Safety and efficacy of abciximab combined with dalteparin in treatment of acute coronary syndromes

Safety and efficacy of abciximab combined with

dalteparin in treatment of acute coronary syndromes

S. James

, P. Armstrong

, R. Califf

, S. Husted

, F. Kontny

, M. Niemminen

,

M. Pfisterer

, M. L. Simoons

and L. Wallentin

1_{Department of Cardiology, Academic Hospital, Uppsala, Sweden;}2_{Department of Medicine, University of Alberta,} Edmonton, Alberta, Cananda;3_{Duke CRI, Durham, NC, USA;}4_{Department of Cardiology, Aarhus, Amtssygehus,}

Aarhus, Denmark;5_{Heart-lung center, Ulleva´l Hospital, Oslo, Norway;}6_{University Hospital, Internal Medicin,} Helsinki, Finland;7University Hospital, Basel, Switzerland;8Thoraxcenter, Erasmus Medical Center, Rotterdam,

The Netherlands

AimsThe safety and efficacy of abciximab in addition to low-molecular-weight-heparin as the primary medical treat-ment of acute coronary syndromes has not previously been investigated.

Methods and Results The GUSTO IV–ACS trial in-cluded 7800 patients with chest pain and either ST-segment depression or a positive troponin test. They were random-ized to abciximab for 24 h, 48 h or placebo. In the dalteparin substudy, 974 patients received 5 days of s.c. dalteparin, instead of a 48 h infusion of unfractionated heparin (UFH). Major and minor bleedings were more frequent for abciximab (24 and 48 h combined) than pla-cebo both in the dalteparin (abciximab 5·0% vs plapla-cebo 1·8% P<0·05) and in the UFH cohort (3·8% vs 1·8%

P<0·001). However, stroke rates were low,c0·6%. At 30

days there were no significant differences in the rate of

death or MI, either in the dalteparin (abciximab 9·6% vs placebo 11·3%: O.R. 0·85; 95% C.I. 0·58–1·25) or in the UFH cohort (8·5% vs 7·6%: O.R.; 1·12: 0·95–1·34).

Conclusion Treatment with abciximab, aspirin and s.c. dalteparin is associated with a low risk of major side effects and is as safe as the combination of abciximab and UFH. Without early coronary intervention there is no indication for abciximab treatment.

(Eur Heart J, 2002; 23: 1538–1545, doi:10.1053/euhj.2002. 3257)

 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

Key Words:Angina, myocardial infarction, coagulation, heparin.

Introduction

In the treatment of acute coronary syndrome (ACS), low-molecular-weight heparin (LMWH) is at least as effective as unfractionated heparin (UFH)[1–3]_{. In spite}

of combination treatment with aspirin and short-term LMWH there is still a 15–25% risk for recurrent ischae-mic events during the first month after the ACS[1,3]_.

Glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitors have consistently been shown to reduce the rate of procedure-related myocardial infarction for patients undergoing coronary intervention in a large number of trials[4–6]_{. Furthermore, it has been shown that GP}

IIb/IIIa inhibitors, on top of aspirin and UFH, have reduced the rate of death and recurrent myocardial infarctions for patients with unstable angina and

suspected myocardial infarctions without ST-segment elevation. The GUSTO–IV ACS was the first large scale evaluation of the safety and efficacy of the GP IIb/IIIa inhibitor abciximab vs placebo on top of aspirin and full dose s.c. dalteparin or UFH as the primary treatment for unstable angina pectoris and non-ST elevation myo-cardial infarction[7]_{. The results indicated that abciximab}

added no benefit when used as the first-line medical treatment in patients admitted with acute coronary syndromes[7]_{. Yet, the overall results of major trials with}

GP IIb/IIIa inhibitors support the upstream use of these agents in patients with unstable coronary artery disease if referred for early invasive procedures[5,8–10]_{. As initial}

treatment with LMWH is part of standard therapy for patients with unstable coronary syndromes[11,12]_{, further}

experience of the combination of GP IIb/IIIa inhibitors with LMWHs are urgently needed. The focus of this report is the prespecified comparison of the safety and efficacy of abciximab within cohorts of patients treated with UFH or with the LMWH, dalteparin.

Revision submitted 25 March 2002, and accepted 27 March 2002.

Correspondence: Stefan James MD, Department of Cardiology,

Methods

The GUSTO IV ACS trial included 7800 patients with acute coronary syndromes between 1999 and 2000[7]_{. In}

Scandinavia, Switzerland and selected sites in the U.S., 72 centres recruited all their patients (n=974) to the dalteparin substudy, referred to as the dalteparin cohort. The non-dalteparin patients recruited in all other centres of the GUSTO IV ACS trial (n=6826) are referred to as the UFH cohort. The primary objective of this study was to evaluate the rate of side-effects, especially bleed-ings, during the initial 7 days in relation to the random-ized abciximab or placebo treatment within the dalteparin cohort as well as between the dalteparin and UFH cohorts. The secondary objective was to evaluate in the dalteparin cohort the primary endpoint from the main trial i.e. outcome at 30 days evaluated as the composite of death or myocardial infarction.

Study design

The design of the main GUSTO–IV ACS trial has been published[7]_{. The target population for recruitment was}

patients with an acute coronary syndrome without persistent ST-segment elevation. Eligible patients were

d21 years of age with one or more episodes of angina

lastingd5 min within the last 24 h. All had to demon-strate either a positive cardiac troponin T or I test (above the upper limit of normal for the local qualitative or quantitative assay) or d0·5 mm of transient or persistent ST-segment depression.

Exclusion criteria were mainly current ST-elevation myocardial infarction, recent or planned coronary interventions and factors associated with an increased bleeding risk[7]_.

The study was conducted in a double-blind fashion with patients randomly assigned to one of three treatment groups; abciximab therapy for 24 h (0·25 mg . kg
1 bolus followed by a 0·125
g . kg
1. min
1 infusion up to a maximum of 10
g . min
1 for 24 h) followed by 24 h of placebo infusion, abciximab therapy for 48 h (same bolus and infusion for a total duration of 48 h), or matching placebo (bolus and 48 h infusion) (Fig. 1). All patients were to receive 150–325 mg of non-enteric coated aspirin orally (or 250–500 mg intravenously) as soon as possible after randomization and for at least 30 days if not contraindicated. In the dalteparin substudy all patients were to receive dalteparin (120 IU . kg
1to a maximum of 10 000 IU) subcutaneously every 12 h for 5–7 days or until a revascularization procedure or discharge. Con-tinuation of dalteparin after the initial treatment was left to the discretion of the investigator. Patients not in the dalteparin substudy received a 70 U . kg
1 UFH bolus (to a maximum of 5000 U) followed by a continuous infusion of 10 U . kg
1/h (to a maximum of 800 U/h) titrated to maintain the aPTT between 50 and 70 s for 48 h following initiation of study drug.

Coronary angiography was not to be performed dur-ing or within 12 h after the completion of study agent

infusion (i.e. within 60 h after randomization) unless the patient had recurrent or continuing ischaemia at rest associated with ischaemic ST-T changes unresponsive to intensive medical therapy. If coronary intervention was required during placebo study drug administration, blinded cross-over to active therapy with abciximab was provided at selected study sites that had facilities for such interventions.

All patients had an ECG examination at baseline, 48 h and at 30 days. Venous blood samples were col-lected at baseline and 8, 16, 24, 36 and 48 h after randomization for a central laboratory analysis of creatinine kinase isotype-MB (CK–MB). Additional samples were to be collected at 0, 8, 16, and 24 h after any ischaemic episode lasting >20 min.

The local ethics committee of each enrolling centre approved the study and all patients signed an informed consent before enrolment.

Bleeding classification

Bleeding was classified as major, minor or insignificant according to the TIMI criteria[13]. Major bleeding during baseline hospitalization (to a maximum of 7 days) was defined as either (1) intracranial haemorrhage or (2) bleeding associated with a haemoglobin drop greater than 5 g . dl
1. Two haemoglobin measurements at baseline and at day 7 (or discharge if earlier) were utilized to calculate blood loss. To estimate the total number of units of blood lost in patients who received blood transfusions, the number of units transfused was added to the observed drop in the haemoglobin. Minor bleeding was defined as any of the following: (1) spontaneous gross haematuria or haematemesis; (2) observed blood loss with decrease of haemoglobin >3 butc5 g . dl
1; or decrease of haemoglobin >4 but

c5 g . dl
1 _{without an identified bleeding site.}

Insignificant bleeding was defined as any bleeding not

Figure 1 Study chart. GUSTO IV–ACS trial. Heparin (H) and dalteparin (D) cohorts.

meeting the criteria for major or minor. Thrombocyto-penia was defined as a platelet count <50 000 . ml
1. An independent neurologist blinded to treatment assign-ment adjudicated all suspected occurrences of stroke or intracranial haemorrhage.

Statistical methods

According to the protocol the outcome analyses were made with the abciximab 24 h and 48 h treatment groups combined. The safety data were analysed for the abciximab groups separately but since there was no major difference between the abciximab groups these results are also presented with the groups combined. Comparisons were then made between the dalteparin and UFH cohorts. All evaluations were made on an ‘intention to treat’ basis. Comparisons between groups were made with Chi2 _{test. Fisher’s Exact test was used} for groups with small numbers. For continuous skewed variables a non-parametric, Mann–Whitney, test was performed. Differences between groups are presented as odds ratios with 95% confidence interval. To evaluate predictors of bleedings a multiple logistic regression analysis was performed. The following co-variates were included in a forward stepwise model; age >/<65 years, sex, body-weight, history of stroke or TIA, diabetes, hypertension, smoking, dalteparin cohort, randomized abciximab treatment, clopidogrel, aspirin, oral anti-coagulant and other LMWH usage. A forward stepwise multiple logistic regression analysis regarding predictors of the primary outcome, death or MI at 30 days was also performed. The covariates; age, gender, body-weight, smoking, previous angina, heart failure, previous revascularization and previous myocardial infarction, diabetes, hypertension, hypercholesterolaemia, ongoing treatment with beta-blockers and nitroglycerin, aspirin treatment prior to inclusion, ST-depression, positive troponin (>0·1
g . l
1), abciximab treatment and dalteparin cohort were included in the analysis. Statisti-cal analyses were performed using the SPSS 10.1 software on a personal computer.

Results

Baseline

The randomized treatment groups were well matched regarding all baseline characteristics. However, as com-pared to the 6826 patients in the UFH treated cohort, the 974 patients in the dalteparin cohort constituted a higher risk population as indicated by higher age and weight, more prior bypass surgery, more often an evolv-ing myocardial infarction and a positive troponin test (Table 1). On the other hand the dalteparin cohort patients had less hypertension, hypercholesterolaemia, diabetes, previous angina and ST-depression at baseline. During study drug infusion the dalteparin cohort

patients received less intravenous nitroglycerin but more often beta-blockers and clopidogrel.

Safety

Major bleedings (not related to coronary artery bypass surgery) were rare in all groups, although numerically doubled by abciximab treatment in both the UFH and dalteparin cohorts. Minor bleedings occurred at similar low rates in the dalteparin and the UFH groups but were also doubled by abciximab treatment in both cohorts (Table 2). In the dalteparin cohort, major and minor bleedings occurred in 5·0% in the abciximab group as compared to 1·8% in the placebo group (O.R. 2·71; 1·14–6·41). In the UFH cohort the difference between the abciximab and placebo groups were similar (3·8% vs 1·8%: O.R. 2·17; 1·52–2·99). Elderly patients in particu-lar (>65 years) had an increased risk of major and minor bleedings with abciximab (Fig. 2). The rate of insignifi-cant bleedings was at least doubled by abciximab in both cohorts and was considerably more common in the dalteparin cohort where it occurred in every fourth patient during placebo treatment. Thus, every second patient had at least one insignificant bleeding by the combination of the dalteparin and abciximab (Table 2). Along with the increased numbers of bleedings, the number of blood transfusions were increased in the dalteparin vs the UFH cohort (4·5% vs 2·6%, O.R. 1·75: 1·25–2·49, P=0·001).

Stroke (any type) was an uncommon event in all groups in the trial. The highest stroke rate was found in the abciximab group (0·6%) of the dalteparin cohort, but this was not statistically different from the placebo group (0%). The UFH treated patients experienced similar stroke rates (0·3% for both abciximab and placebo). Intracranial haemorrhage occurred only in one patient in the dalteparin cohort receiving abciximab 24 h, which was not different from the UFH cohort (Tables 2and3).

Among the 147 patients in the dalteparin cohort who underwent intervention during the initial 7 days only four patients experienced major or minor bleedings. Forty-four patients were operated on and 11 of these had major or minor CABG-related bleedings without any difference between randomized treatment groups. In the UFH cohort the rates were similar.

In a forward stepwise multiple logistic regression analysis age, intervention during the initial 7 days and randomization to abciximab (Fig. 2) were independent predictors of major and minor bleedings (Table 4). Regarding all bleedings (major, minor and insignificant together) however, dalteparin treatment was also an independent predictor.

Thrombocytopenia was more common with abcixi-mab than placebo in the whole patient population. Severe thrombocytopenia (<50·000 . ml
1) occurred only with abciximab, both in the dalteparin (0·8% vs 0·0%, ns) and in the UFH cohort (1·6% vs 0·0%, ns). Moderate thrombocytopenia (<100·000 . ml
1) was

also more frequent with abciximab than placebo in the dalteparin (3·1% vs 1·5%, ns) and in the UFH cohort (6·3% vs 0·9%, P<0·001). Thus, during abciximab

treatment the risk of thrombocytopenia was halved in the dalteparin as compared to the UFH cohort (P<0·01).

Table 1 Baseline characteristics and concomitant treatment. Comparisons between treatment groups and between dalteparin and heparin treated cohorts

Dalteparin Heparin P Dalteparin/ heparin Placebo n=328 % (n) Abciximab n=646 % (n) Placebo n=2270 % (n) Abciximab n=4556 % (n)

Age, years (mean) 66·6 67·0 64·9 64·9 <0·001

Weight, kg (mean) 79·4 79·2 77·4 77·0 <0·001 Male 64·6 (212) 67·2 (434) 61·5 (1397) 62·1 (2827) <0·01 Smoking 25·9 (85) 24·6 (159) 21·4 (485) 22·8 (1041) ns Previous angina 37·8 (122) 42·9 (275) 47·0 (1058) 47·2 (2134) <0·001 Previous MI 33·8 (111)* 27·6 (178) 30·1 (677) 32·0 (1448) ns Previous revasc. 16·8 (55) 16·9 (109) 14·0 (317) 16·7 (758)** ns Previous stroke 1·8 (6) 3·3 (21) 2·4 (55) 2·7 (121) ns Hypertension 34·8 (114) 37·2 (240) 53·8 (1217) 54·5 (2474) <0·001 Diabetes 18·7 (61) 14·9 (96) 22·2 (501) 22·4 (1019) <0·001 Hypercholesterolaemia 24·1 (77) 23·4 (147) 32·5 (694) 32·6 (1400) <0·001 Heart failure 5·8 (19) 8·7 (56) 7·6 (171) 7·5 (341) ns Evolving MI 39·3 (129)*** 28·3 (183) 26·0 (590) 28·3 (1291)* <0·01 ST-depression 68·0 (223) 72·4 (468) 81·5 (1850) 81·4 (3708) <0·001 Troponin >0·1 ug . l
1 69·5 (228) 68·7 (444) 49·3 (1120) 50·8 (2316) <0·001 ST+ troponin 43·0 (141) 44·6 (288) 34·8 (790) 35·8 (1630) <0·001 Therapy during study drug infusion

Aspirin 96·0 (315) 96·4 (623) 97·1 (720) 96·6 (4399) ns Oral anticoagulant 0·6 (2) 0·2 (1) 0·4 (10) 0·2 (10) ns Clopidogrel 3·0 (10) 2·3 (15) 1·1 (25) 1·4 (65) <0·01 Beta-blocker 87·8 (288) 90·2 (583) 74·4 (1689) 75·2 (3425) <0·001 I.v nitroglycerin 42·1 (138) 36·4 (235) 63·9 (1450) 62·9 (2864) <0·001 ACE-inhibitor 21·0 (69) 23·8 (154) 36·3 (825) 37·6 (1713) <0·001 *P<0·05, **P<0·01, ***P<0·001 abciximab vs placebo

MI=myocardial infarction; previous revasc=previous revascularization; Hypercholesterolaemia=history of hypercholesterolaemia requiring medical therapy; Evolving MI=myocardial infarction at the time of randomisation, ST depression=ST-depressiond0·5 mm from baseline; ST+ troponin=ST-depression and troponin T >0·1
g . l
1.

Table 2 Safety at 7 days. Comparisons between placebo, abciximab (24 h+48 h) and between dalteparin and heparin treated cohorts

Dalteparin Heparin Placebo n=328 % (n) Abciximab n=646 % (n) Placebo n=2270 % (n) Abciximab n=4556 % (n) Stroke 0 (0) 0·6 (4) 0·3 (7) 0·3 (14) Intracr. haemorrhage 0 (0) 0·2 (1) 0 (0) 0·1 (4) Major bleeding 0·6 (2) 1·2 (8) 0·2 (5) 0·7 (34)** Minor bleeding 1·2 (4) 3·7 (24)* 1·5 (35) 3·0 (137)*** Insign. bleeding 24·7 (81)††† 46·4 (300)***,††† 5·0 (113) 15·1 (690)*** Blood transfusion 4·9 (16)††† 4·3 (28) 1·9 (44) 3·0 (136)* Platelet count <100·000 . ml
1 1·5 (5) 3·1 (20)††† 0·9 (21) 6·3 (285)*** <50·000 . ml
1 0·0 (0) 0·8 (5) 0 (1) 1·6 (73)*** Platelet transfusion 0·6 (2) 1·7 (11) 0·1 (3) 1·2 (53)*** *P<0·05, **=P<0·01, ***P<0·001. Abciximab vs placebo. †P<0·05, †††P<0·001 Dalteparin vs heparin. Intracr. haemorrhage=Intracranial haemorrhage, Major, minor, insign. bleeding= Bleedings according to TIMI criteria, not related to coronary artery bypass surgery.

Outcome

The outcome at 30 days did not differ statistically significantly between placebo and abciximab in the dalteparin substudy, similar to the main GUSTO–IV ACS trial[7]_{. In the dalteparin cohort the rate of death or}

myocardial infarction in the abciximab groups vs pla-cebo was 9·6% vs 11·3% (O.R. 0·85; 0·58–1·25) while in the UFH cohort the corresponding event rates were 8·5% vs 7·6% (O.R. 1·12; 0·95–1·34) (Fig. 3andTable 5). Thus, there was a trend for a higher event rate in the dalteparin cohort than in the UFH cohort (O.R. 1·27; 1·01–1·58). When correcting for other known predictors of an adverse outcome in a forward stepwise multiple regression analysis the dalteparin cohort did not remain an independent predictor of death or MI at 30 days.

Very few patients underwent revascularization proce-dures during the first 48 h of study infusion, as intended

by the study protocol (Table 5). Only 20 patients in the dalteparin cohort underwent coronary intervention and two coronary bypass surgeries within 48 h. However, at 30 days follow-up 38% of the patients had undergone revascularization which was significantly more frequent than in the UFH treated cohort (29%, P<0·001).

Discussion

Side e

ffects

The safety of abciximab in addition to LMWH and aspirin in the treatment of ACS has not been investigated previously in a large-scale trial. In the current trial the numbers of major and minor bleed-ings were overall low and comparable to other trials of antithrombotic treatments in acute coronary

Table 3 Safety at 7 days. Comparisons between abciximab 24hours and 48 h and between dalteparin and heparin treated cohorts Dalteparin Heparin Abciximab 24 h n=315 % (n) Abciximab 48 h n=331 % (n) Abciximab 24 h n=2275 % (n) Abciximab n=2281 % (n) Stroke 1·0 (3) 0·3 (1) 0·3 (7) 0·3 (7) Intracr. haemorrhage 0·3 (1) 0 (0) 0 (1) 0·1 (3) Major bleeding 1·3 (4) 1·2 (4) 0·5 (12) 1·0 (22) Minor bleeding 3·2 (10) 4·2 (14) 2·5 (56) 3·6 (81)* Insign. bleeding 44·4 (140) 48·3 (160) 13·8 (315) 16·6 (378)* Blood transfusion 2·9 (9) 5·7 (19) 2·6 (59) 3·4 (77)* Platelet count<100·000 . ml
1 3·5 (11) 2·7 (9) 4·8 (110) 7·7 (175)*** <50·000 . ml
1 1·3 (4) 0·3 (1) 1·6 (37) 1·6 (36) Platelet transfusion 1·9 (6) 1·5 (5) 1·2 (28) 1·1 (25) *P<0·05, ***P<0·001 Abciximab 24 h vs Abciximab 48 h.

Intracr. haemorrhage=Intracranial haemorrhage, Major, minor, insign. bleeding=bleedings according to TIMI criteria. Not related to coronary artery bypass surgery.

Table 4 Independent predictors of bleedings in the GUSTO–IV ACS study

O.R.

95% C.I. for O.R.

Lower Upper

Independent predictors for major and minor bleedings*

Age >65 years† 2·81 2·08 3·80

Abciximab treatment 1·62 1·37 1·91

PCI†† during initial 7 days 1·81 1·96 2·57

Independent predictors for all bleedings*

Dalteparin cohort 4·64 3·99 5·39

Abciximab treatment 1·83 1·69 1·97

PCI†† during initial 7 days 1·79 1·49 2·14

Age >65 years† 1·75 1·54 1·99

Female gender 1·45 1·18 1·64

*Bleedings according to TIMI criteria, not related to coronary artery bypass surgery. †Pre-specified cut-off for the outcome analyses and the mean age. ††Coronary intervention. Included variables: age, sex, weight, history of stroke or TIA, diabetes, hypertension, smoking, dalteparin cohort, randomised abciximab treatment, clopidogrel, aspirin, oral anticoagulant and other LMW-heparin usage.

syndromes[13]_{. There were no differences in the types of}

bleedings between use of a full dose of dalteparin and a reduced dose of UFH. The low bleeding rates were, at least partly, reflecting the low number of patients who underwent early angiography and coronary revascularization procedures[4,14]_.

However the addition of abciximab was associated with a doubling in major and minor bleedings in the present trial. Acute coronary syndrome trials with GP IIb/IIIa inhibitors in addition to UFH have reported major bleeding levels, up to 10·8% and minor bleedings in up to 13%[14,15]. In PRISM–PLUS, major TIMI bleedings during the infusion time occurred in 0·8% of the UFH treated patients and in 1·4% in those receiving tirofiban and UFH[8]_{. The intervention rates and}

defi-nitions for major and minor bleedings have, however, varied.

The safety of abciximab and enoxaparin combined as conjunctive therapy to intervention was tested in the open label NICE 4 trial which included 818 patients and did not show an increased incidence of major bleedings or transfusions (0·2% major and 6·8% minor bleedings, 1·2% transfusions)[16]. Tirofiban and enoxaparin vs UFH was evaluated in the ACUTE–II trial which included 525 patients presenting with unstable angina or suspected myocardial infarctions without ST-segment elevation and permitted coronary angiography after 24 h. The combination treatment was well tolerated with low and similar bleeding rates in the two groups, i.e. major 0·6% vs 0·5% and minor 3·9% vs 4·8%[17]_{. These}

results are in accordance with the present findings of a similar rate of major and minor bleedings when UFH or dalteparin was combined with abciximab.

The increased numbers of insignificant bleedings (<3 g l
1 fall in haemoglobin) in the dalteparin

substudy was to a large extent attributable to the subcutaneous dalteparin injections, which commonly create heamatomas. The dalteparin treatment also included extra time at risk with a longer exposure time, 4–7 days vs 48 h with UFH. Yet, it is noteworthy that the combination of abciximab and dalteparin was associated with a bleeding manifestation in one out of two patients compared to only one out of 20 patients on UFH alone. Such a large increase might indicate an inconvenience for some patients. When combining abciximab and dalteparin, lower doses should be evalu-ated for the patient groups with augmented risk of bleedings, such as the elderly (Fig. 2) and females. A recently published dose-finding study of intravenous dalteparin in combination with abciximab for coronary intervention suggests that the dosing of dalteparin, and the subsequent anti-factor X activity is crucial both for the outcome and safety [18]_{. Thus, 60 IU . kg}
1

dalteparin provided more consistent antithrombotic effect than 40 IU . kg
1as reflected by higher anti-Xa activity and less observations of intra-procedural thrombosis but still with a similar low incidence of major bleedings.

As expected, thrombocytopenia was more common with the addition of abciximab both to UFH and dalteparin. Severe thrombocytopenia was, however, rare. Previous trials have reported mild thrombocyto-penia (<100·000 . ml
1) in 2·5–5·6% and severe thrombocytopenia (<50·000 . ml
1) in 0·9–1·6% for abciximab and UFH treated patients[14]_{. The}

signifi-cantly lower number of patients with thrombocyto-penia in the dalteparin cohort as compared to the UFH cohort suggests that UFH is partly responsible for the development of early thrombocytopenia in abcixi-mab treated patients. Therefore concerning the risk of

Table 5 Outcome at 30 days. Comparisons between placebo and abciximab groups and between dalteparin and heparin treated cohorts

Dalteparin Heparin P-value Dalteparin/ heparin Placebo n=328 % (n) Abciximab n=646 % (n) Placebo n=2270 % (n) Abciximab n=4556 % (n) 48 h Death 0·3 (1) 0·6 (4) 0·3 (7) 0·8 (37)* ns MI 1·5 (5) 2·0 (13) 1·3 (29) 1·3 (58) ns Death or MI 1·8 (6) 2·5 (16) 1·5 (34) 2·0 (92) ns 7 days Death 2·1 (7) 1·7 (11) 1·7 (39) 1·8 (81) ns MI 4·9 (16) 3·7 (24) 2·8 (64) 2·5 (112) <0·01 Death or MI 6·4 (21) 4·8 (31) 4·2 (95) 3·9 (178) <0·05 30 days Death 4·3 (14) 3·1 (20) 3·9 (88) 3·9 (179) ns MI 8·5 (28) 7·7 (50) 4·6 (105) 5·5 (249) <0·001 Death or MI 11·3 (37) 9·6 (62) 7–6 (172) 8·5 (388) <0·05 PCI 24·4 (80) 22·3 (144) 19·0 (432) 18·7 (853) <0·01 CABG 14·9 (49) 16·1 (104) 10·7 (243) 10·2 (463) <0·001

thrombocytopenia at abciximab treatment LMWH seems preferable to abciximab.

Outcome

No benefit could be identified with the addition of abciximab to UFH or dalteparin as the primary medical treatment without early coronary revascularization in the present trial as previously presented and discussed in detail[7]. Abciximab did not provide any benefit in combination with dalteparin for patients with a positive troponin test at admission. However, the dalteparin substudy included a patient population at somewhat higher risk, resulting in significantly higher event rates than in the UFH cohort. The event rate in this cohort was in fact similar or even higher than in other ACS trials when differences in endpoint definitions are taken into consideration[1,3,8,9]_{. The higher event rate in the}

dalteparin cohort was mainly attributable to larger proportions of elderly-, male- and troponin-positive patients and not the dalteparin treatment per se.

Conclusion

Addition of abciximab to UFH or LMWH and aspirin as primary treatment of ACS is not associated with any significant reduction in cardiac events but a doubled risk of bleedings. The combination of abciximab with dalteparin seems as safe as its use with UFH, although nuisance bleedings are more common while, on the other hand, thrombocytopenia is more rare. For patients at high risk of new cardiac events a preventive effect is suggested, albeit not statistically significant. The optimal doses in the combination of dalteparin with abciximab remains to be defined and adjustments might be needed

especially in elderly patients and females. Due to the proven efficacy[2]

and practical advantages, LMWH will remain part of the standard treatment of acute coronary syndromes in many countries[12]_{. For patients not}

under-going a coronary intervention abciximab treatment is not indicated. However, in high-risk patients awaiting a coronary intervention abciximab may be added, because of the favourable outcome in previous studies[5,19]_and

because of the safety when combined with dalteparin in GUSTO–IV ACS.

References

[1] Frisc study group. Fragmin during instability in coronary artery disease (FRISC) study group. Low molecular weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561–8.

[2] Eikelboom JW, Anand SS, Malmberg K. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 2000; 355: 1936–42.

Figure 2 Major and minor bleedings in relation to randomized treatment (abciximab/placebo), dalteparin ( )/UFH ( ) cohorts and age (>/< =65 years, which was a pre-specified cut-off for the outcome analyses).

Figure 3 Kaplan–Meier estimate of the cumulative probability of death or MI in the initial 30 days. Unfrac-tionated heparin and dalteparin treated cohorts in the GUSTO IV–ACS. ——=placebo. – – –=abciximab 24 h+48 h.

[3] Antman EM, Cohen M, Radley D et al. Assessment of the treatment effect of enoxaparin for unstable angina/ non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta-analysis. Circulation 1999; 100: 1602–8.

[4] EPIC investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med 1994; 330: 956–61.

[5] The CAPTURE investigators. Randomized placebo con-trolled trial of abciximab before and during coronary inter-vention in refractory unstable angina. Lancet 1997; 349: 1429–35.

[6] The EPILOG investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during coronary revascularization. The EPILOG Investigators. N Engl J Med 1997; 336: 1689–96.

[7] GUSTO IV ACS-investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outome in patients with acute coronary syndromes without early coronary revascularization: The GUSTO IV-ACS randomized trial. Lancet 2001; 357: 1915–24.

[8] PRISM PLUS investigators. Inhibition of the platelet glyco-protein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibi-tion in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998; 338: 1488–97.

[9] PURSUIT investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppres-sion Using Integrilin Therapy. N Engl J Med 1998; 339: 436–43.

[10] Boersma E, Harrington RA, Moliterno DJ et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002; 359: 189–98.

[11] Braunwald E, Antman EM, Beasley JW et al. ACC/AHA guidelines for the management of patients with unstable

angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on the manage-ment of patients with unstable angina). Circulation 2000; 102: 1193–209.

[12] Bertrand ME, Simoons ML, Fox KA et al. Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation; recommendations of the Task Force of the European Society of Cardiology. Eur Heart J 2000; 21: 1406–32.

[13] Rao AK, Pratt C, Berke A et al. Thrombolysis in Myocardial Infarction (TIMI) Trial--phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988; 11: 1–11.

[14] Ferguson JJ, Kereiakes DJ, Adgey AA et al. Safe use of platelet GP IIb/IIIa inhibitors. Eur Heart J 1998; 19 (Suppl D): D40–51.

[15] Blankenship JC. Bleeding complications of glycoprotein IIb-IIIa receptor inhibitors. Am Heart J 1999; 138(4 Pt 2): 287–96.

[16] Kereiakes DJ, Fry E, Matthai W et al. Combination enoxa-parin and abciximab therapy during coronary intervention: ‘NICE guys finish first’. J Invasive Cardiol 2000; 12 (Suppl A): 1A–5A.

[17] Cohen EM, Theroux P, Frey, MJ. Anti-thrombotic combina-tion using Tirofiban and Enoxaparin. The ACUTE II study. Circulation 2000; 102: Abstract 3982.

[18] Kereiakes DJ, Kleiman NS, Fry E et al. Dalteparin in combination with abciximab during coronary intervention. Am Heart J 2001; 141: 348–52.

[19] Cannon CP, Weintraub WS, Demopoulos LA et al. Compari-son of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycopro-tein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344: 1879–87.