Platelet Membrane Receptor Glycoprotein IIb/IIIa Antagonism in Unstable Angina
The Canadian Lamifiban Study
Background Ligand binding to the platelet membrane receptor glycoprotein (GP) IIb/IIIa, the final and obligatory step to platelet aggregation, can now be inhibited by pharmacological agents. This study was designed to evaluate the potential of lamifiban, a novel nonpeptide antagonist of GP IIb/IIIa, for the management of unstable angina.
Methods and Results In a prospective, dose-ranging, double-blind study, 365 patients with unstable angina were randomized to an infusion of 1, 2, 4, or 5 μg/min of lamifiban or of placebo. Treatment was administered for 72 to 120 hours. Outcome events were measured during the infusion period and after 1 month. Concomitant aspirin was administered to all patients and heparin to 28% of patients. Lamifiban, all doses combined, reduced the risk of death, nonfatal myocardial infarction, or the need for an urgent revascularization during the infusion period from 8.1% to 3.3% (P=.04). The rates were 2.5%, 4.9%, 3.3%, and 2.4% with increasing doses. At 1 month, death or nonfatal infarction occurred in 8.1% of patients with placebo and in 2.5% of patients with the two high doses (P=.03). The highest dose of lamifiban additionally prevented the need for an urgent intervention. Lamifiban dose-dependently inhibited platelet aggregation. Bleeding times were significantly prolonged with platelet inhibition of >80%. Major (but neither life-threatening nor intracranial) bleedings occurred in 0.8% of patients with placebo and 2.9% with lamifiban.
Conclusions The nonpeptide GP IIb/IIIa antagonist lamifiban protected patients with unstable angina from severe ischemic events during a 3- to 5-day infusion and reduced the incidence of death and infarction at 1 month, suggesting considerable promise for this new therapeutic approach.
The background of the present investigation includes the role of endovascular thrombus formation in myocardial infarction and unstable angina,1 2 3 the limited efficacy of aspirin and heparin in preventing complications in these acute syndromes,4 5 6 7 and the availability of new potent antithrombotic drugs focusing particularly on direct inhibition of thrombin8 and of the platelet membrane receptor GP IIb/IIIa.9 10 Activation of the platelet GP IIb/IIIa to bind fibrinogen, von Willebrand factor, or fibronectin represents the final common pathway for platelet aggregation. Profound inhibition of platelet aggregation induced by any agonist, including thrombin, is achieved by GP IIb/IIIa antagonism. The Evaluation of c7E3 in the Prevention of Ischemic Complications (EPIC) trial,11 by documenting a 35% risk reduction of acute complications associated with high-risk angioplasty compared with aspirin and heparin, demonstrated the clinical potential of this new therapeutic approach and recently led to the approval of the first GP IIb/IIIa antagonist for this clinical indication, the chimeric monoclonal antibody Fab fragment c7E3. Meanwhile, cyclic Arg-Gly-Asp (RGD)- or Lys-Gly-Asp (KGD)-containing peptides as well as nonpeptide agents have been developed, which may offer significant advantages over a monoclonal antibody. Lamifiban, a synthetic nonpeptide compound of low molecular weight (0.468 kD), is one of the most potent and selective GP IIb/IIIa antagonists available.12 13 14 15 This double-blind randomized controlled trial is the first study exceeding the size of early pilot trials16 17 18 19 20 to evaluate the clinical potential of GP IIb/IIIa inhibition in patients with unstable angina.
Patients were recruited in 15 Canadian centers. The entry criteria defined a population of patients with unstable angina or myocardial infarction without ST-segment elevation. Patients were required to have had chest pain at rest or at minimal exercise, ≥5 minutes in duration, in the 24 hours preceding randomization as well as evidence of coronary artery disease by either ECG ST-T changes (65% of patients), documentation of a previous myocardial infarction (54%), a 201Tl exercise test (15%), or coronary angiography (48%). Exclusion criteria were age >75 years (380 patients); unstable angina precipitated by identifiable factors (67 patients) or occurring within 6 months of coronary angioplasty or 2 months after bypass surgery because of potentially different pathophysiological mechanisms involved (198 patients); a previous stroke (22 patients); a high bleeding risk including trauma, surgery, or active bleeding within the previous month (89 patients); and shock, congestive heart failure, left bundle-branch block, uncontrolled hypertension >200 mm Hg systolic, a life-threatening concomitant illness, platelet count <100 000/mm3, the use of oral anticoagulants or of an investigational drug, the potential for pregnancy, or the inability to obtain informed consent (270 patients). A total of 365 patients were randomized into the study; 3 of these patients did not receive the study drugs, and 2 others were subsequently found not to have coronary artery disease as defined. These 5 patients were included in the intention-to-treat analysis.
Study Design and Randomization
In this dose-ranging study, patients were randomly assigned to one of five parallel study arms by sequential numbers generated centrally and incorporated into double-blind labeling. These arms included placebo and four different doses of lamifiban. An IV bolus of placebo or of active drug was rapidly administered as soon as possible after randomization, followed by an infusion. The bolus plus infusion doses of lamifiban were (1) 150 μg plus 1 μg/min, (2) 300 μg plus 2 μg/min, (3) 600 μg plus 4 μg/min, and (4) 750 μg plus 5 μg/min. The study medication was infused at a rate of 1 mL/h with volumetric pumps. The rate of infusion was decreased to 0.9 mL/h in patients weighing <70 kg, to 0.8 mL/h in patients weighing <60 kg, and to 0.7 mL/h in patients weighing <50 kg.
Randomization blocks were uneven, allowing an equally higher number of patients in the placebo and in the 4.0-μg lamifiban dose group. The rationale for this uneven randomization was to test with sufficient statistical power a dose of 4.0 μg/min, which consistently inhibited ADP-induced platelet aggregation by ≥95% in phase 1 studies.14 Three patients were randomized to lamifiban 4 μg/min or to placebo for one patient in each of the other three groups with different doses of lamifiban.
All patients received aspirin 325 mg before the study drug initiation and daily thereafter. The concomitant use of IV heparin, titrated to an activated partial thromboplastin time twice the control value, was left to the discretion of the treating physician. However, the decision on whether to use heparin had to be taken before randomization. The use of antianginal therapy, including nitrates or nitroglycerin (not IV), β-blockers, and/or calcium antagonists, was recommended. The study drugs were infused per protocol for a total of 72 to 120 hours (mean duration, 84 hours), postponing coronary angiography and invasive interventions until after that period, unless urgently required by clinical deterioration of the patient. The time of discontinuation depended on the clinical status of the patient, the schedule for cardiac catheterization, and the plans for long-term treatment.
Efficacy and Safety End Points
This study was designed to obtain a first evaluation of lamifiban in patients with unstable angina and to determine an optimal dose of the drug for a subsequent pivotal trial on a large scale. Doses that inhibited platelet aggregation in the range of 40%, 60%, 80%, and >95% in normal volunteers were selected. End points were assessed during the infusion period and at 1 month and included all potential ischemic events. Predefined end points included (1) death; (2) nonfatal infarction, based on recurrent chest pain ≥30 minutes in duration after randomization, ECG changes, a new elevation or reelevation of creatine kinase MB fraction values to ≥1.5 times the previous values; (3) refractory ischemia despite maximal medical treatment requiring urgent angioplasty or bypass surgery; (4) recurrent ischemia at rest or minimal exercise, with objective documentation of ischemic ST-T changes; and (5) in the absence of documented ischemia, two or more episodes of angina confirmed by two independent cardiologists as strongly suggestive of infarction. The end points at 1 month were death and nonfatal infarction. Predefined subanalyses were the comparison of all four groups of lamifiban versus placebo, the two high and the two low doses of lamifiban combined versus placebo, the effects of concomitant heparin (nonrandomized) on safety and efficacy, and an analysis of the high-risk subgroup of patients with myocardial infarction at entry. Rehospitalization for recurrent ischemia or for an intervention because of recurrent symptoms was also retained for analysis. Events were all classified by a Critical Event Committee before the study was unblinded. Relevant data and documents without patient/center identifiers were reviewed independently by a panel of two for all patients with any complication or event. In case of disagreement, a consensus decision involving a third member was reached.
Safety parameters, including vital signs, laboratory parameters, and bleeding complications, were closely monitored during the study drug infusion and for the following 24 hours. A complete blood count was obtained at baseline, 12 hours after the bolus infarction, and daily for 5 days. Major bleeding was defined as intracranial hemorrhage, cardiac tamponade, a decrease in blood hemoglobin of ≥5 g/dL, or the need for blood transfusion. Minor bleedings included all bleedings affecting the patients' daily activities. Other bleedings, such as minor bruises or self-limited mucosal bleedings, were classified as insignificant.
Platelet aggregation studies and bleeding times were obtained in 58 patients from three participating centers at baseline, at 2 and 72 hours on steady-state drug infusion, and 2 to 6 hours after its discontinuation. The analyses were done by trained technicians, and the results were not divulged. Platelet aggregation was measured in citrated platelet-rich plasma. Aggregation was induced by 10 μmol ADP (Sigma Chemical Co) and by 100 μmol of a synthetic TRAP (amino acid sequence, SFLLRNPHDKYEPF; Hoffmann La Roche Ltd) and was recorded for 10 minutes. ADP- and TRAP-induced platelet aggregations were expressed as percent of baseline (predrug) aggregation values as measured on the strip-chart recorder. In the case of TRAP-induced aggregation, all values were corrected with the following formula: [measured value (%)×1.25]−25 to account for a 20% change in the maximally observed change in light transmission not due to platelet aggregation since it is also observed when TRAP is added to platelet-rich plasma containing 5 mmol/L EDTA. Bleeding times were measured by a modified Ivy method and expressed as the median of three puncture sites.
Data Management and Statistical Analysis
Data were collected by study coordinators on case-report forms, and 100% source document verification was performed by blinded monitors before data entry. Data were entered twice blindly and independently, and any discrepancies were resolved by local queries. The trial sponsor (F. Hoffmann-La Roche) and the investigators remained blinded to randomization code and study results until all study end points had been agreed on by the Critical Event Committee.
The description of continuous variables is based on group means with SDs and group medians with 25th and 75th percentiles when nonnormally distributed; for qualitative data, relative frequencies and corresponding SEMs are used. The null hypothesis “lamifiban has no effect” was tested in a confirmatory sense by the Cochran Armitage trend test,21 stratified for heparin use, applied to the outcomes of the composite end point, including all predefined hard and soft ischemic events during the infusion period. With the present study design, this test reaches a power22 of 80% for the following cardiac event probabilities in the five study groups: 25%, 23%, 18%, 10%, and 10% (α=.05, two-sided).
Comparisons of end-point data between different treatment groups and the control group, both during infusion and at 1 month, were done by 2×2-table χ2 tests and by log-rank statistics. All data are presented with nominal two-tailed probability values unadjusted for multiple comparisons. Odds ratios and CIs for the treatment effect are given for comparisons reaching significance. A time-to-event analysis for survival without infarction at 1 month is displayed as a Kaplan-Meier survival curve.
A total of 365 patients with unstable angina, 60±10 years old and 72% men, were randomly allocated to five treatment arms. Baseline characteristics, including demographics, risk factors, presenting symptoms, ischemic ECG changes, and concomitant medication, were similar between the two largest study groups, placebo and 4 μg/min lamifiban (Table 1⇓). Overall, 55% of the patients had previously suffered a myocardial infarction; 65% were admitted with ischemic ECG changes and 14% with a myocardial infarction without ST-segment elevation. Twenty percent of the patients were enrolled under heparin (IV or subcutaneous), and an additional 6.0% were subsequently given IV heparin together with the study medication. This was evenly distributed among the treatment arms. Imbalances existed in the three groups with a smaller sample size. Thus, patients administered the lowest dose of lamifiban less often had a non–Q-wave infarction at entry; patients given the second lowest dose were more often women and less frequently had previous infarction.
Table 2⇓ provides the rates of all outcome events in the five study groups during the infusion of the study drug and 1 month later.
During the infusion, the number of events per patient was lower with lamifiban (2.8%) than with placebo (4.1%); counting only the worst event per patient, the rates were 24% and 30%, respectively. The Cochran Armitage trend test revealed a probability value of .14. Death, myocardial infarction, or need for an urgent intervention occurred in 3.3% of lamifiban patients compared with 8.1% of placebo patients, corresponding to an odds ratio of 0.39 (95% CI, 0.15 to 0.99; P=.04) (Fig 1⇓). The event rate was surprisingly low with the lowest dose of lamifiban. No death and no infarction occurred during the infusion of the two high doses of lamifiban. The highest lamifiban dose (5 μg/min), compared with lower doses, had an additional benefit on recurrent ischemia, reducing the composite end point of ischemic events from 30.1% with placebo to 12.2%, for an odds ratio of 0.32 (95% CI, 0.12 to 0.89; P=.02).
At 1 month, death or nonfatal infarction had occurred in 2.5% of patients with the two high lamifiban doses, in 6.2% of patients with the two low doses, and in 8.1% with placebo. The odds ratio of an event with lamifiban compared with placebo was 0.44 (95% CI, 0.16 to 1.2; P=.07) and with the two high doses compared with placebo, 0.29 (95% CI, 0.09 to 0.94; P=.03). Fig 2⇓ shows the curves of survival without infarction. A lower rate of recurrent ischemia and interventions with the 5-μg/min infusin of lamifiban reduced the composite event rate at 1 month in this group from 24.4% with placebo to 9.8% (odds ratio, 0.34; 95% CI, 0.08 to 1.05; P=.045).
Myocardial infarction at entry was associated with a worse outcome at 1 month than unstable angina, with death or recurrent infarction in 11.4% of 44 patients compared with 4.4% of the 321 patients with unstable angina (P=.05). The beneficial effect of lamifiban was apparent in both groups. The rates of death or infarction for patients with non–Q-wave infarction were 4.8%, 14.3%, and 18.8% with doses of lamifiban 4 to 5 μg/min, lamifiban 1 and 2 μg/min, and placebo, respectively. For unstable angina, they were 2.1%, 5.4%, and 6.5%, respectively. Death or infarction occurred in 3 of the 44 patients (6.8%) receiving lamifiban 4 to 5 μg/min in combination with heparin and in 1 of 117 patients (0.9%) receiving lamifiban 4 to 5 μg/min without heparin. The rates of these events were similar with and without heparin in the two low-dose groups and tended to be higher without heparin in the placebo group (Table 2⇑). An IV infusion of nitroglycerin was administered with placebo in 7.3% of patients and with lamifiban 1, 2, 4, and 5 μg/min in 2.5%, 9.8%, 2.5%, and 2.4% of patients, respectively.
Platelet Aggregation Studies and Bleeding Time
The results of ex vivo platelet aggregation and bleeding time measurements obtained from 58 patients at steady-state drug levels are shown in Fig 3⇓. Complete inhibition of platelet aggregation, conventionally induced by ADP, was achieved with the infusions of 4 and 5 μg/min of lamifiban. The prolongation of bleeding time (median values) reached statistical significance, with ADP-induced inhibition of platelet aggregation of >80%. With TRAP, a more potent synthetic platelet agonist mimicking thrombin, a shift to higher lamifiban doses for complete inhibition was observed, as well as a better correlation with the bleeding time prolongation.
The bleeding rates observed in the various study groups are described in Table 3⇓. Minor bleedings during the infusion period were more frequent with lamifiban: 11.1% versus 1.6% of patients (P=.002). Major bleedings occurred in 2.9% of patients treated with lamifiban, all in the 4-μg/min group, and in 0.8% of patients treated with placebo (P=NS); no patient experienced intracranial or life-threatening bleeding. Concomitant therapy with heparin significantly affected the bleeding rates: no serious bleeding occurred with aspirin alone in 94 patients; the bleeding incidence with the combination of aspirin plus lamifiban in 175 patients was 1.7%; with aspirin plus heparin plus placebo in 29 patients, 3.4%; and with the combination of aspirin, heparin, and lamifiban in 67 patients, 6.0%. Reversible thrombocytopenia was observed in 4 patients (3.9%) administered heparin (n=102) and in none treated with lamifiban (n=263).
This double-blind, parallel, dose-ranging study suggests substantial promise for lamifiban in the management of unstable angina. Lamifiban is one of the most potent (IC50 for ADP-induced platelet aggregation, 25 nmol) and selective inhibitors of GP IIb/IIIa in clinical development, and it is a short-lived (pharmacodynamic half-life, ≈4 hours) nonpeptide compound.12 13 14 15 Blockage of the platelet GP IIb/IIIa receptor by snake venoms, monoclonal antibodies, RGD/KGD peptides, or nonpeptide molecules profoundly inhibits platelet aggregation induced by any agonist, including thrombin, which is of special importance in the pathophysiology of plaque rupture in acute coronary syndromes. The recent EPIC trial has shown GP IIb/IIIa inhibition with the monoclonal antibody c7E3 to reduce the rate of acute thrombotic complications in high-risk coronary angioplasty by 35%, although it doubled the incidence of serious bleeding complications.11 23 In unstable angina, this class of agents has so far been tested in preliminary studies only.16 17 18 19 20 The antibody, compared with placebo in 60 patients, prevented recurrent ischemia and improved the angiographic aspect of the culprit coronary artery lesion.17 Integrelin18 and MK-852,19 two synthetic cyclic peptides, and MK-383, a nonpeptidic compound,20 had a favorable influence on the rates of recurrent ischemia.17 18 19
The present study suggests that a significant benefit may be expected from lamifiban in unstable angina. During drug infusion, lamifiban (all doses combined), compared with placebo, reduced the combined event rate of death, myocardial infarction, and urgent interventions. The highest dose additionally reduced the incidence of recurrent ischemia. Of interest, no clinical reactivation occurred after the discontinuation of the infusion, and the initial gain was maintained with a significant reduction in the rate of death and nonfatal infarction at 1 month with the two higher doses of lamifiban, inhibiting platelet aggregation by >80%. This finding may be compared, in some way, with the EPIC data that have documented long-term benefit when c7E3 was administered as a bolus before coronary angioplasty followed by an infusion for 12 hours, as opposed to a loss of the initial gain when the bolus alone was administered.24 Explanations proposed for this prolonged benefit after drug discontinuation after a longer infusion are a better healing process with vessel “passivation,” prevention of the accelerated disease progression associated with unstable angina25 and/or reduced production of growth factors and cytokines.26 Our data with prolonged infusions of high doses extend this concept to suggest that the degree of receptor inhibition with GP IIb/IIIa antagonists may be an additional determinant of clinical benefit.
No clear dose-related incremental clinical benefit could be documented in this study. The event rate was lowest with the low dose of lamifiban. The sample size in this group was small and included fewer patients with a myocardial infarction at entry, which may explain a better prognosis. A good correlation was found between doses and inhibition of ex vivo platelet aggregation and prolongation of bleeding time. The two high doses, which completely inhibited ADP-induced platelet aggregation, prevented the occurrence of the most severe, irreversible clinical events. In addition, the highest dose, which completely inhibited platelet aggregation induced by TRAP and further prolonged bleeding times, was associated with a reduction in the incidence of recurrent ischemia. These data may suggest that near-maximal inhibition of platelet aggregation could be required for maximal clinical benefit in the context of acute unstable angina. However, further studies are required to document this hypothesis. Doses of 1 and 5 μg/min were selected for the larger trial that has been planned after completion of this study; this trial is now ongoing.
In this study, as in others, aspirin was administered to all patients, in the absence of clinical data indicating whether a complementary effect of aspirin on GP IIb/IIIa inhibition exists. Twenty-six percent of the patients received heparin as well. The data do not suggest an additional benefit of heparin added to lamifiban: not only bleeding but also clinical events tended to be more frequent with heparin plus the high doses of lamifiban than with lamifiban alone, contrasting with a lower event rate when heparin was used with placebo and with the low doses of lamifiban. The use of heparin, however, was not randomized in this study, with a possible bias toward its administration in sicker patients; therefore, no conclusions can be drawn. The data only stress the importance of evaluating the relative benefits of the combination of heparin and a GP IIb/IIIa antagonist versus each drug alone in a larger trial. The benefits of GP IIb/IIIa antagonism alone to control the acute coronary syndromes might indeed combine and exceed those of aspirin and of heparin, considering the profound and complete inhibition of platelet aggregation, including thrombin-induced aggregation.
The risk of serious bleeding with lamifiban, on the basis of the data of this study, seems to be low and related predominantly to the additional use of heparin. This corroborates the experience gained with other GP IIb/IIIa inhibitors, including the monoclonal antibody c7E3, suggesting that the initially encountered bleeding excess can possibly be reduced by avoiding or reducing the heparin dose.23 The short half-life of lamifiban may represent a clinical advantage in acute conditions necessitating urgent interventions, but this remains to be studied further.
The present study, although it lacks confirmatory power to assess the clinical efficacy and safety of lamifiban in unstable angina more precisely and definitively, suggests that the drug is one of the promising new antithrombotic compounds presently in development. Further research is required to document the most beneficial dose, the range of clinical benefits, and the usefulness of the combination with heparin. The results will orient the design of future investigations to answer the very critical issues of clinical efficacy, safety, dose-effect relation, and modulation of accelerated atherosclerosis in the exciting and rapidly growing field of antithrombotic therapy for acute coronary syndromes.27
Selected Abbreviations and Acronyms
|TRAP||=||thrombin-receptor agonist peptide|
Steering Committee: Pierre The´roux (chairman), Catherine Kells, Merril Knudtson, Simon Kouz, James Nasmith, Louis Roy, Hans J. Rapold (nonvoting).
Data and Safety Monitoring Board: Eric J. Topol (chairman).
Coagulation Substudies: David R. Anderson, Jean G. Diodati, Pierre The´roux.
Sites, Principal Investigators, Study Coordinators: Centre Hospitalier Re´gional de Lanaudie`re, Joliette, Quebec: Simon Kouz, Micheline Laforest. Centre Hospitalier de la Re´gion de l'Amiante, Thetford-Mines, Quebec: Robert Dupuis, Francine Ouimet. Foothills Hospital, Calgary, Alberta: Merril Knudtson, Diane Galbraith, Heather Watt. Hoˆpital de l'Enfant-Je´sus, Quebec: Jean-Rock Boudreault, Nicole Be´langer. Hoˆpital Maisonneuve-Rosemont, Montreal, Quebec: Denis Gossard, Odette Magnan, Monique Montplaisir. Hoˆpital Notre-Dame, Montreal, Quebec: Pierre Larame´e, Ce´line Roy. Hoˆpital du Sacre´-Coeur, Montreal, Quebec: James Nasmith, Ginette Gaudette. Hoˆtel-Dieu de Le´vis, Quebec: Franc¸ois Delage, Denis Saulnier, Francine Dumont. Institut de Cardiologie de Montre´al, Montreal, Quebec: Pierre The´roux, Faryala Shabani, Johanne Levesque, Marie-Andre´e Se´guin. Institut de Cardiologie de Que´bec, Quebec City: Louis Roy, Marie-Mai Larivie`re. Jewish General Hospital, Montreal, Quebec: Jean G. Diodati, Xu Fu, Eileen Shalit. Ottawa Heart Institute, Ottawa, Ontario: Jean-Franc¸ois Marquis, Heather Dowell. Royal Alexandra Hospital, Edmonton, Alberta: William K. Hui, Linda Kvill. Vancouver General Hospital, Vancouver, British Columbia: Anthony Fung, Cheryl Davies. Victoria General Hospital, Halifax, Nova Scotia: Catherine Kells, David Anderson, Theresa Fawcett.
- Received November 15, 1995.
- Revision received March 28, 1996.
- Accepted April 11, 1996.
- Copyright © 1996 by American Heart Association
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