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(Circulation. 1996;94:2083-2089.)
© 1996 American Heart Association, Inc.

Articles

Effects of Integrelin, a Platelet Glycoprotein IIb/IIIa Receptor Antagonist, in Unstable Angina

A Randomized Multicenter Trial

Steven P. Schulman, MD; Pascal J. Goldschmidt-Clermont, MD; Eric J. Topol, MD; Robert M. Califf, MD; Frank I. Navetta, MD; James T. Willerson, MD; Nisha C. Chandra, MD; Alan D. Guerci, MD; James J. Ferguson, MD; Robert A. Harrington, MD; A. Michael Lincoff, MD; Steven J. Yakubov, MD; Paul F. Bray, MD; Raymond D. Bahr, MD; Christopher L. Wolfe, MD; Paul G. Yock, MD; H. Vernon Anderson, MD; Thomas W. Nygaard, MD; Steven J. Mason, MD; Mark B. Effron, MD; Anil Fatterpacker, MD; Stephen Raskin, MD; Jack Smith, MD; Lori Brashears, RN; Patricia Gottdiener, RN, MS; Charles du Mee, PhD; Michael M. Kitt, MD; Gary Gerstenblith, MD

the Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Md; Cleveland (Ohio) Clinic Foundation; Duke University Medical Center, Durham, NC; Mother Frances Hospital, Tyler, Tex; University of Texas, Houston; St Frances Hospital, Roslyn, NY; Texas Heart Institute, Houston; Riverside Methodist Hospital, Columbus, Ohio; St Agnes Hospital, Baltimore, Md; Moffitt Hospital, University of California, San Francisco; Lynchburg (Va) General Hospital; Franklin Square Hospital, Baltimore, Md; Alameda (Calif) Hospital; St Vincent's Hospital, Erie, Pa; Biometric Research Institute, Arlington, Va; and COR Therapeutics, San Francisco, Calif.

	Abstract

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Background Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina.

Methods and Results Patients received intravenous heparin and standard anti-ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin, 45 µg/kg bolus followed by a 0.5-µg·kg^-1·min^-1 continuous infusion; or placebo aspirin and high-dose Integrelin, 90 µg/kg bolus followed by a 1.0-µg·kg^-1·min^-1 constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24±0.11 ischemic episodes (mean±SEM) on Holter lasting 8.41±5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0±0.33, P<.05) and longer duration (26.2±9.8 minutes, P=.01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms.

Conclusions Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.

Key Words: integrins • angina • platelets • ischemia

	Introduction

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Unstable angina is a frequent and increasing reason for hospitalization in the United States, accounting for more than 570 000 admissions annually.¹ Despite intensive medical therapy, patients with rest angina experience a significant risk of myocardial infarction and need for revascularization to control continued ischemia.^{2 3 4} Angiographic, laboratory, and postmortem studies suggest that one important pathophysiological mechanism in these patients involves plaque instability from ulceration or rupture, with cyclic reductions in coronary flow due to platelet activation and thrombosis.^{5 6 7 8 9 10 11}

The critical role of platelets and thrombus formation in patients with unstable angina is supported by the therapeutic benefits of aspirin in reducing mortality and myocardial infarction.^{12 13} Heparin therapy also reduced myocardial infarction and refractory angina in the study by Theroux and colleagues,¹² but it was of only marginal benefit in the RISC trial.¹⁴ Abrupt discontinuation of heparin may be associated with a rebound in ischemic events.¹⁵ More recently, therapy with thrombolytics, direct thrombin inhibitors, and platelet receptor antibodies have also been evaluated in unstable angina patients.^{16 17 18}

Platelet aggregation is mediated exclusively by the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa.^{19 20} The binding of the receptor with fibrinogen is the final common pathway leading to platelet aggregation and thrombus formation.¹⁹ Integrelin is a cyclic heptapeptide that inhibits platelet aggregation and thrombus formation through specific binding to the IIb/IIIa receptor and therefore inhibits the final pathway leading to platelet aggregation.²¹ This compound is administered intravenously and has a short half-life. In animal models, Integrelin inhibits cyclical flow reductions at injured and stenosed sites of coronary arteries and diminishes platelet aggregation ex vivo in a dose-dependent fashion.²¹ Phase 1 studies in human volunteers show this compound to be well tolerated. The present multicenter study was designed to compare the number and duration of ischemic episodes in unstable angina patients randomized to receive Integrelin and heparin or aspirin and heparin in a prospective, double-blind trial.

	Methods

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Study Population
Subjects were men and women 21 to 80 years old with unstable angina. Unstable angina was defined as the recent onset of a changing pattern of cardiac ischemic symptoms at rest, with one episode lasting at least 10 minutes and occurring within 24 hours of randomization. In addition, all subjects had transient ST-segment depression or elevation in two or more ECG leads during an episode of pain, or if an ECG was not obtained during an episode of ischemic pain, they had known coronary artery disease on the basis of a prior myocardial infarction or cardiac catheterization. Patients were excluded if they had a suspected myocardial infarction in evolution, prior coronary artery bypass graft surgery within 6 months, coronary angioplasty within 72 hours, thrombolytic therapy within 7 days, major surgery within 6 weeks, a history of cerebral vascular disease, major gastrointestinal or genitourinary bleeding within 30 days, significant thrombocytopenia (<100 000/mm³), coagulopathy (receiving coumarin or bleeding time >20 minutes), and if they presented with severe hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >120 mm Hg) or had renal insufficiency with a creatinine level >4 mg/dL.

Treatment Regimen
All patients received standard medical therapy for unstable angina, including intravenous heparin given as a 5000-U bolus followed by a continuous infusion with the dose adjusted so as to maintain activated partial thromboplastin time between 1.5 and 2.5 times control. Patients were treated with intravenous nitroglycerin, ß-blockers, and calcium channel blockers according to the recommendations of their attending physicians.

Patients were randomized in a double-blind, placebo-controlled fashion to one of three treatment groups for 24 to 72 hours (mean, 37.7±1.4 hours). The duration of study drug infusion varied according to the timing of procedures, including cardiac catheterization, angioplasty, and coronary artery bypass graft surgery, at which time the study drug was discontinued. The control group received oral aspirin capsules 325 mg daily initiated immediately upon randomization, plus placebo intravenous Integrelin. The low-dose Integrelin group received placebo aspirin plus Integrelin given as a 45-µg/kg bolus over 3 minutes followed by a continuous 0.5-µg·kg^-1·min^-1 constant infusion. The high-dose Integrelin group was randomized to receive placebo aspirin plus Integrelin with a 90-µg/kg bolus and a constant infusion of 1.0 µg·kg^-1·min^-1. After termination of the study drug, all patients received oral aspirin 325 mg.

ECG Monitoring
Continuous two-channel ECG recordings (Holter) were performed to detect reversible ST-segment changes with a calibrated amplitude-modulated cassette recorder (Oxford MR45 System) during study drug infusion. For patients who did not proceed directly to a revascularization procedure, ECG monitoring was continued after withdrawal of the study drug. Leads were chosen that corresponded to any ECG lead changes noted during an episode of ischemic pain. The monitors were calibrated before and after placement for each 24-hour period. During the same period, the number and duration of symptomatic ischemic episodes were carefully recorded by research nurses. All tapes were scanned by previously published techniques,²² and the number and duration of ischemic episodes on the monitor were defined as reversible ST-segment depression of 1 mm measured 0.08 second after the J-point and lasting >1 minute. A return to the baseline for 1 minute was required after the resolution of an ischemic episode before another discrete episode was counted. Patients with abnormal baseline ST segments were excluded from the Holter analysis.

Platelet Aggregation and Bleeding Time
In one of the centers, platelet aggregometry and bleeding times were measured before the infusion, after 1 and 4 hours of study drug infusion, at termination of drug infusion, and between 1 and 4 hours after infusion. Ex vivo platelet aggregometry was performed on platelet-rich plasma prepared by centrifugation at 150g for 15 minutes. Aggregation was determined in response to 20 µmol/L ADP, which was added to 0.45 mL of platelet-rich plasma having a platelet count of 300 000 to 400 000/µL. The maximum change in light transmission achieved after 5 minutes was recorded, and the values were expressed as percentage of the baseline before study drug infusion. Simplate bleeding times were performed by inflation of a blood pressure cuff to 40 mm Hg followed by an incision on the volar forearm surface. The flow of blood was blotted every 30 seconds until bleeding stopped. Bleeding time was measured as the period between the time of incision and the time the filter paper was no longer stained.

Study End Points
The efficacy end points were the number and duration of ischemic episodes on continuous ECG monitoring over the first 24 hours of study drug infusion as well as for the entire duration of study drug infusion. Twenty-four hours of continuous ECG monitoring was chosen as the primary end point because it was assumed that many patients would be referred for coronary angiography and revascularization after that time. Secondary end points included the number and duration of symptomatic ischemic episodes, the number and duration of ECG episodes of ischemia after study drug withdrawal, and clinical events of death, myocardial infarction, and refractory ischemia defined as ischemic pain unresponsive to standard anti-ischemic therapy requiring intra-aortic balloon counterpulsation, emergent catheterization and angioplasty, or morphine sulfate. Safety end points included bleeding and standard laboratory variables.

Statistical Analysis
Statistical testing of baseline characteristics was performed on selected variables using the ² test. An efficacy analysis of Integrelin relative to the aspirin control group on Holter ischemia was assessed on the basis of an evaluable group. The number and duration of events were compared by the ² and the Kruskal-Wallis statistical tests. To determine the effect of sex on the number and duration of events in a postrandomization analysis, the Cochran-Mantel-Haenszel test statistic was performed for the number of events, and an ANOVA on rank was done for duration of events. The safety of Integrelin and the effect of Integrelin on symptomatic ischemia and the clinical end points of refractory ischemia, death, and myocardial infarction were analyzed with an intention-to-treat analysis. A level of =.05 was considered statistically significant for all statistical analyses. All statistical analyses were done with SAS statistical software version 6.0.²³ Data are expressed in the text as the mean±SEM.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Study Population
Two hundred twenty-seven patients with unstable angina were randomized to the study drug. Table 1 lists their clinical characteristics. The majority had a prior myocardial infarction, and many had prior revascularization procedures. More women tended to be randomized to the high-dose Integrelin group than to the aspirin control group (P=.08). There were no differences in baseline characteristics among the three randomized groups as a whole or between men and women in each of the three randomized groups. Thirty-three percent of the group were entered into the study with transient ischemic ST-segment changes during an episode of chest pain, and the remainder were enrolled with unstable angina and known coronary artery disease.

View this table: [in this window] [in a new window]   Table 1. Subject Characteristics

There were no differences in the types or doses of anti-ischemic therapy used in each of the three treatment groups. One hundred ninety-eight patients (87%) had received aspirin within 3 days before study drug administration (Table 1).

Efficacy Analysis of Study Drug: Holter Ischemia
One hundred sixty-nine randomized patients met Holter monitoring criteria to determine the relative effects of Integrelin and aspirin on the number and duration of ECG ischemic episodes. The reasons for excluding 58 of the enrolled patients from this efficacy analysis include 4 randomized patients who did not receive the study drug, 2 patients with missing data, 27 patients with an abnormal baseline Holter ST segment that precluded ST-segment interpretation, 13 patients with Holter malfunction, 7 excluded for treatment violation (3 receiving the wrong study drug and 4 receiving an incorrect infusion rate), and 5 excluded for eligibility violation (4 with a myocardial infarction and 1 with significant anemia). Baseline characteristics of the patients studied in this efficacy analysis were similar to those of the entire study population, except that significantly more women were randomized to the high-dose Integrelin group than to the aspirin control group and fewer patients randomized to low-dose Integrelin had previous coronary artery bypass graft surgery (Table 1). Transient ischemic ST-segment changes during an episode of chest pain at entry into the study for the efficacy study group occurred in 23% of patients randomized to aspirin, 39% of patients randomized to low-dose Integrelin, and 28% of patients randomized to high-dose Integrelin. Similar numbers of patients were treated with anti-ischemic therapy in the three groups, and equal percentages of patients received aspirin within 3 days before randomization (Table 1).

Ischemia on Holter monitoring over the first 24 hours of study drug infusion occurred in 12 of 57 patients (21%) randomized to aspirin, 11 of 54 (20%) randomized to low-dose Integrelin, and 6 of 58 (10%) randomized to high-dose Integrelin. The mean numbers of Holter-defined ischemic events per 24 hours for each of the three treatment groups are shown in Fig 1, top. After correction for baseline differences in sex distribution, the number of ischemic events per 24 hours was smaller in the patients randomized to high-dose Integrelin, 0.24±0.11, than in those receiving aspirin, 1.0±0.33, P<.05. The number in the low-dose Integrelin group averaged 0.83±0.32 events per 24 hours.

View larger version (41K): [in this window] [in a new window]   Figure 1. Top, Number of ischemic episodes per 24 hours on Holter monitoring for the three groups of patients in the efficacy analysis. Patients randomized to high-dose intravenous Integrelin had significantly fewer episodes of Holter ischemia than the aspirin group. Values are mean±SEM. Bottom, Duration of ischemia per 24 hours on Holter monitoring for the three groups of patients in the efficacy analysis. The duration of Holter ischemia was significantly less in patients randomized to high-dose Integrelin than with aspirin therapy. Values are mean±SEM.

The duration of Holter-defined ischemic events per 24 hours of study drug infusion for the three groups is shown in Fig 1, bottom. The duration of ECG ischemia was less in the patients receiving high-dose Integrelin, 8.41±5.3 minutes, than in those in the aspirin group, 26.23±9.8 minutes (P=.01), after adjustment for the sex distribution. Subjects receiving low-dose Integrelin had an intermediate duration of ischemia over the first 24 hours, 18.20±7.7 minutes. Importantly, activated partial thromboplastin times were similar in the three groups during the 24 hours of study drug infusion (Table 2).

View this table: [in this window] [in a new window]   Table 2. aPTT During 24 Hours of Study Drug Infusion

Over the entire duration of study drug infusion (mean, 37.7±1.4 hours), the mean numbers of ischemic events were 1.68±0.55 in the aspirin group, 1.22±0.49 in the low-dose Integrelin group, and 0.59±0.21 in the high-dose Integrelin group (P=.02, high-dose Integrelin compared with aspirin group). The mean duration of Holter ischemia during the total duration of study drug infusion was 42.39±12.9 minutes in the aspirin group, 23.48±9.3 minutes in the low-dose Integrelin group, and 18.17±8.2 minutes in the high-dose Integrelin group (P=.06 compared with aspirin group). The number and duration of symptomatic ischemic episodes over 24 hours and the entire duration of study drug infusion were similar among the three treatment groups both in the efficacy and intention-to-treat analyses.

Sex Differences in Response to Antiplatelet Therapy
There were significant sex differences in the response to aspirin. In the 102 men randomized to study drug, there were no differences among the three treatment groups in the number or duration of ischemic episodes per 24 hours of study drug infusion (Fig 2). However, the number and duration of ischemic episodes per 24 hours were significantly greater in women than in men randomized to aspirin therapy (P<.05). The sex difference was not present in men and women randomized to high-dose Integrelin because of a significantly smaller number and shorter duration of Holter ischemic episodes in women assigned to this Integrelin dose compared with the number and duration of episodes in those assigned to aspirin (P<.01, Fig 2). There were no differences in heart rate or blood pressure measured at baseline and after 24 hours of study drug infusion among the three groups or between women randomized to aspirin and high-dose Integrelin, which could account for differences in Holter ischemia (Table 3).

View larger version (29K): [in this window] [in a new window]   Figure 2. Top, Number of ischemic episodes per 24 hours on Holter monitoring for men and women in the efficacy analysis randomized to aspirin, low-dose Integrelin, and high-dose Integrelin. Women randomized to aspirin therapy had a significantly greater number of ischemic episodes per 24 hours than men randomized to aspirin therapy. Women randomized to high-dose Integrelin had significantly fewer episodes of Holter ischemia than women randomized to aspirin therapy. Values are mean±SEM. Bottom, Duration of Holter ischemia per 24 hours for men and women in the efficacy analysis randomized to the three treatment groups. Women randomized to aspirin had significantly longer episodes of ischemia than did men receiving aspirin therapy. This sex difference was not present in the high-dose Integrelin group. Values are mean±SEM.

View this table: [in this window] [in a new window]   Table 3. Hemodynamics

Ischemic outcome differences to antiplatelet therapy persisted throughout the study drug infusion in women, such that those randomized to Integrelin had significantly fewer episodes of ischemia, 0.47±0.25 versus 3.71±1.6, and a shorter duration of ischemia, 9.70±7.9 versus 79.35±32.2 minutes, compared with women treated with aspirin.

Clinical Events
During the study drug infusion, there were very few clinical events in the treatment groups. In an intention-to-treat analysis (Table 4), four patients randomized to aspirin developed refractory ischemia. One of these evolved a myocardial infarction. Two patients randomized to low-dose Integrelin experienced a clinical outcome, one with refractory ischemia and one with a myocardial infarction. One patient randomized to high-dose Integrelin developed refractory ischemia.

View this table: [in this window] [in a new window]   Table 4. Clinical Outcomes

Platelet Aggregation and Bleeding Times
Platelet aggregation studies were performed at baseline, at 1 and 4 hours during the infusion, at termination of the infusion, and at 2 and 4 hours after infusion in 46 patients at one center. The percent platelet aggregation compared with baseline for each of the three groups is presented in Fig 3. Integrelin caused a dose-dependent rapid inhibition of platelet aggregation within 1 hour of the start of the infusion. Inhibition of platelet aggregation was significant with both low- and high-dose Integrelin at 1 and 4 hours of infusion and at the end of the infusion. Return to 60% of baseline aggregation occurred within 4 hours after infusion termination. Sixty-one patients underwent simplate bleeding times at baseline and termination of study drug. Pretreatment bleeding times were 6.32±1.44 minutes in the aspirin group, 4.20±0.54 minutes in the low-dose Integrelin group, and 5.42±0.92 minutes in the high-dose Integrelin group. At the time of completion of the study drug infusion, mean bleeding times were 6.43±1.1, 9.80±1.85, and 10.47±2.0 minutes for the aspirin, low-dose Integrelin, and high-dose Integrelin groups, respectively.

View larger version (26K): [in this window] [in a new window]   Figure 3. Platelet aggregation studies performed in 46 patients at baseline, at 1 and 4 hours during the study drug infusion, at termination of the study drug infusion, and 2 and 4 hours after infusion. Infusion of both low-dose () and high-dose () Integrelin resulted in a significant inhibition of platelet aggregation at 1 and 4 hours and at termination of the infusion compared with patients treated with aspirin plus placebo Integrelin (). Platelet aggregation returned toward baseline within 4 hours of termination of study drug.

Bleeding Events
The study drug infusion was well tolerated. Bleeding events are listed in Table 5 according to intention-to-treat analysis. The majority of the bleeding complications were ecchymoses or hematomas, primarily from intravenous line sites. There were no intracranial hemorrhages. There was one episode of rectal bleeding in the aspirin group and one episode of hematuria in the high-dose Integrelin group. The numbers of patients requiring blood transfusions within 24 hours after termination of the study drug were similar among the three groups. Furthermore, the hemoglobin concentrations 24 hours after study drug infusion were similar for the three groups: 12.8±0.2, 12.7±0.2, and 12.7±0.2 g/dL for the aspirin, low-dose Integrelin, and high-dose Integrelin groups, respectively.

View this table: [in this window] [in a new window]   Table 5. Bleeding Events

Withdrawal Ischemia
To determine whether rebound ischemia occurs after withdrawal of the study drug, ECG monitoring was continued in 110 study patients for a mean of 20.7 hours after termination of the study drug. These patients did not proceed to coronary revascularization during this time period. The change (withdrawal minus therapy) in the mean hourly number and duration of ischemic episodes was calculated for each group. There was no significant change in the mean number or duration of ischemic episodes per hour in the 37 patients randomized to aspirin therapy, -0.05±0.05 episodes and -0.80±0.77 minutes, respectively; the 34 subjects who received low-dose Integrelin, 0.03±0.02 episodes and 0.99±0.60 minutes, respectively; or the 39 patients who received high-dose Integrelin, 0.02±0.02 episodes and -0.30±0.36 minutes, respectively.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results indicate that high-dose Integrelin is a potent inhibitor of platelet aggregation that reduces the frequency and duration of ECG ischemia in patients with unstable angina compared with standard antiplatelet therapy with aspirin. Integrelin is well tolerated, its antiplatelet effects are rapidly reversible, and termination of therapy is not associated with rebound ischemia.

Clinical, laboratory, and catheterization evidence suggests that platelet aggregation and thrombosis contribute to clinical instability in unstable angina patients.^{9 24 25} Patients with unstable angina have elevated levels of thromboxane A₂ metabolites and fibrinopeptide A consistent with platelet activation and thrombosis, respectively.^{9 24} Coronary angiography and angioscopy frequently show eccentric stenoses and thrombus in the culprit coronary artery.^{6 25} In contrast to the fibrin-rich thrombi causing acute myocardial infarction, thrombi in patients with unstable angina appear to be rich in platelets.²⁵ Aspirin therapy for patients with unstable angina reduces acute myocardial infarction,^{12 13 14} and in men it reduces mortality as well.¹³ Despite permanent inhibition of cyclooxygenase activity, aspirin is a relatively weak inhibitor of platelet aggregation and does not prevent other agonist-mediated (eg, thrombin, serotonin, ADP, and platelet-activating factor) activation and aggregation.²⁶ These mediators are generated and accumulate at sites of endothelial injury and vascular stenoses in animal models as well as across the coronary bed in humans with unstable angina, and they may be responsible for the described cyclic reductions in flow in these patients.^{10 11}

Integrelin blocks the final common pathway of platelet aggregation by inhibiting the platelet fibrinogen receptor GP IIb/IIIa. GP IIb/IIIa is the most abundant receptor of the integrin family of adhesion receptors, and its GP IIb subunit is found exclusively on megakaryocytes and platelets.^{19 20 27} In the resting state, GP IIb/IIIa binds only to fibrinogen molecules attached to a solid substrate, such as the extracellular matrix. However, on platelet activation, GP IIb/IIIa appears to undergo a conformational change and becomes able to bind several extracellular matrix proteins, among which fibrinogen plays a principal role.²⁷ The triglobular structure of fibrinogen, with two different binding sites for GP IIb/IIIa located at the opposite poles of the molecule, allows it to bind two platelets simultaneously, leading to platelet aggregate formation through the IIb/IIIa receptor.

Recent studies suggest that inhibition of the GP IIb/IIIa receptor in unstable angina patients reduces ischemia. Inhibition of the GP IIb/IIIa receptor by use of the chimeric monoclonal antibody Fab fragment 7E3 reduced ischemia when added to aspirin and heparin in 60 patients with refractory unstable angina who underwent subsequent angioplasty.¹⁷ Preliminary data in 102 unstable angina patients suggest that the use of an intravenous nonpeptide inhibitor of the GP IIb/IIIa receptor also reduces ischemia.²⁸ The present study with Integrelin is the largest investigation to evaluate the efficacy of GP IIb/IIIa receptor blockade in unstable angina patients. Blockade of the GP IIb/IIIa receptor also reduces ischemic complications in angioplasty patients.²⁹

In this population of unstable angina patients, Integrelin induced a rapid dose-dependent inhibition of platelet aggregation that was significantly greater than the platelet inhibition induced by aspirin. Inhibition of platelet aggregation by Integrelin was rapidly reversible, which contrasts to the more prolonged platelet inhibition demonstrated with the chimeric monoclonal antibody Fab fragment 7E3.¹⁷ Despite rapid reversibility of platelet aggregability, patients did not experience an increase in Holter-detected ischemia after termination of Integrelin. All patients received full-dose aspirin at study drug termination, which may have contributed to the lack of any rebound ischemia.¹⁵

Many of the reports evaluating therapy for unstable angina have studied men.^{13 14} In contrast to men, the incidence of acute myocardial infarction in women has increased over the past two decades.³⁰ Furthermore, women with acute myocardial infarction appear to experience worse outcomes than men.^{31 32 33} Although the present study did not prospectively hypothesize that there would be a sex difference in the effects of platelet inhibition on the frequency and duration of Holter ischemia, subgroup analyses showed that women randomized to aspirin experienced a significantly greater number and duration of ischemic episodes than did men randomized to aspirin. There were no sex differences in heart rate or blood pressure that could explain the increase in ischemia in women. Furthermore, the sex difference in Holter ischemia was not present in the Integrelin groups. Preliminary data suggest that in asymptomatic subjects with a family history of early coronary artery disease, ex vivo platelets from women aggregate spontaneously and, on agonist stimulation, to a greater extent than do platelets from men.³⁴ On activation, platelets from women bind a greater number of fibrinogen molecules than platelets from men.³⁴ This sex difference in platelet aggregation and fibrinogen binding to activated platelets in asymptomatic subjects may be a mechanism that explains the sex differences noted in this study of unstable angina patients. The more potent platelet inhibitor Integrelin reduced the number of ischemic episodes and duration of ischemia in women to below the levels present in women treated with aspirin and to a level comparable to that of the men in the three study arms.

The limitations of this report include the fact that the present study was not designed to detect differences in the clinical end points of death, myocardial infarction, and refractory angina among the three groups. However, the clinical predictive value of Holter-detected ischemia was previously reported in the unstable angina population and to some extent may be interpreted as a "surrogate" marker for clinical outcomes.^{22 35} Gottlieb and coworkers^{22 35} demonstrated that in 70 patients with rest angina, ischemia on Holter monitoring was a powerful predictor of myocardial infarction and need for revascularization in both short- and long-term follow-up. The greater incidence of Holter-detected ischemia in that study, 53%, probably arose because heparin was not routinely used. Furthermore, the data on sex differences in response to aspirin therapy in this study represent subgroup analyses in relatively small numbers of women. The lack of a significant decrease in Holter ischemia in the women randomized to low-dose Integrelin probably results from a relatively small sample size. The potential of sex differences and the response to anti-ischemic therapy in unstable angina should be addressed in larger, prospective trials. Finally, the data on Holter ischemia after termination of the study drug was from a select group of patients who did not undergo catheterization or revascularization within 24 hours of study drug initiation and may not represent the entire group of unstable angina patients.

In conclusion, intravenous Integrelin, a GP IIb/IIIa platelet receptor antagonist, is well tolerated in patients with unstable angina, produces a dose-dependent inhibition of ex vivo platelet aggregation greater than that of aspirin, and reduces Holter-detected ischemia. The possible sex differences in this study that suggest the failure of aspirin in combination with heparin to prevent continued ischemia in women with unstable angina deserve further study. Integrelin and other more potent platelet inhibitors may have important therapeutic implications in patients with unstable angina.

	Acknowledgments

 
This study was supported in part by COR Therapeutics, Inc, San Francisco, Calif. The authors wish to recognize Drs R.L. Scarborough and R.L. Swift for their critical review of this manuscript.

	Footnotes

 
Reprint requests to Steven P. Schulman, MD, Carnegie 568, Johns Hopkins Hospital, Baltimore, MD 21287.

Guest editor for this article was Dr Valentin Fuster, Mount Sinai Medical Center, New York, NY.

Drs du Mee and Kitt are employed by COR Therapeutics, which contributed financially to this study.

Received August 21, 1995; revision received May 13, 1996; accepted May 20, 1996.

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