-
REVIEW
Management of Acute Myocardial Infarction in the Very Elderly DANIELE. FORMAN,M.D., Josh LUISGUTIERREZBERNAL,M.D., JEANNEY.WEI, M.D., Ph.D., Boston, Massachusetts
Coronary artery disease is highly prevalent among the elderly, and the incidence of myocardial infarction (Ml) is high. Still, the notion of optimal treatment for the elderly patient with MI remains unclear. !I%is review will first discuss some of the characteristics of the aging myocardium that impact on the care of elderly cardiac patients. Next, the therapeutic options and their appropriateness for the aged patient are presented. Thrombolytic and &blocker therapies are reviewed extensively since they remain among the controversial issue43in geriatric cardiology. Other well-known as well as experimental therapies are also discussed.
From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Hospital, Department of Medicine, Beth Israel Hospital and Harvard Medical School (DEF. JLGB. JYW); and the Geriatric Research Education and Clinical Center West Roxbury/Brockton Veterans Affairs Medical Center (JYW). Boston, Massachusetts. Requestsforreprintsshould beaddressedtoJeanneY. Wei. M.D., Beth Israel Hospital, Department of Medicine, 330 Brookline Avenue, Boston, Massachusetts 02215. Manuscript submitted June 28, 1991, and accepted in revised form April 10, 1992.
A
n increasing proportion of the American population is reaching advanced age. In 1985, there were 28.6 million persons aged 65 years or older (11.9% of the population). By 2030, it is predicted that there will be 34.9 million persons 65 years or older (21.1% of the population) [l]. The proportion of those 80 years or older is the most rapidly expanding subgroup [2]. The implications for the prevalence of cardiovascular disease are enormous. A postmortem study in community-dwelling very elderly persons (over 90 years) found one or more major atherosclerotic occlusions in at least one coronary artery in 70% of subjects [3]. Moreover, approximately 40% of all octogenarians have symptomatic cardiovascular disease [ 11. Despite an overall decline in cardiovascular disease mortality, heart disease remains a common and serious medical problem for the elderly. In fact, age is an independent risk factor for cardiac death [4-6]; adults 65 years or older constitute only about 12% of the population, but 80% of all deaths due to acute myocardial infarction (MI) occur in persons 65 years or older, and 60% of MI deaths occur in patients 75 years or older [7]. Whereas the therapeutic approach to young adult patients with acute MI has evolved to rapid interventional therapy, clinicians are sometimes reluctant to use a similar tact for their elderly patients. To an extent, this is counter-intuitive since the prognosis for elderly cardiac patients is worse than for young adults. The in-hospital case-fatality rate for initial acute MI increases from 5% in patients aged less than 55 years to 32% in those greater than 75 years [6]. In absolute terms, the elderly may derive greater benefit from aggressive therapy than younger adults for whom the underlying cardiac disease and prognosis are often less devastating [a].
RELEVANTAGEmRELATED CHANGESIN THE MYOCARDIUM A constellation of age-related changes in the senescent heart impact on the management of MI. This complex topic is reviewed extensively in the medical literature [l], and only several salient points will be included here. Macroscopically, only a modest increase in left ventricular wall thickness occurs with aging in
September 1992 The American Journal of Medicine
Volume 93
315
healthy, elderly adults as compared with younger individuals, but certain functional changes distinguish the elderly heart. Maximal heart rate attained during physical exercise or in response to other physiologic stimuli declines with age [9]. Early diastolic ventricular filling diminishes with age such that by age 70 years, it is half of that observed at age 30 years [lo]. Opposition to left ventricular ejection (afterload) rises with age, as the ascending aorta becomes stiffer and the cross-sectional area of the peripheral vascular bed is reduced [ll]. Intrinsic muscle performance shows preservation of contractile strength but significant prolongation of the relaxation process with age, even in the absence of hypertrophy [12,13]. Thus, the aged heart has decreased maximal as well as submaximal heart rate responses and impaired diastolic performance with prolonged relaxation. Moreover, the age-associated increases in vessel wall stiffness and lumen radius render the elderly more susceptible to modest changes in plasma volume [13]. These age-related anatomic and physiologic changes may predispose the heart to impaired diastolic relaxation, resulting in higher end-diastolic filling pressures and reduced endocardial perfusion. The resulting ischemia additionally compromises myocardial distensibility, exacerbating ventricular filling abnormalities [l]. Moreover, since the inelastic aged myocardium becomes increasingly dependent on preload filling, especially during ischemic stresses, medications that substantially reduce preload may be particularly destabilizing [U-16]. Although the Baltimore Longitudinal Study reported that cardiac output can be preserved in some older individuals through augmentation of stroke volume [17], the subjects in this cross-sectional study were not typical of the general population at large because all subjects with cardiac disease and comorbidity were excluded. More commonly, recent studies have shown that stroke volume tends to be reduced in elderly persons above age 80 years compared with younger adults [1,18]. The combined effects of delayed cardiac filling and increased afterload are compounded by coronary artery disease, valve disease, and other issues that lessen the ability to augment stroke volume. Atherosclerotic coronary lesions tend to become more diffuse and calcified with advancing age. Elderly patients are more likely to have multivessel disease [19,20]. There is also an apparent change in vascular reactivity; animal studies have shown that, in contrast to young adults, aged rate show a failure of the coronary bed to dilate commensurate with oxygen demands, compounding the predisposition to ischemia [21]. 316
September 1992 The American Journal of Medicine
PATHOPHYSIOLOGY OF ACUTE MYOCARDIAL INFARCTION Several elemental points of the pathophysiology of acute MI are relevant for our discussion of management issues. Most commonly, transmural or Qwave MI is triggered by sudden and sustained coronary artery occlusion. at the site of a pre-existing atherosclerotic plaque, thereby inducing rapid myocardial necrosis [22,23]. Studies to date have not shown substantial differences between the actual lesions in young and elderly cardiac patients, but the high prevalence of atherosclerotic disease among the elderly particularly predisposes them to such vessel occlusion [l]. Similarly, the pathophysiology of non-Q-wave infarction is thought to involve thrombotic occlusions, at least transiently, at sites of atherosclerotic plaque damage [23]. Moreover, factors predisposing to hemodynamic instability tend to be more common in the elderly and result in imbalances between myocardial oxygen supply and demand that may contribute to the higher incidence of non-Q-wave infarctions among the elderly [24]. Intrinsic changes in vessel distensibility, valve disease, arrhythmias, and autonomic dysfunction are all potential hemodynamically destabilizing characteristics that are common in the elderly and that tend to impair cardiac flow reserve. Infarct size is a major determinant of left ventricular function, and left ventricular function is a key determinant of postinfarct survival [25]. Coronary vessel occlusion, myocardial oxygen demands, hemodynamic stresses, and free radical formation all impact on infarct size. Coronary occlusion occurs not only from underlying atherosclerotic plaque, but also from acute changes in the vasculature and chemical milieu that induce platelet aggregation and clot formation [24]. Moreover, myocardial injury from hypoxic stress may be exacerbated by neurohumoral responses: catecholamines increase oxygen demand, and increased afterload secondary to release of angiotensin and/or other vasoconstrictors may contribute to postinfarct remodeling [26]. Reperfusion is also associated with myocardial damage, and studies are under way to clarify the possible related role of free radical formation [27]. Therapeutic goals for MI include restoration of blood flow and oxygen supply to the ischemic myocardium and reducing the need for oxygen by the ischemic myocardium [28]. Thrombolytic therapy and mechanical revascularization are well-known modalities to restore and maximize myocardial perfusion. /3 Blockers and calcium channel blockers tend to blunt myocardial oxygen needs. Other modalities such as anticoagulation and antiplatelet agents are useful adjuncts to prevent reinfarction or other sequelae. Angiotensin converting enzyme
Volume 93
ACUTE MYOCARDIAL
INFARCTION
IN THE VERY ELDERLY
/ FORMAN
ET AL
TABLE I Thrombolytic Therapy: Short-Term Efficacy
Streitt;rse
~65~ 66-75 >75v ISAM
y ’
t70y 70-75 ISIS-2 7oy >8Oy
y y
Pooled totals Younger Older
11,709 7,608 2,886 1.215
5.7 16.6 28.9
7.7 18.1 33.1
-2.0 -1.5 -4.2
-26.0 -8.3 -12.7
5.1 13.0
6.6 9.6
-1.5 f3.4
-22.7 +35.4
i:
4.2 10.6 18.2 20.1
5.8 14.4 21.6 34.2
-1.6 -3.8 -3.4 -14.1
-27.6 -26.4 -15.7 -41.2
0.001 < 0.0001 0.02 0.002
5.4 10.9
6.3 16.4
-5.5
-14.3 -33.5
0%
4.0 9.9
6.1 21.3
-2.1 -11.4
-34.4 -53.5
oNosoo7
6.2 17.2
8.4 20.7
-2.2 -3.5
-25.7 -16.9
1,454 287 17,187 7,720 6,056 3,411 401 5,031
y
APSAC AIMS
t60y 60-70
Active
Difference
% Change
p Value
0.0005 Ii:
1;741
ASSET
~65~ 66-75
Mortality1%) Control
No.
3,352 1,679
-0.9
1,257
v
751 506 36,925
26,941 9,984
< 0.0001 < 0.0001
SSI-1 = Gruppo ltaliano per lo Studrodella Streptcchinasi nell’lnfarto Miocardrco; NS = not significant; ISAM = Intravenous Streptokinase in Acute Myccardial Infarction; ISIS-2 = Second International rdy of Infarct Survival; r&PA = recombinant tissue plasminogenactivator; ASSET= Anglo-ScandinavianStudy of Early Thrombosis; APSAC = anisoylated plasminogenstreptokinase acbvator complex; WS = APSACintervention Mortality Study.
(ACE) inhibitors are thought remodeling [26].
to reduce postinfarct
THERAPY Thrombolytics Chemical thrombolysis has been shown to be effective in recanalizing infarct-related coronary arteries, salvaging ischemic myocardium, preserving ventricular function, and reducing mortality from acute MI [25]. Peripheral thrombolytic therapy has become standard therapy in many patients with suspected transmural infarction, particularly those presenting within 6 hours of the onset of MI
P31.
Not only are the elderly more susceptible to nonQ-wave infarcts for which benefits of thrombolytic therapy are less clear, but the atypical presentations of MI among the elderly often delay the onset of treatment beyond the critical window of maximal thrombolytic efficacy [29]. Even beyond these confounding issues, hemorrhagic sequelae, especially intracerebral hemorrhage, are a concern in treating aged patients with thrombolysis [30-341. Some clinicians believe that concerns about potential hemorrhage outweigh the therapeutic benefita of thrombolysis for the elderly. One study showed a two-fold increase in hemorrhagic compliSaptember
cations, including four of five total hemorrhagic deaths, among elderly people treated with thrombolysis [30]. Similarly, data from the Thrombolysis in Myocardial Infarction (TIMI) Trial showed a higher incidence of hemorrhage in elderly subjects, including fatal intracerebral hemorrhage [33]. In the recent International Study Group Trial, patients older than 70 years had increased intracerebral hemorrhaging relative to the young [34]. It is important to keep in mind, however, that age does not seem to be a good sole criterion by which to judge risk from thrombolysis [35]. Although one study correlated increased hemorrhage to gender, hypertension, and diabetes mellitus, it did not actually isolate age from these other variables [30]. Similarly, reanalysis of the TIM1 data showed that most bleeding occurred at the catheterization site or from other puncture wounds and did not reflect an innate predisposition to hemorrhaging among the elderly [36]. Moreover, hemorrhaging in TIM1 subjects decreased when the lytic doses were reduced [33,37]. Unfortunately, there are no placebo-controlled thrombolysis trials in the elderly to contrast the overall morbidity and mortality in those treated with thrombolysis to those treated conservatively. Tables I and II refer to several well-known, randomized, placebo-controlled mortality trials of lytic 1992
The American
Journal
of Medicine
Volume
93
317
TABLE II Thrombolytic Therapy: Long-Term Efficacy No. Streptokinase GISSI-1 (12-mo F/U) 565~ 66-75~ >75y
Mortality(96) Control
Active
Difference
%Change
p Value
11,696 7,603 2,881 1,212
9.8 26.0 43.1
12.1 25.6 46.1
-2.3 to.4 -3.0
-19.0 t1.6 -6.5
&PA ASSET(6-moF/U) ~65~ 66-75~
5,031 3,352 1,679
1:::
9.1 20.9
-1.2 -5.5
-13.6 -26.3
o.oNo4
APSAC AIMS
1,257 7.5 16.3
11.1 28.0
-3.6 -11.7
-32.4 -41.8
o.oNos2
11.2 28.6
-2.0 -3.0
-18.1 -10.3
0.0003 0.009
(
REVIEW
Management of Acute Myocardial Infarction in the Very Elderly DANIELE. FORMAN,M.D., Josh LUISGUTIERREZBERNAL,M.D., JEANNEY.WEI, M.D., Ph.D., Boston, Massachusetts
Coronary artery disease is highly prevalent among the elderly, and the incidence of myocardial infarction (Ml) is high. Still, the notion of optimal treatment for the elderly patient with MI remains unclear. !I%is review will first discuss some of the characteristics of the aging myocardium that impact on the care of elderly cardiac patients. Next, the therapeutic options and their appropriateness for the aged patient are presented. Thrombolytic and &blocker therapies are reviewed extensively since they remain among the controversial issue43in geriatric cardiology. Other well-known as well as experimental therapies are also discussed.
From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory of Beth Israel Hospital, Department of Medicine, Beth Israel Hospital and Harvard Medical School (DEF. JLGB. JYW); and the Geriatric Research Education and Clinical Center West Roxbury/Brockton Veterans Affairs Medical Center (JYW). Boston, Massachusetts. Requestsforreprintsshould beaddressedtoJeanneY. Wei. M.D., Beth Israel Hospital, Department of Medicine, 330 Brookline Avenue, Boston, Massachusetts 02215. Manuscript submitted June 28, 1991, and accepted in revised form April 10, 1992.
A
n increasing proportion of the American population is reaching advanced age. In 1985, there were 28.6 million persons aged 65 years or older (11.9% of the population). By 2030, it is predicted that there will be 34.9 million persons 65 years or older (21.1% of the population) [l]. The proportion of those 80 years or older is the most rapidly expanding subgroup [2]. The implications for the prevalence of cardiovascular disease are enormous. A postmortem study in community-dwelling very elderly persons (over 90 years) found one or more major atherosclerotic occlusions in at least one coronary artery in 70% of subjects [3]. Moreover, approximately 40% of all octogenarians have symptomatic cardiovascular disease [ 11. Despite an overall decline in cardiovascular disease mortality, heart disease remains a common and serious medical problem for the elderly. In fact, age is an independent risk factor for cardiac death [4-6]; adults 65 years or older constitute only about 12% of the population, but 80% of all deaths due to acute myocardial infarction (MI) occur in persons 65 years or older, and 60% of MI deaths occur in patients 75 years or older [7]. Whereas the therapeutic approach to young adult patients with acute MI has evolved to rapid interventional therapy, clinicians are sometimes reluctant to use a similar tact for their elderly patients. To an extent, this is counter-intuitive since the prognosis for elderly cardiac patients is worse than for young adults. The in-hospital case-fatality rate for initial acute MI increases from 5% in patients aged less than 55 years to 32% in those greater than 75 years [6]. In absolute terms, the elderly may derive greater benefit from aggressive therapy than younger adults for whom the underlying cardiac disease and prognosis are often less devastating [a].
RELEVANTAGEmRELATED CHANGESIN THE MYOCARDIUM A constellation of age-related changes in the senescent heart impact on the management of MI. This complex topic is reviewed extensively in the medical literature [l], and only several salient points will be included here. Macroscopically, only a modest increase in left ventricular wall thickness occurs with aging in
September 1992 The American Journal of Medicine
Volume 93
315
healthy, elderly adults as compared with younger individuals, but certain functional changes distinguish the elderly heart. Maximal heart rate attained during physical exercise or in response to other physiologic stimuli declines with age [9]. Early diastolic ventricular filling diminishes with age such that by age 70 years, it is half of that observed at age 30 years [lo]. Opposition to left ventricular ejection (afterload) rises with age, as the ascending aorta becomes stiffer and the cross-sectional area of the peripheral vascular bed is reduced [ll]. Intrinsic muscle performance shows preservation of contractile strength but significant prolongation of the relaxation process with age, even in the absence of hypertrophy [12,13]. Thus, the aged heart has decreased maximal as well as submaximal heart rate responses and impaired diastolic performance with prolonged relaxation. Moreover, the age-associated increases in vessel wall stiffness and lumen radius render the elderly more susceptible to modest changes in plasma volume [13]. These age-related anatomic and physiologic changes may predispose the heart to impaired diastolic relaxation, resulting in higher end-diastolic filling pressures and reduced endocardial perfusion. The resulting ischemia additionally compromises myocardial distensibility, exacerbating ventricular filling abnormalities [l]. Moreover, since the inelastic aged myocardium becomes increasingly dependent on preload filling, especially during ischemic stresses, medications that substantially reduce preload may be particularly destabilizing [U-16]. Although the Baltimore Longitudinal Study reported that cardiac output can be preserved in some older individuals through augmentation of stroke volume [17], the subjects in this cross-sectional study were not typical of the general population at large because all subjects with cardiac disease and comorbidity were excluded. More commonly, recent studies have shown that stroke volume tends to be reduced in elderly persons above age 80 years compared with younger adults [1,18]. The combined effects of delayed cardiac filling and increased afterload are compounded by coronary artery disease, valve disease, and other issues that lessen the ability to augment stroke volume. Atherosclerotic coronary lesions tend to become more diffuse and calcified with advancing age. Elderly patients are more likely to have multivessel disease [19,20]. There is also an apparent change in vascular reactivity; animal studies have shown that, in contrast to young adults, aged rate show a failure of the coronary bed to dilate commensurate with oxygen demands, compounding the predisposition to ischemia [21]. 316
September 1992 The American Journal of Medicine
PATHOPHYSIOLOGY OF ACUTE MYOCARDIAL INFARCTION Several elemental points of the pathophysiology of acute MI are relevant for our discussion of management issues. Most commonly, transmural or Qwave MI is triggered by sudden and sustained coronary artery occlusion. at the site of a pre-existing atherosclerotic plaque, thereby inducing rapid myocardial necrosis [22,23]. Studies to date have not shown substantial differences between the actual lesions in young and elderly cardiac patients, but the high prevalence of atherosclerotic disease among the elderly particularly predisposes them to such vessel occlusion [l]. Similarly, the pathophysiology of non-Q-wave infarction is thought to involve thrombotic occlusions, at least transiently, at sites of atherosclerotic plaque damage [23]. Moreover, factors predisposing to hemodynamic instability tend to be more common in the elderly and result in imbalances between myocardial oxygen supply and demand that may contribute to the higher incidence of non-Q-wave infarctions among the elderly [24]. Intrinsic changes in vessel distensibility, valve disease, arrhythmias, and autonomic dysfunction are all potential hemodynamically destabilizing characteristics that are common in the elderly and that tend to impair cardiac flow reserve. Infarct size is a major determinant of left ventricular function, and left ventricular function is a key determinant of postinfarct survival [25]. Coronary vessel occlusion, myocardial oxygen demands, hemodynamic stresses, and free radical formation all impact on infarct size. Coronary occlusion occurs not only from underlying atherosclerotic plaque, but also from acute changes in the vasculature and chemical milieu that induce platelet aggregation and clot formation [24]. Moreover, myocardial injury from hypoxic stress may be exacerbated by neurohumoral responses: catecholamines increase oxygen demand, and increased afterload secondary to release of angiotensin and/or other vasoconstrictors may contribute to postinfarct remodeling [26]. Reperfusion is also associated with myocardial damage, and studies are under way to clarify the possible related role of free radical formation [27]. Therapeutic goals for MI include restoration of blood flow and oxygen supply to the ischemic myocardium and reducing the need for oxygen by the ischemic myocardium [28]. Thrombolytic therapy and mechanical revascularization are well-known modalities to restore and maximize myocardial perfusion. /3 Blockers and calcium channel blockers tend to blunt myocardial oxygen needs. Other modalities such as anticoagulation and antiplatelet agents are useful adjuncts to prevent reinfarction or other sequelae. Angiotensin converting enzyme
Volume 93
ACUTE MYOCARDIAL
INFARCTION
IN THE VERY ELDERLY
/ FORMAN
ET AL
TABLE I Thrombolytic Therapy: Short-Term Efficacy
Streitt;rse
~65~ 66-75 >75v ISAM
y ’
t70y 70-75 ISIS-2 7oy >8Oy
y y
Pooled totals Younger Older
11,709 7,608 2,886 1.215
5.7 16.6 28.9
7.7 18.1 33.1
-2.0 -1.5 -4.2
-26.0 -8.3 -12.7
5.1 13.0
6.6 9.6
-1.5 f3.4
-22.7 +35.4
i:
4.2 10.6 18.2 20.1
5.8 14.4 21.6 34.2
-1.6 -3.8 -3.4 -14.1
-27.6 -26.4 -15.7 -41.2
0.001 < 0.0001 0.02 0.002
5.4 10.9
6.3 16.4
-5.5
-14.3 -33.5
0%
4.0 9.9
6.1 21.3
-2.1 -11.4
-34.4 -53.5
oNosoo7
6.2 17.2
8.4 20.7
-2.2 -3.5
-25.7 -16.9
1,454 287 17,187 7,720 6,056 3,411 401 5,031
y
APSAC AIMS
t60y 60-70
Active
Difference
% Change
p Value
0.0005 Ii:
1;741
ASSET
~65~ 66-75
Mortality1%) Control
No.
3,352 1,679
-0.9
1,257
v
751 506 36,925
26,941 9,984
< 0.0001 < 0.0001
SSI-1 = Gruppo ltaliano per lo Studrodella Streptcchinasi nell’lnfarto Miocardrco; NS = not significant; ISAM = Intravenous Streptokinase in Acute Myccardial Infarction; ISIS-2 = Second International rdy of Infarct Survival; r&PA = recombinant tissue plasminogenactivator; ASSET= Anglo-ScandinavianStudy of Early Thrombosis; APSAC = anisoylated plasminogenstreptokinase acbvator complex; WS = APSACintervention Mortality Study.
(ACE) inhibitors are thought remodeling [26].
to reduce postinfarct
THERAPY Thrombolytics Chemical thrombolysis has been shown to be effective in recanalizing infarct-related coronary arteries, salvaging ischemic myocardium, preserving ventricular function, and reducing mortality from acute MI [25]. Peripheral thrombolytic therapy has become standard therapy in many patients with suspected transmural infarction, particularly those presenting within 6 hours of the onset of MI
P31.
Not only are the elderly more susceptible to nonQ-wave infarcts for which benefits of thrombolytic therapy are less clear, but the atypical presentations of MI among the elderly often delay the onset of treatment beyond the critical window of maximal thrombolytic efficacy [29]. Even beyond these confounding issues, hemorrhagic sequelae, especially intracerebral hemorrhage, are a concern in treating aged patients with thrombolysis [30-341. Some clinicians believe that concerns about potential hemorrhage outweigh the therapeutic benefita of thrombolysis for the elderly. One study showed a two-fold increase in hemorrhagic compliSaptember
cations, including four of five total hemorrhagic deaths, among elderly people treated with thrombolysis [30]. Similarly, data from the Thrombolysis in Myocardial Infarction (TIMI) Trial showed a higher incidence of hemorrhage in elderly subjects, including fatal intracerebral hemorrhage [33]. In the recent International Study Group Trial, patients older than 70 years had increased intracerebral hemorrhaging relative to the young [34]. It is important to keep in mind, however, that age does not seem to be a good sole criterion by which to judge risk from thrombolysis [35]. Although one study correlated increased hemorrhage to gender, hypertension, and diabetes mellitus, it did not actually isolate age from these other variables [30]. Similarly, reanalysis of the TIM1 data showed that most bleeding occurred at the catheterization site or from other puncture wounds and did not reflect an innate predisposition to hemorrhaging among the elderly [36]. Moreover, hemorrhaging in TIM1 subjects decreased when the lytic doses were reduced [33,37]. Unfortunately, there are no placebo-controlled thrombolysis trials in the elderly to contrast the overall morbidity and mortality in those treated with thrombolysis to those treated conservatively. Tables I and II refer to several well-known, randomized, placebo-controlled mortality trials of lytic 1992
The American
Journal
of Medicine
Volume
93
317
TABLE II Thrombolytic Therapy: Long-Term Efficacy No. Streptokinase GISSI-1 (12-mo F/U) 565~ 66-75~ >75y
Mortality(96) Control
Active
Difference
%Change
p Value
11,696 7,603 2,881 1,212
9.8 26.0 43.1
12.1 25.6 46.1
-2.3 to.4 -3.0
-19.0 t1.6 -6.5
&PA ASSET(6-moF/U) ~65~ 66-75~
5,031 3,352 1,679
1:::
9.1 20.9
-1.2 -5.5
-13.6 -26.3
o.oNo4
APSAC AIMS
1,257 7.5 16.3
11.1 28.0
-3.6 -11.7
-32.4 -41.8
o.oNos2
11.2 28.6
-2.0 -3.0
-18.1 -10.3
0.0003 0.009
(
