Five-year outcome of patients with acute myocardial infarction enrolled in a randomised trial assessing the value of abciximab during coronary artery stenting

Gjin Ndrepepaa, Adnan Kastratia,*, Franz-Josef Neumannb, Claus Schmitta, Julinda Mehillia and Albert Schömiga

a Deutsches Herzzentrum and Medizinische Klinik rechts der Isar, Technische Universität, Lazarettstr 36, 80636 Munich, Germany
b Herz-Zentrum, Bad Krozingen, Germany

Received February 20, 2004; revised April 20, 2004; accepted April 29, 2004 * Corresponding author. Tel.: +49-89-12184577; fax: +49-89-12184593
kastrati{at}dhm.mhn.de

See page 1562 for the editorial comment on this article1


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Aims The aim of the study was to investigate the long-term (five years) efficacy of glycoprotein IIb/IIIa inhibition with abciximab given as an adjunct therapy to coronary stenting in patients with acute myocardial infarction (MI) using the patient cohort of the Intracoronary Stenting and Antithrombotic Regimen-2 (ISAR-2) randomised trial.

Methods and results The patient cohort of ISAR-2 trial (401patients) was followed up for 5 years after enrolment. There were 201 patients in the abciximab group (stenting plus abciximab) and 200 patients in the control group (stenting without abciximab). The primary end-point of the study was mortality at 5 years. Recurrent MI and target vessel re-vascularisation were also assessed at 5 years after enrolment. On the basis of the Kaplan–Meier analyses, the 5-year mortality was 17.8% (35 patients) in the group with abciximab and 14.6% (29 patients) in the control group (relative risk, 1.20 [95% confidence interval, 0.73–1.96]; ). The 5-year combined incidence of death, recurrent MI and target vessel re-vascularisation was 38.2% (76 patients) in the group of abciximab and 37.7% (75 patients) in the control group (relative risk, 0.97 [95% confidence interval, 0.70–1.33]; ). Multivariable analysis showed no significant independent association of abciximab with 5-year mortality (adjusted hazard ratio, 1.16 [95% confidence interval, 0.70–1.92]; ).

Conclusion These findings are not in support of a sustained clinical benefit at 5 years with the use of abciximab during coronary artery stenting in patients with acute MI.

Key Words: Abciximab • Mortality • Myocardial infarction • Stents


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The strategy of the combined use of percutaneous coronary interventions and glycoprotein IIb/IIIa receptor inhibitors is based on the understanding that glycoprotein IIb/IIIa receptor inhibition achieves a better initial reperfusion and maintains an anti-thrombotic milieu, both at the target lesion and downstream at the microcirculation level. Several trials of patients with acute myocardial infarction (AMI) have demonstrated that abciximab, an inhibitor of glycoprotein IIb/IIIa receptor, when used as adjunct therapy to coronary angioplasty1,2 or stenting,3–5 reduces the 30-day composite end-point of death, recurrent myocardial infarction (MI) and urgent re-vascularisation. In the Controlled Abciximab Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial, the 30 day cumulative incidence of sub-acute thrombosis was lower with abciximab after either angioplasty or stenting.6 The CADILLAC trial also demonstrated a 30-day increase in event-free survival by abciximab predominantly by reducing ischaemia-driven target vessel re-vascularisation rate.6 Contrary to the abundant evidence on short-term benefits from abciximab use, there has been much less evidence on the long-term clinical benefits of abciximab used as adjunct therapy to coronary stenting in patients with AMI.3–6 The dedicated trials have had variable but in general short lengths of follow-up (mostly 6 months or one year) and, importantly they have given contradictory results with some reporting a prolonged survival benefit from glycoprotein IIb/IIIa receptor inhibition4,5 and some not.3,6

The Intracoronary Stenting and Antithrombotic Regimen-2 (ISAR-2) trial was a randomised, open-label trial which included 401 patients with AMI who were randomly assigned to coronary stenting with or without abciximab.3 The 30-day and one-year results from this study have been reported.3 The patient cohort of the ISAR-2 trial was followed up to five years after the randomisation. Thus, the aim of the present study was to investigate the long-term (five years) efficacy of abciximab given as an adjunct therapy to coronary stenting in patients with acute MI using the patient cohort of the ISAR-2 trial.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
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Patient cohort
Briefly, ISAR-2 was a randomised prospective open-label trial that investigated the effect of abciximab on angiographic and clinical restenosis in patients with AMI within 48 h from the pain onset. The diagnosis of AMI was established in the presence of typical anginal pain lasting 30 min accompanied by one of the following criteria: ST-segment elevation of at least 1 mm in two or more contiguous leads, elevation in creatine kinase to at least three times the upper limit of normal with a concomitant rise in MB isoenzyme or coronary artery occlusion with angiographic appearance of fresh thrombus. Patients after failed thrombolysis were also included. The study population consisted of 401 consecutive patients with AMI who were randomly assigned to stenting plus abciximab (abciximab group, 201 patients) or stenting without abciximab (control group, 200 patients) immediately after the decision for stent placement was made. The group with abciximab received a bolus of abciximab (ReoPro, Lilly Deutschland GmbH), 0.25 mg/kg of body weight, followed by a continuous infusion, 10 µg/min for 12 h plus 2500 U heparin intra-arterially. The control group received 10,000 U heparin intra-arterially, followed by an intravenous heparin infusion at a rate of 1000 U/h for the first 12 h after sheath removal. Post-interventional anti-thrombotic therapy consisted of ticlopidine (500 mg/day) for four weeks and aspirin (200 mg/day), indefinitely, for both groups. A follow-up angiography was scheduled to be performed at 6 months or earlier if the patients had recurrent symptoms or signs of myocardial ischaemia. Other details have been reported in the original study.3

Definitions and follow-up
The primary end-point of the original study was late loss obtained by coronary angiography at 6 months after enrolment. Clinical restenosis was also assessed by monitoring target vessel re-vascularisation. A composite end-point of death, recurrent MI and target vessel re-vascularisation at 30 days and one year was assessed and reported previously.3

The primary end-point of this study was mortality at 5 years of follow-up. Recurrent MI and target vessel re-vascularisation were also assessed at 5 years after enrolment. The follow-up protocol beyond the first year after the enrolment consisted of phone interviews at 12-month intervals. Patients were advised to come to the outpatient clinic or their referring physicians if they developed chest pain or other cardiac symptoms. In case of symptoms, at least one clinical, laboratory and electrocardiographic control was performed. The 5-year follow-up was complete in all but 18 patients or 4.5% of the entire population (10 patients in the abciximab group and 8 patients in the control group). The median length [interquartile range] of the follow-up interval for those patients who could not be contacted at 5 years was 2.2 years [1.9–2.9 years], with a range between 0.9 year and 4.4 years.

On the basis of the information obtained from hospital records, death certificates or phone contact with relatives of the patient or attending physician, deaths were classified as cardiovascular or non-cardiovascular. Two definitions were used for the diagnosis of recurrent MI. During the initial hospitalisation, the diagnosis was based on the presence of chest pain with either new ST-segment changes or an increase in creatine kinase (CK) and its MB isoenzyme of at least 50% over the previous trough level in at least 2 samples exceeding 3 times the upper limit of normal. After discharge, the diagnosis was based on the presence of typical chest pain accompanied by either the appearance of pathological Q-waves on electrocardiogram or an increase of CK/CK-MB 2 times the upper limit of normal. Target vessel re-vascularisation was defined as coronary by-pass surgery or repeat percutaneous transluminal coronary angioplasty performed during the follow-up period due to symptoms or signs of myocardial ischaemia.

Statistical analysis
The assumptions used for the sample size calculation have been published previously.3 All data were analysed on an intention-to-treat basis using 2-sided statistical tests. Discrete variables were presented as counts (percentages) and continuous variables were presented as mean±SD. The test was used to test for differences between study groups regarding discrete variables. The Kaplan–Meier method was used to estimate survival, survival free of MI and event-free survival. Comparisons between the study groups were performed by the log-rank test which also allowed the calculation of the relative risk with its 95% confidence interval. The Cox proportional hazards model was used to investigate the independent association of demographic and clinical variables with mortality. The following variables with potentially prognostic value were entered into the multivariable model: age, sex, arterial hypertension, diabetes, multi-vessel disease, Killip class, anterior wall localization of MI, ST-segment elevation MI, prior thrombolytic therapy and CK peak value. We tested for fulfilment of the assumptions of linearity and proportional hazards. The use of restrictive cubic spline function7 showed that the relation between the 2 continuous variables in the model – age and CK peak value – and the hazard ratio did not deviate from the linear form. The assumption of proportional hazards was tested for each co-variate using the method based on weighted residuals.7 Two variables, Killip class and prior thrombolytic therapy, did not meet this assumption and were included as stratification factors. The final model included only factors that met the proportional-hazards assumption. All analyses were performed using the S-Plus statistical package. A P-value of less than 0.05 was considered to indicate statistical significance.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Basic characteristics of the patients included in the ISAR-2 trial are shown in Table 1 . The 30-day and one-year clinical results as well as 6-month angiographic measures of the ISAR-2 trial have previously been reported and show an improved clinical outcome with abciximab.3


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Table 1 Baseline characteristics

 
Five-year clinical outcome
On the basis of the Kaplan–Meier analyses, the 5-year mortality was 17.8% (35 patients) in the group with abciximab and 14.6% (29 patients) in the control group (relative risk, 1.20 [95% confidence interval, 0.73–1.96]; ). Fig. 1 shows the survival curves for the 2 groups. Of 64 cases of death, 13 could be categorised as having a non-cardiovascular origin: 6 in the abciximab group and 7 in the control group. For patients who died, the median interval to death was 631 days [interquartile range, 80–1282 days] in the abciximab group and 172 days [interquartile range, 8–640 days] in the control group, (using the non-parametric Wilcoxon test).



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Fig. 1 Five-year survival curves in the 2 study groups.

 
Recurrent MI occurred in 7 patients (3.5%) in the group with abciximab and 7 patients (3.5%) in the control group (relative risk, 0.99 [0.35, 2.84]; ). Target vessel re-vascularisation was performed in 42 patients (20.9%) of the abciximab group and in 47 patients (23.5%) of the control group (relative risk, 0.89 [0.59, 1.35]; ). The 5-year combined incidence of death, recurrent MI and target vessel re-vascularisation was 38.2% (76 patients) in the group of abciximab and 37.7% (75 patients) in the control group (relative risk, 0.97 [0.70–1.33]; ). Fig. 2 shows the event-free survival curves for the 2 groups. In addition, non-target vessel re-vascularisations were performed in 38 patients (18.9%) of the abciximab group and 37 (18.5%) of those of the control group (relative risk, 1.02 [0.65, 1.61]; ).



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Fig. 2 Five-year event-free survival in the 2 study groups.

 
Table 2 shows the 5-year event rates and the relative risks connected with the assignment to abciximab therapy in the entire population and in relevant subsets including patients without prior thrombolysis, patients with ST-segment elevation MI, patients with anterior MI and those with presentation to hospital within 6 h from symptom onset.


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Table 2 Analysis of the adverse events at 5 years in the entire population and in subgroups

 
Results of the multivariable analysis
Only 4 of the demographic and clinical variables entered into the Cox proportional hazards model (see Methods for the list of variables) were found to be independently associated with 5-year mortality: diabetes (hazards ratio, 2.57 [95% confidence interval, 1.47–4.49]; ), multi-vessel disease (hazards ratio, 2.33 [1.22–4.43]; ), age (hazards ratio for a 10-year increment, 1.39 [1.07–1.82]; ), and CK peak value (hazards ratio for an increase of 400 U/L, 1.10 [1.01–1.21]; ). The multivariable analysis showed no significant independent association of abciximab with 5-year mortality (adjusted hazard ratio, 1.15 [0.69–1.92, ).


    Discussion
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 Methods
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 Discussion
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Reperfusion therapy, either pharmacological or mechanical, has produced long-term survival benefits in patients with acute MI.8–10 Clinical trials have also demonstrated that abciximab, an inhibitor of glycoprotein IIb/IIIa receptor, reduces the incidence of death or MI in the immediate period after intervention and is associated with a survival benefit at 6 months to 3 years following percutaneous coronary interventions in a mixed collective including patients with stable angina and acute coronary syndromes.11,12 In a recent study, Anderson et al.,11 pooled eight randomised studies of abciximab used as an adjunct therapy to coronary stenting or angioplasty.2–4,6,13–16 The studies were of variable follow-up (mostly 6 months to 1 year) and included patients with varying clinical indications (stable angina, unstable angina and AMI). The abciximab use was associated with an overall 0.9% absolute increase in survival at one year of follow-up.11 Interestingly, this pooled analysis showed that the survival benefit associated with the use of abciximab was less prominent in patients with AMI and those treated with coronary stenting as compared to patients without MI and those treated with balloon angioplasty alone, respectively.11 In a separate analysis of patients without MI and those treated with balloon angioplasty only, the use of abciximab was associated with a statistically significant reduction in the long-term mortality.11 Furthermore, the pooled analysis by Anderson et al.,11 and the Evaluation of Platelet Inhibition in STENTing (EPISTENT) trial 17 have shown that only 9–15% of late deaths occurred in patients who have suffered a peri-procedural MI. Since a reduction in the incidence of peri-procedural MI cannot explain the long-term benefit, long-term survival benefit of abciximab has been explained by the "passivation" of diseased coronary arteries, which implies transformation of vessel surface from an inflamed state to a state that no longer attracts platelets or promotes thrombus formation.12 In other randomised trials, no benefit in 1-year survival has been demonstrated with the use of abciximab during coronary stenting.6 The CADILLAC trial reported an enhanced 30-day event-free survival but no significant 1-year difference in the composite of death, MI or stroke associated with the use of abciximab.6 The ISAR-2 trial reported a 5.5% absolute reduction in the 30-day incidence of death, recurrent MI and target lesion re-vascularisation in the abciximab group. By 1 year, the absolute reduction in the incidence of adverse cardiac events was preserved but the statistical significance was lost.3 In a recent editorial that also included a pooled analysis of trials on abciximab in AMI, Topol et al.,18 noted that the benefits of the drug may be more pronounced in patients with a higher baseline risk.

The present report of the ISAR-2 trial represents the longest follow-up to date of a series of patients with acute MI treated with coronary artery stenting plus abciximab. The study shows no survival benefit with abciximab at 5 years after randomisation. Furthermore, abciximab offered no benefit in the incidence of recurrent MI, or target vessel revascularisation. Event-free survival curves converged rather than diverged through the 5-year follow-up interval showing that the initial clinical benefit of abciximab diminishes over time. One limitation of the present study that should be taken into account during the interpretation of results is that the sample size calculation of the original ISAR-2 trial was based on measures of restenosis.3 Therefore, the present study is not sufficiently powered to assess clinical outcomes. In fact, the actual size of the population provides the study with a 68% power to detect a 30% difference in the 5-year combined incidence of death, recurrent MI and target vessel re-vascularisation. A meta-analysis of the long-term results of the trials on the value of abciximab in patients with AMI treated with percutaneous coronary interventions may offer a more precise answer to this issue.

In the light of the available information on the short-term efficacy of abciximab used as an adjunct therapy to percutaneous coronary interventions in patients with AMI, the results of this study are difficult to explain. In the era of modern reperfusion therapies, good short-term prognosis and survival without heart failure are possible even in patients with extensive MI.19 Abciximab improves the Thrombolysis in Myocardial Infarction (TIMI) 3 flow grade4 and recovery of the microvascular function and contractile function in the area at risk.20 Although these effects may improve the short-term survival, late deaths may not be influenced, or may even be increased, because the patients with extensive damage who survive the acute phase due to efficacious reperfusion therapy may die later in the course of the disease. In this line, previous thrombolytic studies in patients with AMI have demonstrated a significant improvement in the short-term survival but a lack of effect of the thrombolytic therapy on the left ventricular function at follow-up.21,22 In an attempt to offer an explanation for similar findings, Van De Werf has hypothesised that a poorer long-term survival following successful thrombolytic therapy may occur in patients with poor residual left ventricular function who survive the hospital phase because of effective reperfusion at the time of admission.23 The high post-discharge mortality in these patients neutralises the early survival benefit observed in successfully treated patients.23,24 The findings of this study, by demonstrating that the early beneficial effects of abciximab are not maintained at five years after coronary stenting in patients with AMI, together with the trend for a prolonged interval to death in the abciximab group, seem to provide further support to this hypothesis.23,24 The present results also suggest that abciximab may not belong to those reperfusion treatment strategies with a documented sustained benefit in patients with AMI.8,10

In conclusion, these findings are not in support of a sustained clinical benefit at 5 years with the use of abciximab during coronary artery stenting in patients with AMI.


    Footnotes
 
1 doi:10.1016/j.ehj.2004.07.024. Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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