European Heart Journal (2002) 23, 1538–1545 doi:10.1053/euhj.2002.3257, available online at http://www.idealibrary.com on

Safety and efficacy of abciximab combined with dalteparin in treatment of acute coronary syndromes S. James1, P. Armstrong2, R. Califf3, S. Husted4, F. Kontny5, M. Niemminen6, M. Pfisterer7, M. L. Simoons8 and L. Wallentin1 1

Department of Cardiology, Academic Hospital, Uppsala, Sweden; 2Department of Medicine, University of Alberta, Edmonton, Alberta, Cananda; 3Duke CRI, Durham, NC, USA; 4Department of Cardiology, Aarhus, Amtssygehus, Aarhus, Denmark; 5Heart-lung center, Ulleva´l Hospital, Oslo, Norway; 6University Hospital, Internal Medicin, Helsinki, Finland; 7University Hospital, Basel, Switzerland; 8Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands

Aims The safety and efficacy of abciximab in addition to low-molecular-weight-heparin as the primary medical treatment of acute coronary syndromes has not previously been investigated. Methods and Results The GUSTO IV–ACS trial included 7800 patients with chest pain and either ST-segment depression or a positive troponin test. They were randomized 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 placebo both in the dalteparin (abciximab 5·0% vs placebo 1·8% P3 but c5 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 Eur Heart J, Vol. 23, issue 19, October 2002

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meeting the criteria for major or minor. Thrombocytopenia was defined as a platelet count /0·1
g . l
1), abciximab treatment and dalteparin cohort were included in the analysis. Statistical 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 compared 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 evolving 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 Eur Heart J, Vol. 23, issue 19, October 2002

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 particular (>65 years) had an increased risk of major and minor bleedings with abciximab (Fig. 2). The rate of insignificant 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 2 and 3). 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 abciximab than placebo in the whole patient population. Severe thrombocytopenia (