CLINICAL PERSPECTIVE

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(Circulation. 2006;114:2040-2046.)
© 2006 American Heart Association, Inc.

Interventional Cardiology

Age-Dependent Effect of Abciximab in Patients With Acute Coronary Syndromes Treated With Percutaneous Coronary Interventions

Gjin Ndrepepa, MD; Adnan Kastrati, MD; Julinda Mehilli, MD; Franz-Josef Neumann, MD; Jurriën ten Berg, MD; Olga Bruskina, MD; Franz Dotzer, MD; Melchior Seyfarth, MD; Jürgen Pache, MD; Josef Dirschinger, MD; Kurt Ulm, PhD; Peter B. Berger, MD; Albert Schömig, MD

From Deutsches Herzzentrum (G.N., A.K., J.M., O.B., M.S., J.P., A.S.), Medizinische Klinik rechts der Isar (J.D., A.S.), and Institut für Medizinische Statistik und Epidemiologie (K.U.), Technische Universität, Munich, Germany; Herz-Zentrum (F.-J.N.), Bad Krozingen, Germany; St. Antonius Ziekenhuis (J.t.B.), Nieuwegein, Netherlands; Klinikum Garmisch-Partenkirchen (F.D.), Garmisch-Partenkirchen, Germany; and Geisinger Center for Health Research (P.B.B.), Danville, Pa.

Correspondence to Adnan Kastrati, MD, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 München, Germany. E-mail kastrati{at}dhm.mhn.de

Received April 8, 2006; de novo received May 30, 2006; revision received June 17, 2006; accepted August 11, 2006.

	Abstract

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Background— No studies have specifically performed an age-based analysis of the efficacy of abciximab in patients with non–ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention (PCI). The aim of the study was to assess whether there are age-dependent differences in the clinical benefit of abciximab in patients with acute coronary syndrome treated with PCI.

Methods and Results— We performed this retrospective analysis of 2022 patients with acute coronary syndrome enrolled in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) study and randomized to receive abciximab or placebo during a PCI procedure. The incidence of major adverse cardiac events (MACE) during the 30 days after PCI was the primary end point of the study. On the basis of the cutoff age value provided by logistic regression in connection with bootstrap resampling, patients were divided into those younger (n=1220) and older (n=802) than 70 years. Among younger patients, the incidence of MACE was 7.7% in the abciximab group versus 13.3% in the placebo group (relative risk 0.57, 95% confidence interval 0.40 to 0.80, P=0.001). In contrast, no difference was observed among older patients: The incidence of MACE was 10.9% in the abciximab group versus 9.9% in the placebo group (relative risk 1.10, 95% confidence interval 0.72 to 1.69, P=0.65). After adjustment for other variables, including cardiac troponin, there was a significant interaction between age and abciximab (P=0.04) with respect to MACE reduction, with abciximab being more effective in younger patients.

Conclusions— In patients with non–ST-elevation acute coronary syndromes undergoing PCI, the efficacy of abciximab appears to be age-dependent, with greater benefit among younger patients.

Key Words: aging • angina • angioplasty • coronary disease • infarction • platelets • stents

	Introduction

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Advanced age is an important associate of poor outcome during coronary interventions or the use of drugs such as thrombolytic agents. In Western countries, the number of elderly people with symptomatic coronary artery disease and the number of older patients being treated invasively is progressively increasing.^1,2 On the basis of 2004 data, persons 65 years of age represent 12.4% (or 36.3 million) of the US population; projections indicate that the proportion of persons 65 years of age will increase to 20% (or 71.5 million) of the US population by 2030.³ Acute coronary syndromes (ACS) are a common cause of emergency hospital admission and a major cause of morbidity and mortality.⁴ Non–ST-segment elevation ACS constitute nearly 50% of ACS, and their incidence has gradually increased during the last 3 decades.⁵ It has been estimated that non–ST-segment elevation ACS account for 2.5 million hospitalizations per year worldwide.⁶ Patients with ACS need urgent hospital admission, early intervention, and close coronary monitoring. Given the marked prevalence of heart disease, and ACS in particular, in elderly patients, the progressive growth of the proportion of the elderly population in the years to come, and the dramatic increase in the number of percutaneous coronary interventions (PCIs), testing the efficacy and safety of coronary interventions and their adjunct medications in older patients is an issue of increasing importance. Because no studies have specifically performed an age-based analysis of the efficacy of glycoprotein IIb/IIIa receptor blockers, whether these agents are as safe and effective in older patients with non–ST-segment elevation ACS is largely unknown.

Editorial p 2004

Clinical Perspective p 2046

The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) trial was a randomized, double-blind, multicenter study that tested the efficacy of abciximab in patients with high-risk ACS undergoing an early PCI after pretreatment with a 600-mg loading dose of clopidogrel.⁷ The study demonstrated that abciximab reduces the 30-day incidence of major adverse cardiac events (MACE).

The objective of the present study was to assess whether there are age-dependent differences in the clinical benefit of glycoprotein IIb/IIIa receptor blockade with abciximab in patients with non–ST-segment elevation ACS treated with PCI.

	Methods

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Patients
Between March 2003 and December 2005, 2022 high-risk patients with non–ST-segment elevation ACS pretreated with 600 mg of clopidogrel at least 2 hours before a PCI were randomized to receive abciximab or placebo in the ISAR-REACT 2 trial.⁷ Criteria for enrollment included (1) an episode of angina (with an accelerating pattern or prolonged [>20 minutes] or recurrent episodes at rest or with minimal effort) within the preceding 48 hours and either an elevated troponin T level (>0.03 µg/L), newly developed ST-segment depression of 0.1 mV, transient (<20 minutes) ST-segment elevation of at least 0.1 mV, or new or presumed new bundle-branch block; and (2) 1 significant stenosis in a native coronary vessel or venous bypass graft amenable to and requiring a PCI.

Exclusion criteria included ST-segment elevation (0.1 mV in 2 contiguous ECG leads); hemodynamic instability (pericarditis; life expectancy <1 year; increased risk of bleeding; stroke within the preceding 3 months; active bleeding or bleeding diathesis; recent trauma or major surgery within the last month; suspected aortic dissection; oral anticoagulation; or the use of glycoprotein IIb/IIIa receptor inhibitors within the last 2 weeks); high blood pressure (>180 mm Hg) unresponsive to therapy; a hemoglobin level <100 g/L, hematocrit <34%, or platelet count <100x10⁹/L or >600x10⁹/L; known allergy to any of the study medications; and pregnancy (present or suspected).

All patients included in the study provided written informed consent. Institutional ethics committee approval was obtained in all participating centers.

Details of Study Protocol
The ISAR-REACT 2 trial study protocol has been published elsewhere.⁷ In brief, all patients who were included received 600 mg of clopidogrel at least 2 hours before the PCI and 500 mg of aspirin. After a decision to perform PCI was made, patients were randomly assigned in a double-blind manner to receive either abciximab or placebo by use of sealed opaque envelopes that contained the block randomization sequence for each participating center. Patients in the abciximab arm received a bolus of abciximab 0.25 mg/kg weight followed by an infusion of 0.125 µg · kg^–1 · min^–1 (a maximum of 10 µg/min) for 12 hours and a 70 U/kg bolus of heparin intravenously. Patients in the placebo arm received a bolus and a 12-hour continuous infusion of placebo, as well as a 140 U/kg bolus of intravenous heparin. Double blinding was achieved by use of identically appearing vials in both study groups. Postinterventional antithrombotic therapy consisted of aspirin 100 to 325 mg indefinitely and clopidogrel 75 mg twice daily for the remainder of the hospitalization up to 3 days, followed by a recommendation of 75 mg/d for at least 6 months. Other cardiac medications were prescribed at the discretion of the patient’s physician. Other details of the study protocol were published previously.⁷ The local research coordinators collected data and forwarded them to the data coordinating center. A high quality of data collection was ensured by checking source documentation in random samples.

All patients were either seen by their physician or interviewed by phone at 30 days; patients with cardiac complaints underwent a complete clinical, ECG, and laboratory checkup. The primary end point of the ISAR-REACT 2 trial was the incidence of MACE (combined incidence of death, myocardial infarction, and urgent target-vessel revascularization [coronary artery bypass surgery or PCI] due to myocardial ischemia) within 30 days of randomization. The secondary end point of the trial was in-hospital incidence of major and minor bleeding. Detailed definitions of trial end points were reported in the primary publication.⁷ All events were adjudicated and classified by an adjudication committee blinded to the assigned treatment.

Statistical Analysis
Data are presented as mean±SD, counts, or proportions (%). The study population was divided into 2 groups according to age. The cutoff age value was determined by application of a bivariate logistic regression model with MACE as a dependent variable and age, abciximab, and their interaction term (age*abciximab) as independent variables. We used bootstrap resampling based on 100 samples to calculate the lower fifth percentile of age beyond which no benefit with abciximab was predictable by the logistic regression model. This was used as the cutoff value for dividing the population into 2 groups. Continuous data were compared with the use of a 2-tailed t test. Categorical data were compared with the use of a ² test or Fisher exact test when expected cell values were <5. Analysis of survival and analysis of survival free of MACE were performed by application of the Kaplan-Meier method and log-rank test, which allowed the calculation of relative risk (RR [95% confidence interval]) associated with abciximab in the 2 age groups. Multiple logistic regression analysis was used to identify independent correlates of MACE and to assess the adjusted interaction between age and abciximab. All analyses were performed with the S-plus statistical package (S-PLUS, Insightful Corp, Seattle, Wash). A probability value <0.05 was considered to indicate statistical significance.

The authors had full access to the data and take full responsibility for their integrity. All authors have read and agree to the manuscript as written.

	Results

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Figure 1 summarizes the distribution of adverse events among age decades according to the study treatment group, abciximab or placebo. From the bivariate logistic regression model (see "Statistical Analysis"), there was a significant interaction between age and abciximab effect on MACE (P=0.01). The cutoff age value beyond which no benefit with abciximab was predicted by this model was 69.7 years. Thus, we divided the patient population into 2 groups: patients 70 years old or younger and patients older than 70 years.

View larger version (20K): [in this window] [in a new window]   Figure 1. Incidence of major bleeding (top), 30-day mortality (middle), and 30-day combined incidence of death, myocardial infarction, and urgent target-vessel revascularization (TVR) according to age quartiles and assigned treatment. MI denotes myocardial infarction; and TVR, target-vessel revascularization.

Baseline Characteristics
Baseline clinical characteristics of the patients are shown in Table 1. In the group of younger patients, the baseline characteristics of those randomized to abciximab and placebo were similar with the exception that there was a higher proportion of patients with diabetes mellitus in the placebo group. In the group of older patients, baseline characteristics were similar among those who received abciximab and placebo.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics

Baseline angiographic data are shown in Table 2. Angiographic characteristics were similar among patients who received abciximab or placebo in both age groups.

View this table: [in this window] [in a new window]   TABLE 2. Angiographic and Procedural Characteristics

Interaction Between Age and Abciximab Effect
Multiple logistic regression analysis was used to identify independent correlates of MACE in the 30 days after enrollment in the study. The following variables were entered into the model: age group (older than 70 years or not), sex, diabetes mellitus, arterial hypertension, body mass index, smoking, hypercholesterolemia, prior myocardial infarction, prior PCI, prior coronary artery bypass surgery, interval from clopidogrel loading, serum creatinine, elevated troponin level, elevated creatine kinase-MB level, therapy at discharge, left ventricular ejection fraction, vessel treated, multivessel disease, complex lesions, type of intervention (stent versus balloon angioplasty), and interaction term "age group*abciximab." Factors independently associated with MACE are shown in Table 3 with their respective regression coefficients and adjusted probability values. There was a significant interaction between age group and abciximab (P=0.04), with abciximab being more effective in younger patients than in older patients.

View this table: [in this window] [in a new window]   TABLE 3. Predictors of MACE at 30 Days

Abciximab in Younger Patients
Table 4 shows the 30-day outcome in younger patients. There were 2 deaths (0.3%) among patients who received abciximab versus 9 deaths (1.5%) among patients who received placebo (RR 0.20, 95% confidence interval [CI] 0.05 to 0.81, P=0.02). The combined incidence of death or myocardial infarction was 7.6% in the abciximab group versus 13.0% in the placebo group (RR 0.57, CI 0.40 to 0.81, P=0.002). The incidence of MACE was 7.7% in the abciximab group versus 13.3% in the placebo group (RR 0.57, CI 0.40 to 0.80, P=0.001; Figure 2). The benefit was mostly confined to younger patients with elevated troponin level (11.7% in the abciximab group versus 21.3% in the placebo group, P=0.001), whereas no significant difference was observed among younger patients with normal troponin levels (4.0% in the abciximab group versus 4.9% in the placebo group, P=0.57). However, the interaction between troponin level and abciximab effect in the subset of younger patients was statistically not significant (P=0.20). Among younger patients with diabetes mellitus, the incidence of MACE was 9.0% in the abciximab group and 11.8% in the placebo group (P=0.43). Among younger patients without diabetes mellitus, the incidence of MACE was 7.4% in the abciximab group and 13.9% in the placebo group (P=0.001).

View this table: [in this window] [in a new window]   TABLE 4. Thirty-Day Clinical Outcome

View larger version (12K): [in this window] [in a new window]   Figure 2. Thirty-day cumulative incidence of the primary end point (death, myocardial infarction, or urgent target-vessel revascularization) in patients 70 years according to assigned treatment.

Abciximab in Older Patients
Table 4 also shows the 30-day outcome in older patients. There were no significant differences in mortality, incidence of myocardial infarction, or target-vessel revascularization between abciximab and placebo groups in this age group. The combined incidence of death or myocardial infarction was 10.3% in the abciximab group versus 9.4% in the placebo group (RR 1.11, CI 0.72 to 1.71, P=0.65). The incidence of MACE was 10.9% in the abciximab group versus 9.9% in the placebo group (RR 1.10, CI 0.72 to 1.69, P=0.65; Figure 3). The lack of benefit with abciximab was observed for both older patients with an elevated troponin level (15.2% in the abciximab group versus 14.5% in the placebo group, P=0.83) and older patients with normal troponin levels (5.8% in the abciximab group versus 4.2% in the placebo group, P=0.49). No significant difference between the abciximab and placebo groups regarding the incidence of bleeding was observed, but blood transfusion was needed more often among patients who received abciximab than among those who received placebo.

View larger version (12K): [in this window] [in a new window]   Figure 3. Thirty-day cumulative incidence of the primary end point (death, myocardial infarction, or urgent target-vessel revascularization) in patients >70 years according to assigned treatment.

	Discussion

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Several randomized trials have reported the ability of glycoprotein IIb/IIIa receptor inhibitors to reduce death or myocardial infarction when used as adjunctive therapy to PCI.^8–13 Accordingly, glycoprotein IIb/IIIa receptor inhibitors are recommended by the American College of Cardiology/American Heart Association guidelines¹⁴ and European Society of Cardiology Guidelines for Percutaneous Coronary Interventions¹⁵ for use in patients with ACS. However, whether the age of patients influences the efficacy of these agents is largely unknown. Subgroup analyses from the randomized studies have provided conflicting results, with some of them showing greater benefit in younger patients^8–10 and others showing greater benefit in older patients.^11–13 Another source of uncertainty regarding the treatment of elderly patients with ischemic heart disease comes from the fact that patients of older age are underrepresented in the randomized controlled trials of patients with ACS over the last 25 years.¹⁶ Older age remains an important correlate of failure to administer fibrinolytic and other important therapies of proven benefit^17,18 and for the performance of coronary angiography and invasive treatment procedures in patients.¹⁹

This was a post hoc analysis of a randomized trial. Although we acknowledge this limitation, the findings of the present study are strengthened by a significant interaction between age and efficacy of abciximab. This analysis reveals that older patients with non–ST-segment elevation ACS undergoing PCI had a greater incidence of death, bleeding, and thrombocytopenia and more often needed blood transfusion than younger patients within 30 days after PCI procedure. This finding coincides with previous studies that have reported a worse outcome,^19,20 more bleeding complications,²¹ and an increased incidence of thrombocytopenia²² in older patients. Curiously, when we looked at the placebo group, younger patients showed a trend toward a higher incidence of MACE than older patients (13.3% versus 10.6%). This apparently paradoxical finding may be explained by the fact that most of the MACE were postprocedural myocardial infarctions. Younger patients presented a greater thrombus burden at baseline, which conveys an increased risk of myocardial infarction. But the main finding of the present study is the striking age-dependent difference in the efficacy of abciximab used as adjunct therapy to PCI in patients with non–ST-segment elevation ACS. In younger patients, the incidence of the primary end point was reduced by >50% by abciximab. Abciximab therapy did not reduce the 30-day incidence of death or any other component of MACE in older patients.

Although bleeding complications and the need for blood transfusion were encountered more often in older patients, abciximab therapy did not significantly increase the incidence of bleeding in younger or older patients. A prior study of pooled data of 3 randomized trials^8–10 showed that thrombocytopenia associated with abciximab used during PCI was more frequent in older patients.²² The present study also showed that abciximab therapy was associated with thrombocytopenia significantly more often in older than in younger patients.

The mechanism underlying the apparent lack of efficacy of abciximab therapy in older patients with non–ST-segment elevation ACS undergoing PCI is not entirely clear. Prior studies have shown increased platelet reactivity with advancing age.^23,24 Because platelet reactivity is one of the key predictors for the growth of arterial thrombus and consequent tissue damage, one might anticipate greater benefits of platelet inhibition in older patients. In contrast, the present study showed that abciximab therapy was only effective in younger patients. Older patients in the present study had a greater atherosclerotic burden, as evidenced by a greater proportion of patients with multivessel coronary artery disease and a higher degree of complexity of lesions. It has been reported that aging is associated with vascular wall changes at the level of extracellular matrix,²⁵ endothelial dysfunction,^26,27 and reduced production of nitric oxide in the endothelium.²⁸ In fact, the success of PCI in restoring normal epicardial TIMI (Thrombolysis in Myocardial Infarction) flow was similar across the age and treatment groups. It is well known, however, that a major part of abciximab benefit when used as an adjunct to PCI is exercised at the level of the microcirculation.²⁹ Coronary microcirculation in older patients may already be impaired by factors beyond those linked to embolization of platelet aggregates, which are minimally, if at all, influenced by abciximab therapy. Clinical studies have demonstrated that, in patients with myocardial infarction, impaired coronary microcirculation is associated with reduced myocardial salvage³⁰ and increased in-hospital mortality.³¹ Second, thrombotic burden estimated by amount of thrombotic material over the culprit lesions and the proportion of patients with TIMI flow grade 0 and 1 was greater in patients of younger age. It may be hypothesized that greater thrombotic burden may provide a better substrate for abciximab action. Although it remains speculative as a cause of greater thrombotic burden, a greater prevalence of the Pl^A2 gene polymorphism of glycoprotein IIIa in patients having a coronary event before the age of 60 years has been reported.³² Pl^A1,A2-positive platelets exert a greater thrombotic tendency than Pl^A1,A1 platelets, and they are more sensitive to inhibition by aspirin and abciximab.³³

In conclusion, in patients with non–ST-elevation ACS undergoing PCI, the efficacy of abciximab appears to be age-dependent, with greater benefit in younger patients.

	Acknowledgments

 
Sources of Funding

This trial was supported in part by the grant Kommission für Klinische Forschung (KKF) 04-03 from Deutsches Herzzentrum, Munich, Germany.

Disclosures

Dr Kastrati reports having received lecture fees from Bristol-Myers Squibb, Lilly, and Sanofi Aventis. Dr Berger reports having received unrestricted educational grants from Lilly, Sankyo, Bristol-Myers Squibb, and Sanofi-Aventis; he has also received research support from Guilford, research grants from Schering Plough, and lecture fees from Bristol-Myers Squibb and Sanofi-Aventis. The remaining authors report no conflicts.

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CLINICAL PERSPECTIVE

It is not known whether age interferes with the efficacy of abciximab in patients with non–ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention. We assessed this issue in 2022 patients with acute coronary syndromes enrolled in a randomized, double-blind, placebo-controlled trial on the value of abciximab during percutaneous coronary interventions. The incidence of major adverse cardiac events (death, myocardial infarction, and urgent revascularization) for 30 days after randomization was the primary end point of the study. Patients were divided into those younger (n=1220) and older (n=802) than 70 years. Among younger patients, the incidence of major adverse cardiac events was 7.7% in the abciximab group and 13.3% in the placebo group (relative risk 0.57, 95% confidence interval 0.40 to 0.80, P=0.001). In contrast, no difference was observed among older patients: The incidence of major adverse cardiac events was 10.9% in the abciximab group and 9.9% in the placebo group (relative risk 1.10, 95% confidence interval 0.72 to 1.69, P=0.65). After adjustment for other variables, there was a significant interaction between age and abciximab (P=0.04) with respect to the reduction of major adverse cardiac events, with abciximab being more effective in younger patients. Thus, in patients with non–ST-elevation acute coronary syndromes undergoing percutaneous coronary intervention, the efficacy of abciximab appears to be age-dependent, with greater benefit observed among younger patients. These findings may help in fine-tuning the adjunct antithrombotic therapy during percutaneous coronary interventions.

	Footnotes

 
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00133003.

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