Streptokinase

Summary

Synopsis

Thrombolytic therapy with streptokinase and other agents reduces mortality and is now well accepted as the mainstay of revascularisation options for most patients after an acute myocardial infarction.

Streptokinase is as efficacious as alteplase (recombinant tissue plasminogen activator; rt-PA) when given as a 3-hour infusion, anistreplase, reteplase and saruplase in reducing mortality. However, in the Global Utilization of Streptokinase and Tissue Plasminogen Activatorfor Occluded Coronary Arteries (GUSTO) trial, an accelerated alteplase regimen (1.5-hour infusion) plus intravenous heparin demonstrated a statistically significant 1% absolute mortality reduction compared with streptokinase plus heparin.

Treatment with streptokinase is consistently clinically superior to conventional treatment and is cost effective: the marginal cost per year of life saved (cost/YLS) is less than $US/$Can20 000 (1990 or 1991 currency) assuming 5-year survival. In addition, streptokinase treatment is associated with fewer intensive care days and total days spent in hospital and a decrease in the use of intensive care services compared with conventional therapy. Importantly, the cost/YLS of treating older patients (70 to 80 years) with streptokinase is similar to that in younger patients (≈$US22 000, 1990 currency). In 1 study, the cost of in-hospital treatment and associated 1-year follow-up costs did not differ significantly regardless of whether patients received streptokinase or anistreplase. In the most comprehensive cost-effectiveness analysis to date, GUSTO investigators determined that the incremental cost/YLS in patients who received the accelerated alteplase regimen instead of streptokinase was $US32 678 (1993 currency); the projected life expectancy was about 15 years.

Thrombolytic therapy is generally more cost effective in patients at high risk than in those at low risk. The cost effectiveness of streptokinase is dependent on infarct location and time to treatment, but is more favourable in patients with anterior than inferior infarctions and those treated as soon as possible after symptom onset. There are as yet no comparative data to indicate a clinical benefit for one thrombolytic agent over another in patients treated more than 6 hours after symptom onset; therefore, in all likelihood, streptokinase will be preferred on the basis of cost minimisation. Streptokinase is associated with a slightly higher rate of severe bleeding than alteplase but a lower incidence ofstroke.

Although quality-of-life information comparing thrombolytics is unavailable, most patients who received streptokinase or alteplase rated their quality of life as high on the basis of results from time trade-off assessments and health surveys.

In summary, streptokinase is undeniably cost effective compared with conventional treatment. It is up to individuaI healthcare systems to determine whether the mortality advantage and cost differential of the accelerated alteplase regimen over streptokinase, as seen in the GUSTO trial, are affordable and justifiable. However, it is important to realise that treatment options may be limited by healthcare resources; thus, streptokinase can be regarded as a cost-effective thrombolytic strategy which is both efficacious and affordable within the constraints of most healthcare budgets.

Disease Considerafions

Coronary heart disease is the leading cause of death in Western nations. Globally, an estimated 4 million people die annually from an acute myocardial infarction, more than 50% before reaching hospital.

Thrombolytic therapy, percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) are the major reperfusion techniques used in patients with acute myocardial infarction. The efficacy of thrombolytic agents, including streptokinase, has been definitively proven in major clinical trials and, as a result, thrombolysis has become the mainstay of revascularisation strategies in eligible patients. CABG and PTCA are primarily used in patients who have failed thrombolysis or in whom thrombolysis is contraindicated.

Direct costs of thrombolytic strategies, which include drug and hospital costs and physicians' fees, have been estimated to be $US24 895 to $US27 740 (1993 currency) for the l-year post-infarction period. These costs may vary great1y if patients have a complicated or incomplete recovery; regional differences in costs and standard medical practices may also account for substantial variation.

Indirect costs which may result from reduced productivity after an acute myocardial infarction are more difficult to quantify but are estimated to account for billions of dollars per year. Although about 60 to 90% of patients return to work, many are not able to attain their previous level of function. Residual disability resulting in lost income and reduced quality of life would be expected to have more of an impact in younger than in older patients since they have more years of life remaining.

Factors Influencing the Pharmacoeconomic Appraisal of 5treptokinase

Healthcare decision makers must consider the clinical efficacy, tolerability and cost of various treatment options. In patients with an acute myocardial infarction, thrombolysis clearly reduces mortality. Age, site of infarct and time to treatment are clinically useful predictors of outcome, relative benefits and risks, and associated costs of thrombolytic treatment.

Streptokinase is as efficacious as alteplase (when given as a 3-hour infusion), anistreplase, reteplase and saruplase in reducing mortality in patients with an acute myocardial infarction. The accelerated alteplase regimen plus intravenous heparin used in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial showed a significant l% mortality advantage over streptokinase plus heparin. In general, the magnitude of survival benefit of thrombolysis, regardless of the agent administered, is greatest in patients with an anterior infarction, the elderly and those who receive treatment as soon as possible after the onset of symptoms.

The risk of serious bleeding or stroke is an important consideration when deciding whether thrombolytic therapy is appropriate. Although streptokinase is associated with a slight1y greater tendency toward major bleeding complications than alteplase, anistreplase or reteplase, overall, the incidence of stroke is lower in patients who receive streptokinase than those treated with the other agents.

The antigenicity of streptokinase usually precludes its being readministered for at least 12 months.

Pharmacoeconomic Appraisal

Most pharmacoeconomic reports of streptokinase thrombolysis were conducted retrospectively using clinical trial data to construct baseline assumptions and decision analysis models to predict comparative costs and benefits; they may, therefore, be less relevant than more recent comparative studies. Because comparative long term survival data between thrombolytic agents are lacking, predictions of life expectancy were also made. Differences between reports in study methodology, perspective and assumptions must be considered carefully when attempting to generalise and apply their results to clinical practice.

Early noncomparative or placebo-controlled trials verified that treatment with streptokinase was more expensive than conventional treatment but, generally, at a marginal cost per year of life saved (cost/YLS) of less than $US/$Can20 000 (1990 or 1991 currency) assuming 5 years of survival. These trials also demonstrated that cost effectiveness varies depending on infarct location but is retained in the elderly. For example, from a Health Maintenance Organisation perspective, the marginal cost per life saved of streptokinase compared with conventional treatment was $US12 305 (currency year not stated) in patients with anterior infarcts and $US69 522 for those with inferior infarcts. Important1y, the cost/YLS of treating elderly patients (aged 70 to 80 years) with streptokinase was similar to that reported in younger patients (≈$US22 000; 1990 currency), and remained less than $US55 000 over a wide range of assumptions regarding costs, mortality and YLS.

Because most clinical experience has been gained with streptokinase, it has become the standard thrombolytic agent and been used as the baseline in comparative pharmacoeconomic analyses. In l study, no significant difference in in-hospital costs or l-year follow-up costs was seen between treatment groups regardless of whether patients received streptokinase, anistreplase or alteplase (as a standard 3-hour infusion). However, costs were calculated on the basis of an overall efficacy score determined by coronary artery patency and left ventricular function, rather than mortality, which reduces the applicability of this comparison.

The most extensive prospective cost-effectiveness analysis to date was conducted in conjunction with the GUSTO trial. Investigators considered a cost-effectiveness value of up to $US50 000 (1993 currency) to be an acceptable use of healthcare resources. The incremental cost/YLS for the accelerated alteplase regimen compared with streptokinase was calculated to be $US32 678 based on an increase in life expectancy of 0.14 undiscounted years for those treated with alteplase (projected life expectancies of 15.41 and 15.27 years for alteplase and streptokinase), at an increased cost of $US2845 per patient. Subgroup analysis indicated that treatment with alteplase was cost effective in those aged ≥41 years with anterior infarcts and those aged >60 years regardless of infarct location. Under the conditions of the GUSTO trial, treatment with streptokinase would be more favourable in younger patients (≤60 years of age) with inferior infarctions and some patients (≤40 years of age) with anterior infarctions. In situations where the comparative efficacy of agents is uncertain, such as in patients treated 6 or more hours after symptom onset, streptokinase is likely to be preferred on the basis of cost minimisation.

When a decision analysis model was used to retrospectively analyse l-year mortality data from the GUSTO trial, the incremental cost-utility value for the accelerated alteplase regimen was estimated to be $US27 400 (1992 currency) per additional quality-adjusted life-year. Another decision analysis model (pre-GUSTO but one which assumed a l% short term survival advantage for alteplase) calculated the additional cost/YLS of alteplase treatment to be $Can58 600 (1988 currency) assuming no difference in annual hazard rates between treatments. As in the main GUSTO trial, the incremental costs for treatment with alteplase rather than streptokinase in these models were acutely sensitive to changes in mortality rates and life expectancy and less sensitive to differences in drug costs and stroke or reinfarction rates.

In l study, in-hospital costs were lower in patients who received streptokinase than in those allocated to receive primary PTCA, although total 1-year costs were similar. The marginal cost-effectiveness ratio was calculated to be $US3010 (1992 currency) per event-free survivor, where event was defined as reinfarction, stroke or additional revascularisation procedures.

Comparative quality-of-life data between streptokinase and other thrombolytic agents are lacking. However, pooled information clearly shows that thrombolytic therapy resulted in a high quality of life based on results from time trade-off assessments and health surveys.