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Thrombolytic agents are a first-line therapeutic option for establishing coronary artery patency in acute myocardial infarction. Three fibrin-specific thrombolytics--alteplase, reteplase, and tenecteplase--are available in the United States and have undergone preliminary patency trials and large randomized, comparative, survival studies. Patency rates differ among them, although overall mortality benefit is similar. Because of this fact and the economic impact of the drugs, competition in this market is significant. Distinguishing features of the drugs will likely influence selection. Reteplase and tenecteplase offer ease of administration with bolus dosing. Increased fibrin specificity appears to play a significant role in separating them. Tenecteplase, the most highly fibrin specific, is associated with decreased risk of noncerebral bleeding and reduced need for blood transfusions in all patients, as well as longer survival in those with late presentation acute myocardial infarction. Current trials will reveal the role of these agents in combination with glycoprotein lIb-IIIa receptor antagonists.
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PMID:A review of available fibrin-specific thrombolytic agents used in acute myocardial infarction. 1121 58

The publication of the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) trial of alteplase (a recombinant tissue plasminogen activator; rt-PA) for acute stroke patients in 1995 and its approval by the US Food and Drug Administration as well as the American Academy of Neurology and American Heart Association increased the interest and attention of the medical community in acute stroke treatment. However, the implication of this NINDS Stroke Study and other thrombolytic trials in clinical practice remains controversial and debated. Furthermore, the recent publication of the results from the European Cooperative Acute Stroke Study II (ECASS II) and Alteplase Thrombolysis of Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) studies will feed the controversy, since the results of these two studies are disappointing and do not confirm the positive results of the NINDS Stroke Study as expected by clinicians managing patients with acute stroke. The Standard Treatment with Alteplase to Reverse Stroke (STARS) and Cleveland studies, which involved a large number of community hospitals to assess the safety profile and the benefit of rt-PA thrombolysis for acute stroke patients in clinical practice, have shown controversial results. Consequently, the issue arises of which is the more reasonable position concerning thrombolysis by alteplase, which seems to work but has not been proven yet beyond reasonable doubt? The recent publication of the results from the Prolyse in Acute Cerebral Thromboembolism (PROACT II) study has shown that intra-arterial thrombolysis with prourokinase is a benefit treatment in stroke patients with a proven middle cerebral artery occlusion within 6 h of stroke onset. Numerous trials devoted to neuroprotection against acute ischemic stroke have been prematurely stopped because of safety concerns or poor risk-benefit ratios, but some new neuroprotective drugs seem promising and are being tested in ongoing studies. The third issue under study concerns the use of antithrombotic drugs in the acute phase of stroke, particularly the new potent platelet glycoprotein IIb/IIIa antagonists such as abciximab. In this paper, we have reviewed selected recent clinical trials focusing on recent advances in acute stroke therapy.
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PMID:Recent progress in drug treatment for acute ischemic stroke. 1124 3

Intraoperative intraarterial thrombolysis is a valuable adjunct for the removal of residual arterial thrombi after mechanical thromboembolectomy. Early reports by some investigators indicated high rates of bleeding complications, most likely caused by inappropriately high doses of plasminogen activators infused over long periods of time, which led to systemic lytic effects. Animal models and controlled human experiments subsequently have shown the potential efficacy and safety of intraarterial thrombolysis. Since urokinase (UK) has been withdrawn from the market, recombinant tissue-type plasminogen activator (rt-PA) has become the plasminogen activator of choice. Reteplase and other plasminogen activators may be beneficial (and safe); however, data on intraoperative use currently are not available. The most common methods of delivery into the distal arterial tree are bolus infusion with inflow occlusion, drip infusion after restoration of arterial inflow, and the isolated limb perfusion technique. The number of distal vessels involved, the amount of residual thrombus, and severity of ischemia guide the dose of plasminogen activator, volume of perfusate, and the technique and duration of infusion.
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PMID:Intraoperative lytic therapy: agents and methods of administration. 1140 89

We evaluated the efficacy and safety of alteplase to restore central venous line (CVL) patency in a consecutive cohort study. A uniform, weight-dependent protocol for alteplase administration was established prospectively. For children < or =10 kg, a dose of 0.5 mg was used; for children >10 kg, doses of 1 to 2 mg were used. The alteplase remained instilled for 1 to 4 hours or overnight. Retrospective data accrual found that 25 children received alteplase for a total of 34 courses; 29 (85%) of the 34 courses of alteplase completely restored CVL patency. Alteplase appears to be a safe and effective thrombolytic agent for CVL patency restoration in children.
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PMID:The use of alteplase to restore patency of central venous lines in pediatric patients: a cohort study. 1144 11

While thrombolytic agents have demonstrated improved mortality over the use of placebo, this has come at the expense of bleeding complications such as intracranial hemorrhage (ICH). Tenecteplase (TNK-tPA) is a novel thrombolytic agent engineered to improve upon the ease of use and safety of alteplase (t-PA). Given its longer half-life, TNK-tPA can be administered as a single bolus. The dosing of TNK-tPA has been weight optimized to enhance both safety and efficacy outcomes. Weight-optimized TNK-tPA dosing requires body weight estimation, which may introduce the potential for medication error. However, data from TNK-tPA clinical trials suggest that body weight estimates can err by up to 20 kg (44 lb) without an increased risk of ICH or death. Furthermore, the results of TNK-tPA clinical trials showed that even at the highest weight-optimized dosage of 50 mg, ICH rates were among the lowest reported in clinical trials of thrombolytics for acute myocardial infarction. In elderly female patients of low body weight, the use of weight-optimized TNK-tPA lowered the risk of ICH compared with the use of t-PA, expanding the potential use of thrombolytics to this high-risk patient population. Tenecteplase has demonstrated clinical equivalence to t-PA, but with a wider therapeutic margin of safety.
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PMID:Issues in the assessment of the safety and efficacy of tenecteplase (TNK-tPA). 1155 38

We present a case of the use of alteplase for the lysis of a large urinary bladder clot. A neonate presented with respiratory failure, secondary to a left diaphragmatic hernia necessitating the need for extracorporeal membrane oxygenation (ECMO) support. On day 3 of ECMO support, hematuria was noted, and a subsequent urinary bladder ultrasound revealed a significant urinary bladder clot. Alteplase (0.5-1 mg) was instilled into the urinary bladder via a 10 French Foley catheter (Sherwood Medical, St. Louis, MO). The catheter was clamped for 1 hour, followed by irrigation with normal saline. Multiple doses of alteplase were administered, resulting in complete resolution of the bladder clot. No adverse effects were attributed to the use of the intravesical alteplase. Alteplase seems to be safe and effective for the resolution of bladder clots, thereby potentially avoiding more invasive surgical procedures.
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PMID:The use of alteplase for the resolution of an intravesical clot in a neonate receiving extracorporeal membrane oxygenation. 1157 39

Tissue type plasminogen activator is available, through recombinant technology, for thrombolytic use as alteplase. Alteplase is relatively clot specific and should cause less bleeding side effects than the non-specific agents such as streptokinase. Alteplase has been used successfully in evolving myocardial infarction (MI) to reopen occluded coronary arteries. It is probably equally effective or superior to streptokinase in opening arteries and reducing mortality in MI. Alteplase is most effective when given early in MI and is probably ineffective when given 12 h after the onset of symptoms. The effectiveness of alteplase in MI can be increased by front loading with a bolus of 15 mg, followed by an infusion of 50 mg over 30 min and 35 mg over 60 min. Percutaneous transluminal coronary angioplasty or stenting is associated with a greater patency and lower rates of serious bleeding, recurrent ischaemia and death than alteplase in MI and is likely to take over from alteplase as the standard MI treatment. A reduced dose of alteplase to increase coronary artery patency prior to angioplasty may be useful in MI. An exciting new indication for the use of alteplase is in stroke, where it has become the first beneficial intervention. Alteplase is used to reopen occluded cerebral vessels but is associated with an increased risk of intracerebral haemorrhage. Alteplase is beneficial if given within 3 h of the onset of stroke but not after this time period. Therefore, the next challenge is to increase the percentage of people being diagnosed and treated within this period. Clinical trials have not established a role for alteplase in the treatment of acute coronary syndromes or deep vein thrombosis. However, alteplase is useful in treating pulmonary thromboembolism and peripheral vascular disease.
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PMID:Alteplase: descendancy in myocardial infarction, ascendancy in stroke. 1177 4

When hemodialysis catheters allow only poor or no blood flow, it has become established practice in many centers to instill a thrombolytic agent in an attempt to clear the catheter. The catheter survival advantage gained by repeated use of such treatment is not known. In a prospective study, we analyzed all uses of alteplase in the setting of inadequate catheter blood flow in a cohort of 570 catheters over a 2(1/2)-year period. The time from alteplase instillation to the next episode in which it was required or catheter removal for nonfunction or thrombosis was recorded. Survival analysis was used to estimate the additional catheter survival afforded by each treatment. After censoring for elective catheter removal, the overall catheter half-life was 10.2 months. Catheter malfunction or thrombosis was the most common indication for catheter removal (36.3% of all catheters removed). Alteplase instillation was necessary in 2.77% of dialysis sessions. The median time from the first to second treatment or catheter removal for nonfunction or thrombosis was 27 days (95% confidence interval, 15.7 to 32.3). Additional median survival advantage gained from each subsequent treatment ranged from 10 to 18 days. Treatment of recurrent catheter malfunction with alteplase allows for a median of only five to seven additional dialysis sessions before the treatment must be repeated or the catheter must be exchanged. Although associated with minimal disruption to the dialysis schedule, the ultimate clinical benefit and cost-effectiveness of such treatment is doubtful.
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PMID:A longitudinal study of the repeated use of alteplase as therapy for tunneled hemodialysis catheter dysfunction. 1177 6

Two angiographic trials, RAPID 1 in 606 patients and RAPID 2 in 324 patients, assessed angiographic patency after acute myocardial infarction following treatment with reteplase and alteplase. RAPID 1 evaluated three bolus regimens of reteplase in comparison with a 3 h infusion of alteplase. RAPID 2 compared the 10 MU + 10 MU double bolus regimen of reteplase with the accelerated regimen (90 min infusion) of alteplase. The results of these studies showed that reteplase opened more arteries more quickly than did alteplase. Angiography at both 60 and 90 min showed a higher rate of patency and greater TIMI (Thrombolysis in Myocardial Infarction perfusion grade) 3 flow rates with reteplase than with alteplase. In RAPID 1, at 90 min, TIMI 3 flow rates were 63% for reteplase compared to 49% for alteplase (P < 0.05), and in RAPID 2, TIMI 3 flow was 60% vs 45%, respectively, (P < 0.05). Reteplase was convenient and simple to administer, and there were no unexpected complications. Fewer interventional procedures were performed after therapy with reteplase than with alteplase, primarily because coronary angioplasty was required less frequently following acute angiography in patients receiving reteplase. The angiographic profile for reteplase demonstrated in these two trials suggests that this new thrombolytic drug has potential advantages over alteplase: notably, its use can result in earlier and more complete coronary patency. The clinical significance of this finding must be determined in larger clinical trials.
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PMID:Results of the RAPID 1 and RAPID 2 thrombolytic trials in acute myocardial infarction. 1182 98

As treatments for acute myocardial infarction have grown in number and effectiveness, the post-infarction mortality rate has fallen, and new therapies can provide only a small additional advantage in extending survival. To prove such an advantage of a new drug over its predecessors in the same drug class requires a trial of at least 20,000 patients. Proving 'equivalence' rather than superiority requires only 6000 patients. The INJECT trial was designed with the modest goal of determining whether the novel agent reteplase (recombinant plasminogen activator) has an effect on mortality equivalent to that of streptokinase. Between August 1993 and September 1994, 6010 patients were randomized to receive either reteplase (n = 3004) or streptokinase (n = 3006). Both treatment groups had similar rates of bleeding events, extension or recurrence of myocardial infarction, and in-hospital stroke followed by 6 months of disability. Reteplase recipients had a lower incidence of cardiac events in hospital and fewer allergic reactions. Although the number of diagnosed haemorrhagic strokes was higher in reteplase recipients, more patients receiving streptokinase had strokes of uncertain aetiology. At 35 days, the mortality rate associated with reteplase use was approximately 0.5% lower than that associated with streptokinase administration, and the upper limit of the 90% confidence interval for the difference between these rates was a superiority of streptokinase of 0.73%. Because the INJECT trial provided a probability of 0.95 that the mortality rate associated with reteplase use would be either lower than that with streptokinase administration or at most 0.73% worse, reteplase and streptokinase were proved equivalent according to the trial definition and limits.
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PMID:Mega-trials and equivalence trials: experience from the INJECT study. 1182 1


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