Clincal Resarch Article |
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Expanding Role of Tenecteplase in Patients with Cardiovascular Diseases
S Bansal, Department of Cardiology
Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi
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TNK-t-PA (Tenecteplase) is the latest (and probably the hottest) kid on the block among the thrombolytics. One has come a long way since the earliest days of streptokinase being used as a thrombolytic agent in acute myocardial infarction over two decades ago. Tenecteplase is a variant of the native tissue-type plasminogen activator (tPA) molecule that has 14-fold greater fibrin specificity than alteplase, a longer half-life, slower plasma clearance, and 80-fold greater resistance to inhibition by plasminogen activator inhibitor type 1. Its half-life of approximately 18 minutes allows single-bolus administration. In comparative clinical trials, tenecteplase was found to have equivalent efficacy to recombinant tPA (alteplase). The rate of intracranial hemorrhage with tenecteplase was similar to that with alteplase, and tenecteplase was associated with fewer non-cerebral complications and less need for blood transfusions (1). These refinements in the thrombolytic agents have gone hand in hand with the expanding (sometimes even unusual) indications for their usage well beyond the classical indications of acute myocardial infarction. This article aims to review some such expanding and unusual indications wherein Tenecteplase has been used.
Expanding indications wherein Tenecteplase has been used or tried may be categorized as under:
1. Cardiac indications-
a. Coronary indications other than classical acute myocardial infarction.
b. Pericardial indications
c. Other cardiac indications
2. Pulmonary thromboembolism.
3. Peripheral arterial and venous indications
4. Miscellaneous indications.
Coronary indications other than classical acute myocardial infarction
Besides the classical indication of acute myocardial infarction coronary thrombosis of several other etiologies have been treated with tenecteplase. Based on observational case reports it has been suggested that adjunctive use of tenecteplase in primary PCI in STEMI may be useful. TIMI 49 - A Safety/Efficacy Study of Intra-Coronary Tenecteplase
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During Balloon Angioplasty to Treat Heart Attacks (NCT00604695) is an ongoing study to gather preliminary data regarding the angiographic efficacy of the administration of low-dose adjunctive intra-coronary (IC) tenecteplase during primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) (2).It is hypothesized that low-dose IC tenecteplase will enhance fibrinolysis at the site of the culprit lesion leading to reduced micro-vascular dysfunction. As reduced dose tenecteplase will be injected directly into the coronary artery increasing local concentration of the drug with minor systemic effects, an improved safety profile is also expected from this mode of administration.
Tenecteplase has also been used in management of sub-acute and late stent related thrombosis (3). Currently the best treatment in management of sub-acute and late stent related thrombosis is to have 24 hours facilities for urgent coronary angiography and needful thereto. Sciahbasi et al, mention 4 cases that underwent treatment with tenecteplase. All their patients had a very short symptom-to-treatment time (median of 50 min) and were successfully treated with tenecteplase. The subsequent coronary angiography confirmed complete resolution of the thrombosis and the patients were discharged without further PCIs performed. Others have used a combination of tenecteplase and abciximab in similar settings. (4).
A few have reported use of tenecteplase in unusual causes of coronary thrombosis such as in a coronary aneurysm (5) and it is recommended when thrombolysis is indicated in Kawasaki disease (6).
Another new area of coronary thrombolysis is pregnancy wherein thrombolytic therapy has been an absolute contraindication. There are now case reports (7, 8) wherein pregnant women in very late or even early pregnancy were safely thrombolysed for acute myocardial infarction and had subsequently had normal healthy babies also. This area appears exciting.
Pericardial indications
Pericardial effusions may necessitate placement of a catheter into the pericardial space for continuous drainage. If the effusion material is fibrinous or loculated, drainage may slow or cease over time, allowing re accumulation. A case is mentioned wherein patient received three doses of tenecteplase—15 mg, 7.5 mg, and 7.5 mg—over 3 days, resulting in significant drainage . It may also offset the need to repeatedly replace the catheter if flow subsides despite continued presence of fluid in the pericardial space in many cases (9).
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Correspomdence: Dr.Sandeep Bansal, Department of Cardiology, VMMC and Safderjang Hospital, New Delhi, India
Email: drbansalr@yahool.com |
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Indian Heart J. 2009; 61: 459-461 |
S Bansal |
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Other cardiac indications
One major indication where tenecteplase has been extensively tried and failed is in cardiac arrest. A case report showed that administration of tenecteplase was associated with complete neurological in a patient with undifferentiated cardiac arrest with a return of spontaneous circulation after 1 hour of resuscitation (10). Another case report described the clinical course in a 49-year-old man with repeated cardiac arrests due to massive pulmonary embolism. He was successfully treated with intravenous tenecteplase and external cooling. (11). Other investigators have used thrombolysis with trans-cutaneous pacing for ventricular standstill. (12). These encouraging findings led investigators to believe that empiric use of fibrinolytic agents in sudden cardiac arrest is safe and may improve outcomes in sudden cardiac arrest as approximately 70% of persons who have an out-of-hospital cardiac arrest have underlying acute myocardial infarction or pulmonary embolism. This led to small controlled randomized trials initially (13) to determine the proportion of patients that respond to empiric fibrinolysis with tenecteplase (TNK) after failing to respond to Advanced Cardiac Life Support (ACLS) measures. In one trial of 50 patients and 113 controls , Return Of Spontaneous Circulation (ROSC) was seen in 26% of TNK patients compared to 12.4% among ACLS controls (p=.04) and 12% (4.5-24%) of TNK patients survived to admission compared to none in the control group (p=.0007).The 24 hour survival and hospital discharge rates however were no different . Similar results were obtained in the TICA trial. (14)These data led to the planning of the TROICA study. (15) The results of these were published recently. (16). The trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenecteplase was administered to 525 patients and placebo to 525 patients. The primary end point of 30-day survival (14.7% vs. 17.0%; P = 0.36; relative risk, 0.87) was no different in the two groups as were the secondary endpoints of hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome. The data and safety monitoring board recommended discontinuation of enrollment of asystolic patients because of low survival. Several possible reasons for the lack of benefit were cited-a) the survival in the study was already so good that with the given study design a significant benefit could not have been seen with tenecteplase b) use of heparin is a must in such situations but was not done in the study .The authors still believe that tenecteplase is beneficial in patients in whom massive pulmonary thromboembolism is the cause of cardiac arrest but these patients were excluded from the trial.
The fibrin specificity, ease of administration and effectiveness of Tenecteplase have led to its being tried in several unusual indications of thrombosis e.g. prosthetic heart valve thrombosis in a pregnant woman(17) , an indication where thrombolysis would not have been used. |
It has been used (in case reports) to treat intra-cardiac thrombi (18) such as LA thrombus and thrombi on artificial hearts like the Jarvik – 2000. (19)
Pulmonary indications
Initial reports mentioned use of Tenecteplase in massive (20) and sub-massive (21) pulmonary embolism. A review of this subject (22) in Journal of Thrombosis and Thrombolysis shows case reports wherein 14 cases with acute pulmonary embolism were treated with tenecteplase. Tenecteplase has at least three properties that favor its use to treat acute pulmonary embolism in the emergency department setting. First, single-dose bolus infusion may reduce confusion and debate over the correct dosing and infusion protocol for alteplase to treat PE. Second, bolus-dosing might reduce the confusion surrounding the decision to continue or discontinue co-infusion of heparin while thrombolytic is being infused. Third, bolus-dose infusion may allow more rapid formation of plasmin, possibly allowing more rapid clearance of clot and quicker resolution of symptoms compared with a 2 h infusion regimen of alteplase. A phase II Italian study (23), Tenecteplase Pulmonary Embolism Italian Study studied efficacy and safety of Tenecteplase versus Placebo in normotensive patients with sub-massive Pulmonary Embolism and Right Ventricular Dysfunction (RVD) with all receiving un-fractionated heparin (UFH). A continuation of this study is currently underway. A case study interestingly reported a 92 year old man in whom pulmonary thromboembolism was managed with a bolus of tenecteplase (24) highlighting its excellent safety profile.
Peripheral arterial and venous indications
Because of its enhanced safety profile, TNK may be a desirable agent for peripheral vascular applications (25). In a study of 18 patients with arterial or venous peripheral disease technical success was achieved in all 18 patients (100%). Clinical success was achieved in 11 of 13 arterial cases (85%) and in four of five (80%) venous cases (26). In another study 63 nonconsecutive patients underwent catheter-directed thrombolytic therapy with either 0.25 mg/h or 0.50 mg/h of TNK in a nonrandomized, open-label study. Of these, 55 patients (60 limbs) were treated for DVT) or peripheral arterial occlusions. The primary endpoints were major bleeding complications and angiographic reduction in clot burden.. Twenty-one (87.5%) patients with occlusive disease had marked or complete lysis of clot. Thirty (83.3%) limbs with DVT had either marked or complete resolution of thrombus.(27). Yet others have used a combination of tenecteplase and eptifibatide (28) with higher (91%) success and shorter duration (12.1 hours vs 18 hours). A recent study (29) revealed that lower loading dose (1.5mg vs 5 mg) and lower infusion rates (.125mg/h vs .25mg/h) was associated with equal success and lower complications. Paget-Schroetter syndrome (effort |
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Indian Heart J. 2009; 61: 459-460 |
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Expanding Role of Tenecteplase in Patients with CVD |
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thrombosis of the subclavian vein), is another peripheral vascular condition where strategy of tenecteplase followed by surgery has benefited.(30)
Miscellaneous indications
Review of literature reveals several other interesting scenarios where the beneficial properties of tenecteplase have been used in unusual indications. Animal studies show that Fluorescence-tagged tenecteplase can penetrate all the layers of the retina of porcine eyes after intravitreal injection. Intravitreal tenecteplase may be useful in the in the management of subretinal hemorrhage (31), submacular haemorrhage (32) and retinal vein thrombosis.
Tenecteplase has been used in the treatment of thrombosed hemodialysis grafts (33) using a modified 'lyse and wait" technique with percutaneous transluminal angioplasty (PTA) to treat thrombosed hemodialysis arteriovenous grafts (AVG)s. Technical and clinical success rates were 100% and 88%, respectively. No major complications occurred. A phase III study TROPICS 3 (A Study of Tenecteplase for Restoration of Function in Dysfunctional Hemodialysis Catheters) has just been completed and detailed results are awaited. (34)
Another unusual indication has been the use in carotid stent grafts (35).
Utility of tenecteplase in restoration of function in dysfunctional central venous catheters has been just evaluated in a phase III study entitled TROPICS 2(A Study of Tenecteplase for Restoration of Function in Dysfunctional Central Venous Access Catheters) .The study has been completed in Aug 2009 and results are awaited.(36). Tenecteplase therefore offers newer vistas beyond its use in Acute MI. It may be judiciously used in these conditions.
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Indian Heart J. 2009; 61:467-469 |
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