Influence of abciximab on evolution of left ventricular function in patients with non-ST-segment elevation acute coronary syndromes undergoing PCI after clopidogrel pretreatment: lessons from the ISAR-REACT 2 trial
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- Schulz, S., Mehilli, J., Ndrepepa, G. et al. Clin Res Cardiol (2011) 100: 691. doi:10.1007/s00392-011-0299-y
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Abciximab reduced the combined endpoint of death, myocardial infarction (MI) and target vessel revascularization in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation after a 600-mg loading dose of clopidogrel. The aim of the present study was to investigate the impact of abciximab on the evolution of left ventricular ejection fraction (LVEF) in these patients.
The current study included 1,158 patients enrolled in the randomized, double-blind ISAR-REACT 2 (the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial who had paired angiograms obtained at baseline and 6–8 months after randomization. Of them, 586 patients received abciximab and 572 patients received placebo. The primary outcome analysis was LVEF at 6–8-month follow-up.
Baseline LVEF was comparable in patients assigned to abciximab or placebo (53.2 ± 12.6 vs. 53.7 ± 12.1%; P = 0.393). At 6–8-month follow-up angiography, there was no difference in LVEF between the abciximab and placebo groups (55.4 ± 11.5 vs. 55.8 ± 11.2%; P = 0.743). Subgroup analysis of patients with elevated baseline troponin (>0.03 μg/L) also revealed comparable LVEF at follow-up in both treatment groups (P = 0.527). The multivariate analysis identified age, arterial hypertension, prior MI, prior coronary artery bypass graft surgery, baseline LVEF, MI at 30 days and repeat PCI as independent correlates of follow-up LVEF.
Although abciximab reduced the 30-day and 1-year incidence of major adverse cardiac events in patients with NSTE-ACS undergoing primary PCI after pre-treatment with a 600-mg loading dose of clopidogrel, the agent did not improve or impact on the evolution of LVEF over 6–8 months of follow-up.
The use of glycoprotein IIb/IIIa receptor blockers in patients with acute myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) not only improves acute vessel patency but also tissue perfusion (by protecting microvascular function) and the recovery of contractile function [1–4]. Most of these studies, however, have been performed in the era of no or inadequate clopidogrel pretreatment and involved mostly patients with acute ST-segment elevation MI. The impact of abciximab on left ventricular function in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI) after pretreatment with 600 mg clopidogrel has not been investigated.
The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) trial was a randomized, double-blind, multicenter study that tested the efficacy of abciximab in patients with high-risk ACS undergoing early PCI after pretreatment with a 600-mg loading dose of clopidogrel . The study demonstrated a significant reduction in the combined end point of death, MI or target vessel revascularization with abciximab compared to placebo at 30 days  and 1 year . Meanwhile, a troponin-based subgroup analysis revealed that the benefit of abciximab was confined to patients with elevated baseline troponin (>0.03 μg/L) . However, it remains unclear whether these beneficial effects would translate into enhanced left ventricular function at long-term follow-up. The goal of the present study was to investigate the effect of abciximab on systolic left ventricular function in patients with NSTE-ACS undergoing PCI after treatment with a 600-mg loading dose clopidogrel.
Details of the ISAR-REACT 2 trial design have been published previously . In brief, the trial was conducted from March 2003 through December 2005 and included 2,022 patients with NSTE-ACS undergoing PCI after pretreatment with 600 mg clopidogrel. All patients included in the study had given their written, informed consent. The study protocol was approved by the ethics committees of the participating centers and adhered to the Declaration of Helsinki. The present study included patients from three participating centers: the Deutsches Herzzentrum in Munich, the 1. Medizinische Klinik, Klinikum rechts der Isar in Munich and the Klinikum Garmisch-Partenkirchen. Of the 1,634 patients enrolled in these three centers, paired angiograms of adequate quality, at baseline (before intervention) and at 6–8 months thereafter were available in 1,158 patients who were included in the present study.
Details of study protocol
Patients received 600 mg clopidogrel at least 2 h prior to PCI, as well as 500 mg aspirin. The recommended strategy was an early PCI with stenting within 6 h from the diagnosis of ACS. After the decision to perform the PCI but before the guide wire had crossed the lesion, patients were randomly assigned in a double blind manner to receive either abciximab or placebo using sealed opaque envelopes containing the block randomization sequence for each participating center. Patients in the abciximab arm received a 0.25 mg per kilogram body weight bolus of abciximab, followed by an infusion 0.125 μg per kilogram per minute (maximum 10 μg/min) for 12 h and 70 Units of unfractionated heparin per kilogram body weight. Patients in the placebo arm received a placebo bolus and infusion for 12 h as well as 140 Units of unfractionated heparin per kilogram body weight. Double blinding was achieved by using identically appearing vials in both study groups.
Post-interventional antithrombotic therapy consisted of aspirin 200 mg per day indefinitely and clopidogrel 75 mg twice daily for the remainder of the hospitalization (but not more than 3 days) followed by 75 mg a day for at least 6 months. Other cardiac medications were prescribed at the discretion of the patient’s physician. All patients were scheduled to undergo coronary angiography 6–8 months after the procedure or whenever they showed symptoms or signs of myocardial ischemia. More details of the study protocol were reported in the primary publication .
Outcomes and definitions
The primary outcome of this analysis is left ventricular ejection fraction (LVEF) at 6–8-month follow-up. The diagnosis of MI was made according to the Thrombolysis In Myocardial Infarction (TIMI) criteria  and was based on the development of new abnormal Q waves (≥30 ms in duration and ≥0.1 mV in depth) in two or more contiguous precordial leads or in two or more adjacent limb leads, considered to be distinct from the evolution of the index MI; elevation of CK-MB isoenzyme levels (or total CK levels if CK-MB levels were not available) to three times the upper limit of normal or greater and, if the pre-PCI CK-MB (or total CK) level was higher than the upper limit of normal, both an increase by at least 50% over the previous value and documentation that the level of CK-MB (or total CK) was decreasing prior to the suspected recurrent MI; recurrent anginal symptoms or new electrocardiographic changes compatible with MI associated with an elevation of CK-MB level to 50% or more above the peak level prior to randomization for patients in whom there had been no documented decrease of initially elevated CK-MB level prior to randomization; or a CK-MB level more than ten times the upper limit of normal for patients undergoing coronary artery bypass graft surgery (CABG).
Single plane left ventricular angiograms at baseline and 6–8 months were obtained using the same, 30° right anterior oblique projection. Angiographic parameters were analyzed offline in the Angiographic Core Laboratory by operators blinded to treatment assignment using an automated edge detection system (CMS version 7.1, Medis Medical Imaging Systems, Leiden, the Netherlands). Global LVEF was determined by applying the area length method .
Data are presented as mean ± standard deviation (SD), counts (%) or median (interquartile range). Pre-specified subgroup analysis was performed according to baseline troponin value (>0.03 μg/L). Differences between the two groups were assessed using the χ2 test or Fisher’s exact test for categorical data, and the nonparametric Wilcoxon rank-sum test or Student’s t test for continuous data. Multiple linear regression analysis was used to identify independent predictors of LVEF at 6–8-month follow-up. For an a posteriori sample size calculation, nQuery Advisor version 4.0 was used. All other analyses were performed with S-PLUS statistical package (Version 4.5, Insightful Corporation, Seattle, WA, USA). A two-sided P value of less than 0.05 was considered to indicate statistical significance.
Baseline clinical and angiographic characteristics
Abciximab (n = 586)
Placebo (n = 572)
Age (years ± SD)
65.4 ± 10.8
66.2 ± 11.1
Male, n (%)
Diabetes mellitus, n (%)
On insulin therapy, n (%)
Arterial hypertension, n (%)
Smoker, n (%)
Hypercholesterolemia, n (%)
Body-mass index (kg/m2)
27.3 ± 3.8
27.2 ± 4.0
Prior myocardial infarction, n (%)
Prior coronary artery bypass graft surgery, n (%)
Elevated baseline troponin (>0.03 μg/L), n (%)
Elevated baseline creatinine kinase MB ( >24 U/L), n (%)
ST-segment changes, n (%)
Angiographic and procedural characteristics
Multivessel disease, n (%)
Vessel affected, n (%)
Left anterior descending coronary artery
Left circumflex coronary artery
Right coronary artery
Venous bypass grafts
Complex lesions, n (%)
Lesion length (mm ± SD)
14.5 ± 7.6
15.0 ± 8.2
Vessel size (mm ± SD)
2.9 ± 0.5
2.8 ± 0.5
Minimal lumen diameter before intervention, mm
0.9 ± 0.5
0.9 ± 0.5
Diameter stenosis before intervention (%)
68 ± 17
70 ± 16
Intervention, n (%)
Percutaneous transluminal coronary angioplasty
Medical therapy at discharge
Clopidogrel pretreatment interval (h ± SD)
5.6 ± 5.5
5.4 ± 5.3
Statins, n (%)
Betablockers, n (%)
Angiotensin-converting enzyme-inhibitors and angiotensin II receptor antagonists, n (%)
Nitrates, n (%)
Calcium antagonists, n (%)
Evolution of left ventricular ejection fraction
Left ventricular ejection fraction
All patients (n = 1,158)
n = 586
n = 572
Baseline LVEF (%)
53.2 ± 12.6
53.7 ± 12.1
Follow-up LVEF (%)
55.4 ± 11.5
55.8 ± 11.2
Troponin-positive patients (n = 538)
n = 270
n = 268
Baseline LVEF (%)
49.5 ± 12.8
50.8 ± 12.1
Follow-up LVEF (%)
53.3 ± 12.9
54.2 ± 11.9
Troponin-negative patients (n = 620)
n = 316
n = 304
Baseline LVEF (%)
56.4 ± 11.5
56.4 ± 11.5
Follow-up LVEF (%)
57.1 ± 9.8
57.1 ± 10.4
LVEF according to troponin level
A subgroup analysis was performed according to baseline troponin level (dichotomized at a troponin level of 0.03 μg/L). There were 538 patients with increased baseline troponin level (troponin-positive patients) and 620 patients with baseline troponin level ≤0.03 μg/L (troponin-negative patients).
Baseline LVEF was lower in troponin-positive patients compared to troponin-negative patients (50.1 ± 12.5 vs. 56.4 ± 11.5%; P < 0.001). In troponin-positive patients, there was an improvement in LVEF during follow-up (50.1 ± 12.5 vs. 53.8 ± 12.4%; P < 0.001; Fig. 2). No such improvement in LVEF was observed in troponin-negative patients (56.4 ± 11.5% at baseline vs. 57.1 ± 10.0% at 6–8-month follow-up; P = 0.390; Fig. 2).
In troponin-positive patients, there was no difference in LVEF between patients assigned to abciximab or placebo at baseline (49.5 ± 12.8 vs. 50.8 ± 12.1%; P = 0.299) or at follow-up (53.3 ± 12.9 vs. 54.2 ± 11.9%; P = 0.527; Table 2; Fig. 1). Likewise, there were no significant differences in baseline LVEF (56.4 ± 11.5 vs. 56.4 ± 11.5%; P = 0.618) or follow-up LVEF (57.1 ± 9.8 vs. 57.1 ± 10.4%; P = 0.966) among troponin-negative patients assigned to abciximab or placebo (Table 2; Fig. 1).
Myocardial infarction and LVEF
During 30-day follow-up, 104 patients suffered myocardial infarction (MI): 39 patients (7%) in the abciximab group and 65 patients (11%) in the placebo group (P = 0.005). In patients who had MI within the first 30 days after PCI, LVEF at baseline (49.1 ± 11.3 vs. 53.9 ± 12.4%; P < 0.001) and at 6–8-month follow-up (51.9 ± 11.5 vs. 55.9 ± 11.2%; P < 0.001) was significantly lower compared to patients remaining free of MI at 30 days of follow-up.
Repeat PCI and LVEF
During the follow-up, repeat PCI of the target vessel was required in 205 patients: 90 patients (15%) in the abciximab group and 115 patients (20%) in the placebo group (P = 0.034). In patients who had repeat PCI, baseline LVEF did not differ significantly compared to patients who did not have repeat PCI during the follow-up (52.5 ± 12.5 vs. 53.7 ± 12.3%; P = 0.227). At 6–8-month follow-up, however, LVEF was significantly lower in patients who underwent repeat PCI compared to patients who did not undergo repeat PCI (53.7 ± 11.6 vs. 56.0 ± 11.2%; P = 0.009).
Multivariable analysis: independent predictors of LVEF at 6–8-month FU
Prior coronary artery bypass graft surgery
Myocardial infarction within 30 days after PCI
The main finding of the present study is that abciximab use in patients with NSTE-ACS undergoing early PCI who were pre-treated with a 600 mg loading dose of clopidogrel did not improve LVEF over 6–8 months of follow-up.
Systolic LV function has been considered as one of the strongest independent prognostic predictors after myocardial infarction since the pre-thrombolytic era [11–13], and it has retained its predictive value in the contemporary interventional cardiology [14–17]. Modern reperfusion therapy have enhanced myocardial salvage and improved functional myocardial recovery [18–20]. The efficacy of several pharmacological agents [21, 22] and cell-based therapies [23, 24] has been investigated by quantification of their impact on the LVEF. In prior studies, the glycoprotein IIb/IIIa inhibitor abciximab, when used as adjunctive therapy to PCI, has improved not only vessel patency but also recovery of microvascular and contractile myocardial function [1–4]. Since none of these studies included patients with adequate clopidogrel pre-treatment , they do not reflect the current practice of interventional cardiology. Recent studies have shown that pretreatment with a loading dose of 600 mg clopidogrel blunted the benefits achieved with periprocedural abciximab use in patients with stable coronary artery disease  and acute ST-segment elevation MI [26, 27] undergoing PCI. Moreover, an updated meta-analysis  could not confirm previous reduction in mortality and reinfarction observed with abciximab [29, 30] after the inclusion of two recent acute MI trials [26, 31] that used abciximab on top of clopidogrel pretreatment. Whether the very early use of abciximab has the potential to increase myocardial salvage and improve outcomes of STEMI patients is still a matter of ongoing discussion [32–34]. The randomized ISAR-REACT 2 trial showed a significant reduction in composite major adverse cardiac events with abciximab as compared to placebo in patients with NSTE-ACS undergoing PCI after 600 mg clopidogrel at 30 days  and 1 year . The reduction in adverse events was achieved by a non-significant reduction of all three components of the primary end point (death, MI and target vessel revascularization) by abciximab, with the greatest reduction observed in the occurrence of MI (8.7% versus 11.3%) and the need for target vessel revascularization (13.2% versus 16.2%). Although the ISAR-REACT 2 trial was underpowered for mortality, there was no significant difference in survival between the two groups at 1 year (4.5 vs. 4.9%). According to an a posteriori sample size calculation, detection of an improvement of LVEF at follow-up of 5% compared to the placebo group (follow-up LVEF of 55.8 ± 11.2% in the placebo group) at an alpha level of 0.05 and with 80% power would have required the inclusion of 80 patients per group. Thus, the current study had more than 99% power to detect a difference of 5% in LVEF at follow-up which was deemed to be clinically meaningful.
The ISAR-REACT 2 study showed that abciximab use reduced the incidence of MI within the first 30 days after PCI and the need for target vessel revascularization over one-year follow-up. Both variables were identified as independent predictors of follow-up LVEF in the present study. Nevertheless, the agent failed to improve left ventricular function. The explanation for this apparent paradox is not entirely clear. The impact of peri-procedural MI on patients’ outcome has long been a matter of debate among interventional cardiologists [35–37]. Some studies have shown a strong impact of peri-procedural MI on patients’ prognosis [38, 39]. Other studies, however, failed to show an association between moderate creatine kinase release and outcome, especially in otherwise successful interventions [40–42]. While the debate on the creatine kinase defined periprocedural MI continues, there is little doubt about the importance of large Q-wave MIs in the setting of major procedural complications . In this regard it must be acknowledged that in the present analysis only 11 of 104 MIs (10.6%) were classified as Q-wave MIs. Interestingly, patients suffering from MI during 30-day follow-up in the current study already had a lower LVEF at baseline. In a previous study of 7,773 patients with NSTE-ACS undergoing PCI, the occurrence of periprocedural MI was not found to be an independent predictor of prognosis but rather a marker of the underlying arteriosclerotic burden and procedural complexity .
The finding that repeat PCI is associated with reduced LVEF at follow-up is an important finding. Baseline LVEF was not different in patients incurring repeat PCI or not. The results may suggest a negative impact of restenosis on the evolution of LV function in patients with NSTE-ACS. However, the clinical implications of restenosis are even more contentious than those of periprocedural MI . On the one hand, there are suggestions that restenosis is not a benign process, and its occurrence is associated with increased risk of acute MI and mortality [45, 46]. On the other hand, the most powerful tool for prevention of restenosis, i.e. drug-eluting stents, could not improve long-term prognosis of patients treated with these devices . However, there are suggestions that the benefits of restenosis reduction achieved by drug-eluting stents are offset by an increased risk of late stent thromboses compared with bare metal stents . Regarding the current findings, it may be speculated that reduction of the need for repeat PCI with abciximab may not compensate for the negative impact of restenosis on LVEF or that repeat PCI per se may cause some impairment in left ventricular function through distal embolization. However, the relationship between repeat PCI and LVEF needs investigation in further studies.
Even though the prevalence of NSTE-ACS is considerably higher than that of acute ST-segment elevation MI and it keeps increasing , most information on the evolution of LVEF stems from patients with STEMI. The current study expands previous data of our group on the evolution of LVEF in STEMI patients  in that it shows an improvement in systolic LV function also in patients with NSTE-ACS during follow-up. This improvement was evident regardless of whether the patient received abciximab or placebo.
In the ISAR-REACT 2 trial, the clinical benefit of abciximab was confined to patients with an elevated baseline troponin (>0.03 μg/L) . As expected, those patients with an elevated baseline troponin value were found to have a lower LVEF at baseline compared to patients with negative baseline troponin (≤0.03 μg/L). The present analysis showed that improvements in LVEF during follow-up were confined to patients with elevated baseline troponin level. This is consistent with previous studies on the evolution of LVEF after acute MI that have shown the greatest improvement in LV function in patients with the lowest baseline LVEF . Yet, even in patients with elevated baseline troponin level, abciximab failed to improve left ventricular function compared to placebo.
The present analysis has several limitations. First, since only patients with repeat angiography were included, no conclusion can be drawn about patients who died before this time point and who probably represent the sickest subset of patients. Second, although left ventricular angiography is still considered the gold standard technique for LVEF measurement, new and probably more accurate and reproducible methods for assessment of LV function such as magnetic resonance tomography have emerged . Third, since we used single plane ventriculography, wall motion abnormalities in the posterolateral wall could not be detected. This may be considered to most likely affect patients in whom the circumflex artery was the target vessel. However, since the distribution of the target vessel was not different in both study groups, this is unlikely to have impacted the results. Fourth, the assessment of global LVEF does not rule out changes in regional LV function. Fifth, the present analysis is a post-hoc analysis of a larger randomized clinical trial and therefore subject to inherent limitations of such analyses. Finally, the lack of significant impact of abciximab on left ventricular ejection fraction as shown in this study may not be strong enough to justify modifications of guidelines about the need of abciximab in patients with acute coronary syndromes. We cannot exclude that reduction in periprocedural myocardial infarction observed with abciximab in troponin-positive patients with acute coronary syndrome may require a period longer than 6–8 months before showing an impact on left ventricular function.
In conclusion, although abciximab reduced the 30-day and 1-year incidence of major adverse cardiac events in patients with NSTE-ACS undergoing primary PCI after pre-treatment with a 600 mg loading dose of clopidogrel, the agent did not improve or impact on the evolution of LVEF over 6–8 months of follow-up. This finding may have implications concerning the long-term benefits of abciximab in patients with NSTE-ACS undergoing PCI.
The ISAR-REACT 2 trial was supported in part by the grant KKF 04-03 from Deutsches Herzzentrum, Munich, Germany.
Conflict of interest
AK has received honoraria from Eli Lilly, Astra-Zeneca and Bristol-Myers Squibb.