injection.21 The TIMI-3 ﬂow rate was similar to that observed in the control group, receiving front-loaded alteplase. The safety of TNKase in STEMI was investigated in ASSENT-1;22 3235 patients received either 30 or 40 or 50 mg TNKase as a bolus injection. The total stroke rate at 30 days was 1.5% and the intracranial hemorrhage (ICH) rate was 0.8%, without signiﬁcant differences between groups. Serious bleeding, requiring blood transfusion, occurred in 1.4% of patients in the TNKase group and in 7% of those treated with front-loaded alteplase. Importantly, TIMI-10B and ASSENT-1 showed the importance of reducing the heparin dose in conjunction with TNKase, to minimize the risk of ICH.23 Survival data with TNKase have been tested in compari- son with those achieved using front-loaded alteplase in the large, multicenter, conﬁrmation ASSENT-2 trial. A total of 16,949 patients with STEMI in the ﬁrst 6 hours from the onset of symptoms received either weight-adjusted TNKase over 5 to 10 seconds (less than 60 kg: 30 mg; 60–69.9 kg: 35 mg; 70–79.9 kg: 40 mg; 80–89.9 kg: 45 mg; and more than 90 kg: 50 mg) or front-loaded alteplase, along with aspirin and reduced-dose unfractionated heparin.24 This was an equivalence trial and all-cause mortality at 30 days was the primary end-point. There was no difference between TNKase and alteplase in mortality (6.18% vs 6.15%) and stroke rate, including ICH (0.93% vs 0.94%, respectively). Moreover, in the TNKase group there was a decreased rate in non-cerebral bleeds (26.43% vs 28.95%, p = 0.0003), in major bleeds (4.68% vs 5.94%, p = 0.0002) and in the need for blood transfusion (4.25% vs 5.49%, p = 0.0002) (Table 2). There was also a tendency for ICH to be decreased by TNKase among the high-risk population of females of more than 75 years old who weighed 67 kg Table 2 Clinical studies with TNKase in STEMI Trial (year) Patients Comparison ASSENT-2 (1999) 16,949 TNKase vs rt-PA ASSENT-3 (2001) 6,095 ENOX vs ABX vs UFHa ENTIRE-TIMI 23 (2002) 483 ENOX vs ABX vs UFHa ASSENT-3-PLUS (2003) 1,639 ENOX vs UFHa, pre-hospital delivery CAPITAL-AMI (2005) 170 F-PCIc vs TNKasea ASSENT-4 (2006) 1,667 F-PCIc vs P-PCIb WEST (2006) 304 TNKase vs F-PCIc vs P-PCI GRACIA-2 (2007) 212 TNKased vs P-PCI aAll patients in the trial received TNKase. bP-PCI: Primary angioplasty. cF-PCI: Primary angioplasty, facilitated by TNKase. dTNKase followed by routine angioplasty within 3–12 hours (“pharmaco-invasive” approach). Vascular Health and Risk Management 2009:5 TNKase in acute myocardial infarction (1.14% vs 3.02%).25 The general ASSENT-2 trial results were conﬁrmed in all major subgroups, including those related to age, gender, infarct location, Killip class and diabetes status. Interestingly, mortality was signiﬁcantly lower in the TNKase group when treatment was given more than 4 hours after the onset of symptoms (7.0% vs 9.2%, p = 0.018), a ﬁnding that could be attributed to the drug’s fibrin specificity leading to better dissolution of older coronary clots and conﬁrms from a clinical standpoint the improved pharmacologic proﬁle of this molecule. Among other in-hospital outcomes, TNKase also reduced the rate of congestive heart failure (ie, Killip class 1: 6.1% vs 7.0%, p = 0.025). Thus, the ASSENT-2 trial indicates that single-bolus TNKase is equivalent to the more complex accelerated alteplase infusion, in terms of mortality and mortality/stroke combination, with the further advantage of a decrease in major bleeding rate. These positive results were persisting after 1 year.26 TNKase and the adjunctive use of antithrombotic therapy and of mechanical intervention The possibility of further improving the effects of TNKase by means of new adjunctive treatments has been explored in ASSENT-3 and ENTIRE-TIMI 23 studies.27,28 In ASSENT-3 a total of 6095 patients with STEMI in the ﬁrst 6 hours from the onset of symptoms were treated with either full-dose TNKase plus unfractionated heparin (UFH), full-dose TNKase plus enoxaparin (ENOX), or half-dose TNKase plus UFH and the GPIIB-IIIA inhibitor abciximab (ABX). Compared with UFH, the primary end-point (30-day mortality plus Main ﬁndings TNKase and rt-PA equivalent, ↓ major bleeding with TNKase ENOX and ABX better than UFH ENOX and ABX better than UFH, ↑ bleeding with ABX ↓ reinfarction with ENOX, ↑ stroke/intracranial bleed ↓ residual ischemia with F-PCI ↑ death/ischemia/bleeding in the F-PCI group TNKase and F-PCI comparable to P-PCI ↑ reperfusion with TNKased Similar ventricular damage 251