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Alteplase

A Reappraisal of its Pharmacological Properties and Therapeutic Use in Acute Myocardial Infarction

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Abstract

Synopsis

Alteplase (recombinant tissue-type plasminogen activator) stimulates the fibrinolysis of blood clots by converting plasminogen to plasmin.

The efficacy of intravenous alteplase in the early treatment of patients with acute myocardial infarction has been unequivocally proven, and recent results from the GUSTO trial indicate a significant advantage in 30-day survival for alteplase in an accelerated dosage regimen (≤100mg infused over 90 minutes rather than 3 hours) over streptokinase. The advantage of the accelerated alteplase dosage regimen seems to be maintained for at least 1 year. The role of heparin as adjunctive therapy to thrombolysis remains to be fully defined but heparin administration appears to be more important in conjunction with alteplase than with streptokinase.

Ideally, patients should receive alteplase as soon as possible after the onset of symptoms of acute myocardial infarction and, while therapy is most beneficial when administered early, survival is improved when the drug is administered up to 12 hours after symptom onset. The accelerated regimen of alteplase used in the GUSTO trial demonstrated a survival advantage in patients ≤ 75 as well as those > 75 years of age which was at least as great as that seen with streptokinase. Similarly, alteplase reduces mortality in patients with both anterior and inferior infarctions; however, those with anterior wall infarctions show an improved outcome over those with inferior infarcts.

On the basis of pharmacoeconomic analysis of GUSTO data, the accelerated alteplase regimen cost an estimated additional $US32 678 per year of life saved compared with a conventional streptokinase regimen. Cumulative 1-year costs were greater in patients who received the accelerated alteplase regimen but survival was significantly greater than in patients who received streptokinase. No difference in quality of life was evident in patients who received either treatment.

The incidence of major haemorrhage associated with alteplase therapy appears to be similar to that seen with other fibrinolytic agents, increasing with increasing dose; however, the risk of stroke, particularly haemorrhagic stroke, is higher with alteplase than with streptokinase.

Thus, alteplase has become firmly established as a first-line option in the management of acute myocardial infarction. On the basis of accumulated evidence, the greatest risk reduction with alteplase therapy may be in certain high risk groups, such as those with anterior infarcts, selected elderly patients and those who present late after symptom onset.

Overview of Pharmacodynamic Properties

Alteplase is a serine protease, produced by recombinant DNA technology, which is chemically identical to human endogenous tissue-type plasminogen activator. Fibrinolysis of blood clots is stimulated when alteplase converts inactive endogenous plasminogen to plasmin in a manner similar to that of endogenous tissue-type plasminogen activator. Plasmin subsequently causes the breakdown of insoluble fibrin. Alteplase is relatively fibrin-specific (its activity is increased in the presence of fibrin), resulting in less depletion of plasma fibrinogen and fewer degradation products in the plasma of treated individuals than is seen with streptokinase, urokinase or saruplase.

The thrombolytic activity of alteplase has been adequately demonstrated in animal models of thrombosis, and the drug has been used clinically for several years. Alteplase has been associated with rebound antifibrinolytic effects possibly caused by potentiation of platelet aggregation which may be a partial cause of reocclusion in successfully treated patients.

Overview of Pharmacokinetic Properties

Because of its large molecular size, alteplase cannot easily diffuse across biological membranes and must be administered parenterally, usually intravenously.

After therapeutic doses of alteplase 90 to 100mg a maximal plasma concentration (Cmax) of 3 to 4 mg/L is achieved. When alteplase was administered in an accelerated regimen (90-minute infusion), steady-state alteplase concentrations (Css) for the initial infusion period were 45% higher than those for the standard administration protocol. Volume of distribution determinations for the central compartment ranged from 2.8 to 4.6L and were approximately one-half the volume of distribution at steady state.

Alteplase is cleared rapidly from plasma by the liver, with more than 50% removed within 5 minutes of drug administration. The rapid disappearance was most often described by use of a biexponential equation representing a 2-compartment model. The half-life associated with the initial phase of biphasic elimination in healthy individuals and patients with acute myocardial infarction ranged from 3.5 to 4.4 minutes. The area under the alteplase plasma concentration versus time curve (AUC) for the dominant initial phase of elimination accounted for 85 to 88% of the total AUC. Values for the terminal elimination half-life (t½β) were between 39 and 72 minutes. Total body clearance in healthy volunteers and most patients with acute myocardial infarction ranged from 34.3 to 38.4 L/h. Data regarding the pharmacokinetic profile of alteplase following an accelerated dosage regimen are limited but, other than a higher Css for the initial infusion period, appeared to be consistent with the profile reported for the original administration format.

Therapeutic Efficacy

The efficacy of alteplase in improving survival of patients with acute myocardial infarction is unequivocal. The benefit of adding aspirin to thrombolytic treatment is now firmly established, and the use of intravenous heparin in combination with alteplase has become widely accepted in clinical practice, despite a lack of definitive conclusions regarding its importance.

Improvements in various indices of left ventricular function, or differences in the degree of improvement, have been difficult to demonstrate consistently when comparing alteplase with other thrombolytic agents. On the basis of angiographic comparisons, patency was re-established more rapidly after administration of alteplase than after streptokinase, anistreplase or urokinase, although a ‘catch-up’ phenomenon resulted in virtually no difference between groups after the first few hours. Despite the theoretical associations between patency, left ventricular function and mortality, no survival advantage for any regimen was shown in the GISSI-2/ISG or ISIS-3 trials which compared alteplase (or duteplase) with streptokinase or anistreplase. However, the GUSTO trial showed a statistically robust (p ≤ 0.04) advantage in terms of reduced mortality at both 24 hours and 30 days for alteplase in an accelerated regimen (≤ 100 mg/90 min) plus intravenous heparin (30-day mortality rate 6.3% compared with 7.4% for streptokinase plus intravenous heparin, 7.2% for streptokinase plus subcutaneous heparin and 7% for the combination of alteplase and streptokinase plus intravenous heparin). In addition, the combined end-points of 30-day mortality and nonfatal stroke, nonfatal nonhaemorrhagic stroke or nonfatal disabling stroke also showed a significant (p ≤ 0.006) benefit in clinical outcome in patients who received the accelerated alteplase regimen compared with those in the streptokinase groups. A preliminary report indicates that the survival advantage of alteplase has persisted for at least 1 year.

Paradoxically, the achievement of more rapid coronary artery patency with alteplase than streptokinase and urokinase may actually provide coronary arteries with more opportunity to reocclude and, thus, may explain the higher reocclusion rates seen with alteplase in some trials. However, in the GUSTO angiographic study, no significant difference in reocclusion rates was reported between the 4 treatment groups on the basis of thrombolytic agent or patency. Although the combination of alteplase and streptokinase or urokinase produced lower reocclusion rates, no significant reduction in mortality resulted from this approach or from combining alteplase with percutaneous transluminal coronary angioplasty.

Several factors may be clinically useful predictors of patient outcome after an acute myocardial infarction and may help determine the benefit-to-risk ratio for the use of thrombolytic therapy. In general, there is a higher mortality rate associated with an anterior than an inferior infarction; thus, patients with anterior infarcts are likely to benefit more from aggressive thrombolytic therapy. The accelerated alteplase regimen used in the GUSTO trial reduced mortality in patients with both anterior and inferior infarcts compared with streptokinase; however, the magnitude of benefit was greater in those with anterior infarcts.

Increasing age is recognised as an independent risk factor in patients who experience acute myocardial infarction. In the GUSTO trial, subgroup analysis indicated that the accelerated alteplase regimen was at least as effective as streptokinase in patients both ≤ 75 or > 75 years of age and preliminary data on the basis of further age stratification suggested that alteplase was as effective in patients up to the age of 85 years.

Historically, thrombolytic therapy was reserved for patients receiving treatment 4 to 6 hours from symptom onset. The degree of benefit from alteplase, as with other thrombolytics, is clearly time-dependent; however, recent trial data, particularly from the LATE study, provided convincing evidence for a survival advantage using alteplase up to 12 hours after the onset of symptoms.

The cost-effectiveness value of using the accelerated alteplase regimen rather than the conventional streptokinase regimen in the GUSTO trial has been calculated to be $US32 678 per year of life saved. Although cumulative costs after the first year of treatment were higher in patients who received alteplase than streptokinase, these patients also showed a significantly greater survival benefit. No difference in quality of life was detected by patients on the basis of thrombolytic allocation.

Tolerability

The most significant risk associated with thrombolytic therapy is severe systemic or intracranial haemorrhage. In the GISSI-2/ISG, ISIS-3 and GUSTO trials, the incidence of major bleeding in patients with acute myocardial infarction after treatment with alteplase (or duteplase) was comparable to or less than that seen after streptokinase or anistreplase. In the GISSI-2/ISG and ISIS-3 trials, patients randomised to receive subcutaneous heparin experienced significantly more occurrences of major bleeding, but not stroke, than those who were not.

However, in the GISSI-2/ISG, ISIS-3 and GUSTO trials, total and haemorrhagic stroke occurred more frequently in alteplase (or duteplase) recipients than in those who received streptokinase or anistreplase, especially in patients older than 70 or 75 years. Combination thrombolytic therapy with alteplase and streptokinase increases the risk of stroke compared with monotherapy.

Allergic reactions and hypotension were reported more frequently after administration of streptokinase or anistreplase than alteplase.

Dosage and Administration

Treatment with alteplase should be initiated as soon as possible after the onset of symptoms of acute myocardial infarction. The original dosage regimen for alteplase consists of a 3-hour intravenous infusion where 60mg is administered in the first hour (of which 6 to 10mg is administered as a bolus injection over the first 1 to 2 minutes), 20mg over the second hour and 20mg over the third hour. In the US, smaller patients (< 65kg) should receive a dose of 1.25 mg/kg and, in the UK, patients weighing less than 67kg should receive a total dose of 1.5 mg/kg, both over 3 hours as described above. In addition, the US has now approved the administration of a more rapid (90-minute) infusion of alteplase. The accelerated alteplase dosage schedule in patients > 67kg consists of a 15mg intravenous bolus dose, followed by 50mg infused over the next 30 minutes and then 35mg infused over the next 60 minutes. In lower weight patients (≤ 67kg), the initial alteplase 15mg bolus dose should be followed by a 0.75 mg/kg infusion (not to exceed 50mg) over 30 minutes and then 0.5 mg/kg (not to exceed 35mg) infused over the next 60 minutes.

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    Jane C. Gillis, Antona J. Wagstaff & Karen L. Goa

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Various sections of the manuscript reviewed by: F. Andreotti, Facoltà di Medicina e Chirurgia ‘Agostino Gemelli’, Università Cattolica del Sacro Cuore, Rome, Italy; D.P. de Bono, Department of Cardiology, Glenfield General Hospital, Leicester, England; S.R.M. Holmberg, Cardiac Department, Royal Sussex City Hospital, Brighton, Sussex, England; P. Sleight, Cardiac Department, John Radcliffe Hospital, Oxford, England; B.E. Sobel, Department of Medicine, Medical Center Hospital of Vermont, Burlington, Vermont, USA; A.J. Tiefenbrunn, Cardiovascular Division, Washington University School of Medicine/Barnes Hospital, St. Louis, Missouri, USA; E.J. Topol, Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA; H.D. White, Cardiology Department, Green Lane Hospital, Auckland, New Zealand; R.G. Wilcox, Division of Cardiovascular Medicine, University Hospital, Nottingham, England.

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Gillis, J.C., Wagstaff, A.J. & Goa, K.L. Alteplase. Drugs 50, 102–136 (1995). https://doi.org/10.2165/00003495-199550010-00008

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