Drugs & Aging 2 (6): 461-468, 1992 1170-229X/92/0011-0461/$04.00/0 © Adis International Limited. All rights reserved. DRA1137
Should Older Patients with Acute Myocardial Infarction Receive Thrombolytic Therapy? Brian D. Williamson, David W.M. Muller and Eric J. Topol Division of Cardiology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan and Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
The elderly represent a group at high risk for significant morbidity and mortality from acute myocardial infarction. Three-quarters of all deaths from myocardial infarction occur in patients older than 65 years (Report of the Working Group on Arteriosclerosis of the National Heart, Lung and Blood Institute 1981). Furthermore, patients more than 60 years old have 3 to 4 times the mortality of younger patients suffering an acute myocardial infarction. As the elderly come to represent an increasingly large segment of the population, the optimal treatment for myocardial infarction in this age group will acquire an even greater significance. It has been well established that the early administration of thrombolytic agents can restore patency of the infarct-related coronary artery in a high proportion of treated patients (Topol 1989). In addition, successful thrombolysis has been shown to preserve ventricular function (Topol 1989) and to reduce mortality in a number of large clinical trials (GISSI Study Group 1986; ISIS-2 Collaborative Group 1988). The experience from clinical trials has also made it clear, however, that the decision to administer thrombolytic therapy requires a careful assessment of the benefit to risk ratio. This therapy may result in fibrinolysis of not only coronary artery thrombi, but also haemostatic plugs elsewhere in the arterial tree leading to potentially life-threatening bleeding. In particular, intracranial haemorrhage may result in serious permanent morbidity or mortality. Because of concern over
the potential for haemorrhagic complications in the elderly, many of the clinical trials evaluating thrombolytic agents have excluded this group from entry. Accordingly, thrombolytic agents have been used primarily in low risk patients, while high risk groups such as the elderly have been treated conservati vely. The poor clinical outcome of patients with myocardial infarction who are considered to be ineligible for thrombolytic therapy was recently highlighted in a study by Cragg and colleagues (1991). Of 1471 patients treated in a large communitybased hospital, 16% (230 patients) received thrombolytic therapy according to protocol. Another 7% (97 patients) received nonprotocol therapy (primarily balloon angioplasty) to restore vessel patency, and the remaining 78% (1144 patients) were treated conventionally without reperfusion therapy. The patients who did not receive thrombolytic therapy were older, were more likely to have a previous history of myocardial infarction, and had a mortality nearly 5 times that of those receiving thrombolytic therapy (19 vs 4% mortality). The mortality of those more than 76 years of age was 28%. Age greater than 76 years, stroke or bleeding risk, and 2 or more exclusion criteria were independent predictors for increased mortality (fig. 1). These data suggest that the elderly are at particularly high risk following myocardial infarction and that these patients may therefore have the most to
Drugs & Aging 2 (6) 1992
462
0" " ' - - Treated ECG Inei 9,ble No. of pts: 163
323
Contra· Too late Too old Other IIldJCalion (> 4h) (age > 76y)
99
186
324
111
Fig. 1. Mortality rates for patients treated with intravenous alteplase (tissue plasminogen activator; rtPA) and for those excluded from treatment in one study; ECG = electrocardiogram. [Adapted from Cragg et al. (1991) and reprinted from Muller & Topol (1990) with permission from the American College of Physicians.]
gain from an aggressive approach to myocardial reperfusion.
1. Risk of Haemorrhage from Thrombolytic Therapy The principal hazard of thrombolytic therapy in the elderly is life-threatening bleeding. The definition of major haemorrhagic events has varied among the clinical thrombolytic studies. In the Thrombolysis in Myocardial Infarction (TIMI) trials, major haemorrhagic events were defined as a decrease in haemoglobin greater than 50 giL (or more than 15% drop in haematocrit), pericardial bleeding resulting in cardiac tamponade or any intracranial bleeding (Bovill et al. 1991; Rao et al. 1988). In phase II of the TIMI trial (1989), 3339 patients aged less than 76 years received 150mg (n = 520) or 100mg (n = 2819) intravenous alteplase (tissue plasminogen activator; rtPA) within 4 hours of the onset of symptoms of acute myocardial infarction. Each patient was also treated with immediate systemic heparin, which was continued to achieve a partial thromboplastin time of 1.5 to 2 times control for 5 days, and then 10 OOOU twice daily subcutaneously until hospital discharge at 8 to 10 days. After admission, patients were then also
randomly assigned to either an invasive interventional strategy, consisting of cardiac catheterisation between 18 and 48 hours after the administration of thrombolytic therapy, or to a conservative strategy of coronary angiography prior to hospital discharge only if myocardial ischaemia recurred spontaneously or was inducible by exercise stress testing. Haemorrhagic events occurred more frequently in patients assigned to the invasive group (18.5 vs 12.8%, p < 0.001) and correlated with the extent of fibrinogen breakdown, peak alteplase concentrations, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70kg or less, female gender and signs of cardiac decompensation. Patient age was associated with the frequency of haemorrhagic events in patients assigned to the invasive group but not in patients treated conservatively (Bovill et al. 1991). Several other studies have examined the relationship between age and risk of haemorrhagic complications from thrombolytic therapy. In a small study by Lew and others (1987), patients over the age of 75 (n = 24) had a 2-fold greater risk of major haemorrhage compared with those under the age of75 (n = 96). Four of the 5 deaths related to haemorrhage occurred in patients over the age of 75 years. In an earlier study by the TIMI investigators of 756 patients aged less than 75 years, the incidence of major haemorrhage rose with advancing age from 8.7% in those less than 65 years old, to 14.5% for those 65 to 69 years old, and to 24.7% for those between 70 and 75 years (Chaitman et al. 1989). The need for blood transfusion was also significantly higher in patients over 65 years old (fig. 2). The majority of haemorrhagic events were related to catheterisation or intravascular access sites. Other variables that impacted on the risk of bleeding were the dosing protocol, dose per bodyweight and elevated diastolic blood pressure. In contrast, Califf and others (1988) did not find age to be an independent risk factor for haemorrhagic complications after controlling for other clinical parameters. The most potentially devastating complication of thrombolytic therapy is intracranial haemor-
463
Thrombolytic Therapy for AMI
30
o No transfuSion III Transfusion
~ 20 C)
c:
'g
ill
10
o
< 65
65-69
> 69
Age (years)
Fig. 2. Incidence of major haemorrhagic events and blood transfusion in patients not undergoing cardiac surgery. The incidence of bleeding increased significantly with age (p < 0.001) [adapted from Chaitman et al. (1989)].
rhage. The risk of intracranial haemorrhage may, in part, be dose- and weight-related rather than agerelated. In the TIMI phase II trial (Bovill et al. 1991), intracranial haemorrhage occurred in 2.1 % of patients treated with 150mg alteplase and 0.5% of patients treated with a dose of 100mg alteplase (p < 0.001). All patients received a 5000U heparin bolus followed by 1000 U /h as well as daily aspirin. The 6-week mortality of the 23 patients with intracerebral haemorrhage was 47.8% (Gore et al. 1991). The Thrombolysis and Angioplasty in Myocardial Infarction (T AMI) investigators (O'Connor et al. 1990) reported an overall stroke rate of 1.8% (13 of 708 patients) in the T AMI I, II, and III trials in patients under the age of 75 years treated with alteplase (in doses ranging from a fixed dosage of 100 to 150mg to a weight-adjusted dosage of 1.5 mg/kg). Thorough neurologic evaluation, including neurologic consultation and routine use of computed topographic scanning, identified 4 haem orrhagic and 9 nonhaemorrhagic strokes. Only the occurrence of a large anterior wall myocardial infarction with depressed left ventricular function was a risk factor for nonhaemorrhagic stroke. No clinical parameter (including patient age) was predictive for haemorrhagic stroke in this relatively small study population. Interestingly, the GISSI-2/lnternational alteplase-streptokinase trial (1990) showed a higher incidence of intracranial haemorrhage in patients older than 70 years after administration of
alteplase compared with streptokinase (2.7 vs 1.6%) [fig. 3]. The subsequent third International Study of Infarct Survival (ISIS-3) trial also found a difference in the incidence of haemorrhagic stroke in the elderly between these agents (Peto 1991). Although intracranial haemorrhage is clearly associated with a very high early mortality in patients treated with thrombolytic therapy, the overall incidence of stroke (haemorrhagic and nonhaemorrhagic) does not appear to be increased (ISIS-2 Collaborative Group 1988; Wilcox et al. 1988). This is most likely because the increased risk of haemorrhagic stroke is largely offset by a decrease in the risk of thromboembolic stroke due to reduction in infarct size and a reduction in the subsequent development ofleft ventricular mural thrombi (Eigler et al. 1984). In the prethrombolytic era, a stroke rate of approximately 3% was typically observed at the time of infarction or during the hospital stay (Konrad et al. 1978; Thompson & Robinson 1978). Care must be taken in comparing the incidence of stroke in the prethrombolytic era with that observed in the thrombolytic trials, as the later trials excluded those at higher risk of stroke. It is probable, however, that thrombolytic therapy for acute myocardial infarction in the elderly reduces the risk of thromboembolic stroke, and, in addition, may possibly also reduce the risk of potentially fatal pulmonary thromboembolism.
2. Thrombolytic Therapy and Mortality Reduction While the elderly do appear to have a greater risk of adverse events with reperfusion therapy, they also clearly represent a high risk group if managed conservatively. In the study by Weaver and colleagues (1991), 31 % of patients over age 65 developed new congestive heart failure following myocardial infarction compared with 19% of those under age 65 years (p < 0.0001). They also had a higher overall risk of stroke (independent of the use of thrombolytic therapy); 3.9% of those over the age of 75% suffered a stroke prior to hospital discharge, compared with 1.4% of those under the age of 55 years (p = 0.0004). The risk of reinfarc-
Drugs & Aging 2 (6) 1992
464
• Streptokinase ~
rtPA
Age "" 70 years
Age
~
70 years
Fig. 3. Influence of age and choice of thrombolytic agent on the overall incidence of stroke in the GISSI-2/Intemational Study (1990). rtPA = alteplase.
tion prior to discharge was also higher in the elderly, with a reinfarction rate of 5.5% in those over 75 years compared with 2.6% for those under 55 years. There was a striking rise in mortality with advancing age, with a mortality rate of 17.8% for those over 75 compared with a rate of 2% for those under the age of 55 years. Subgroup analyses in several large thrombolytic trials in which older patients were not excluded have demonstrated a considerable survival advantage for older patients who receive thrombolytic therapy. The second International Study of Infarct Survival (ISIS-2 1988) did not have an upper age limit cut off. The combination of streptokinase and aspirin reduced mortality in those over 80 years of age from 37% in the placebo group to 20% in the treated group (fig. 4). In comparison, patients under the age of 60 had a reduction in mortality from only 6 to 4%. While mortality was clearly higher in the elderly, thrombolytic therapy also appeared to have the most dramatic impact on mortality in this high risk group. A similar age-related benefit of thrombolytic therapy was apparent in the AngloScandinavian Study of Early Thrombolysis (Wilcox et al. 1988) which excluded patients over the age of 75 years. The subgroup of patients 66 to 75 years of age demonstrated the greatest reduction in mortality, from 16.4 to 10.8%, after administration of alteplase. This benefit compared favourably with that seen in patients under the age of 55 years (reduction in mortality from 4.4 to 3.8% with treatment). The results of the ISIS-3 study demonstrate a similar survival advantage for elderly patients treated with thrombolytic agents (Peto 1991).
The risk-benefit analysis would therefore appear to favour treating the elderly with thrombolytic agents. If we assume that the baseline risk of haemorrhagic stroke following myocardial infarction were doubled by the administration of thrombolytic agents from I to 2% overall, and assuming that 50% of these patients died as a result (Gore et al. 1991), then administering thrombolytic agents to 1000 elderly patients would result in 5 additional deaths per 1000 patients treated. In the ISIS-2 (1988) trial those patients over 80 years of age treated with thrombolytic agents had a 20% 5-week mortality compared with a 37% mortality in the untreated patients, or a mortality reduction of 170 lives saved per 1000 patients treated. Even if the mortality from intracranial haemorrhage were actually 2 or 3 times the figure of 5 per 1000 patients, it is clear that more than 150 lives could be saved per 1000 patients treated by the administration of thrombolytic agents in spite of a small increased mortality secondary to haemorrhagic stroke.
3. Limitations in the Elderly Although age in itself does not appear to be a contraindication to thrombolysis, the routine use of fibrinolytic therapy in the elderly is complicated by the frequent presence of other factors that may exclude them from treatment. For example, several clinical trials have established that the greatest benefit from thrombolytic agents occurs from administration early after the onset of symptoms. It has been observed, however, that the elderly are more likely to present late after symptom onset. Wea ver and colleagues (1991) examined the effect of age on the use of thrombolytic therapy and on the mortality of acute myocardial infarction in 3256 consecutive patients admitted to one of 19 hospitals in the Seattle area during 1988 and early 1989. These investigators found that while 29% of patients under the age of75 received thrombolytic therapy, only 5% of patients older than 75 years received this treatment. There was a statistically significant increase with advancing age in the average delay from the onset on symptoms until the time of presentation to the hospital. Whereas patients under
465
Thrombolytic Therapy for AMI
Inlemalional rtPA/$K Irial
1515-2
25
o
rtPA
~
SK
.~
0; 1:
o 1
~
n: 3438 3448 ~
854
70 Age (years)
23792388 > 70
n: 7983 7996
852
> 70
~
70
Age (years)
Fig. 4. Mortality of patients treated in the ISIS-2 and International Alteplase (rtPA)fStreptokinase (SK) Studies according to age and choice ofthrombolytic agent. Five-week vascular mortality increased substantially with age but the impact of thrombolytic therapy on mortality was greatest in the oldest patients. [Data adapted frolll ISIS-2 Collaborative Study (1988) and International Study (1990).]
the age of 55 presented after an average of 4.1 hours after symptom onset, this increased to 5.2 hours for patients aged 55 to 64 years, 5.1 hours for those aged 65 to 74, and 6.1 hours (or patients over 75 years (fig. 5). A total of 24% of patients over the age of 75 years presented more than 6 hours after the onset of symptoms. The elderly are also more likely to have an atypical electrocardiogram (ECG) at the time of presentation. In the study of Weaver and colleagues (1991), 63% of a random subset of patients with acute myocardial infarction had typical ST segment elevation, while only 54% of patients over the age of 75 years had ST elevation (p < 0.05). Kudenchuk and colleagues (1991) found that even after accounting for previous myocardial infarction, the elderly were still more likely to present with an atypical ECG; there is also evidence that the elderly are more likely to present with non-Q wave myocardial infarction (Goldberg et al. 1989). The elderly are less likely than younger patients to present with symptoms typical of myocardial infarction. In the study of Weaver and colleagues (1991), 24% of those with myocardial infarction who were under the age of 55 years did not have chest discomfort, while 41 % of those over 75 years did not have chest pain (p < 0.0001). In addition,
in this siudy the elderly were more likely to be excluded from thrombolytic therapy because of an increased bleeding risk due to factors other than advanced age (present in 28% of those over the age of75 years compared with 21 % for those under the age of 55; p = 0.02). Figure 6 demonstrates the striking fall with age of the percentage of patients considered suitable for thrombolytic therapy based on present criteria. Overall, while 52% of those patients with acute infarction under the age of 55 years were potentially eligible for thrombolytic
8
Should Older Patients with Acute Myocardial Infarction Receive Thrombolytic Therapy? Brian D. Williamson, David W.M. Muller and Eric J. Topol Division of Cardiology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan and Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
The elderly represent a group at high risk for significant morbidity and mortality from acute myocardial infarction. Three-quarters of all deaths from myocardial infarction occur in patients older than 65 years (Report of the Working Group on Arteriosclerosis of the National Heart, Lung and Blood Institute 1981). Furthermore, patients more than 60 years old have 3 to 4 times the mortality of younger patients suffering an acute myocardial infarction. As the elderly come to represent an increasingly large segment of the population, the optimal treatment for myocardial infarction in this age group will acquire an even greater significance. It has been well established that the early administration of thrombolytic agents can restore patency of the infarct-related coronary artery in a high proportion of treated patients (Topol 1989). In addition, successful thrombolysis has been shown to preserve ventricular function (Topol 1989) and to reduce mortality in a number of large clinical trials (GISSI Study Group 1986; ISIS-2 Collaborative Group 1988). The experience from clinical trials has also made it clear, however, that the decision to administer thrombolytic therapy requires a careful assessment of the benefit to risk ratio. This therapy may result in fibrinolysis of not only coronary artery thrombi, but also haemostatic plugs elsewhere in the arterial tree leading to potentially life-threatening bleeding. In particular, intracranial haemorrhage may result in serious permanent morbidity or mortality. Because of concern over
the potential for haemorrhagic complications in the elderly, many of the clinical trials evaluating thrombolytic agents have excluded this group from entry. Accordingly, thrombolytic agents have been used primarily in low risk patients, while high risk groups such as the elderly have been treated conservati vely. The poor clinical outcome of patients with myocardial infarction who are considered to be ineligible for thrombolytic therapy was recently highlighted in a study by Cragg and colleagues (1991). Of 1471 patients treated in a large communitybased hospital, 16% (230 patients) received thrombolytic therapy according to protocol. Another 7% (97 patients) received nonprotocol therapy (primarily balloon angioplasty) to restore vessel patency, and the remaining 78% (1144 patients) were treated conventionally without reperfusion therapy. The patients who did not receive thrombolytic therapy were older, were more likely to have a previous history of myocardial infarction, and had a mortality nearly 5 times that of those receiving thrombolytic therapy (19 vs 4% mortality). The mortality of those more than 76 years of age was 28%. Age greater than 76 years, stroke or bleeding risk, and 2 or more exclusion criteria were independent predictors for increased mortality (fig. 1). These data suggest that the elderly are at particularly high risk following myocardial infarction and that these patients may therefore have the most to
Drugs & Aging 2 (6) 1992
462
0" " ' - - Treated ECG Inei 9,ble No. of pts: 163
323
Contra· Too late Too old Other IIldJCalion (> 4h) (age > 76y)
99
186
324
111
Fig. 1. Mortality rates for patients treated with intravenous alteplase (tissue plasminogen activator; rtPA) and for those excluded from treatment in one study; ECG = electrocardiogram. [Adapted from Cragg et al. (1991) and reprinted from Muller & Topol (1990) with permission from the American College of Physicians.]
gain from an aggressive approach to myocardial reperfusion.
1. Risk of Haemorrhage from Thrombolytic Therapy The principal hazard of thrombolytic therapy in the elderly is life-threatening bleeding. The definition of major haemorrhagic events has varied among the clinical thrombolytic studies. In the Thrombolysis in Myocardial Infarction (TIMI) trials, major haemorrhagic events were defined as a decrease in haemoglobin greater than 50 giL (or more than 15% drop in haematocrit), pericardial bleeding resulting in cardiac tamponade or any intracranial bleeding (Bovill et al. 1991; Rao et al. 1988). In phase II of the TIMI trial (1989), 3339 patients aged less than 76 years received 150mg (n = 520) or 100mg (n = 2819) intravenous alteplase (tissue plasminogen activator; rtPA) within 4 hours of the onset of symptoms of acute myocardial infarction. Each patient was also treated with immediate systemic heparin, which was continued to achieve a partial thromboplastin time of 1.5 to 2 times control for 5 days, and then 10 OOOU twice daily subcutaneously until hospital discharge at 8 to 10 days. After admission, patients were then also
randomly assigned to either an invasive interventional strategy, consisting of cardiac catheterisation between 18 and 48 hours after the administration of thrombolytic therapy, or to a conservative strategy of coronary angiography prior to hospital discharge only if myocardial ischaemia recurred spontaneously or was inducible by exercise stress testing. Haemorrhagic events occurred more frequently in patients assigned to the invasive group (18.5 vs 12.8%, p < 0.001) and correlated with the extent of fibrinogen breakdown, peak alteplase concentrations, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70kg or less, female gender and signs of cardiac decompensation. Patient age was associated with the frequency of haemorrhagic events in patients assigned to the invasive group but not in patients treated conservatively (Bovill et al. 1991). Several other studies have examined the relationship between age and risk of haemorrhagic complications from thrombolytic therapy. In a small study by Lew and others (1987), patients over the age of 75 (n = 24) had a 2-fold greater risk of major haemorrhage compared with those under the age of75 (n = 96). Four of the 5 deaths related to haemorrhage occurred in patients over the age of 75 years. In an earlier study by the TIMI investigators of 756 patients aged less than 75 years, the incidence of major haemorrhage rose with advancing age from 8.7% in those less than 65 years old, to 14.5% for those 65 to 69 years old, and to 24.7% for those between 70 and 75 years (Chaitman et al. 1989). The need for blood transfusion was also significantly higher in patients over 65 years old (fig. 2). The majority of haemorrhagic events were related to catheterisation or intravascular access sites. Other variables that impacted on the risk of bleeding were the dosing protocol, dose per bodyweight and elevated diastolic blood pressure. In contrast, Califf and others (1988) did not find age to be an independent risk factor for haemorrhagic complications after controlling for other clinical parameters. The most potentially devastating complication of thrombolytic therapy is intracranial haemor-
463
Thrombolytic Therapy for AMI
30
o No transfuSion III Transfusion
~ 20 C)
c:
'g
ill
10
o
< 65
65-69
> 69
Age (years)
Fig. 2. Incidence of major haemorrhagic events and blood transfusion in patients not undergoing cardiac surgery. The incidence of bleeding increased significantly with age (p < 0.001) [adapted from Chaitman et al. (1989)].
rhage. The risk of intracranial haemorrhage may, in part, be dose- and weight-related rather than agerelated. In the TIMI phase II trial (Bovill et al. 1991), intracranial haemorrhage occurred in 2.1 % of patients treated with 150mg alteplase and 0.5% of patients treated with a dose of 100mg alteplase (p < 0.001). All patients received a 5000U heparin bolus followed by 1000 U /h as well as daily aspirin. The 6-week mortality of the 23 patients with intracerebral haemorrhage was 47.8% (Gore et al. 1991). The Thrombolysis and Angioplasty in Myocardial Infarction (T AMI) investigators (O'Connor et al. 1990) reported an overall stroke rate of 1.8% (13 of 708 patients) in the T AMI I, II, and III trials in patients under the age of 75 years treated with alteplase (in doses ranging from a fixed dosage of 100 to 150mg to a weight-adjusted dosage of 1.5 mg/kg). Thorough neurologic evaluation, including neurologic consultation and routine use of computed topographic scanning, identified 4 haem orrhagic and 9 nonhaemorrhagic strokes. Only the occurrence of a large anterior wall myocardial infarction with depressed left ventricular function was a risk factor for nonhaemorrhagic stroke. No clinical parameter (including patient age) was predictive for haemorrhagic stroke in this relatively small study population. Interestingly, the GISSI-2/lnternational alteplase-streptokinase trial (1990) showed a higher incidence of intracranial haemorrhage in patients older than 70 years after administration of
alteplase compared with streptokinase (2.7 vs 1.6%) [fig. 3]. The subsequent third International Study of Infarct Survival (ISIS-3) trial also found a difference in the incidence of haemorrhagic stroke in the elderly between these agents (Peto 1991). Although intracranial haemorrhage is clearly associated with a very high early mortality in patients treated with thrombolytic therapy, the overall incidence of stroke (haemorrhagic and nonhaemorrhagic) does not appear to be increased (ISIS-2 Collaborative Group 1988; Wilcox et al. 1988). This is most likely because the increased risk of haemorrhagic stroke is largely offset by a decrease in the risk of thromboembolic stroke due to reduction in infarct size and a reduction in the subsequent development ofleft ventricular mural thrombi (Eigler et al. 1984). In the prethrombolytic era, a stroke rate of approximately 3% was typically observed at the time of infarction or during the hospital stay (Konrad et al. 1978; Thompson & Robinson 1978). Care must be taken in comparing the incidence of stroke in the prethrombolytic era with that observed in the thrombolytic trials, as the later trials excluded those at higher risk of stroke. It is probable, however, that thrombolytic therapy for acute myocardial infarction in the elderly reduces the risk of thromboembolic stroke, and, in addition, may possibly also reduce the risk of potentially fatal pulmonary thromboembolism.
2. Thrombolytic Therapy and Mortality Reduction While the elderly do appear to have a greater risk of adverse events with reperfusion therapy, they also clearly represent a high risk group if managed conservatively. In the study by Weaver and colleagues (1991), 31 % of patients over age 65 developed new congestive heart failure following myocardial infarction compared with 19% of those under age 65 years (p < 0.0001). They also had a higher overall risk of stroke (independent of the use of thrombolytic therapy); 3.9% of those over the age of 75% suffered a stroke prior to hospital discharge, compared with 1.4% of those under the age of 55 years (p = 0.0004). The risk of reinfarc-
Drugs & Aging 2 (6) 1992
464
• Streptokinase ~
rtPA
Age "" 70 years
Age
~
70 years
Fig. 3. Influence of age and choice of thrombolytic agent on the overall incidence of stroke in the GISSI-2/Intemational Study (1990). rtPA = alteplase.
tion prior to discharge was also higher in the elderly, with a reinfarction rate of 5.5% in those over 75 years compared with 2.6% for those under 55 years. There was a striking rise in mortality with advancing age, with a mortality rate of 17.8% for those over 75 compared with a rate of 2% for those under the age of 55 years. Subgroup analyses in several large thrombolytic trials in which older patients were not excluded have demonstrated a considerable survival advantage for older patients who receive thrombolytic therapy. The second International Study of Infarct Survival (ISIS-2 1988) did not have an upper age limit cut off. The combination of streptokinase and aspirin reduced mortality in those over 80 years of age from 37% in the placebo group to 20% in the treated group (fig. 4). In comparison, patients under the age of 60 had a reduction in mortality from only 6 to 4%. While mortality was clearly higher in the elderly, thrombolytic therapy also appeared to have the most dramatic impact on mortality in this high risk group. A similar age-related benefit of thrombolytic therapy was apparent in the AngloScandinavian Study of Early Thrombolysis (Wilcox et al. 1988) which excluded patients over the age of 75 years. The subgroup of patients 66 to 75 years of age demonstrated the greatest reduction in mortality, from 16.4 to 10.8%, after administration of alteplase. This benefit compared favourably with that seen in patients under the age of 55 years (reduction in mortality from 4.4 to 3.8% with treatment). The results of the ISIS-3 study demonstrate a similar survival advantage for elderly patients treated with thrombolytic agents (Peto 1991).
The risk-benefit analysis would therefore appear to favour treating the elderly with thrombolytic agents. If we assume that the baseline risk of haemorrhagic stroke following myocardial infarction were doubled by the administration of thrombolytic agents from I to 2% overall, and assuming that 50% of these patients died as a result (Gore et al. 1991), then administering thrombolytic agents to 1000 elderly patients would result in 5 additional deaths per 1000 patients treated. In the ISIS-2 (1988) trial those patients over 80 years of age treated with thrombolytic agents had a 20% 5-week mortality compared with a 37% mortality in the untreated patients, or a mortality reduction of 170 lives saved per 1000 patients treated. Even if the mortality from intracranial haemorrhage were actually 2 or 3 times the figure of 5 per 1000 patients, it is clear that more than 150 lives could be saved per 1000 patients treated by the administration of thrombolytic agents in spite of a small increased mortality secondary to haemorrhagic stroke.
3. Limitations in the Elderly Although age in itself does not appear to be a contraindication to thrombolysis, the routine use of fibrinolytic therapy in the elderly is complicated by the frequent presence of other factors that may exclude them from treatment. For example, several clinical trials have established that the greatest benefit from thrombolytic agents occurs from administration early after the onset of symptoms. It has been observed, however, that the elderly are more likely to present late after symptom onset. Wea ver and colleagues (1991) examined the effect of age on the use of thrombolytic therapy and on the mortality of acute myocardial infarction in 3256 consecutive patients admitted to one of 19 hospitals in the Seattle area during 1988 and early 1989. These investigators found that while 29% of patients under the age of75 received thrombolytic therapy, only 5% of patients older than 75 years received this treatment. There was a statistically significant increase with advancing age in the average delay from the onset on symptoms until the time of presentation to the hospital. Whereas patients under
465
Thrombolytic Therapy for AMI
Inlemalional rtPA/$K Irial
1515-2
25
o
rtPA
~
SK
.~
0; 1:
o 1
~
n: 3438 3448 ~
854
70 Age (years)
23792388 > 70
n: 7983 7996
852
> 70
~
70
Age (years)
Fig. 4. Mortality of patients treated in the ISIS-2 and International Alteplase (rtPA)fStreptokinase (SK) Studies according to age and choice ofthrombolytic agent. Five-week vascular mortality increased substantially with age but the impact of thrombolytic therapy on mortality was greatest in the oldest patients. [Data adapted frolll ISIS-2 Collaborative Study (1988) and International Study (1990).]
the age of 55 presented after an average of 4.1 hours after symptom onset, this increased to 5.2 hours for patients aged 55 to 64 years, 5.1 hours for those aged 65 to 74, and 6.1 hours (or patients over 75 years (fig. 5). A total of 24% of patients over the age of 75 years presented more than 6 hours after the onset of symptoms. The elderly are also more likely to have an atypical electrocardiogram (ECG) at the time of presentation. In the study of Weaver and colleagues (1991), 63% of a random subset of patients with acute myocardial infarction had typical ST segment elevation, while only 54% of patients over the age of 75 years had ST elevation (p < 0.05). Kudenchuk and colleagues (1991) found that even after accounting for previous myocardial infarction, the elderly were still more likely to present with an atypical ECG; there is also evidence that the elderly are more likely to present with non-Q wave myocardial infarction (Goldberg et al. 1989). The elderly are less likely than younger patients to present with symptoms typical of myocardial infarction. In the study of Weaver and colleagues (1991), 24% of those with myocardial infarction who were under the age of 55 years did not have chest discomfort, while 41 % of those over 75 years did not have chest pain (p < 0.0001). In addition,
in this siudy the elderly were more likely to be excluded from thrombolytic therapy because of an increased bleeding risk due to factors other than advanced age (present in 28% of those over the age of75 years compared with 21 % for those under the age of 55; p = 0.02). Figure 6 demonstrates the striking fall with age of the percentage of patients considered suitable for thrombolytic therapy based on present criteria. Overall, while 52% of those patients with acute infarction under the age of 55 years were potentially eligible for thrombolytic
8
