Tenecteplase in the Treatment of Acute Myocardial Infarction
K. Sarat Chandra, Pankaj Jariwala, Pravir Lathi
Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, Andhra Pradesh
Introduction
Among all the thrombolytic agents available for treatment of acute myocardial infarction, Tenecteplase is the most promising. It is supported by several large scale trials done in the recent times involving nearly thirty thousand patients. On account of its long half life it is possible to use it as a bolus therapy which makes it particularly attractive for pre-hospital thrombolysis. It has 80 times greater resistance to PAI-1 (Plasminogen Activator Inhibitor) compared to Alteplase. Its fibrin specificity makes it less prone for bleeding complications. Together these characters have made it one of the most commonly used thrombolytic agents for acute MI. If given early after MI it is very competitive with primary PCI.
Thrombolytic therapy versus primary angioplasty
Acute myocardial infarction presenting with ST-segment elevation (STEMI) is usually precipitated by plaque disruption with coronary thrombosis. The quick recanalization by either thrombolysis (TBL) or primary angioplasty (P-PCI) is the most important goal during the early hours of acute MI. Current American and European guidelines “prefer” Primary angioplasty. However there are a number of limitations to adopt primary angioplasty universally like non-availability of functioning cath labs at many places. Even if a cath lab is available it may be preoccupied with scheduled cases. During the non-working hours, availability of experienced interventional cardiologists, technicians and nurses could be a problem. In addition in the Indian setting obtaining consent from the patient and family members (especially in relation to financial concerns) can sometimes take considerable time and this may delay definitive therapy. All these factors together make the treating physician to consider thrombolytic therapy strongly in a large number of cases.
Currently, only 25% of American hospitals provide primary angioplasty and the majority of patients must be transferred to receive the mechanical intervention.1 As a consequence, only approximately 4% of transferred patients receive P-PCI within 90 minutes from first medical contact.2
Pre-hospital thrombolytic therapy
There are several reasons which make thrombolytic therapy attractive like its immediate availability. It only takes a few minutes to make a decision following electrocardiogram and a drug like tenectaplase (TNKase) which is given as a bolus shortens the time delay further.
Thrombolytic therapy can be delivered everywhere and particularly when used in the pre-hospital setting is extremely competitive with P-PCI, as demonstrated by the CAPTIM study.3 In the recently published MINAP registry the prehospital use of thrombolytic therapy (nearly always TNKase) ranked among the strongest independent predictors of in-hospital survival in the United Kingdom.4 The American College of Cardiology/American Heart Association guidelines encourage the recording of the 12-lead electrocardiogram “on-scene” and performing pre-hospital TBL within 30 minutes.5 Since time is so crucial, it is believed that most benefit may be achieved by treating as many patients as possible in the first 3 hours from the onset of symptoms, regardless of whether TBL or P-PCI is used.6 It is now possible that an efficient ambulance network can offer pre-hospital TBL in the first 3 hours in approximately 50% to 60% of STEMI patients.7 TBL can be further improved by reducing the re-infarction rate by adjunctive use of clopidogrel and enoxaparin as soon as possible, ideally pre-hospital8,9.
Pharmacologic properties of TNKase in acute myocardial Infarction
TNKase is basically modified Alteplase molecule with three point mutations and has a molecular weight of 65,000 kD. These mutations prolong the half-life and increase the resistance to plasminogen activator inhibitor-1 (80 times more resistance compared to Alteplase). Compared with other molecules used in clinical practice, TNKase has the highest degree of fibrin specificity and binding. Fibrin specificity, in turn, implies a reduced propensity for causing major non-cerebral bleeds, because lytic activity is restricted to plasmin on the fibrin surface, thus avoiding the breakdown of fibrinogen, factor V, factor VIII and α2-antiplasmin.10 The TNKase conformational change reduces its elimination and prolongs its plasma half life (α-half-life 11–20 minutes, β-half-life 41–138 minutes).
E-mail: saratkoduganti@hotmail.com
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These properties allow single bolus infusion and prevent drug inactivation at the site of platelet-rich coronary thrombosis. In addition, TNKase has more intense antiplatelet properties both in vitro and in vivo compared with those of alteplase.11 In experimental models the thrombolytic potency of TNKase is 3-fold higher than that of alteplase.12
Clinical use of TNKase in acute myocardial infarction
Tenectaplase usage is supported by a large number of trials done in a systematic manner as shown in the table 1. The dose finding studies were TIMI-10A and TIMI-10B. The TIMI-10A trial showed a dose dependent increase in TIMI-3 flow rates in the 5 to 50 mg dose range.13 The TIMI 10B patency trial which involved 886 patients, bolus TNKase injection achieved increasing TIMI-3 flow rates of 55%, 63% and 66% at 90 minutes after 30, 40 and 50 mg injection.14
ASSENT-1 is a safety and efficacy trial of TNKase in STEMI involving 3235 patients who received either 30 or 40 or 50 mg TNKase as a bolus injection.15 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 who were treated with front-loaded alteplase. TIMI-10B and ASSENT-1 trials showed the importance of reducing the heparin dose in conjunction with TNKase, to minimize the risk of ICH.
reduced-dose unfractionated heparin. 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). 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 (1.14% vs 3.02%).17 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. Also of importance is the fact that the 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.
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.18
Tenectaplase and adjunctive use of anti-thrombotic therapy
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.19, 20 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. in-hospital reinfarction and in-hospital refractory ischemia) was reduced by ENOXAPARIN (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.21
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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 Enoxaparin 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.22 Thus ASSENT-3, ENTIRE-TIMI- 23 and INTEGRITI trials indicate that GPIIB-IIIA blockers should not be combined with thrombolytic drugs (similar to what is seen in GUSTO-V data 23).
ASSENT-3-PLUS study tested the same hypothesis of combination of tenectaplase and anti-coagulation in the pre-hospital phase of STEMI.24 In this trial, after electrocardiographic confirmation was obtained in the field, 1639 patients were treated with TNKase and randomly allocated to Enoxaparin or UFH adjunctive treatment. 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 Enoxaparin 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 effi cacy plus safety end-point, also including the rate of ICH or major bleeding (18.3% vs 20.3%, p = NS). Enoxaparin 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. 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 = 0.003.25 Among the 1049 patients who required urgent revascularization 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.9
Facilitated PCI
immediate revascularization by PCI or to conservative management. The primary end-point was the composite of death, reinfarction, 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 primary 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.
ASSENT-4 Trial
These encouraging results from the CAPITALAMI led to the large ASSENT-4 PCI trial, 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 Primary angioplasty was anticipated 27. The trial design was open-label and the primary end-point was the composite of death or congestive 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 angioplasty followed Tenectaplase (6% vs 3%, p = 0.0105). The median time from Tenectaplase injection to first balloon inflation was 104 minutes. A TIMI-3 flow was achieved before angioplasty in 43% of Tenectaplase treated patients and in 15% of patients in the control group (p _ 0.0001). The primary end-point at 90 days was increased in the facilitated group (19% vs 13%, p = 0.0045), along with the stroke rate (1.8% vs 0%, p _ 0.0001). These disappointing results could be due either to an alleged pro-thrombotic effect of Thrombolytic therapy or to creating an intra-plaque hemorrhage by inflating the balloon in the first 2 hours after thrombolysis (i.e., in a lytic state). In retrospect, the risk of death at 90 days was reduced by Tenectaplase when patients were randomized in ambulance and increased when patients were recruited in angioplasty capable hospitals (in which case the duration between Tenectaplase administration and balloon inflation is likely to be shorter). Nearly 45% patients were actually enrolled in angioplasty capable hospitals
More pertinent to investigating the role of Tenectaplase facilitation is the WEST study, a randomized, open-label, feasibility study of 304 STEMI patients enrolled in the community (40% enrolled pre-hospital)28. All patients received aspirin and Enoxaparin and were randomized to either Tenectaplase, or to Tenectaplase followed by PCI within 24 hours (including rescue PCI for reperfusion failure) or to P-PCI. The time from the onset of symptoms to randomization was 113, 130 and 176 minutes respectively. There were no differences between the three groups in the primary composite of death or reinfarction, refractory ischemia, congestive heart failure, cardiogenic shock or major ventricular arrhythmia (25% vs 24% vs 23%, p = NS). In the group receiving plain
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Tenectaplase there was a higher rate of the death/reinfarction combination (13.0% vs 6.7% vs 4.0%, p = 0.021), but not of death (4.0% vs 1.0% vs 1.0%, p = NS). Thus, the WEST trial confirms the results from CAPTIM trial that when delivered very rapidly, possibly in the pre-hospital phase, Tenectaplase is very competitive with Primary angioplasty. This is a very simple and effective treatment, more so if subsequent PCI is adopted in those patients with recurrent ischemia or deemed at high clinical risk 3.
GRACIA-2 Study: This is a small but interesting hypothesis generating study. Tenectaplase followed by early routine PCI (within 3–12 hours, so called “pharmaco-invasive” approach) has been compared with Primary angioplasty in 212 patients.29 This is a non-inferiority trial designed to evaluate whether a lytic strategy represents a reasonable option for STEMI patients, irrespective of geographic or logistic barriers, when compared with Primary angioplasty. The primary end-points were epicardial and myocardial reperfusion and the extent of left ventricular damage (as assessed by infarct size and left ventricular function). Complete ST-segment resolution was observed more frequently in the TNKase group (61% vs 43%, p = 0.01). Infarct size and left ventricular ejection fraction were similar in the two groups.
An important conclusion of GRACIA-2 (in combination with ASSENT-4) is that routine PCI after tenetaplase should be postponed for at least 3 to 12 hours to achieve the best results.
Transfer AMI Trial: This is a recent trial published in 2009. A total of 1059 high risk patients with STEMI who received thrombolytic therapy with tenetaplase at centers which did not have capability of performing PCI were randomized to either standard treatment (including rescue PCI, if required, or delayed angiography) or a strategy of immediate transfer to another hospital and PCI within 6 hours after fibrinolysis.30 Cardiac catheterization was performed in 88.7% of the patients assigned to standard treatment a median of 32.5 hours after randomization and in 98.5% of the patient assigned to routine early PCI a median of 2.8 hours after randomization. PCI was performed when persistent occlusion or substantial stenosis of the infarct-related artery was present. The primary end point occurred in 11.0% of the patients in the early-PCI group and in 17.2% of the patients in the standard-treatment group (relative risk with early PCI, 0.64; 95% confidence interval (CI), 0.47 to 0.87;P=0.004). There were also significantly lower rates in the early-PCI group than in the standard-treatment group of recurrent ischemia (0.2% vs. 2.1%) and new or worsening congestive heart failure (3.0% vs. 5.6%). At 6 months, the rates of reinfarction and of death or reinfarction did not differ significantly between the two groups. There were more mild bleeding events, with the early-PCI strategy than with the standard-treatment strategy (13.0% vs. 9.0%, P=0.04) but there was no significant difference in the rates of major bleeding, transfusions or intracranial hemorrhage.The primary end point, a composite of death, reinfarction, recurrent ischemia, congestive heart failure, or cardiogenic shock at 30 days, occurred significantly less frequently with the early-PCI strategy than with standard therapy. Thus it appears that when there is a sufficient gap of two to three hours after thrombolysis before PCI is performed, the strategy is quite safe and effective in reducing further events.
Some of the registries which used Tenectaplase in the pre-hospital setting are worth mentioning in this regard.
FAST MI Registry: A total of 1714 patients from 223 centres in France over a period of one month were recruited in this study.31 The aim of the study was to compare thrombolytic therapy (predominantly tenectaplase) followed by early angio/PCI with primary angioplasty.
The time to reperfusion therapy was significantly shorter with thrombolysis than PPCI (130 vs 300). In-hospital mortality was 4.3% for thrombolysis and 5.0% for PPCI. In patients with thrombolysis 30 day mortality was 9.2% when PCI was not used and 3.9% when PCI was used. One year survival was 94% for thrombolysis and 92% for PPCI. The authors concluded that Pharmaco invasive therapy that involved thrombolysis followed by early PCI yields early and one year survival rates comparable to primary PCI.
The German Pre-hospital MI Registry (PREMIR):
This study sought to evaluate the in-hospital fate of patients with ST segment elevation myocardial infarction (STEMI) diagnosed already in the prehospital phase by physican equipped ambulances.32 A total of 2326 consecutive STEMI patients were included in PREMIR. Themedian time between symptom onset and 12-lead ECGwas 85 min. Themedian time intervals between the diagnostic 12-lead ECG and prehospital fibrinolysis were 10 min, until inhospital fibrinolysis 52 min and until primary PCI 86 min, respectively. Reperfusion therapy with prehospital fibrinolysis (24%), inhospital fibrinolysis (13%) or primary PCI (45%) was performed in 82% of the patients. Inhospital mortality was 6.0% in patients with prehospital fibrinolysis (n = 504), 5.8% in patients with inhospital fibrinolysis (n = 278), 4.5% in patients with primary percutaneous coronary intervention (n = 962) and 16.2% in patients without early reperfusion therapy (n = 377), respectively. In the multivariate propensity score analysis comparing prehospital fibrinolysis and primary PCI, no significant difference was observed in the odds for in-hospital mortality (odds ratio: 1.57, 95% CI: 0.94–2.63). The final discharge diagnosis was STEMI in 90% of the patients, in patients with prehospital fibrinolysis 95%. The authors concluded that in patients with STEMI already diagnosed in the prehospital phase the ischemic time is short, accuracy of the diagnosis is high and
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reperfusion therapy is performed in over 82%. Inhospital mortality was not different between prehospital fibrinolysis and primary PCI.
Indian Experience: Satyamurthy et al published the results of a registry of tenectaplase administration in 507 patients with STEMI who were treated with weight-adjusted tenecteplase within median chest pain to drug interval of 120 minutes.33 Resolution of chest pain within median interval of 45 minutes occurred in 436 patients with median duration required for ≥50% resolution of ST segment of 75 minutes. Clinically successful thrombolysis was reported in 80.67% patients. Five patients suffered intra-cranial hemorrhage (ICH), of which 3 patients had received Gp IIb/IIIa inhibitors. Incidence of intra-cranial hemorrhage attributable to tenecteplase was 0.39% (2 out of 507 patients). Incidence of myocardial re-infarction was 2.96% (15 out of 507 patients). There were 12 deaths (2.36%). The authors concluded that tenecteplase is safe and effective in patients with STEMI and that the results conform to the ASSENT-2 trial data.
Trials of early PCI after fibrinolysis that were performed in the time before stents were used did not show a clinical benefit of this strategy and showed higher rates of major bleeding complications.10 The implantation of coronary stents and the use of glycoprotein IIb/IIIa antagonists and thienopyridines reduce the incidence of reocclusion after successful PCI.18-20 It is also possible that higher rates of bleeding episodes with early PCI may have offset any benefit achieved with this intervention. Bleeding rates after PCI have been reduced with the use of smaller sheaths, earlier removal of sheaths, radial access, the administration of lower doses of anticoagulants, and the elimination of post procedural heparin infusions. The use of highly fibrin-specific fibrinolytic agents such as teneteplase is associated with lower rates of noncerebral bleeding.
Conclusions
Tenectaplase as a molecule has several distinct advantages over other thrombolytic agents with prolonged half life and considerable resistance to PAI-1 (80 times more than Alteplase). These features allow the agent to be particularly suitable for pre-hospital thrombolysis as it can be given as a bolus within a few seconds. ASSENT-1 & 2 trials have established the efficacy of tenectaplase vis a vis alteplase. There is no evidence of increased risk of bleeding following tenetaplase if dose adjustment against the weight of the patient is taken care of. It is essential to use anti-thrombotic therapy in the form of UFH/Enox as an adjunct. GpIIb/IIIa agents should not be combined with tenectaplase for fear of excess risk of bleeding as demonstrated in the ASSENT-3, ENTIRE TIMI 23 and INTEGRITI trials. Angioplasty following tenectaplase should be postponed at least 3 to 12 hours to achieve the best results (GRACIA-2). For all the above considerations the American College of Chest Physicians (ACCP) recognizes TNKase as a Class 1A recommendation in the treatment of STEMI patients within 12 hours from the onset of symptoms.34
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