TNK-tPA (Tenecteplase)
Sameer Mehta, Estefanía Oliveros, Salomon Cohen, Esther Falcão, Ana I. Flores
Miller School of Medicine, University of Miami & Mercy Medical Center, Miami, Florida
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HISTORY AND EVOLUTION OF FIBRINOLYTIC THERAPY
The discovery of the fibrinolytic therapy was in the year 1947, when the existence of an agent present in the animal tissues that activated plasminogen was demonstrated; it was initially called fibrinokinase. During the 1970s, α2-antiplasmin was discovered; in addition, the group of Reich in New York found that malignant tumors had substances with plasminogen activator (PA) activity, and the malignancy was correlated to the levels of malignant protease secreted.1
In the following years, melanoma cell cultures were obtained from which PA was extracted and purified. Investigators from the Netherlands developed a method for purifying PA from the human uteri. Simultaneously, a model for physiological fibrinolysis was published at the VII International Congress on Thrombosis and Hemostasis, establishing the concept of the fibrin-specificity of tPA. These lines of research created the basis for the development of an alternative drug to the nonfibrin specific PA, streptokinase and urokinase. 1
clots and fibrinous exudates, began. Originally, it was used to treat hemothorax but afterwards took its place in the management of acute myocardial infarction (MI). SK went through a process of several trials until the mid-1980s when there was a clear demonstration with angiographic proof that direct intracoronary use of the drug could successfully achieve culprit vessel recanalization and improved survival. 2, 3
FIBRINOLYTIC AGENTS
The agents can be grouped into direct and indirect PAs and into first, second and third generation agents. 3 We will now discuss the individual thrombolytic agent in detail and review the clinical trials that lead to their respective clinical use.
FIRST GENERATION: ALTEPLASE, STREPTOKINASE AND UROKINASE
These agents are characterized by low specificity for fibrin, increased risk for allergic reactions and short half-life. 4, 5
ALTEPLASE (tPA)
Alteplase is cloned from endogenous human tPA and is made up of a 70-kd serine protease composed of a single polypeptide chain of 527 aminoE-mail: mehtas@bellsouth.net
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acids. 6 Early works with tPA was done in the Global Utilization of Streptokinase and Tissue-Type Plasminogen Activator for Occluded Coronary Arteries (GUSTO)-I trial. Through this work, the drug was shown to reduce mortality (Table 1). 3, 4
STREPTOKINASE (SK)
SK is an indirect fibrinolytic agent that binds to plasminogen that converts it into a plasmin-like molecule. It produces plasminemia which results in the depletion of fibrinogen, plasminogen and factors V and VIII, and resulting in a hypocoagulable state with low risk of rethrombosis. 3 The GISSI (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico)-1 and ISIS (Second International Study of Infarct Survival)-2 trials showed a mortality reduction of 23% and 30%, respectively. The 30-day mortality was approximately 7.5%. 6 As a negative attribute, SK has an antigenic profile and a propensity to cause hemorrhagic complications (Table 1). 4
UROKINASE
Less antigenic than SK, urokinase has found its niche in treating peripheral vascular occlusions. 3 It has been used as a thrombolytic agent, but it has not offered any advantages over the other lytic agents.
SECOND GENERATION: SARUPLASE AND ANISTREPLASE
They offer some advantages over the previous generation, such as prolonged half-life, increased fibrin specificity and increased resistance to inhibition by PAs.
SARUPLASE
The drug is a single-chain precursor to urokinase, with little intrinsic enzymatic activity. It circulates bound to a specific inhibitor, producing an inactivated catalytic activity. 3
ANISTREPLASE
It is bound to lys-plasminogen increasing its affinity for fibrin, hence forming an activator complex. This drug has a longer half-life (approximately 100 minutes); therefore, it can be administered as a single bolus. 3
Experience with the second generation lytic agents began with a flourish but was cut short because of rapid progress that was gained with the development of the third generation lytic agents.
THIRD GENERATION: RETEPLASE, LATENOPLASE AND TENECTEPLASE
RETEPLASE (rPA)
Two large early clinical trials made it possible to understand the potential of the third generation thrombolytic agents. Firstly, in the RAPID (Recombinant Plasminogen Activator Angiographic Phase II International Dose-finding) I and II trials, rPA was demonstrated to be superior with respect to patency of the infarct-related coronary artery (IRA). 7 Secondly, in the GUSTO-III trial, rPA and tPA showed similar 30-day mortality rates (7.5% and 7.2%). 3, 7
LATENOPLASE (nPA)
nPA is another deletion mutant of naturally occurring tPA. It has one of the longest half-lives of the mutant tPA molecules permitting a single-bolus administration. It presents a low affinity for fibrin compared to tPA. 7
TENECTEPLASE (TNK-tPA)
TNK-tPA is a mutant recombinant tissue PA. It is similar to wild-type tPA but has amino acid substitutions at three sites (Tables 1 and 2). 2, 4 The molecule is expressed in Chinese hamster ovary cells with carbohydrate side chains linked to the glycosylation sites of the polypeptide. At the N domain, the substitution was made to increase the fibrin specificity by focusing the enzymatic activity at the clot rather than the periphery thereby minimizing the induction of a systemic fibrinolytic state. In fact, levels of fibrinogen, fibrin degradation products, and other coagulation factors are fairly stable following TNK-tPA administration. 8, 9 TNK-tPA is 14 times more fibrin specific than standard tPA. 10 The blood clot has a fibrin portion that can be dissolved by PAs, exposing the clot-bound thrombin and, in turn, stimulates platelet aggregation. The plasminogen activator inhibitor-1 (PAI-1) is an enzyme attached to the surface of platelets that interacts with thrombolytics to inhibit their activity. TNK-tPA is 80–fold more resistant to inhibition from PAI- 1 than tPA. 8, 10 Liver metabolism is the major clearance mechanism of TNK-tPA. 8 In an animal model of acute arterial occlusion, a bolus of TNK-tPA was found to produce a 6 to 12-fold rapid recanalization and a greater degree of clot lysis on a µg.kg-1 basis, compared with a front-loaded tPA regimen. 10, 12 TNK-tPA is compatible for combination with a broad range of other medications, such as glycoprotein (GP) IIb/IIIa and low-molecular-weight heparin, while rPA and tPA may precipitate with the administration of heparin, a drug commonly used in treating acute MI. 8,10
ROLE OF THROMBOLYTICS FOR ACUTE MYOCARDIAL INFARCTION
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According to the acute STEMI guidelines presented in CHEST, a patient presenting with an acute MI of ≤ 12 hours in duration and persistent ST elevation should undergo rapid reperfusion therapy and have a reperfusion strategy established promptly after contact with the health care system. 7,12 The ACC/AHA STEMI guidelines recommend mechanical reperfusion using percutaneous coronary intervention (PCI) as the initial approach to management of STEMI, considering the center has a skilled catheterization laboratory and initiates therapy <90-minutes. 14, 15
Fibrinolytic therapy, on the other hand is an attractive option when such facilities are not immediately available. It should be recommended when primary PCI (PPCI) is not available in patients presenting an acute MI of ≤ 12 hours duration, and in left bundle-branch block (BBB) with associated ST elevation change (Grade 1B); ECG findings consistent with a true posterior MI (Grade 2B); and on high risk patients with ongoing symptoms characteristic of acute MI or hemodynamic compromise and duration of 12 to 24 -hours who have persistent STE or left BBB with STE changes (Grade 2B). 16 Most critically, fibrinolytic therapy administration should be within 30 minutes of arrival or PPCI within 90 minutes of arrival. PPCI is associated with nearly half the in-hospital mortality compared to the treatment with fibrinolytic therapy. 16, 17
The impact on the global management of acute STEMI with fibrinolytics has transformed the therapeutic approach. The benefits of rapid reperfusion with a systemic intravenous bolus or infusion are remarkable. Numerous discoveries were made over the past decade regarding the use of fibrinolytic therapy for acute STEMI taking into consideration that early achievement of TIMI II-III flow in the IRA is associated with reduced infarct-size, minimized myocardial damage, preserved left ventricular function, and reduced mortality and morbidity. 12, 18
Noteworthy is the striking data supporting benefits of very early thrombolysis, and the concept of the “golden hour.” A large myocardial infarction will compromise more viable myocardium, therefore making it more vulnerable to subsequent ischemia and infarction. 19, 20
The use of SK, anistreplase, tPA, rPA, or TNK-tPA is preferred over no fibrinolytic therapy if the electrocardiogram ST elevation and symptoms have duration of ≤ 12 -hours (Grade 1A). 7, 16
Administration of tPA (Grade 1A) or TNK-tPA (Grade 1A) over SK is preferred for patients with symptom duration ≤ 6 hours (Grade 1A) (Table 1). 4
There is still no preference in reperfusion therapy in patients who present within 3 hours after symptom onset. 14, 18 The clinical trials’ designs were oriented to the development of guidelines. Initially, the purpose was to find the correct dosing of thrombolytics to achieve a successful reperfusion, while taking into consideration the risks of dreaded complications, such as reinfarction, intracranial and systemic hemorrhage, and need for transfusion.
CLINICAL TRIALS RELEVANT TO THE DEVELOPMENT OF TENECTEPLASE
TIMI-10A
The Thrombolysis in Myocardial Infarction (TIMI)-10A Trial was a phase I, dose-ranging, pilot trial designed to evaluate the pharmacokinetics, safety and efficacy of the TNK-tPA in humans (Table 3). Furthermore, it assessed the effects of increasing doses of TNK-tPA on the coagulation parameters and evaluated efficacy of using TIMI III flow and TIMI frame count.12 The study enrolled 113 patients with STEMI presenting within 12 hours of symptom onset who had no contraindications for thrombolysis. To establish the pharmacokinetic profile of the drug, the researchers used a small dose-escalation system, ranging from 5 to 50-mg bolus dose over 5 to 10 seconds.12 The results demonstrated a plasma clearance ranged from 125±25 to 216±98 mL/min and a prolonged half-life ranged from 11±5 to 20±6 minutes, allowing the administration of the drug as a single bolus. 12 The fact that this thrombolytic agent can be administered in a bolus brings clear benefits. 3, 12 In addition to the speed and ease of use, the potential for errors is reduced.
This is an important consideration as some studies have reported incorrect dosing in up to 5% to 12% of the time, when using fibrinolytic therapy in the urgent setting of an acute STEMI. 21 Furthermore, mortality is increased in patients receiving incorrect doses of other thrombolytics, such as SK and tPA, which require IV infusion based on weight. The incorrect dosing may also be associated with increased ICH. 3, 18, 22
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The timing of drug administration also is critical, and TNK-tPA has an advantage in contrast with other drugs. The duration of the tPA infusion may be either too long or too short. The timing of the second bolus of rPA at 30 min may occur too early or too late, or may be missed entirely. The bolus of rPA may be given more or less rapidly over 2min. 8
Additionally, TNK-tPA offers the potential to facilitate immediate thrombolysis in a pre-hospital setting and thus maximising myocardial salvage, considering that treatment time saved equates to salvage of the cardiac muscle.
There are additional pharmacokinetic considerations too - the consumption of α2-antiplasmin, fluid-phase inhibitor of plasmin, and a consequent increase in plasmin/α2-antiplasmin complexes, vary depending on the dose of TNK-tPA. There was a constant reduction on average at all dose levels in fibrinogen and plasminogen, 3% and 13% respectively. Results can be compared from those obtained with front-loaded tPA, which produce a decrease of 50% in fibrinogen and of 60% in plasminogen at 3 hours. Despite this, TNK-tPA is more fibrin specific than tPA. 12 The “plasminogen steal” phenomenon is produced by very low systemic levels of plasminogen leading to its diffusion out from the thrombus, depleting the substrate and decreasing the amount of plasmin generated on the clot surface, therefore decreasing clot lysis. In the case of double-bolus tPA, a lower rate of TIMI III flow and IRA patency is observed. Because the double-bolus regimen can be associated with depletion of systemic plasminogen, a hypothesis states that plasminogen steal may reduce the efficacy of a more aggressive regimen. As such, the fibrin specificity of TNK-tPA should permit rapid plasminogen activation in the clot to proceed, even when given as a single bolus. 12 More than half of the patients (57-64%) experienced TIMI III flow at 90-minutes when treated with the 30 to 50-mg doses. Truly normal flow (TIMI frame count 27) was achieved by 45% of patients treated with higher doses of TNK-tPA, whereas only 27% of patients treated with tPA in the TIMI 4 trial achieved truly normal flow by 90-minutes (P<0.01). 12
Any discussion about thrombolytic therapy is less relevant unless the major complication of bleeding is discussed in detail. Lower rates of surgical site bleeding were observed in animal studies compared with tPA and a relatively low rate of major hemorrhage was observed in the TIMI-10A trial (6.2 vs. 11%-23%) in other recent studies with front-loaded tPA, suggesting that TNK-tPA may be associated with a lower rate of hemorrhage. 12 Seven patients (6%) developed a major hemorrhage under the following doses: one patient at 15-mg; two patients at 20-mg; one patient at 30-mg; two patients at 40-mg; and one patient at 50-mg.8 Mortality at 30-days was 3.5%. Reinfarction was observed in 4.4% of patients, and new-onset pulmonary edema occurred in 2.7% No antibodies were detected at 30 days. 10, 12
The TIMI-10A trial lead to further evaluation of the dosing ranges between 30 to 50-mg.
TIMI-10B
The TIMI-10B was a phase II, dose-ranging angiographic study, made to compare the efficacy of TNK-tPA (different doses) with tPA (Table 3). The study population included 886 patients with acute STEMI presenting within 12 hours of symptoms onset.They were randomized in a non-weight- adjusted fashion to a single bolus of 30 or 50 mg of TNK-tPA or the accelerated regimen of rtPA. 23 The trial demonstrated that a 40-mg dose of TNK-tPA resulted in similar rates of TIMI III flow to that of a 90-minute regimen of tPA (62.8 vs. 62.7%, respectively). 2, 23 The 30-mg dose produced a significantly lower rate (54.3%; p = 0.035), and the 50-mg dose produced a similar rate (65.8%). The analysis showed that higher weight-corrected doses improved TIMI III flow until a plateau was reached approximately at 0.5 mg/kg of TNK-tPA. The TIMI frame count had no significant difference between TNK-tPA and tPA in the rate of <28 frames. The drop in plasminogen was only 10% to 15% after TNK-tPA, in comparison to a 50% drop post tPA. The consumption of α2-antiplasmin, the fluid-phase inhibitor of plasmin and a consequent increase in plasmin- α2-antiplasmin complexes were 4 to 5 times greater with tPA than with TNK-tPA at any of the 3 doses. 9, 23
Overall, 78 patients were treated with 50 mg of TNK-tPA plus heparin. From this group, three patients (mean weight 77.2 kg) manifested intracranial hemorrhage (ICH), so the dose was replaced with 40-mg bolus. 2, 23 Therefore, adjustments were made to the protocol, no additional heparin would be given previously to diagnostic angiography, and reduced-weight-adjusted heparin doses were implemented. Rates of ICH for TNK-tPA were 1% for the 30 mg dose, 1.9% for the 40 mg dose, and 3.8% for the 50 mg dose. The ICH rate for tPA was 1.9%. Consequently, the rates of ICH associated with TNK-tPA treatment were diminished from 1.82 to 0.73% (p=0.046). The ICH was a critical issue and it required considerable evaluation of data. Retrospective analysis demonstrated that the heparin dose played a far greater role than TNK-tPA dose in the ICH incidence. Although TNK-tPA has proven to be more fibrin specific compared with tPA, the trial documents this does not prevent ICH. It has become subsequently clear that ICH is caused by thrombolytics when there is lysis of microthrombi in cerebral vessels. This can be sustained by stating that both elderly patients and those with established cerebrovascular disease are at 5 to 10 times increased risk of ICH, as documented in the TIMI 2 and GUSTO-I trials. The plasmin on the cerebral vasculature may also induce ICH. 22, 24
Non ICH bleeding rates are as follows: serious bleeding rates for TNK-PA were 1.9% for the 30-mg dose, 5.2% for the 40-mg dose, and 11.5% for the 50-mg dose. The serious bleeding rate for tPA was 8.5%. It also appears that bleeding rates are higher than those generally observed in large-scale safety trials and in clinical practice, most likely because of the need for vessel instrumentation in the angioplasty, and the higher heparin dosing used in these trials due to adjunctive or rescue percutaneous coronary intervention within 12 hours after failed fibrinolysis for patients with continuing or recurrent myocardial ischemia). 8, 16
The mortality rate for TNK-tPA 50 mg was 3.8%, and the resultant net clinical benefit (death or nonfatal intracranial hemorrhage) was 5.1%.24 Reinfarction was present in 5.4% of the patients, not significantly different among both drugs.
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ASSENT-1
The Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-1 was a phase II trial conducted at the same time as the TIMI-10B study (Table 3). In the ASSENT-1 study, 3301 patients were enrolled. The population manifested with STEMI and was treated with a single bolus of TNK- tPA, the doses chosen were 30, 40 and 50-mg. The onset of symptoms was 12 hours. Since the TIMI-10B trial made the observation regarding the bleeding complications associated with the 50-mg dose, it was adjusted to a 40-mg dose. 23 The only difference that remained was that heparin was dosed according to the heparin protocol amendment. Initially, they received an initial bolus of 5000 U, but it was reduced to 4000 U for patients ≤67kg, followed by an infusion of 1000 U/hr (>67 kg) or 800 U/hr (≤67 kg). These changes decreased the incidence of ICH in the 30-mg TNK-tPA group and influenced the low rates of hemorrhagic stroke. 25 The safety profile was similar to that observed with tPA; there was no difference in the incidence of total stroke (1.5% for 30 and 40-mg), ICH (0.77%), death (5.7%), or severe bleeding (1.6%) among the treatment groups. The ICH complications in patients treated within six hours of the onset of myocardial infarction was 0.56% with 30-mg, 0.58% with 40-mg and 0.72% with a reduced dose of heparin. 25 TNK-tPA doses of 0.5-mg/kg were selected based on the results on the TIMI-10B and the ASSENT-1 leading to comparisons with the front-loaded tPA in a phase III trial.
ASSENT-2
The ASSENT-2 was a phase III, double-blind, randomized, controlled trial, which compared TNK-tPA to tPA in 16,949 patients with STEMI worldwide, presenting within 6 hours of symptom onset (Table 3). Overall, the stroke rate was 1.78% with TNK-tPA versus 1.66% with tPA. The rate of ICH was similar in both groups, although the group receiving TNK-tPA manifested a non-significant, but higher rate of ischemic and total stroke. However, the rate of noncerebral bleeding complications (26.1% versus 28.4%) and need for transfusion (4.3% versus 5.5%) were significantly lower with TNK-tPA. 26 These results may translate into greater cost effectiveness, i.e. taking into account fewer days in the intensive care unit, the costs of imaging studies to determine the site of bleeding, the cost of therapeutic modalities such as endoscopy, among others. 8 Females had higher risk of noncerebral major bleeds, and those with body weight ≤ 67 kg had higher manifestations of ICH. 24 Diastolic BP ≤ 70 mmHg was a major risk factor for noncerebral hemorrhage with OR 1.33 (1.14-1.54), similar to the findings in the GUSTO-I study with OR 0.94 for diastolic BP 90 vs. 80 mmHg, 95% CI, 1.12-1.57. 24 Total mortality after 30-days with TNK-tPA and tPA were almost identical, 6.18% and 6.15%, respectively. The only group that manifested lower mortality had received TNK-tPA after 4 hours. 26 This might be related to the greater fibrin specificity of TNK-tPA. 3
The improved safety profile of TNK-tPA may reflect only minimal depletion of fibrinogen and weight-adjusted dosing. The rates were also similar to those observed in the GUSTO-III study, which compared rPA with tPA (i.e., 0.91 % for rPA and 0.87% for tPA), leading to state that the higher the fibrin specificity of TNK-tPA the better dissolution of the older fibrin clot and, consequently, an improved clinical outcome. In general, the ASSENT-2 study confirmed that weight-optimized dosing of TNK-tPA could be utilized to treat patients with AMI effectively and more safely. 8 Demographic risk factors for ICH include older age, lighter body weight, female sex, high blood pressure on admission, prior cerebrovascular disease and hypertension. Independent predictors of major bleeding complications are older age, lighter body weight, female sex and African ancestry in addition to use of coronary artery bypass surgery and invasive procedures. 6 Overall, patients with TNK-tPA were associated with fewer tendencies to experience a major bleeding event than if they were treated with rtPA, particularly in the high risk subgroup of females >75 years of age and weight <67 kg. 6
ASSENT-3
Suboptimal macroperfusion and microperfusion, recurrent ischemia, reinfarction and ICH were still major challenges to overcome with the use of TNK-tPA in patients with acute STEMI (Table 3). In all the previous trials, unfractioned heparin (UFH) was routinely given to most patients. More recently low-molecular-weight heparin (LMWH) has been combined with fibrinolytics. This has brought benefits because LMWH has more predictable kinetics, less protein-bound, less potential for platelet activation and requires no monitoring, providing a strong rationale for potentially better outcomes when given in combination with fibrinolytics. Several studies show lower rates of reocclusion, late patency of the IRA or a reduction in reinfarction rate when compared with UFH. 27
The introduction of platelet GP IIb/IIIa inhibitors as adjunctive therapy with fibrinolytic agents has demonstrated better patency of the epicardial IRA and signs of improved tissue reperfusion.
Considering all the knowledge recollected from previous works, the ASSENT-3 trial randomized 6,095 patients with STEMI into 3 groups receiving: full-dose TNK-tPA plus enoxaparin; half-dose TNK-tPA plus weight-adjusted, reduced dose UFH plus abciximab; or full dose TNK-tPA plus weight-adjusted UFH. With respect to the primary efficacy end point (30-day mortality, in-hospital reinfarction, or in-hospital refractory ischemia), the patients that received the combination therapy of half-dose TNK-tPA plus abciximab presented lower event rates than the other groups. 27 The results from the patients receiving full-dose TNK-tPA plus the UFH were
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were consistent with the previous findings of the ASSENT-2 trial. Nevertheless, the bleeding complications (2.2% vs. 4.7%) and the need for blood transfusion (2.3% vs. 4.3%) were diminished in this trial.
The use of Abciximab or enoxaparin reduces ischemic complications of acute MI treated with TNK-tPA. 27
GUSTO V was a phase III trial that studied half-dose rPA and abciximab, compared with full-dose rPA. They were unsuccessful to demonstrate a decrease in 30-day mortality, and showed an increase in non-cerebral bleeding complications. 4, 27 They helped sustained the concept that a more potent antiplatelet agent increases flow in the IRA. The benefits of the drugs were achieved in the GUSTO V and in the ASSENT-3, but this also brought higher rates of thrombocytopenia, major bleeding complications and blood transfusions. The combination of full dose TNK-tPA and long-term administration of enoxaparin (7-day course) was the most successful of this trial. The benefits are the simplicity of the medication regimen and the lack of need for monitoring anticoagulation.
ASSENT-3 PLUS
Prehospital fibrinolysis has shown to significantly reduce time to treatment around the world, particularly in rural or congested urban areas where transportation times are long or when PCI facilities are not readily available, there is a preference over no therapy (Grade 1A). 16,18,28 The CAPTIM (Comparison of Angioplasty to Prehospital Thrombolysis trial In Myocardial Infarction) and PRAGUE (Primary Angioplasty in patients transported from general community hospitals to specialized PTCA Units with or without emergency thrombolysis) - 2 trials showed that primary percutaneous coronary intervention (PPCI) had no survival advantage as compared with rapid pharmacological reperfusion in the prehospital setting. 18, 28 The patients stratified according to treatment within 2 hours of symptom onset. The 30-day survival favored fibrinolysis. 28 The ASSENT-3 PLUS is a randomized trial in acute MI that studied 1,639 patients with STEMI within 6 hours in 12 countries, who were treated with prehospital fibrinolysis (Table 3). The patients received TNK-tPA plus UFH or enoxaparin. The median time from symptom onset until initiation of treatment with prehospital fibrinolysis was 115 minutes; 47 minutes earlier than the intra-hospital fibrinolysis shown in the ASSENT-3 trial. The group that received enoxaparin had reduced 30-day mortality, intrahospital reinfarction or in-hospital refractory ischemia but augmented stroke and ICH rates (especially in patients >75 years). The marked differences found among the different countries enrolled in the study may help explain delays in time to treatment and time from symptom onset to first medical contact. Simple things not even related to the health system, such as traffic, will alter the outcome of thepatient. The presence of a physician in the prehospital setting was associated with greater adherence to protocol mandated treatments and procedures but created delays in time to treatment. In other countries the evaluation is made by EMS units with physicians, and the limitation is the insufficient number of units. 28
ASSENT-4 PCI
The ASSENT-4 PCI study made a review in the administration of a full-dose TNK-tPA before a delayed PCI (Table 3). They enrolled 1,667 patients with acute STEMI of less than 6 hours duration that were prepared for PPCI with an anticipated delay of 1-3 hours or preceded by full dose TNK-tPA. 29, 30 Early pharmacological approaches prior to mechanical intervention was a key point to be studied. Up to date, the prospective randomized trials that have assessed facilitated angioplasty in patients with STEMI are ASSENT-4, FINESSE (Facilitated Intervention with Enhanced reperfusion Speed to Stop Events) and CARESS AMI (Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction). 4, 31 Delays in transfer between health facilities, to provide PPCI as reperfusion strategy, have become the cornerstone of providing a proper management. There is controversy as to whether treatment delays in PPCI are less important than those in fibrinolytic therapy. 32 In ASSENT-4 the PCI occurred at a median of 104 min after thrombolysis. There was a higher in-hospital mortality in the facilitated (6%) than in the standard PCI (3%) group (p=0.0105). Manifestation of stroke was increased with facilitated compared to standard PCI, 1.8% and 0% (p<0.0001) respectively. 30 Most likely, this was a consequence of a pro-thrombotic, post fibrinolytic milieu. There is a prothrombotic state following fibrinolytic therapy that may be responsible of all the complications in the patients that went through PCI. Rates of reinfarction (6% vs. 4%, p=0.0279) and need for repeat of target vessel revascularization (7% vs. 3%, p=0.0041) were also predominant in the facilitated PCI group. Full-dose TNK-tPA plus antithrombotic co-therapy was given to reduce thrombus burden, as used in this trial, preceding PCI by 1-3 hours. This was associated with more major adverse events than PCI alone in STEMI and cannot be recommended.30
OTHER RELEVANT TRIALS
WEST
The WEST (Which Early ST-elevation myocardial infarction therapy) trial randomized 304 patients to TNK alone, TNK combined with cardiac catheterization (and PCI, if required), or PPCI. This trial showed similar low mortality rates in all groups, hence the importance of a rapid delivery system formed by a regimented rescue (rapid diagnosis) and routine coronary intervention within 24 hours of initial therapy. 15, 33, 34
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In the GRACIA-2 study, they found delays in both treatments, associated with higher 6-month mortality in patients with STEMI receiving reperfusion therapy. Furthermore, this relationship appeared to be less steep in patients undergoing PPCI than in those receiving fibrinolytic therapy. The efficacy of fibrinolytic therapy at re-establishing TIMI 3 flow diminishes with longer treatment delays leading to worse clinical outcomes. This is potentially due to enhanced thrombus organization over time within the IRA. PPCI mechanically disrupts the thrombus, and therefore its ability to re-establish TIMI III flow is less time-dependent. 32 STEMI patients can go through a routine stent-angioplasty within 3-12 hours of fibrinolysis and it can be considered safe and equivalent to primary stenting in preserving myocardial function. 32
The difference between ASSENT-4 and the GRACIA-2 trial was that in the latter study primary and facilitated cases had to receive intervention within an identical short delay: 1-3 hours from randomization. PPCI was considered to be superior to facilitated angioplasty when the intervention is performed with a similar delay. 32 Primary and facilitated PCI had a low and identical incidence of ischemic events and 6-week angiographic reocclusion. In spite of the longer intervention delay, post-fibrinolysis intervention resulted in an equivalent infarct size and ventricular outcome when compared with primary stent-angioplasty under Abciximab protection. 32 The time window between fibrinolysis and angioplasty can be safely widened up to 6 hours after first medical contact. 32
TRANSFER-AMI
The TRANSFER-AMI (Trial of Routine ANgioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in Acute Myocardial Infarction) was a pilot study conducted in Canada in high-risk STEMI patients that were transferred from community hospitals to regional PCI centers for urgent PCI within 6 hours of thrombolysis. The pilot phase enrolled 20 patients (Table 3). No complications during transfer and no major bleeding related to the PCI procedure were seen. Thrombolysis fails to restore IRA patency within 90-min in approximately 20% of patients and achieves TIMI III flow in less than 60% of patients. Over 20% of patients with TIMI III flow have absent myocardial perfusion at the tissue level. Even after successful thrombolysis, patients remain at risk for reocclusion, reinfarction and recurrent ischemia. 34
other trial, heparin bolus and infusion or enoxaparin was chosen. 34 Delays imposed by long transfer time impeded PPCI. Most likely the causes were challenging, timely interhospital transfers in large urban centers and ambulance limitation availability. 34
VIENNA STEMI REGISTRY
In the Vienna STEMI registry, the data was recollected among 1053 patients with acute STEMI (Table 3). The in-hospital mortality statistics in patients with acute STEMI was reduced from 16% to 9.5% due to the use of PPCI or thrombolytic therapy in the facilities without catheterization. 35
EXPERIENCE OF TNK-tPA IN INDIA
By 2020, coronary heart disease (CHD) will be the most common cause of death globally, including in India. 36 Mortality data from the Registrar General of India shows that cardiovascular diseases are a major cause of death in India now. 37 The prevalence rates are higher in urban (40%) than in rural (30%) India. These rates have increased in urban areas from about 2% in 1960 to 10.5% in 2000; while in rural areas, it increased from 2% in 1970 to 4.5% in 2000. In terms of absolute numbers, this translates into 30 million CHD patients in the country. Even more troublesome is the fact that the disease occurs at a much younger age in Indians as compared to those in North America and in Western Europe. CHD is also high among people with Indian origins who are now living abroad. 36, 37
When reviewing the use of thrombolytic therapy, the critical points to review are the promptness of thrombolysis and the actual strategy. In doing so, one is confronted with the troublesome statistics: around 25% to 40% of patients, worldwide, who present with clinical signs of acute STEMI, do not receive any reperfusion therapy at all. A formidable challenge in the contemporary era is to extend the use of reperfusion therapies to all who are likely to benefit. Longer times to treatment are inversely related to mortality with both thrombolytic therapy and PPCI. 35
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Table 3. Clinical trials of tenecteplase
TRIAL |
n |
TRIAL DESIGN |
RESULTS |
CONCLUSIONS |
TIMI 10A |
113 |
Patients with acute MI presenting within 12 h received a single bolus of TNK-tPA over 5-10 seconds with doses from 5 to 50 mg, and were compared with a group receiving tPA. |
TNK-tPA: CLp=151±55 mL/min. T1/2=17±7 min. Drop in systemic fibrinogen (3%) and plasminogen(13%). TIMI III at 90 min with 30-50 mg doses was between 59-64% (p=.032). Outcome: Mortality at 30 days=3.5%, reinfarction= 4.4%, major hemorrhage= 6.2%.tPA: Clp=572±132 mL/min. T1/2=3.5±1.4 min. |
TNK-tPA has a prolonged half-life; therefore administration as a single bolus is possible. It is fibrin specific. |
TIMI 10B |
886 |
Patients with acute MI presenting within 12 h received a single bolus of 30 or 50 mg of TNK-tPA, or front-loaded tPA, followed by a coronary angiography. Heparin was given to the discretion of the physician, until high doses showed increased ICH, so it was weight-adjusted. TNK-tPA 50-mg dose was related with ICH, so it was replaced with a 40 mg bolus, and heparin doses were reduced. |
Characteristics: TIMI III at 90 min= TNK-tPA 40 mg and tPA had similar rates (62.8% vs. 62.7%, p=NS). The 30-mg dose was 54.3% (p=0.035), and the 50-mg dose achieved 65.8% (p=0.62 compared to tPA; p=0.03 compared to TNK-tPA doses).TIMI frame count= <40 (low reperfusion) with TNK-tPA 30-mg compared with tPA. TIMI III= 62-63% for doses of ≈0.5 mg/kg. Safety results: ICH rates= 1.0% for 30 mg TNK-tPA, 1.9% for 40 mg, and 3.8% for 50 mg, and 1.9% for tPA. Serious bleeding= 1.9%, 5.2%, and 11.5% (p=0.001) of patients treated with the 30-, 40-, and 50-mg doses of TNK-tPA, compared with 8.5% for tPA. Clinical Outcome: Mortality at 30 days was 4.9% and reinfarction was 5.4%, without differences between TNK-tPA or tPA. |
The TIMI III flow at 40-mg dose of TNK-tPA was similar to that with the 90-minute regimen of tPA. Weight-adjustment dosing is important in optimizing reperfusion and safety. Adjunctive heparin dosing has a role in bleeding complications, with a favorable safety profile when using reduced heparin dose. |
3,301 |
Patients received single bolus of TNK-tPA doses: 30, 40, 50-mg. The 50-mg dose was related with ICH, so it was replaced with 40-mg bolus, and heparin doses were weight-adjusted and reduced. |
Total stroke rate at 30-days=1.5%. ICH= 0.77%; 0.94% in the 30-mg group; and 0.62% in the 40-mg group. Patients treated within 6 hours after symptom onset ICH were 0.56% (30-mg) and 0.58% (40-mg). Death, stroke, severe hemorrhage occurred in 6.4%, 7.4%, and 2.8%, respectively. |
Single bolus of 30 to 50-mg TNK-tPA is comparable in safety and efficacy to that of accelerated rtPA. |
1,6949 |
In 1021 hospitals, patients with acute MI <6 hours received a rapid infusion with tPA or a single bolus weight-adjusted dose of TNK-tPA. All patients received ASA and heparin. |
Total stroke rate was 1.78% with TNK-tPA vs.1.66% with tPA. . ICH was similar (0.93% for TNK-tPA vs. 0.94% for tPA).Noncerebral bleeding complications (26.1% vs. 28.4%) and need for transfusions (4.3% vs. 5.5%) were lower with TNK-tPA. Diastolic BP ≤ 70 mmHg was a major risk factor for noncerebral hemorrhage with OR 1.33 (1.14-1.54). Total mortality after 30-days with TNK-tPA and tPA were 6.18% and 6.15%, respectively. The group with lower mortality had received TNK-tPA after 4h. |
TNK-tPA and tPA were equivalent for 30-day mortality. |
6095 |
Patients with acute STEMI were randomized in 3 groups: Full dose TNK-tPA + enoxaparin; Half-dose TNK-tPA + Weight-adjusted, reduced dose UFH + abciximab; Full dose TNK-tPA + Weight-adjusted UFH. All the patients received ASA. |
Primary efficacy endpoint: (30-day mortality, in-hospital reinfarction or in-hospital refractory ischemia) in 11.4% of the TNK-tPA + enoxaparin group, 11.1% of the TNK-tPA + abciximab group and 15.4% of the TNK-tPA + UFH group (p = 0.0001). Primary efficacy + safety endpoint (in-hospital ICH or in-hospital major bleeding) : occurred in 13.7% of the TNK-tPA + enoxaparin group, 14.2% in the TNK-tPA + abciximab group and 17.0% of those in the TNK-tPA + UFH group (p = 0.0081) |
Clinical outcomes after elective PCI were similar with the three antithrombotic co-therapies studied |
|
ASSENT 3 PLUS |
1,639 |
In 12 countries, patients presenting with STEMI within 6 hours were treated with prehospital fibrinolysis. The patients received TNK-tPA + UFH or enoxaparin. |
The median time from symptom onset until initiation of prehospital fibrinolysis was 115 minutes. The group that received enoxaparin had reduced 30-day mortality, intrahospital reinfarction or in-hospital refractory ischemia but augmented stroke and ICH rates (especially in patients >75 years). |
Benefits of enoxaparin used with TNK-tPA, but should be used with caution in elderly patients. |
TRANSFER-AMI |
20 |
High-risk STEMI patients transferred from community hospitals to regional PCI centers for urgent PCI within 6 h of thrombolysis. |
Eighteen patients were transferred and underwent PCI a median of 3.9 hours post thrombolysis. One death due to failed reperfusion and cardiogenic shock. Five patients had minor access-site bleeding, |
Transfer high risk STEMI patients for urgent PCI within 6 hours after thrombolysis appears feasible. |
ASSENT 4 PCI |
4,000 |
Patients with acute STEMI <6 hours duration were prepared for PPCI with an anticipated delay of 1-3 hours or preceded by full dose TNK-tPA. All patients received ASA and UFH (single bolus). |
PCI median after thrombolysis = 104 min. Higher in-hospital mortality in the facilitated (6%) than in standard PCI (3%) group (p=0.0105). Primary endpoint in 19% of patients assigned facilitated PCI versus 13% of those randomised to primary PCI (RR 1.39, 95% CI 1.11-1.74; p=0.0045). Stroke increased with facilitated compared to standard PCI, 1.8% and 0% (p<0.0001) respectively. Major non-cerebral bleeding complications (6% vs. 4% , p=0.3118), were reported with facilitated rather than standard PCI. Reinfarction (6% vs. 4%, p=0.0279) and need for repeat of target vessel revascularization (7% vs. 3%, p=0.0041) were predominant in the facilitated PCI group. |
A strategy of full-dose TNK-tPA with antithrombotic co-therapy, as used in this study and preceding PCI by 1-3 h, was associated with more major adverse events than PCI alone in STEMI and cannot be recommended |
VIENNA |
1,053 |
The ambulance system was organized for diagnosis and triage of acute STEMI, 5 centers were used for PPCI, and the fastest (2-3 h from onset symptoms) therapy was chosen, either PPCI or thrombolytic therapy. |
The rate of patients receiving reperfusion therapy increased from 66 to 86.6%. PPCI increased from 16 to 60%, while thrombolytic therapy decreased from 50.5% to 26.7%. In-hospital mortality was reduced from 16% to 9.5%. PPCI was more effective in acute STEMI of >3 hours but <12 hours’ duration. |
Guideline implementation for the treatment of acute STEMI by an organized network will improve the clinical outcome. |
Cantor et. al |
1,059 |
Patients were randomized into 2 groups: high risk STEMI patients that were receiving TNK-tPA at centers without PCI (some underwent rescue PCI, or delayed angiography), or a strategy of immediate transfer with PCI 6 hours after fibrinolysis. All patients received ASA, heparin or enoxaparin and clopidogrel. |
Catheterization was performed in 88.7% of the patients receiving standard treatment (median 32.5 hours) and in 98.5% of the group that had routine early PCI (median 2.8 hours). The primary end point at 30-days (Death, reinfarction, recurrent ischemia, new or worsening CHF and cardiogenic shock) was present among 11% of the group of routine early PCI vs. 17.2% of the standard treatment group (RR with early PCI 0.64; 95%CI, 0.47 to 0.87; p=0.004). |
High-risk STEMI patients should undergo transfer for PCI within 6 hours after fibrinolysis |
|
catheterization improves mortality and remains one the points to be further studied. 4,17 In the study conducted by Gibson et al., the National Registry of Myocardial Infarction in the US was recompiled and showed a significant decline in mortality with improved door-to-needle (D2N) and door-to-balloon (D2B) times, relative adjustments of 16.3% and 7.5% respectively. The proper D2N time is in a range in which small changes in the myocardium have happened; thereby there will be great myocardial salvage. 17 NRMI-3 and 4 highlighted that only 4% of the patients transferred achieved D2B <90-min.18 Fibrinolysis is preferred when there is a delay to implementing an invasive strategy such that D2B time minus D2N time exceeds 1 hour. 18 Even when PPCI has proven superiority over fibrinolytic therapy in mortality, it is important to recognize that the statement is not applicable for all patients. In these situations, TNK-tPA may be a better alternative for reperfusion therapy, considering age, the infarct-related artery or delays in the system of activating the catheterization laboratory. 17, 38
TNK-tPA (brand Elaxim™) has been recently manufactured in India and is available at one third of the initial cost of the imported brand. Experience has now been gained in several thousand patients at more than a hundred large and small hospitals. Drug comparability to the original agent has been proven and dosing studies meticulously performed. Three doses of 30 my, 40 mg and 50 mg offer critical weight adjustments that offer a dual advantage – of lowering the risk of bleeding and in reducing the cost of the drug – there is considerable price savings between the three agents. Finally, the ease of use with a rapid, single bolus is being recognized as Elaxim finds greater adaptation in primary, secondary and tertiary centers.
These hypothetical advantages have been subjected to rigorous animal and human studies and a burgeoning Indian Elaxim Registry has been created. Overall, there appears a confluence between data obtained from the Indian patients receiving TNK-tPA with the results obtained in the ASSENT-2 trial. The earliest data with Elaxim was gathered in a pilot study of 58 Indian patients with STEMI using TNK-tPA - pain relief occurred in 89%, the reperfusion rate (>50%STR at 90-min) was 90%, and peak of CKMB rise in 12-hours was 80%. 40
Following this pilot trial was a larger study by Sathyamurthy et al. that was published in 2008. It enrolled 507 patients with STEMI who received treatment with weight-adjusted TNK-tPA and had a median chest pain to drug interval of 120-minutes. 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 80.76% of patients. Incidence of ICH was 0.99%, re-infarction was 2.96% and death was 2.63%. 39
What about the use of PCI after early administration of lytic therapy? As corroborated by GRACIA-2 and WEST trials, routine fibrinolysis followed by angioplasty within 3-12 hours seems to be cost-effective and most suitable for developing countries. Furthermore, early use of thrombolysis can treat the infarction and it can dramatically reduce mortality when given during the first 1-2 hours of onset.15
by increased platelet activation and aggregation, and stent implantation early after fibrinolysis without adequate antiplatelet therapy may be associated with increased rates of acute stent thrombosis. When the delay between fibrinolysis and PCI is too long, patients are exposed to the risk of reinfarction and recurrent ischemia while they await PCI, and patients in whom reperfusion after fibrinolysis is not successful may not be able to undergo rescue PCI quickly enough to salvage myocardium. 41 Transfer should be considered when fibrinolysis has failed, and can probably wait until the day after fibrinolytic therapy is given. Fibrinolysis should be followed by an early invasive approach.
CONCLUSIONS
STEMI remains a killer of mankind whose scourge is felt more in developing nations such as in India. Although PPCI demonstrates clinical superiority over thrombolytic therapy, wide-spread adoption of this strategy remains hampered by its high-cost and by other daunting hurdles. Thrombolytic therapy, in particular the use of newer fibrin-specific agents, remains a viable alternative provided the appropriate agent is delivered urgently.42
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