Melandri et al in-hospital reinfarction and in-hospital refractory ischemia) was reduced by ENOX (11.4% vs 15.4%, p = 0.0002) and by the combination of UFH plus ABX (11.1%, p = 0.0001). When in-hospital ICH or major bleeds were added to the primary end-point (so called efﬁcacy plus safety end-point), again, a signiﬁcant reduction was observed both in the ENOX group (13.7% vs 17.0%, p = 0.0037) and in the UFH plus ABX group (14.2%, p = 0.01416). ABX increased the rate of thrombocytopenia compared to both ENOX and UFH (3.2% vs 1.2% and 1.3% respectively, p = 0.0001) and it also increased the cost of treatment.29 Similar results were observed in the smaller ENTIRE- TIMI 23 trial.28 This trial had a design very similar to that of ASSENT-3, although there was a further group receiving ENOX in combination with ABX and half-dose TNKase. Overall, the adjunctive use of ENOX with TNKase, com- pared with UFH, reduced the combined incidence of death/ myocardial infarction at 30 days (4.4% vs 15.9%, p = 0.005). ABX did not further decrease the end-point; rather, ABX increased the risk of major bleeding (5.2% vs 2.4% compared with UFH alone and 8.5% vs 1.9% compared with ENOX alone). Major bleeding was also increased when half-dose TNKase was combined with eptiﬁbatide, a small-molecule GP IIB-IIIA inhibitor in the INTEGRITI study.30 In conjunc- tion with the GUSTO-V data,31 ASSENT-3, ENTIRE-TIMI- 23 and INTEGRITI indicate that GPIIB-IIIA agents should not be associated with thrombolytic drugs. In conclusion, ASSENT-3 and ENTIRE-TIMI 23 showed that a much simpler thrombolytic regimen is feasible, permit- ting bolus administration of both TNKase and of adjunctive low-molecular-weight heparin. This new regimen was tested in the pre-hospital phase of STEMI treatment in the ASSENT-3-PLUS study.32 In this trial, after electrocardiographic conﬁrmation was obtained in the ﬁeld, 1639 patients were treated with TNKase and randomly allocated to ENOX or UFH adjunctive treat- ment. Of interest, 53% of patients could be treated in the ﬁrst 2 hours, a much higher proportion compared with that observed in previous studies. In the pre-hospital setting ENOX tended to reduce the composite of 30-day mortality or in-hospital reinfarction or in-hospital refractory ischemia (14.2% vs 17.4%, p = 0.08), but there was no difference in the efﬁcacy plus safety end-point, also including the rate of ICH or major bleeding (18.3% vs 20.3%, p = NS). ENOX reduced the reinfarction rate (3.5% vs 5.8%, p = 0.028), but increased the rate of total stroke (2.9% vs 1.3%, p = 0.026) and of ICH (2.20% vs 0.97%, p = 0.047). The increase in ICH occurred in the group of patients more than 75 years old. 252 A pre-speciﬁed pooled analysis of data from ASSENT-3 and ASSENT-3-PLUS trials largely conﬁrmed the utility of using ENOX instead of UFH in conjunction with TNKase, reducing the primary efﬁcacy end-point (composite of death, reinfarction and refractory ischemia) from 16.0% to 12.2%, p 0.001 and the primary efﬁcacy plus safety (ICH or major bleeding) end-point from 18.0% to 15.0%, p = 0.003.33 Among the 1049 patients who required urgent revasculariza- tion the ENOX beneﬁcial effect was even larger (15.4% vs 10.1%, p = 0.013). The excess in stroke rates observed with ENOX (1.3% vs 0.9%), although not signiﬁcant, was mainly due to an excess in ICH among women of more than 75 years old in ASSENT-3-PLUS. Following these observations, the intravenous bolus of ENOX was omitted and the maintenance dose was reduced by 25% in patients of more than 75 years old in the large deﬁnitive conﬁrmation EXTRACT-TIMI 25 trial.15 The role of the routine, immediate use of coronary angioplasty (so called “facilitated” angioplasty, F-PCI) after treatment with TNKase was ﬁrst explored in CAPITAL- AMI.34 This was a small study randomizing 170 high-risk STEMI patients treated with TNKase toward immediate revascularization by PCI or to conservative management. The primary end-point was the composite of death, rein- farction, recurrent unstable ischemia, or stroke at 6 months. The median time from the onset of symptoms to TNKase administration was 120 minutes and the median time from symptoms to balloon inﬂation 204 minutes. Overall, the pri- mary end-point was reduced by immediate PCI from 24.4% to 11.6% (p = 0.04), a result driven mainly by the reduction in the rate of recurrent unstable ischemia (p = 0.03). There were no differences in death, reinfarction, stroke or major bleeding. These encouraging results stimulated the planning of the larger ASSENT-4 PCI trial,35 a trial designed to investigate whether TNKase facilitation would improve the prognosis of patients for whom a time-delay of 1 to 3 hours before P-PCI was anticipated. The trial design was open-label and the primary end-point was the composite of death or con- gestive heart failure or shock within 90 days. Only 1667 of the originally planned 4000 patients were enrolled, because the trial was prematurely interrupted by the data and safety monitoring board for an excess of in-hospital mortality in the group where P-PCI was facilitated by TNKase (6% vs 3%, p = 0.0105). The median time from TNKase injection to ﬁrst balloon inﬂation was 104 minutes. A TIMI-3 ﬂow was achieved before P-PCI in 43% of TNKase-treated patients and in 15% of patients in the control group (p 0.0001). Vascular Health and Risk Management 2009:5