India Heart Jouranl 448-453

Clinical Research Article

“Tenecteplase – The Best Among the Equals”
RK Saran, R Sethi, M Nagori,
Department of Cardiology, CSM Medical University, Lucknow

Abstract:
Tenecteplase is a genetically engineered product of the Alteplase molecule. Mutations of Alteplase at three locations result in a more fibrin specific thrombolytic agent with a longer half life. Such properties would allow bolus administration, leading to faster reperfusion of occluded arteries. Tenecteplase is equivalent to front loaded Alteplase in terms of mortality and is the only bolus thrombolytic drug for which equivalence has been demonstrated. Tenecteplase seems more potent than Alteplase when symptoms duration is more than 4 hours. Moreover, Tenecteplase significantly reduces the rate of major bleeds and the need for blood transfusion. The efficacy of Tenecteplase may be further improved by reducing re-infarction rate by enoxaparin instead of unfractionated heparin.

Several large scale Clinical trials of Tenecteplase in acute myocardial infarction (MI) has been done making this drug truly evidence based. Available randomized studies and international clinical registries reveal that pre hospital thrombolysis by Tenecteplase is as effective as primary angioplasty. In fact Tenecteplase is now included in many pre-hospital thrombolytic reperfusion protocols, such as the Vienna STEMI registry, The Mayoclinic STEMI protocol and the French FAST-MI registry.

Tenecteplase with so many evidence based advantages is a fair option in acute MI patients in whom primary PCI can not be offered due to logistic reasons.

Keywords: Tenecteplase, Pre-hospital thrombolysis,

Introduction
Patient who present with Acute ST Elevation Myocardial Infarction (STEMI) are usually treated with either thrombolytic therapy or Primary Percutaneous Coronary Intervention (PCI) as the initial modality of reperfusion. Goals of reperfusion therapy are to achieve early patency and thereby increased myocardial salvage, preserve left ventricular function and lower mortality. PCI is an effective procedure for reestablishing coronary artery perfusion in STEMI that gives a very good short term (Six month) and long term (five year) outcome 1, 2. Current American and European guidelines prefer primary PCI, usually believed to achieve better coronary re-canalization rates, prevent re-infarction and ultimately, improved Survival 3. However, many conceptual and practical items dispute this presumed superiority of primary PCI as shown in table 1.

Table 1 Thrombolysis vs PCI

Thrombolysis is easily and immediately available everywhere.
Unavailability of skilled PCI lab with surgical back up at all hospitals
The time-delay to perform Primary-PCI exceeds 90 minutes in majority of patients
Primary-PCI does not reduce mortality consistently
Pre-hospital Thrombolysis within 3 hours of AMI as effective as Primary PCI.

The claim that primary PCI leads to a mortality reduction has never been shown in any single trial and is only suggested by an meta-analysis of 23 small trials, with only 2 trials enrolling more than 1000 patients 2. Furthermore, this small advantage is no longer significant when the comparison is made with the accelerated infusion of Alteplase 4. The frequently quoted mortality reduction observed in patients treated with primary PCI in registries is largely biased by intangible confounders, and by the entry in the primary PCI cohort of only those patients actually being treated and not those patients intended to treat5.

Why thrombolysis in acute MI still continues?

Currently, only 25% of American hospitals provide primary angioplasty and the majority of patients must be transferred to receive the mechanical intervention 6. As a consequence, only approximately 4% of transferred patients receive primary PCI within 90 minutes from first medical contact7. The situation is still worse in our country. In the national PCI registry from last 3 years primary PCI accounts for approximately less than 5% of total PCI procedures being done per year. Attempts to improve this situation so far

Correspondence: Dr. Ajit Mullasari, Institute of Cardio-Vascular Diseases, Madras Medical Mission, Chennai, Tamil Nadu, India
E-mail: rksaran@sify.com

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Tenecteplase – The Best Among the Equals

have required “huge” efforts, with a negligible mortality yield8. Further difficulties arise during weekends and at night again jeopardizing quality. Therefore thrombolytic therapy still remains the prevailing treatment in most countries including ours. Third generation fibrinolytic agents like Reteplase and Tenectaplase are more fibrin specific, can be given as a bolus and achieve TIMI 3 flow in around 60%, with less incidence of major bleeding and hence make a better thrombolytic option. The present discussion is on the critical evaluation of Tenectaplase in acute MI settings in the present day scenario.

Fibrinolytic Agents in a nutshell
Thrombolytic agent are classified in 3 generations, first generation agent include Streptokinase (STK), Urokinase (UPA) and Anistreplase (APSAC). In second generation, Alteplase (rtPA), rscu-PA, Prourokinase, Saruplase and A74187 are included. Third generation, has reteplase (rPA), Tenecteplase (Tenecteplase), Lanoteplase (nPA), Monteplase(E6010), Pamiteplase (YM866), Vampire bat tPA (DSPAa1), Amediplase(K2tu-PA) and Pegylated variants of Staphylokinase (PEG-Sak). Comparison of various approved thrombolytic agents is shown in Table 2

Table 2 Comparison of approved fibrinolytic agents

	Streptokinase	Alteplase	Reteplase	Tenecteplase
Dose	1.5MU in 30-60 min	Up to 100 mg in 90 min (based on weight)	10Ux2 (30 min apart) each over 2 min	30-50 mg base on weight
Bolus administration	No	No	Yes	Yes
Antigenic	Yes	No	No	No
Allergic reactions (Hypotension most common)	Yes	No	No	No
Systemic fibrinogen depletion	Marked	Mild	Moderate	Minimal
90-min patency rate (%)	≈50	≈75	≈75	≈75
TIMI grade 3 flow (%)	32	54	60	63
Cost per dose (U.S. $)	568	2750	2750`	2750 for 50 mg

Tenecteplase

Tenecteplase is a fibrin selective, single dose fibrinolytic agent. It has a molecular weight of 65,000kD. It is produced by recombinant DNA technology using an established mammalian cell line. It consists of the Alteplase molecule with the exception of 3 point mutations. It is made by substituting 3 single amino acids at the T (threonine), N (asparagines) & K (lysine) domains. These mutations confer longer plasma half life of approximately 20min to Tenecteplase so that it can be administered by IV bolus9.Compared with the Alteplase molecule no domain is missing in the Tenecteplase molecule, so its fibrin selectivity is relatively high. Fibrin specificity in turn implies a reduced propensity

for causing major non-cerebral bleeds. It is resistant to PAI-1 (80 times compared to Alteplase). Following administration of 30, 40, or 50mg of Tenecteplase, there are decreases in circulating fibrinogen (4%–15%) and plasminogen (11%–24%). A single bolus dose should be administered over 5 seconds TIMI reflow grade III at 90 min is in >60% cases. Biological potency is determined by an in vitro clot lysis assay and is expressed in Tenecteplase-specific units. The specific activity of Tenecteplase has been defined as 200units/mg. Liver metabolism is the major clearance mechanism for Tenecteplase

It is the only thrombolytic which is administered in a weight tiered dosage thereby ensuring maximum risk/benefit ratio. Since risk of ICH increases in the elderly, weight adjusted regimens of Tenecteplase may be beneficial. The recommended total dose should not exceed 50 mg. Table 3

Table 3 Weight adjusted dosing of Tenecteplase

Patient Weight (kg)	Tenecteplase (mg)	Volume Tenecteplase *(mL)
<60	30	6
≥ 60 to <70	35	7
≥ 70 to <80	40	8
≥ 80 to <90	45	9
≥ 90	50	10

*From one vial of Tenecteplase reconstituted with 10 mL of fluid provided.

Table-4 Tenecteplase: Why a favored fibrinolytic?

Ease of administration- iv bolus over 5 sec
Rapid action-induces 50% lysis 3 times faster than tPA
Potency-13.5 fold more potent in lysing platelet rich clots in vivo than tPA
Weight adjusted dosing-0.53mg/kg
Fibrin specificity-14 fold greater than tPA
Reduced plasma clearance-50% remained in circulation after 15 min of injection (1% tPA)
High PAI-1 resistance-80 fold more than tPA
Non cerebral bleed less than tPA
Clinical efficacy comparable with tPA
Prehospital thrombolysis –best suited

Tenecteplase may be recommended for high risk patients of acute MI who have the potential for a large therapeutic benefit, for example, anterior AMI, BBB related AMI or poor prognosis inferior AMI (that is, with right ventricular involvement, anterior reciprocal ST depression or lateral & posterior extension), time <6 hours and age <75 years .

Tenecteplase in Clinical Trials

Tenecteplase has been tested extensively in clinical trials (Table 5). The first experience of Tenecteplase in STEMI began in the phase 1 TIMI 10 A dose ranging trial which included a total of 113 patients. The efficacy & safety profile of Tenecteplase was encouraging. The trial showed a dose dependent increase in TIMI 3 flow rates in the 5 to 50 mg dose range (p= 0.032) 10. At 90 min, TIMI grade 3 flow was achieved in 59% & 64% of patients treated with the 30 & 50mg doses respectively. The sample size was too small for statistical significance.

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Table 5 Clinical studies with Tenecteplase in STEMI

Trial (year)	Patients	Comparison	Main findings
TIMI 10 A (1997)	113	TNKase doses	Dose dependent in efficacy
TIMI 10 B (1998)	886	TNKase vs rt-PA	TNKase and rt-PA equivalent,
ASSENT1 (1999)	3235	TNKase vs rt-PA	TNKase and rt-PA equivalent, major bleeding with TNKase
ASSENT-2 (1999)	16,949	TNKase vs rt-PA	TNKase and rt-PA equivalent, major bleeding with TNKase
ASSENT-3 (2001)	6,095	ENOX vs ABX vs UFHa	ENOX and ABX better than UFH
ENTIRE-TIMI 23 (2002)	483	ENOX vs ABX vs UFHa	ENOX and ABX better than UFH, bleeding with ABX
ASSENT-3-PLUS (2003)	1,639	ENOX vs UFHa, pre-hospital delivery	reinfarction with ENOX, stroke/intracranial bleed
CAPITAL-AMI (2005)	170	F-PCIcvs TNKasea	residual ischemia with F-PCI
ASSENT-4 (2006)	1,667	F-PCI vs P-PCI	death/ischemia/bleeding in the F-PCI group
WEST (2006)	304	TNKase vs F-PCI vs P-PCI	TNKase and F-PCI comparable to P-PCI
GRACIA-2 (2007)	212	TNKase vs P-PCI	reperfusion with TNKase Similar ventricular damage

TNKase (Tenecteplase), ENOX (Enoxaparin), ABX (Abciximab), UFH (Unfractionated Heparin), F-PCI (Facilitated Percutaneous Coronary Intervention), P-PCI (Primary Percutaneous Coronary Intervention).

In the phase II randomized ASSENT-1 (Assessment of Safety & Efficacy of a New Thrombolytic) trial, 3235 inpatients with acute myocardial Infarction were included. In them a single bolus Tenecteplase was proved to be safe. With respect to Intracranial bleeding complications, the rate in patients treated within six hours of the onset of MI was 0.56% with 30mg & 0.58% with 40mg Tenecteplase11.The incidences of death, stroke or severe bleeding complications were low (6.45,7.4% & 1.6% respectively) without significant differences between treatment groups.
In the non blind randomized phase II dose escalating TIMI 10 B (Thrombolysis In Myocardial Infarction) patency trial 886 patients were randomized to Tenecteplase ( 30,40 or 50 mg) or accelerated tPA (100mg).Single bolus administration of 40mg Tenecteplase achieved the same rate of patency at 90 minutes after institution of thrombolytic therapy as Alteplase in the accelerated (initial bolus followed by an infusion over 90 min) regimen did12.
In the phase III, randomized, double blind trial ASSENT-2(Assessment of the Safety & Efficacy of a New Thrombolytic-second) weight adjusted Tenecteplase(as a 30-50mg bolus over 5-10 seconds) and accelerated rtPA (<=100mg) were compared in 16949 patients with STEMI of <6 hours duration. Thirty day mortality rates were identical for Tenecteplase (6.18%) and rtPA (6.15%), as was intracranial hemorrhage (ICH). However, major non cerebral bleeding was lower with the more fibrin selective Tenecteplase (4.66% vs. 5.94%) as was need for blood transfusion 13. Subgroup analysis of results of ASSENT-2 showed that the 30 day mortality for patients treated after 4 hours of symptom onset was 7% with Tenecteplase compared to 9.2% with Alteplase.(p=0.018). This is attributed to the drugs fibrin specificity leading to better dissolution of oldest coronary clots and confirms from a clinical standpoint the improved pharmacologic profile of this molecule. Thus Tenecteplase seems more effective in late-treated patients (>4 hours).

Efficacy and safety of Tenecteplase in Indian patients with ST segment elevation myocardial infraction has been assessed by Sathyamurthy et al 14 in 507 patients and they showed that Tenecteplase is safe and effective in Indian patients with STEMI and conforms to the international ASSENT-2 trial data.

Tenecteplase and the Adjunctive Use of Heparin
Early heparin is required in post thrombolytic cases with this fibrin specific agent. Adjunctive therapy with the LMWH Enoxaparin is an attractive alternative to unfractionated heparin with standard dose Tenecteplase as tested in ASSENT-3 randomized trial15. A total of 6095 patients with STEMI in the first 6 hours from the onset of symptoms were treated with full-dose Tenecteplase plus unfractionated heparin (UFH), full-dose Tenecteplase 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 ENOX (11.4% vs 15.4%, p =0.0002) and by the combination of UFH plus ABX (11.1%, p <0.0001). Similar results were observed in the smaller ENTIRE-TIMI 23 trial 16. In conclusion, ASSENT-3 and ENTIRE-TIMI 23 showed that a much simpler thrombolytic regimen is feasible, permitting bolus administration of both Tenecteplase 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.
In the ASSENT-3 Plus trial17, 1639 patients of STEMI were treated with Tenecteplase and randomly allocated to Enoxaparin or UFH adjunctive treatment. 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 =0.297).
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 Tenecteplase. In patients older than 75 years intravenous bolus of Enoxaparin is to be omitted and the maintenance dose reduced by 25% as shown in EXTRACT-TIMI 25 trial 18.

Tenecteplase as a part of facilitated PCI
The role of the routine, immediate use of coronary angioplasty (so called “facilitated” angioplasty) after treatment with Tenecteplase was first explored in CAPITAL AMI19. This was a small study randomizing 170 high-risk STEMI patients treated with Tenecteplase followed by 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. Overall, the primary end-point was reduced by immediate PCI from 21.4% to 9.3 %( p=0.034) & was not associated with an increase in major bleeding complications.
These encouraging results stimulated the planning of the larger ASSENT-4 PCI trial20, a trial designed to investigate whether Tenecteplase facilitation would improve the prognosis of patients for whom a time-delay of 1 to 3 hours before primary PCI was anticipated. 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 primary PCI was facilitated by Tenceteplase (6% vs 3%, p = 0.0105).

More pertinent to investigating the role of Tenecteplase facilitation is the WEST study21. It was a randomized, open-label, feasibility-study of 304 STEMI patients in the community. All patients received aspirin and ENOX and were randomized to either Tenecteplase, or to Tenecteplase followed by PCI within 24 hours (including rescue PCI for reperfusion failure) or to primary PCI. There were no differences between the three groups in the primary composite of death or re-infarction, refractory ischemia, congestive heart failure, cardiogenic shock or major ventricular arrhythmia (25% vs 24% vs 23%, p =NS).In the group receiving plain Tenecteplase there was a higher rate of the death/ re-infarction 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 data from CAPTIM22 : when delivered very rapidly, possibly in the pre-hospital phase, Tenecteplase is very competitive with primary PCI and may offer a very simple and effective treatment, particularly if subsequent PCI is offered to those patients with recurrent ischemia or deemed at high clinical risk

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Strategy of In Ambulance Thrombolysis Followed by Routine PCI in AMI

possibly in the pre-hospital phase, Tenecteplase is very competitive with primary PCI and may offer a very simple and effective treatment, particularly if subsequent PCI is offered to those patients with recurrent ischemia or deemed at high clinical risk.
Tenecteplase followed by early routine PCI (within 3–12 hours, so called “pharmaco-invasive” approach) has also been compared with primary PCI in 212 patients enrolled in the GRACIA-2 study23.This is a non-inferiority randomized controlled trial designed to evaluate whether a lytic based early routine PCI strategy represents a reasonable option for STEMI patients, irrespective of geographic or logistic barriers, when compared with primary PCI. 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 at the electrocardiogram was observed more frequently in the Tenecteplase group (61% vs 43%, p =0.01), implying an improved myocardial perfusion as measured by the TIMI myocardial perfusion grade (TMPG 3) at 60 minutes. Infarct size and left ventricular ejection fraction were similar in the two groups. Therefore the findings suggested that early routine post fibrinolysis angioplasty safely results in better myocardial perfusion than primary angioplasty.
It may be concluded that the results of the WEST study are confirmed by GRACIA-2, suggesting the comparable efficacy of Tenecteplase (with rescue/routine PCI) and primary PCI. Most relevant to patho-physiology and clinical practice, is the finding of GRACIA-2 (in combination with ASSENT-4 PCI) that routine PCI after Tenecteplase should be postponed at least 3 to 12 hours to achieve the benefit.

Pre-Hospital Thrombolysis: Hope revived with Tenecteplase
The American college of Cardiology/American heart Association guidelines encourage recording 12 lead ECG at the first medical contact with the patient and giving pre-hospital thrombolysis within 30 minutes 3. Small benefit of primary PCI rapidly diminishes if delay of more than 90 minutes occurs between door to balloon insertion. In younger patients with large myocardial infarction this advantage diminishes even much earlier24. As time is muscle, most benefit may be achieved by treating as many patients as possible in the first 3 hours from the onset of symptoms. During this initial period Pre Hospital thrombolysis and primary PCI are equally competent as far as major endpoint of survival is concerned. In MINAP registry done in UK pre hospital thrombolysis (in which Tenecteplase was used almost always) was the strongest independent predictor of in hospital survival25. In the Emilia-Romagna STEMI network26 it was demonstrated that pre-hospital thrombolysis can be offered within first 3 hrs to as many as 50-60% of STEMI patients. Therefore, every attempt needs to be made by health care professionals to deliver pre hospital Thrombolysis as early as possible.

Conclusions
Tenecteplase therapy in acute MI is backed by large number of clinical trials, involving thousands of patients of acute MI. The easy way it can be given as a single bolus in ambulance & high fibrin specificity makes Tenecteplase an attractive option.
Based on the evidences American College of Chest Physicians recognizes Tenecteplase as a class I recommendation in the management of acute MI

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within 12 hours from onset of symptoms. In the first 3 hours Tenecteplase seems as effective as primary PCI. Tenecteplase has again revived the hope of pre-hospital thrombolysis in acute MI. Infact many registries in different countries have included Tenecteplase as the only thrombolytic agent in pre hospital thrombolysis programs, such as the Vienna STEMI Registry27 , the French FAST-AMI registry28 and the Mayo Clinic STEMI protocol29. In spite of robust evidence in favor of primary PCI in acute MI from last 6 years, a large number of patients even in developed countries are not getting primary PCI mainly due to logistic reasons. Therefore Tenecteplase with so many evidence based advantages is a fair option in acute MI patients in whom primary PCI can not be offered.

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