Alteplase

Summary

Synopsis

Alteplase (recombinant tissue plasminogen activator; rt-PA) is a thrombolytic agent that when given in an accelerated regimen with intravenous heparin has survival advantages compared with streptokinase in the treatment of acute myocardial infarction, as shown by the results of the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial. Although alteplase is more fibrin-specific than streptokinase, alteplase therapy is associated with a small relative increase in the incidence of haemorrhagic stroke, but appears to cause a small relative decrease in the incidence of major bleeding.

Because alteplase has a higher acquisition cost than alternative thrombolytic agents, analyses have been undertaken to assess whether administration of alteplase after myocardial infarction is a cost-effective use of healthcare resources. In retrospective analyses undertaken before completion of the GUSTO trial, it was generally assumed, on the basis of better 90-minute patency rates, that alteplase would provide survival advantages compared with streptokinase or conventional nonthrombolytic therapy. Alteplase had acceptable cost-effectiveness ratios compared with conventional therapy and streptokinase therapy from both third-party payer and hospital perspectives. Subgroup analyses demonstrated that alteplase was more cost effective when given early after symptom onset and when given to patients with large infarcts.

Prospective evaluations of the cost effectiveness of alteplase in 3-hour and accelerated regimens have similarly demonstrated that alteplase therapy after myocardial infarction improves survival at an ‘acceptable’ cost. The largest prospective evaluation undertaken to date was performed in conjunction with the GUSTO trial. Primary analysis, on the basis of the clinical findings of the GUSTO trial and prospective collection of cost data from US patients, revealed that the cost-effectiveness ratio for accelerated alteplase therapy compared with streptokinase was $US32 687 (1993 dollars) per year of life saved (YLS). This value is most relevant for US patients and lies within the definition of ‘cost effective’ if $US50 000/YLS is the benchmark for acceptable use of resources. The cost-effectiveness ratio for alteplase was most sensitive to assumptions regarding long term survival and cost differences after the first year following treatment. In subgroup analyses, alteplase was a cost-effective treatment option for all elderly patients (>60 years of age) and all patients >40 years of age with anterior infarction.

Alteplase therapy appears to have in-hospital costs/charges similar to those for primary percutaneous transluminal coronary angioplasty (PTCA), mainly because PTC A appears to have a favourable effect on duration of hospitalisation. Given the technical expertise and facilities required for PTCA, it is likely that thrombolytic therapy will remain the management option of choice in most centres.

In conclusion, under the conditions of the GUSTO study, accelerated alteplase in combination with intravenous heparin confers survival advantages compared with streptokinase therapy. While decision-makers must choose how best to use their available healthcare resources, pharmacoeconomic evaluations have confirmed that, on the basis of accepted benchmark values, alteplase therapy is a cost-effective therapeutic option for the treatment of acute myocardial infarction, especially in elderly patients with either anterior or inferior infarcts and nearly all patients with anterior myocardial infarction. Thus, on the basis of clinical and economic data, predominantly provided by the GUSTO trial, alteplase is a cost-effective first-line management option for acute myocardial infarction.

Disease Considerations

A total of 4 million deaths worldwide result from acute myocardial infarction annually, and coronary artery disease is the leading cause of death in the US. Thrombolytic therapy has reduced in-hospital mortality. It is predicted that further lives could be saved if thrombolysis was offered to larger groups of patients, including those aged over 75 years and those presenting within 6 to 12 hours after the onset of symptoms.

The costs of management of acute myocardial infarction vary depending on the healthcare setting and the follow-up procedures undertaken; coronary angioplasty and bypass surgery add considerably to the overall direct costs, as does the duration of hospitalisation. Total direct costs per patient for the initial hospitalisation have been estimated as $Can6144 (1991 Canadian dollars — costs to third-party payer) in Canada, $US4224 (1985 dollars — costs to third-party payer for uncomplicated myocardial infarction) in the US and ECU4869 (European Community monetary units, currency year not stated — mean in-hospital costs) in France.

Indirect costs resulting from loss of productivity after an acute myocardial infarction may be considerable and successful therapy may reduce the indirect costs of the disease to society. From a patient’s perspective, quality of life after a myocardial infarction may be the most important consideration. Several instruments to assess quality of life have been designed, and results using these tools appear to correlate well with physicians’ assessments using the New York Heart Association classification.

Factors Influencing the Pharmacoeconomic Assessment of Alteplase

Factors predicting the clinical benefit-to-risk ratio for thrombolytic therapy may also help determine the cost effectiveness of thrombolytic therapy in subgroups of patients. Thrombolytic therapy appears to provide a greater survival advantage in patients with an anterior infarct, those treated within 6 hours of symptom onset (although therapeutic benefits are observed even when there is a treatment delay of up to 12 hours) and the elderly.

Although earlier clinical trials reported no difference in clinical efficacy or overall tolerability between alteplase (recombinant tissue plasminogen activator; rt-PA) and other thrombolytic agents, the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial demonstrated a 1% survival advantage (14% risk reduction) for an accelerated alteplase and intravenous heparin regimen compared with streptokinase/heparin regimens. However, in the GUSTO trial, some features of which have been subject to criticism (and defence), alteplase was associated with an overall increased incidence of stroke compared with streptokinase regimens of 1 to 2 fatal strokes per 1000 alteplase-treated patients. Nonetheless, the 1% 30-day survival advantage of accelerated alteplase compared with pooled streptokinase regimens was maintained at 1 year.

Pharmacoeconomic Analyses

Interpretation of economic analyses must be undertaken with an understanding of the generalisability of the data. The clinical relevance of the baseline assumptions made regarding clinical outcomes and interventions, the costs included in the study and the study perspective all affect the relevance of the data for any specific healthcare setting.

Even before the clinical benefits of accelerated alteplase were confirmed in the GUSTO trial, most cost-effectiveness studies assumed survival advantages for alteplase on the basis of its improved early infarct-related vessel patency rates. The majority of such studies undertaken to date have been retrospective analyses, often using decision analysis techniques to model baseline data. One US study demonstrated that, assuming a cost of $US100 000/1-year survivor is acceptable, intravenous alteplase was the optimal treatment for a patient with a moderate-sized infarct, while intravenous alteplase and routine coronary angioplasty was optimal for patients presenting with large infarcts. Aggressive alteplase-containing regimens (i.e. those including routine invasive procedures) were cost effective compared with matched streptokinase-based regimens if the acquisition cost of alteplase remained below $US2800 (compared with a streptokinase cost of $US300). Cost-effectiveness and cost-utility ratios determined prospectively in a Swedish study indicated that compared with conventional treatment alteplase is a highly cost-effective option for the treatment of suspected myocardial infarction.

As thrombolytic therapy for eligible patients is now standard, prospective economic analyses comparing different thrombolytic agents are probably of more interest to clinicians. In common with the majority of comparative clinical trials, economic analyses have generally compared alteplase with streptokinase. In the smaller of 2 prospective comparative analyses, total hospital costs were comparable for alteplase and the 2 comparator thrombolytic agents streptokinase and anistreplase. The cost-effectiveness ratio (using an overall efficacy score of patency and left ventricular function as the measure of effectiveness) for alteplase (ECU548) was between that for streptokinase (ECU405) and anistreplase (ECU570). The much larger prospective analysis of the US arm of the GUSTO trial, which used mortality as the efficacy end-point, assessed the cost effectiveness of accelerated alteplase plus intravenous heparin versus that of streptokinase plus subcutaneous or intravenous heparin. When $US50 000 per year of life saved was used as the benchmark for ‘acceptable’ use of healthcare resources, primary analysis revealed accelerated alteplase to be a cost-effective treatment option. As expected on the basis of clinical data, subgroup analysis demonstrated that accelerated alteplase was most cost effective in the elderly and in patients with anterior infarcts. Sensitivity analysis established that the cost-effectiveness ratio for accelerated alteplase was most sensitive to assumptions made regarding long term costs and benefits (i.e. accelerated alteplase was not cost effective when the incremental survival benefit was <7 years per 100 patients or the cost differences between the groups observed in the first year were maintained for the entire lifetime). The cost-effectiveness ratio for accelerated alteplase was relatively unaffected by changes in assumptions regarding first-year costs, costs related to stroke and the cost differential between alteplase and streptokinase.

Although retrospective analyses are generally subject to a greater number of assumptions and thus yield less generalisable data than prospective studies, the results of such analyses tend to support those obtained prospectively. The results of 4 such studies indicated that alteplase had a favourable cost-effectiveness ratio compared with streptokinase or placebo. For example, 2 Canadian studies found that, compared with streptokinase or placebo, alteplase treatment provided cost-effectiveness ratios comparable to many other interventions funded by the Canadian government. Importantly, a retrospective analysis of the GUSTO data, using a decision analysis model, revealed that accelerated alteplase is cost effective compared with streptokinase if the clinical survival advantage of alteplase is at least half of that reported in the GUSTO trial. In contrast, a single French study that differentiated costs only on the basis of thrombolytic drug acquisition costs estimated that alteplase cost 10- to 20-fold more than streptokinase with or without aspirin (acetylsalicylic acid) [i.e. from a pharmacy budget perspective].

Data on quality-of-life changes associated with alteplase compared with those associated with streptokinase have not been routinely or rigorously collected, and no differences have been observed to date. However, self-reported quality of life was high in most patients treated with thrombolytic therapy, with the exception of those who had experienced a reinfarction or treatment-related stroke.