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European Heart Journal Advance Access originally published online on May 8, 2006
European Heart Journal 2006 27(12):1401-1407; doi:10.1093/eurheartj/ehl004
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

A comparison of dual vs. triple antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndrome: results of the ELISA-2 trial

Saman Rasoul1, Jan Paul Ottervanger1, Menko-Jan de Boer1, Kor Miedema2, Jan C.A. Hoorntje1, Marcel Gosselink1, Felix Zijlstra3, Harry Suryapranata1, Jan-Henk E. Dambrink1 and Arnoud W.J. van 't Hof1,*

1 Isala Klinieken, Department of Cardiology, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands
2 Isala Klinieken, locatie Weezenlanden, Department of Clinical Chemistry, Zwolle, The Netherlands
3 University Medical Center Groningen, University of Groningen, The Netherlands

Received 4 October 2005; revised 29 March 2006; accepted 6 April 2006; online publish-ahead-of-print 8 May 2006.

* Corresponding author. Tel: +31 38 4242198; fax: +31 38 4243222. E-mail address: v.r.c.derks{at}isala.nl


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims To compare dual vs. triple antiplatelet pre-treatment in patients with non-ST-elevation acute coronary syndrome (NSTE ACS) who were planned for early catheterization.

Methods and results A total of 328 consecutive patients with NSTE ACS were included and were randomized to pre-treatment with dual (n=166, aspirin, clopidogrel 600 mg) or triple antiplatelet therapy (n=162, aspirin, clopidogrel 300 mg, and Tirofiban). The primary endpoint was enzymatic infarct size, defined as cumulative LDH release (LDHQ48). Initial TIMI flow of the culprit vessel was a pre-specified secondary endpoint. Angiography was performed in 98% of patients at a median of 23 h after admission. Enzymatic infarct size (median, 25–75%) was 166 (60–349) IU/L in the triple group compared with 193 (75–466) IU/L in the dual group (P=0.2). Initial TIMI 3 flow of the culprit vessel was significantly more often observed after triple antiplatelet therapy (67 vs. 47%, P=0.002). At 30 days follow-up, myocardial infarction (MI) occurred in 46% of patients in the triple antiplatelet group, compared with 57% in the dual antiplatelet group, P=0.052. No significant difference in bleeding was present.

Conclusion This study showed that in patients with NSTE ACS, triple antiplatelet pre-treatment was associated with a non-significant reduction in enzymatic infarct size, a significantly better initial perfusion of the culprit vessel, and a trend towards a better survival without death or MI. Further, large-scale studies should be performed to find whether the beneficial trend in favour of triple antiplatelet pre-treatment can be reproduced.

Key Words: Non-ST-elevation acute coronary syndrome • Antiplatelet therapy • Myocardial infarct size • TIMI flow


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
Previous studies showed that glycoprotein (GP) IIb/IIIa blockers improve outcome in high-risk patients with non-ST-elevation acute coronary syndrome (NSTE ACS), especially in those patients who undergo an early invasive strategy.1–3 These studies, however, were performed without the routine co-administration of clopidogrel. In the past few years, clopidogrel has been shown to be effective as pre-treatment in patients undergoing angioplasty. These effects were shown both in patients undergoing elective percutaneous coronary intervention (PCI)4 and in patients with NSTE ACS.5 In addition, it was found that a loading dose of 600 mg was associated with faster platelet aggregation inhibition, when compared with the regular 300 mg loading dose.6 In the ELISA-1 study, it was shown that a strategy of delayed angiography with concomitant pre-treatment with tirofiban was associated with improved angiographic outcomes and less initial enzyme release.7 These brought us to compare a dual antiplatelet strategy of aspirin and 600 mg of clopidogrel with a triple antiplatelet strategy of aspirin, clopidogrel 300 mg, and the GP IIb/IIIa blocker tirofiban in patients with NSTE ACS who were all scheduled for angiography within 48 h.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Consecutive patients with NSTE ACS were enrolled in the ELISA-2 trial. Inclusion criteria were ischaemic chest pain classified as Braunwald class 3 and the presence of at least one of the following criteria: new ST-depression of more than 1 mm in at least two ECG leads or a positive biomarker (Cardiac troponin T >0.05 µg/L or creatine kinase (CK)-MB elevation more than the upper limit of normal). Patients were excluded for the following reasons: age >80, persistent ST-segment elevation, previous PCI within the preceding 6 months, cardiogenic shock, or a contraindication for the use of triple antiplatelet therapy or invasive therapy. All patients were treated with low molecular weight heparin, beta-blockers, statins, nitroglycerin, and angiotensin-converting enzyme-inhibition when appropriate. After the patients gave written informed consent, they were randomized by a computerized randomization procedure. Patients were randomized to pre-treatment with either dual (aspirin, clopidogrel 600 mg) or triple antiplatelet therapy (aspirin, clopidogrel 300 mg, and tirofiban 10 µg/kg bolus, 0.15 µg/kg/min maintenance) (Figure 1). Study medication was given in an open-label manner. All patients were scheduled for coronary angiography within 48 h after admission. Type of revascularization, PCI or coronary artery bypass grafting (CABG), was left at the discretion of the operator. In the triple antiplatelet group, tirofiban was continued for 12 h in case PCI was performed.


Figure 0041
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  		Figure 1 Study flow chart.

 
Upstream tirofiban bailout in the dual antiplatelet patients was defined as initiation of tirofiban because of recurrent or persistent ischaemia before angiography. The bailout use of tirofiban downstream was left at the discretion of the operator. Event-free survival was defined as freedom of death or myocardial infarction (MI). The primary endpoint was enzymatic infarct size. Initial TIMI flow of the culprit vessel was a pre-specified secondary endpoint. Both endpoints were analysed by an independent core lab (Diagram B.V., Zwolle, The Netherlands) by technicians who were unaware of the clinical data.

Enzyme release and enzymatic infarct size
Blood samples were obtained on admission and every 6–12 h hereafter up to 72 h. In case PCI was performed later than 72 h after admission, cardiac enzymes were measured at 6 and 12 h after PCI. Enzymatic infarct size (LDHQ48) was calculated based upon enzyme concentrations of lactate dehydrogenase (LDH) as the reference enzyme, in which an area under the curve was calculated from at least 5 measurements. A two-compartment model was used, which has been validated in studies on the turnover of radio labeled plasma proteins and circulating enzymes.8–10 In addition, as an alternative assessment of enzymatic infarct size, peak CK was defined as the highest level of CK during admission, with the exception of patients who underwent CABG during the index hospital admission.

Angiographic data analysis
All angiograms were analysed by an independent core lab without the knowledge of clinical data. TIMI flow grades of the culprit vessel were assessed before and after the angioplasty procedure, as previously described.11

Clinical outcome
Total death and MI were assessed at 30-day follow-up. MI was defined as a CK-MB elevation of >6% of total CK, whenever CK was above 200 U/L (men) or above 170 U/L (women). After CABG, MI was defined as the development of new Q-waves on the post-CABG electrocardiogram. Major bleeding was defined as the need for at least two units of blood and a fall in haemoglobin of >2 mmol/L, corrective groin surgery, gastro-intestinal, cerebrovascular haemorrhage, or retro peritoneal bleeding.

Statistical analysis
Sample size calculation
Sample size calculation was made based on the findings of ELISA-1 trial.7 Our hypothesis was that a strategy of triple antiplatelet therapy would reduce enzymatic infarct size by 30%. It was calculated, assuming an infarct size of 500 IU/L for the dual and 350 IU/L for the triple antiplatelet group with a standard deviation of 500 and assuming normal distribution of enzymatic infarct size, that 330 patients were needed to prove superiority of triple over dual antiplatelet therapy with a power of 80% and assuming a type I error of 5%.

Final analysis
The primary endpoint was compared using the Mann–Whitney test and expressed as median and 25th–75th percentiles. The secondary endpoint, initial TIMI 3 flow of the culprit vessel, was compared using {chi}2 analysis. The Fisher's exact test was used when the expected cell value was <5. Data were analysed according to the intention to treat principle. The difference in the occurrence of death or MI between the groups during 30-day follow-up was assessed by the Kaplan–Meier method using the log-rank test. A P-value <0.05 was considered statistically significant. All tests were two-sided.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
From September 2002 to January 2005, 328 patients were included, 166 were randomized to dual, and 162 to triple antiplatelet therapy. Baseline characteristics were not different between the groups (Table 1), except for a higher age in the dual antiplatelet group (65 vs. 62 years, P<0.05). Seventy-eight per cent of patients had a positive troponin T at the time of inclusion and 61% had at least 1 mm of ST-depression at electrocardiography on admission. Angiography was performed in 98% of patients after a median of 23 h after admission, without a difference between the groups (P=0.9).


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  		Table 1 Baseline and angiographic data

 
Primary and secondary endpoints
Enzymatic infarct size as assessed by LDHQ48 or peak CK is shown in Table 2 and Figure 2 and could be assessed in 256 (78%) and 327 (99,9%) patients, respectively. LDHQ48 median was 166 in the triple vs. 193 IU/L in the group who received dual pre-treatment, [relative reduction (RR) 14%, P=0.2]. Peak CK was 216 IU/L in the triple antiplatelet group and 261 IU/L in the dual antiplatelet group (RR 17%, P=0.3).


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  		Table 2 Enzyme release

 

Figure 0042
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  		Figure 2 Box and Whisker plots of enzymatic infarct size: (A) LDHQ 48 (IU/L) and (B) peak CK (IU/L).

 
Table 3 shows the angiographic parameters. Initial TIMI flow could be assessed in 248 out of 281 (86%) patients with a confirmed diagnosis of an ACS. Initial TIMI 3 flow of the culprit vessel was present in 67% in the triple antiplatelet group, when compared with 47% in the dual antiplatelet group (P=0.002). At initial angiography, thrombus was present in 6% in the triple antiplatelet group compared with 11% in the dual antiplatelet group (P=0.1). After multivariate analysis, correcting for all parameters which were borderline different (P<0.10) between the two groups (Table 1), the results of the primary and secondary endpoints did not change, no significant effect was found on enzymatic infarct size (OR 0.85, 95% CI 0.52–1.40, P=0.6). However, triple antiplatelet pre-treatment remained independently associated with a higher initial patency of the culprit lesion (OR 2.5, 95% CI 1.5–4.4, P=0.001). PCI and CABG were performed equally in both groups. TIMI 3 flow after PCI was 97 vs. 91% in the triple and dual antiplatelet group, respectively (P=0.10).


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  		Table 3 Angiography

 
Bailout use of tirofiban
Bailout tirofiban was used in 37 patients (22%) allocated to the dual antiplatelet group. In eight patients (5%), upstream tirofiban was given because of persistent symptoms of ischaemia before angiography. Another 29 patients (17%) were treated with tirofiban after angiography or PCI (downstream).

Medication
On discharge, the fast majority of the patients received aspirin, beta-blockers, statins, and clopidogrel (Table 4).


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  		Table 4 Discharge medication

 
Clinical outcome
Table 5 shows 30-day outcomes. Thirty-day follow-up was available in 325 (99%) of patients. Death or MI at 30-day follow-up occurred in 46% of patients in the triple antiplatelet group when compared with 57% in the dual antiplatelet group (P=0.052) (Figure 3) according to the intention to treat analysis. Whether MI was present on admission or occurred later as evolving or peri-procedural is given in Table 5 as well. Three patients had an MI on admission as well as after PCI and were counted in both groups.


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  		Table 5 Patient outcomes at 30 days

 

Figure 0043
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  		Figure 3 Kaplan–Meier survival-free of death or MI: (A) 96 h and (B) 30 days. AP, antiplatelet.

 
Safety
Sixteen patients (10%) in the dual group and 20 patients in the triple group (12%) had major bleeding complication (P=0.5). CABG-related bleeding occurred 10 and 14 patients, respectively. Six patients underwent surgical re-exploration because of tamponade. Intracranial haemorrhage did not occur in either treatment.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
This is the first study that compared an oral antiplatelet drug regimen of aspirin and high dose clopidogrel with a drug regimen containing aspirin, clopidogrel, and intravenous tirofiban as upstream therapy in patients with NSTE ACSs, who were all scheduled for early angiography. Only a small, non-significant decrease of enzymatic infarct size (primary endpoint) was observed after triple antiplatelet therapy. However, initial TIMI 3 flow of the culprit vessel, a pre-specified secondary endpoint, was more often present in patients pre-treated with the triple antiplatelet regimen.

This is in accordance with the findings of the ELISA-1 study7 and the PRISM-PLUS angiographic substudy12 which found a better initial perfusion and a lower presence of thrombus of the culprit vessel in patients pre-treated with tirofiban when compared with no tirofiban. In the latter study, the difference in angiographic outcome closely paralleled the differences in clinical outcome.

The beneficial value of upstream use of GP IIb/IIIa inhibitors on reduction of thrombus and improvement of initial patency has been described earlier; however, it is questionable whether the improved angiographic outcome pre-PCI translates into a better outcome after PCI. A TACTICS-TIMI 18 substudy showed that longer pre-treatment with tirofiban was associated with improved pre- and post-PCI myocardial perfusion.13 Also the PRISM-PLUS angiographic substudy found that initial TIMI 3 flow was associated with a better post-PCI TIMI flow.12 In our study, there was a trend towards a better post-PCI TIMI flow in patients treated with triple antiplatelet pre-treatment.

Enzymatic infarct size in NSTE ACS
In patients with NSTE ACS, changing the definition of MI may have important consequences. This was recently shown in the ICTUS trial, where outcome was different when the TACTICS criteria for MI were used.14 In our study, however, outcome did not change when three times the upper limit of normal value was used as cut-off. In Table 5, MI is given depending on the time of occurrence. Evolving MI tended to occur less often in the patients allocated to triple antiplatelet pre-treatment; however, peri-procedural infarction may be masked by the presenting ACS, especially when PCI is performed very early after admission. This is why we chose enzymatic infarct size over a period of time. This takes total enzyme release over a period of time into account and may better quantify the effect of distal micro-embolization, especially in patients whose enzymes have not returned to normal values on the moment of intervention. ELISA-1 showed that by using total enzyme release over a period of time, it was possible to detect an effect of treatment, which not became evident when only the incidence of (recurrent) MI was assessed.7 Previous studies which also evaluated enzymatic infarct size in patients with NSTE ACS found that enzymatic infarct size well correlated with clinical outcome.15

Comparison with other studies
In previous studies which compared dual with triple antiplatelet pre-treatment, patients with ACS were excluded. The ISAR-REACT trial performed in patients undergoing elective PCI did not find a difference in outcome between the groups.16 The CLEAR PLATELETS study showed that, in elective stenting, the use of a GP IIb/IIIa inhibitor on top of clopidogrel produced superior platelet inhibition and lower myocardial necrosis compared with high-dose (600 mg) or standard-dose (300 mg) clopidogrel alone.17 In our study, in patients with NSTE ACS, the addition of tirofiban to aspirin and clopidogrel was associated with a non-significant trend towards a better outcome and a beneficial effect on angiographic outcome. However, due to the small sample size of the trial, it is not possible to draw definite conclusions from our study. With the present level and difference of enzymatic infarct size between the groups, around 2.310 patients would have been needed to demonstrate a significant difference. The ongoing early ACS study, with a comparable design as ELISA-2, has planned to include more than 10.000 patients to find a difference in a combined clinical endpoint.18 Therefore, according to these results, there is no reason to change the most recent guidelines on PCI which recommend both clopidogrel 600 mg and a GP IIb/IIIa inhibitor in high-risk patients with ACS undergoing PCI.19

Safety
No significant difference in bleeding was observed between the two groups and intracranial haemorrhage did not occur in either treatment. However, among CABG-treated patients 10 out of 24 in the dual and 14 out of 28 in the triple antiplatelet-treated patients had procedural bleedings. In 18 patients, a fall in haemoglobin of >2 mmol/L requiring blood transfusion was present. In six patients, surgical re-exploration was performed because of pericardial tamponade. Despite this relatively high incidence of bleeding, clinical outcome was good in the patients who underwent CABG. So far, there are no large trials with concomitant use of GP IIb/IIIa inhibitor and high-dose clopidogrel in NSTE ACS patients. The ISAR-REACT trial,16 in patients undergoing elective PCI, showed no difference in major or minor bleeding; however, the incidence of minor bleeding complications, i.e. thrombocytopenia and the transfusion of blood products, was higher in the triple group. Also the CLEAR PLATELETS study showed no difference in bleedings complication between dual and triple antiplatelet therapy.17 To draw definitive conclusions on the safety of triple antiplatelet therapy in high-risk ACS patients, larger-scale clinical trials are needed.

Limitations
The dose of clopidogrel in the triple antiplatelet group was 300 mg, compared with 600 mg in the dual group. The lower dose was chosen because no data existed on the combination of intravenous tirofiban and 600 mg clopidogrel on a possible higher risk of bleeding at the moment the study was designed in 2001. However Gurbel et al.17 found that platelet inhibition does not differ when a GP IIb/IIIa inhibitor is combined with either 600 or 300 mg clopidogrel. Another limitation of the study is that LDHQ48 is not an established endpoint in NSTE ACS trials. However, previous trials showed that enzymatic infarct size is well correlated with clinical parameters.15,20 Another limitation of our study is the slight difference in baseline characteristics; however, after performing a multivariate analysis correcting for the borderline differences between the two groups (P<0.10), the results of primary and secondary endpoints did not change. Finally, enzymatic infarct size was not calculated in 22% of the patients (Figure 1); however, in these patients, median CKs were not different between the two groups, [135 (80–269) and 124 (71–226)] in the dual and triple group, respectively.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
This study showed that in patients with NSTE ACS, triple antiplatelet therapy was associated with a non-significant reduction in enzymatic infarct size, a significantly better initial perfusion of the culprit vessel, and a trend towards a better survival without death or MI. This study supports the current guideline18 that recommend the use of both clopidogrel and a GP IIb/IIIa inhibitor in high-risk patients with an NSTE ACS planned for invasive therapy.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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