days Death or MI Death, MI or Death MI 6 Months Death or MI Death, MI or Death MI End Point (% of Patients) Placebo ⴙ Heparin (n ⴝ 4,739) PURSUIT* Table 4. Randomized Acute Ischemic Syndrome Trials—Efficacy End Points 1110 JACC Vol. 35, No. 5, 2000 April 2000:1103–15 JACC Vol. 35, No. 5, 2000 April 2000:1103–15 Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade 1111 Figure 4. Composite 30-day composite end point of death or myocardial (re-) infarction in the four glycoprotein IIb/IIIa unstable ischemic syndrome trials. Efficacy data are not provided for the low-dose eptifibatide group PURSUIT and the tirofiban plus placebo group PRISM PLUS treatment arms, which were discontinued before completion of the trials. *p ⫽ 0.03 in PRISM PLUS did not reach the prespecified level of p ⫽ 0.025 for a three group trial; †Heparin use in PURSUIT was encouraged, but not mandated, and was administered to 89.9% and 89.7% of patients randomized to placebo and eptifibatide, respectively. PARAGON ⫽ Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome events in the Global Organization Network; PRISM PLUS ⫽ Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs; PURSUIT ⫽ Platelet IIb/IIIa in Unstable Angina: Receptor Supression Using Integrilin Therapy. 10.2% and 5.9% in the placebo and tirofiban groups, respectively (4.3% absolute risk reduction, p ⫽ 0.12). With medical management, 30-day end point rates were reduced from 10.1% to 7.8% (p ⫽ NS). Hemorrhagic risk. Rates of hemorrhagic complications (unassociated with coronary artery bypass surgery) are summarized in Table 5. The excess bleeding risk associated with glycoprotein IIb/IIIa blockade ranged from 0 to 30 events per 1,000 patients treated. Variability in the incremental risks of bleeding among the trials likely reflects differences in underlying patient risk factors, protocols for heparin dosing and monitoring, schedules for ascertainment of hemoglobin values during and after study drug infusion and utilization of invasive revascularization procedures. Despite the prolonged duration of glycoprotein IIb/IIIa therapy in these trials, no increase in the risk of intracranial hemorrhage was observed (39). SYNTHESIS OF THE CLINICAL TRIALS Efficacy. The consistent finding among over 33,000 patients is a reduction in important acute ischemic events by glycoprotein IIb/IIIa receptor blockade during percutaneous coronary revascularization or in the management of unstable angina or MI without ST elevation. The greatest magnitude of clinical benefit with these agents appears to be achieved in patients undergoing coronary intervention (up to 65 acute ischemic events prevented per 1,000 patients treated), wherein the timing of plaque injury and the role of acute platelet aggregation are precisely defined. Inhibition of acute ischemic events is achieved primarily in the first 12 to 48 h after revascularization and maintained over long-term (up to three year) follow-up. No demographic, clinical, angiographic or procedural characteristic has been observed that will identify patients who do not benefit from glycoprotein IIb/IIIa blockade during coronary revascularization. The clinical efficacy of abciximab after stenting is incremental to that achieved with conventional antiplatelet therapy with theinopyridines and aspirin (28,29). In contrast, patients with unstable ischemic syndromes are more heterogeneous with regard to pathophysiology, duration of plaque erosion and the extent of established thrombosis versus ongoing platelet aggregation and, consequently, may be somewhat less responsive to empiric glycoprotein IIb/IIIa receptor blockade. Nevertheless, the observed absolute treatment effect of 15 to 32 events prevented per 1,000 patients treated represents an incremental therapeutic advance over aspirin and heparin. Clinical benefit 1112 Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade JACC Vol. 35, No. 5, 2000 April 2000:1103–15 Table 5. Randomized Acute Ischemic Syndrome Trials— In-Hospital Bleeding (Unassociated with CABG) PURSUIT Trial‡ Placebo Eptifibatide PRISM PLUS Trial‡ Heparin Tirofiban ⫹ heparin PRISM Trial Heparin Tirofiban PARAGON Trial Placebo Lamifiban low dose Lamifiban high dose Major Bleeding (%) Blood Transfusion (%) Intracranial Hemorrhage (%) 1.3 3.0* 1.8 4.4* 0.1 0.1 0.8 1.4 2.8 4.0 0 0 0.4 0.4 1.4 2.4 0.1 0.1 3.0 3.0 6.0* 4.5† 4.5† 9.3† 0 0 0.1 Major Bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria (57) as intracranial hemorrhage or bleeding associated with a decrease in hemoglobin of ⱖ5 gm/dl. *p ⬍ 0.05; †times of transfusions and relationship to CABG were not recorded in PARAGON, thus, total transfusion rates (including CABG-associated) are provided; ‡safety data are not provided for the low-dose eptifibatide group of PURSUIT and the tirofiban plus placebo group of PRISM PLUS treatment arms, which were discontinued before completion of the trials to avoid inappropriate comparisons of patients who were not contemporaneously enrolled. CABG ⫽ coronary artery bypass surgery. For Trial Acronyms see “Abbreviations and Acronyms.” accrues during the two to four day period of drug infusion and is durable over late (six month) follow-up. The treatment effect of these agents appears to be greatest among those who undergo early percutaneous coronary revascularization, with clear evidence of stabilization during the period before intervention as well as suppression of postprocedural ischemic events. Glycoprotein IIb/IIIa blockade with a less aggressive strategy of medical management also appears to provide benefit. Differences in efficacy among the agents. Although all of the agents tested reduce ischemic risk, there does seem to be heterogeneity among the drugs with regard to the magnitude and durability of treatment effect, at least in the setting of percutaneous coronary revascularization. Importantly, direct comparative trials have not been performed. Apparent variability among agents in efficacy may, in part, be due to pharmacodynamics of receptor binding, with the slow dissociation of abciximab contrasting with the rapid reversibility of the other agents. Additionally, the nonspecific blockade by abciximab of both the IIb/IIIa receptor, and the alphavbeta3 receptor may theoretically provide an advantage over the specific agents, as ex vivo studies have suggested that dual receptor blockade more completely suppresses platelet-mediated thrombin generation than does inhibition of either receptor alone (46). For eptifibatide, the relatively modest treatment effect in IMPACT II was almost certainly due, in part, to inadequate dosing based upon Phase II studies that used sodium citrate as an anticoagulant for platelet aggregation measurements. Subsequent to IMPACT II, it was observed that the binding of eptifibatide to the glycoprotein IIb/IIIa receptor was exaggerated in blood anticoagulated by citrate (which chelates calcium) relative to that which would occur at physiologic calcium concentrations (47). The potential for higher doses of eptifibatide to more effectively reduce ischemic complications is suggested by the substantial treatment effect among patients in PURSUIT who underwent early percutaneous coronary revascularization. In the trials of acute ischemic syndromes without mandated percutaneous revascularization, the greatest treatment effect was observed in PRISM PLUS among patients receiving tirofiban combined with heparin (Fig. 4). Confidence intervals around this estimate were wide, however, and the magnitude of risk reduction was not statistically different from that seen in other trials. It is likely that similar outcomes would be obtained with any of the reversible IIb/IIIa inhibitors in this clinical setting. Safety. The reduction in bleeding risk with IIb/IIIa inhibitors during the trials of percutaneous coronary revascularization demonstrates that reduction of concomitant heparin doses, as well as early vascular sheath removal, ameliorate excess hemorrhagic risk in this setting. Bleeding may nevertheless occur in certain patients, such as those who receive these agents as an unplanned or “bailout” intervention in the setting of full-dose heparinization or fibrinolytic therapy. For patients who develop refractory or life-threatening bleeding, the antiplatelet effect of abciximab may be reversed by discontinuation of drug infusion and by platelet transfusion after the ⬃10 to 30 min required for clearance of circulating drug. After transfusion, abciximab redistributes from old to new platelets, reducing the mean level of receptor blockade (R. Jordan, Centocor, Inc., personal communication). Platelet transfusions should rarely be necessary with the rapidly reversible agents eptifibatide and tirofiban and, in fact, might not be expected to be effective during the ⬃2 h required for elimination of these agents from the circulating plasma phase. Emergency coronary artery bypass surgery. There has been concern regarding the risk of excessive perioperative bleeding among patients who require urgent coronary artery bypass surgery after administration of a glycoprotein IIb/ IIIa inhibitor. In this regard, the rapidly reversible agents eptifibatide and tirofiban present little in the way of bleeding risk (40,41). With abciximab, platelet transfusions (after discontinuation of abciximab infusion) appear to reduce hemorrhagic risk (48,49), and blood loss was only modestly increased among patients who required emergency surgery in the EPILOG and EPISTENT trials (50). Thrombocytopenia. Thrombocytopenia occurs infrequently with glycoprotein IIb/IIIa inhibition but may be precipitous and profound (platelet count ⬍50,000 mm⫺3); the excess risk of profound thrombocytopenia associated JACC Vol. 35, No. 5, 2000 April 2000:1103–15 with abciximab (0.4% to 1.1%) is higher than with eptifibatide (0%– 0.2%), tirofiban (0.1% to 0.3%) or lamifiban (0% to 0.1%). The mechanism of thrombocytopenia is unknown, but there is little evidence of ongoing platelet clearance after discontinuation of the glycoprotein IIb/IIIa antagonist. Platelet transfusions are protective for profound thrombocytopenia with or without serious bleeding induced by glycoprotein IIb/IIIa inhibitors. Platelet counts should, therefore, be measured early (within the first 2 to 4 h) after administering these agents and followed for the duration of therapy. Readministration. The development of a human antichimeric antibody (HACA) response in approximately 5% to 6% of patients within the first month after receiving abciximab (20) raises the question of safety of readministration of this agent. No antibodies have been observed to develop in response to treatment with eptifibatide, tirofiban or lamifiban. A prospective abciximab readministration registry of 500 patients found no instances of hypersensitivity or anaphylactic reactions after abciximab readministration, and efficacy of the agent in reducing ischemic complications appears to be similar with readministration as with first-time use (51). Rates of thrombocytopenia after readministration were somewhat higher, however, than those seen with first time administration, although the presence or absence of a positive HACA titer was not predictive of a lack of clinical effectiveness, development of thrombocytopenia or other sequelae in patients undergoing readministration. Indications for therapy and choice of agent. Although trial data support the use of glycoprotein IIb/IIIa inhibitors in virtually all patients undergoing percutaneous coronary revascularization, these agents are not universally employed in clinical practice due, in part, to economic considerations and concerns regarding safety issues. Although the economic aspects of GP IIb/IIIa blockade are beyond the scope of this review, it is important to recognize that cost savings derived from reduction in ischemic events offset much of the acquisition cost of these agents. Moreover, the costeffectiveness of abciximab in reducing mortality during coronary stenting appears quite favorable, in the range of other accepted medical therapies (37). Economic considerations aside, the benefits of this therapy should certainly be provided to patients at elevated risk for periprocedural complications, such as those with unstable angina or acute MI, complex lesion morphology, extensive myocardium at jeopardy, multivessel or multilesion interventions or diabetes mellitus. The current efficacy standard during and after percutaneous coronary intervention is abciximab administered as a bolus followed by a 12-h infusion. Aspirin, heparin and ticlopidine or clopidogrel (in patients receiving stents) should also be administered (52). A pretreatment regimen of abciximab is effective in stabilizing patients before coronary revascularization, but offers no clear advantage in stable patients or even in unstable patients for whom Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade 1113 revascularization can be immediately performed. Regardless of whether or not a period of pretreatment with abciximab is used, the 12-h postprocedural infusion appears to be necessary for optimal clinical benefit. Although anecdotal data suggest that abciximab may be useful in an unplanned or “bailout” fashion to reverse thrombotic complications of coronary intervention (53), this approach has never been tested in a randomized fashion and must be regarded as suboptimal relative to planned use. Eptifibatide or tirofiban are effective as empiric therapy among patients with unstable ischemic symptoms associated with either electrocardiographic or enzymatic evidence of myocardial ischemia or necrosis, particularly if revascularization is subsequently performed. Given the heterogeneity of acuity and risk for complications of patients admitted with the diagnosis of “unstable angina,” these agents will likely prove most beneficial if focused on those with high risk features such as recurrent or prolonged rest symptoms, ischemic heart failure, dynamic electrocardiographic changes, hemodynamic instability (54), elevated troponin or creatine kinase (55) or prior aspirin use. Treatment with abciximab in this setting has not yet been evaluated and cannot be recommended. Once a course of empiric therapy with eptifibatide or tirofiban is initiated, it should be continued for 24 h after percutaneous coronary intervention (if performed). The available pharmacodynamic and clinical data strongly suggest that, with eptifibatide, the dose of 180 g/kg bolus and 2.0 g/kg-min infusion be utilized. Conjunctive heparin. During coronary intervention, the low-dose, weight-adjusted heparin regimen (initial bolus of 70 U/kg, maximum 7000 U, adjusted to maintain an activated clotting time ⱖ200 s) is safe and effective with abciximab therapy (21). Postprocedural heparin likely provides no additional benefit, even in patients with acute ischemic syndromes, and vascular access sheaths can typically be removed 2 to 6 h after the procedure. Optimal heparin dosing during coronary intervention in patients receiving eptifibatide or tirofiban has not been investigated, but a dose of 100 U/kg (maximum 10,000 U) adjusted to an activated clotting time ⱖ300 s is currently recommended. The role of heparin among patients receiving glycoprotein IIb/IIIa antagonists during the medical management of unstable angina remains unresolved. Evidence from the randomized trials and other studies (56) suggests that heparin likely adds clinical benefit to glycoprotein IIb/IIIa blockade in the acute ischemic syndromes, although the optimal intensity and duration of therapy has not been defined. Conclusions. Platelet glycoprotein IIb/IIIa receptor blockade represents a significant advance in the practice of interventional cardiology and the management of acute ischemic syndromes. Topics for future study include the role of these agents among patients treated with thrombolytic therapy for acute MI, economic aspects and development of less costly alternatives, the effectiveness of these agents when 1114 Lincoff et al. Platelet Glycoprotein IIb/IIIa Blockade used in an unplanned fashion during coronary intervention, the role of oral glycoprotein IIb/IIIa antagonists and the potential for combining glycoprotein IIb/IIIa antagonists with novel inhibitors of thrombin or other components of the coagulation cascade. 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