PHARMACOECONOMICS Drugs & Aging 1996 Apr: 8 (4): 237-244 1170-229X/96/0004-0237/$04.oo/0

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Thrombolytic Therapy in the Elderly Pharmacoeconomic Considerations

Krishnan Ramanathan, Christopher J. Ellis and Harvey D. White

Cardiology Department, Green Lane Hospital, Auckland, New Zealand

Contents Summary ......... . ... . . .. . ... . .. . ... . 237

238 238 239 240 240 242

1. Thrombolytic Therapy . . .. ............. . 2. Evidence for Benefits of Thrombolytic Therapy in the Elderly . 3. Comparative Thrombolytic Trials in the Elderly 4. GUSTO and 'Accelerated' Alteplase 5. GUSTO Outcomes for the Elderly . 6. Conclusion . . . . . . . . . . . . . . .

Summary Elderly patients have the highest absolute risk of death following an acute myocardial infarction (M!); 16.1 % for those aged between 65 and 74 years, and 25.3% for those older than 75 years. Therefore, this age-group potentially may benefit most from the use of thrombolytic therapy.

Cost-effectiveness analysis of streptokinase therapy has estimated that in pa­tients aged 70 to 80 years, the cost per life-year saved is between $US21 200 and $US22 400 (1990 dollars) compared with placebo treatment. Additional mortal­ity benefits have been shown for accelerated alteplase compared with streptoki­nase-treated patients (30-day mortality for alteplase and streptokinase was 6.3% and 7.3%, respectively; p = 0.001). A prospective cost-effectiveness study for all age groups concluded that the cost of an additional year of life saved with al­teplase compared with streptokinase was $US32 678 (1993 dollars). This extra cost of alteplase treatment declined to $US 13 410 and $US 16 246 with patients older than 75 years with anterior and inferior MI, respectively. In patients aged 40 years or younger with an anterior or inferior MI, and for those aged up to 60 years with an inferior infarction, the accepted cost-effectiveness ratio of $US50 000 was exceeded.

Alteplase appears to be a cost-effective therapy for the treatment of elderly patients with acute Ml.

A general aging of the population is the most significant demographic issue that has confronted physicians and health economists over recent years. The consequence of an older population and a progressive increase in life span will mean that the prevalence of coronary artery disease is un­likely to decline in the immediate future, even if

preventive measures are able to decrease its actual incidence. As a result, an increasing number of pa­tients can be expected to be admitted to hospital with an acute myocardial infarction (MI). The need to optimise the treatment of MI and ensure its cost effectiveness is important now, and will be increas­ingly so in the future)l]

238

Cardiovascular disease is the most common cause of death and disability in the elderly.121 The incidence of acute MI among patients of 75 years of age and older is twice that of younger patients.l31

Nearly 50% of all patients who die during hospital­isation for acute MI are aged over 75 yearsPI Fur­thermore, their post-discharge mortality is twice the rate of younger patients.l41 Increased age has also been shown to be the most important long term adverse prognostic factor following acute M1.15- 111

1. Thrombolytic Therapy

There is evidence that thrombolytic therapy is effective in elderly patients,1121 despite the fact that no randomised, placebo-controlled thrombolytic trial has been designed to show specific benefits in the elderly. Despite this evidence, there has been a widespread reluctance on the part of physicians to administer thrombolytic therapy to older patients who present with the signs and symptoms of acute MI and fulfil the conventional ECG criteria for its administration. Patients of 75 years of age and older are 6 times less likely to receive thrombolytic therapy than younger patients. llO,121 In a recent registry representing a sample of all patients hav­ing MIs at North American centres involved in the first Global Utilisation of Streptokinase and tPA in Occluded Coronary Arteries (GUSTO-I) trial, 30.1 % of the patients were over age 75, but com­prised only 17.8% of those enrolled in the study.!131

There are several possible reasons for the infre­quent use of thrombolytic agents in older patients. First, many early clinical trials of intravenous thrombolytic therapy imposed an upper age limit of 70 to 75 years and, as a result, there was initial uncertainty as to whether elderly patients would benefit. For example, an American College of Cardiology/American Heart Association task force in 1990 stressed that physicians should be judi­cious in the selection of older patients for throm­bolysis and suggested that treatment of patients over the age of 75 years was not well established by evidence.l 14J Secondly, the elderly often have little or no chest discomfort at presentation, and are more likely to have nondiagnostic ECGS[15J and to

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Ramanathan et al.

present late'! 161 Thirdly, elderly patients have more comorbid disease, and many have relative contra­dictions to thrombolytic therapy, including an in­creased risk of intracranial haemorrhage or sys­temic bleeding. Fourthly, probably the main reason for withholding thrombolytic treatment in the el­derly is the fear of inducing a catastrophic haemor­rhagic stroke. Finally, the cost effectiveness of us­ing thrombolytic therapy in the elderly has been unknown until recently and this uncertainty may have contributed to its limited use.

2. Evidence for Benefits of Thrombolytic Therapy in the Elderly

There have been 9 randomised, controlled trials of intravenous thrombolytic therapy [streptoki­nase, alteplase (tissue plasminogen activator; tPA), anistreplase (anisoylated plasminogen streptoki­nase activator complex; APSAC), urokinase] that have enrolled more than 1000 patients.!17-25J These have recently been reviewed by the Fibrinolytic Therapy Trialists (FTT) Collaborative Group,ll2J Among the 45 000 patients presenting with ST­segment elevation or bundle branch block who re­ceived thrombolytic therapy, there was a signifi­cant absolute mortality reduction of about 30 per 1000 patients for those presenting within 6 hours, and of about 20 per 1000 patients for those present­ing between 6 and 12 hours, after the onset of symptoms.

Older patients were at a higher absolute risk of death from an acute MI in these trials. At 35 days, mortality without thrombolytic therapy was 4.6% for those aged less than 55 years, 8.9% for those aged between 55 and 64, 16.1 % for those aged be­tween 65 and 74, and 25.3% for those aged over 75 years. Only 10% of the patients were '?75 years of age, with the APSAC Intervention Mortality Study (AIMS) [::;70 years],[191 Anglo-Scandinavian Study of Early Thrombolysis (ASSET) [::;75 years]l201 and Intravenous Streptokinase in Acute Myocar­dial Infarction (IS AM) [:575 years][21 1 trials specif­ically enrolling only younger patients. Despite the under-representation of elderly patients, a statisti­cally significant mortality reduction with thrombo-

Drugs & Aging 1996 Apr; 8 (4)

Thrombolytic Therapy

lytic therapy was observed in the elderly group of 65 to 74 years (16.1 % vs 13.5%; p < 0.00001), with a trend towards significance in the small 'very el­derly' group aged 75 years and over (25.3% vs 24.3%; not statistically significant).l12]

The Gruppo Italiano per 10 Studio della Strepto­chinasi nell'Infarto Miocardico (GISSI-l) tria}[l?] separately reported the outcome of patients aged 75 years and older at 1 year. There was a trend toward decreased mortality with streptokinase ver­sus control in these patients: 28.9% for streptoki­nase versus 33.1 % for control at 21 days and43 .1 % for streptokinase versus 46.1 % for control at 1 year.II?1

Cost-effectiveness analyses of these earlier tri­als compared thrombolytic therapy with placebo treatmentJ26-28] Krumholz and colleagues[29] sug­gested that streptokinase therapy is cost effective in the elderly (70 to 80 years) after incorporating data from the GISSI-l and ISIS-2 trials into a decision-analysis model. Calculated costs of be­tween $US21 200 and $US22 400 (1990 dollars) per life saved are well below a US benchmark fig­ure of $50000 per year of life saved[29] (the upper limit for an acceptable cost-effectiveness ratio re­mains controversial, but values of more than $US 100 000 per year of life saved are generally considered too high).l30] The costs remained below $US50 000 per year of life saved even when sen­sitivity analysis was undertaken incorporating an overall stroke rate of 2% vs 1.3% for treatment vs placebo, or if the years of life gained was decreased from the assumed 2 to 4 years using the coronary heart disease policy model to only 1 year in a model using 80-year-old patients.

This model[29] contained many assumptions, including the inaccuracy that all haemorrhagic strokes led to death. This overestimated the poten­tial harm caused by use of thrombolytic therapy. The authors of the analysis also underestimated the true mortality rate among those elderly patients with MI who are not treated with thrombolysis. Furthermore, there were other limitations, with a lack of uniformity of stratification of age group, length of follow-up and definition of mortality (the

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239

GISSI trial used total mortality and ISIS-2 reported vascular mortality).[29] Despite these assumptions, which tended to bias the analysis against the use of thrombolytic therapy, the cost-effectiveness ratio remained acceptable.

3. Comparative Thrombolytic Trials in the Elderly

Two large mortality trials have compared sur­vival in patients treated with intravenous strepto­kinase or alteplaseJ23,31,32] There were no age lim­its for patients admitted to these trials. In the Gruppo Italiano per 10 Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2)[31] and Interna­tional Trial,[32] 20 749 patients presenting within 6 hours of the onset of chest pain were randomised in an open manner to receive either streptokinase 1.5MU over 30 to 60 minutes or alteplase 100mg over 3 hours. The in-hospital mortality rates were similar, 8.9% for alteplase and 8.5% for streptoki­nase. Major cardiac complications were also sim­ilar for both treatment groups. However, there were more total strokes with alteplase, 1.3% vs 0.9% (relative risk 1.41,95% confidence interval 1.09 to 1.83).

In the Third International Study of Infarct Sur­vival (ISIS-3),[23]41 299 patients were randomised to receive streptokinase 1.5MU over 1 hour, dute­plase (double-stranded tPA) at 0.60 MU/kg infused over 4 hours, or a 30U bolus of anistreplase over 3 minutes. The 35-day mortality was equivalent for the 3 groups: 10.5% for streptokinase, 10.3% for duteplase and 10.6% for anistreplase. The respec­tive stroke rates were 1.1 %, 1.5% and 1.5%; most of the excess in the rate of stroke with duteplase and anistreplase was due to an increased incidence of intracerebral haemorrhage (0.7% and 0.6%, re­spectively) compared with streptokinase (0.3%; p < 0.0001).

For elderly patients in ISIS-3,f23] the 35-day mortality for patients >70 years of age was 20.3% with streptokinase and 19.7% with duteplase (not statistically significant) [ISIS-3 collaborative group, personal communication]. In the GISSI-2 and In­ternational Trial, 6-month mortality for patients

Drugs & Aging 1996 Apr; 8 (4)

240

aged >70 years was 19.1 % with streptokinase and 19.4% with alteplase.[31 ,32] Since no overall mortality differences were evident between these tPAs and streptokinase, it is not surprising that no differential benefit was seen in the elderly, either from a clinical viewpoint[23,32] or when these fig­ures were subjected to cost -effectiveness stud­ies.[33,34]

4. GUSTO and 'Accelerated' Alteplase

In the initial studies, the standard regimen for alteplase was a dose of 100mg given intravenously over 3 hours. The rationale for this prolonged regi­men was to prevent early reocclusion of the infarct­related artery, as alteplase has a short elimination half-life of approximately 5 minutes. However, al­teplase given more rapidly or as boluses results in better 90-minute patency rates)35,36]

To test the hypothesis that 'accelerated' alte­plase would result in a clinical advantage, the multicentre GUSTO trial[37] enrolled 41 021 pa­tients to 4 treatment regiments: • streptokinase 1.5MU plus subcutaneous heparin

12 500U twice daily (the ISIS-3 regimen); • streptokinase 1.5MU plus intravenous heparin

following a 5000U bolus; • 'accelerated' alteplase (1 OOmg over 90 minutes)

plus intravenous heparin; • streptokinase IMU plus weight-adjusted al­

teplase 1 mg/kg (not to exceed 90mg over 3 hours) plus intravenous heparin. Patients of all ages were eligible for enrolment

and the study included one man aged 110 years)38J 30-day mortality in the alteplase-treated patients was 6.3% compared with 7.3% in the pooled strep­tokinase groups (p = 0.001).[37] Subsequent multi­variate analysis identified age as the most signifi­cant factor influencing 30-day mortality, with rates of 1.1 % in the youngest decile «45 years) and 20.5% in patients >75 years (adjusted X2 = 717, P < 0.0001).[8]

The major advance from the GUSTO trial was the information obtained from the angiographic sub study. [39] This strongly correlated the mecha­nism of the mortality benefit of accelerated alte-

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Ramanathan et al.

Table I. Alteplase (tissue plasminogen activator; tPA) dosage (mg) by time in GUSTO[37j compared with the standard regimen in GISSI-2[31j

Time GUSTO GISSI-2 (min) accelerated combination standard

alteplase (alteplase + alteplase streptokinase lMU)

30 65 40 35

60 82.5 80 60

90 100 80 70

Abbreviations: GISSI-2 = Gruppo Italiano per 10 Studio della Sopravvivenza nell'lnfarto Miocardico; GUSTO = Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries.

plase with early patency of the infarct-related ar­tery. In the alteplase group at 90 minutes, there was a complete patency rate (TIM I grade 3) of 54%, compared with 29% and 33% for the 2 streptoki­nase groups)40] This improvement in patency and survival with accelerated alteplase (90 minutes) over standard alteplase (180 minutes) may be ex­plained by the amount of alteplase administered in 90 minutes (table 1))41] Furthermore, when patency was correlated with survival, independent of the thrombolytic therapy used, an occluded infarct­related artery (TIMI grade 0) was associated with an 8.4% mortality rate, and a completely patent infarct related artery (TIMI 3) with a 4.0% mortal­ity rate, at 30 days)401

5. GUSTO Outcomes for the Elderly

In the GUSTO trial, all but the oldest patients (>85 years) had a lower mortality with accelerated alteplase, with these very elderly patients showing a trend toward increased survival with streptoki­nase plus subcutaneous heparin (26.4% vs 30.0%). The net clinical benefit (reduction in death and nonfatal disabling stroke) was also in favour of al­teplase therapy for patients aged ~85 years)42]

Two major cost analyses have been carried out on the GUSTO data,[30,43] with similar results being reported by both groupS)44] One study was spon­sored by a manufacturer of streptokinase[43] and the other was funded in part by the manufacturers of alteplase. [30J

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Thrombolytic Therapy

Kalish and colleagues[43) used a decision­analysis model and expressed costs in 1992 SUS, discounting at a rate of 5% per year. Hospitalisa­tion cost estimates were derived from the Medicare Diagnosis-Related Group (DRG) data (figures for reimbursement to the Brigham and Women's Hos­pital). The cost of thrombolytic therapy was $US313 for streptokinase and $US2244 for alte­plase. Their calculations included treatment ex­penses for long term coronary disease ($US2452/ year) and disabling stroke ($US29 293/year). Mor­tality data was directly translated from the GUSTO findings with the average life expectancy after MI derived from the Worcester Heart Attack studyJ31 The Worcester study population had a mean age of 64.9 years similar to the 62 years among partici­pants in the GUSTO trial. The analysis by Kalish et aIJ43) concluded that the cost benefit of alteplase was $US30 300 per additional quality-adjusted life year (QALY) gained, compared with streptoki­nase. This value declined to $US27 400 per addi­tional QALY if I-year mortality data was used in­stead of mortality at 30 days. Sensitivity analysis showed the differential I-year mortality (9.0% for alteplase and 10.1 % for streptokinase) to be the most important variable. In addition, their model was sensitive to the cost of thrombolytic therapy, but relati vel y insensiti ve to the incidence of throm­bolytic therapy-related strokes and the reinfarc­tion rate following thrombolysis. The cost effec­tiveness of aJteplase using 30-day mortality data was also sensitive to age, with varying assump­tions made regarding life expectancy. When life expectancy was projected to 5 years, the costs ef­fectiveness of treatment with alteplase for patients 75 years and older was $US48 800/QALy' This was lower than the cost of $US60 OOO/QALY for patients under 75 years of age.

A separate cost-effectiveness substudy using the GUSTO trial data was carried out by Mark and colleagues,[30) this time using 1993 SUS to express costs. Their data were prospectively collected as a prior design of the GUSTO trial and were based on the medical resources consumed during initial hospitalisation from all 23 105 US patients en-

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241

rolled in the trial. Information on the use of medi­cal resources post-discharge and quality oflife was obtained by a structured interview of 2600 US pa­tients randomly selected from the GUSTO trial. Initial hospitalisation costs were determined from the Duke Transition One cost-accounting system,[45) and costs for rehospitalisation and follow-up clinic visits were based on DRG reimbursement. This study found the cost of thrombolytic therapy cal­culated from wholesale prices (Drug Topics Red Book average) to be $US320 for streptokinase and $US2750 for alteplase. All costs and survival were discounted at a rate of 5%. Survival beyond 1 year was projected from the Duke Databank for Cardio­vascular Diseasef46] and it was assumed that the increase in I-year survival observed with alteplase, over treatment with streptokinase, would be sus­tained beyond this.f47.50] Overall, the investigators found the cost-effectiveness ratio for the additional lifetime cost required to add an extra year of life after treatment with accelerated alteplase com­pared with streptokinase was $US32 678.f30)

Secondary analyses were carried out for 8 sub­groups as defined by patient age and the location of the MI (table II). In specific subgroups, patients 40 years of age or younger with an inferior MI, and those up to age 60 years with an inferior MI, the cost-effectiveness ratio of $US50 000 was ex­ceeded. This reflects the finding that the average number of life years added by treatment with al­teplase was greater for older than younger pa­tients.f30)

In the initial 30 days after treatment, there was a net increase of 1 disabling nonfatal stroke pen

Table II. Cost per additional year of life for accelerated alteplase (tissue plasminogen activator; tPA) versus streptokinase after myocardial infarction (MI) in selected patient subgroups ($US; 1993 values)I301

Age of patient (y)

$40

41-60

61-75

>75

Cost per additional life-year

anterior MI

123609

49877

20601

13410

inferiorMI

203071

74896

27873

16246

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1000 patients treated with alteplase compared with streptokinase. The extent to which the increase in haemorrhagic stroke rate produced by alteplase may change the results was analysed in 2 separate ways. First, when disabling nonfatal stroke was considered equivalent to in-hospital mortality, the projected undiscounted life expectancy of 0.14 years per patient gained with alteplase, compared with treatment with streptokinase, was decreased to 0.13. This increased the primary cost-effectiveness ratio to $US35 538. Secondly, the cost-effectiveness ratio increased to $US42400 when the most un­favourable assumptions (that patients with strokes had no increase in survival due to alteplase and that each patient would require 15 years of institu­tional care) were applied to the costs incurred by a single patient with nonfatal disabling stroke among 1000 patients receiving alteplase. The 2 new cost­effectiveness ratios were still below the acceptable level of $US50 000.[30]

The investigators[30] argued that the cost­effectiveness ratio values in the primary and sec­ondary analyses were derived from published aver­age wholesale prices of the 2 drugs, which tended to overstate the costs hospitals actually pay for these agents. However, future costs (beyond the GUSTO trial) are unpredictable. Although both major papers[43.30] assessing the GUSTO trial pro­duced similar results, opposing views have still been published.l51 ,52] In a very simple analysis, one group has estimated the cost of each life saved at I year of follow-up to be $US260 000. [52] There are no benchmarks for this type of analysis, making comparisons with other treatments difficult.

6. Conclusion

With competing demand for healthcare re­sources, it is important that assessments are made to calculate the cost effectiveness of different ther­apies in the treatment of acute MI. Ideally, these should be done prospectively in a well controlled study. However, it should be noted that clinical tri­als enrol patients who often have a lower mortality than expected in a general population and, there­fore, the benefits of a therapy may be underesti-

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Ramanathan et al.

mated. Conversely, a clinical trial may not enrol patients with comorbidity and thus may underesti­mate the adverse effects of a therapy if it were given routinely in a community hospital. Also, cost structures vary in different communities, and the practice of medicine, including indications, thresh­old for interventions, duration of hospital stay and readmission rates, differ widely.

Although there are many uncertainties and as­sumptions in the cost-effectiveness models for the treatment of elderly patients with an MI, acceler­ated alteplase appears to be cost effective.

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Correspondence and reprints: Dr Harvey White, Cardiology Department, Green Lane Hospital, Auckland, New Zea­land.

Drugs & Aging 1996 Apr; 8 (4)