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Effectiveness of Thrombolytic Therapy for Acute Myocardial Infarction in the Elderly
Cause for Concern in the Old-Old
Stephen B. Soumerai, ScD;
Thomas J. McLaughlin, ScD;
Dennis Ross-Degnan, ScD;
Cindy L. Christiansen, PhD;
Jerry H. Gurwitz, MD
Arch Intern Med. 2002;162:561-568.
ABSTRACT
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Background National guidelines have encouraged increased use of thrombolytic therapy
for elderly patients with acute myocardial infarction (AMI). However, evidence
supporting thrombolytic therapy in patients 75 years and older is lacking.
In a retrospective cohort study of 2659 elderly AMI patients, we determined
the association between thrombolytic use and in-hospital mortality by age
and among patients with or without absolute or relative contraindications
to thrombolytic treatment.
Methods We abstracted the medical records of 2659 elderly patients admitted
with AMI at 37 Minnesota community hospitals between 1992 and 1996. The main
outcome measure was in-hospital mortality, controlling for demographic, clinical,
comorbidity, and severity-of-illness variables.
Results Sixty-three percent of 719 eligible patients received thrombolytic therapy.
Twenty-seven percent of thrombolytic recipients had absolute contraindications
to treatment. Patients receiving thrombolytic agents had fewer and less severe
comorbidities than those not receiving thrombolytic therapy. There was a 4%
increase in the odds of death for every 1-year increase in age for all thrombolytic
recipients vs nonrecipients (odds ratio [OR], 1.04 per year; 95% confidence
interval [CI], 1.01-1.08; P = .03). Among patients
with 1 or more contraindication, the OR for death associated with thrombolytic
use was 1.57 (95% CI, 1.03-2.40; P = .04). The adjusted
odds of death among eligible thrombolytic recipients (vs nonrecipients) increased
significantly with age (OR, 1.08 per year; 95% CI, 1.02-1.14; P = .008). Among eligible patients aged 80 to 90 years, the predicted
odds of death among thrombolytic recipients vs nonrecipients was 1.4. Among
eligible patients younger than 80 years, thrombolytic use was associated with
reduced mortality.
Conclusions Our findings suggest the need for more research on the effectiveness
of thrombolytic therapy for AMI patients 75 years and older and for more careful
selection of elderly patients for this treatment.
INTRODUCTION
LARGE randomized clinical trials1-10
involving about 60 000 patients worldwide have confirmed that thrombolytic
therapy can substantially increase survival among patients with acute myocardial
infarction (AMI), reducing absolute mortality by 20 to 30 per thousand treated.10 As a result, many national treatment guidelines and
quality assurance programs have strongly recommended use of these agents among
younger and elderly AMI patients.11-14
Although the population benefits of thrombolytic therapy outweigh the
risks in eligible middle-aged AMI patients and those aged 65 to 74 years,
the evidence supporting use of thrombolytic therapy for patients 75 years
and older is less clear. A systematic overview of 9 large trials of thrombolytic
treatment in AMI cases showed that fewer than 10% of patients were 75 years
or older,10 although this group experiences
in-hospital mortality rates almost 10 times higher than among patients younger
than 65 years (nonelderly).15 Moreover, the
pooled effect of thrombolytic therapy on survival among patients 75 years
and older was not statistically significant.10
Despite the substantial rise in use of thrombolytic therapy among elderly
patients ( 65 years) since 1990,16 many
physicians are still reluctant to prescribe them for the oldest patients and
for those with severe comorbidities because of the risks of bleeding and hemorrhagic
stroke.14, 17 Several mechanisms
could justify such caution in the old-old (80 years): (1) the likelihood
of delay from initial symptoms to hospital arrival (6 hours) is increased
in this group18; such delay is associated with
substantially reduced survival benefits of thrombolysis11, 19;
absolute or relative contraindications are more likely in elderly patients12; and the risk of bleeding and hemorrhagic stroke
is markedly increased among thrombolytic recipients 75 years and older.10, 20-21 Thus, the balance
of risks and benefits of thrombolytic therapy may be different in the oldest
age groups.22 Increased comorbidity in this
group may also adversely affect patient outcomes and has been demonstrated
to affect clinical decision making relating to the use of thrombolytic therapy.17
Because of the relative exclusion of the oldest patients in the randomized
clinical trials of thrombolytic therapy, the differences between results achieved
in randomized clinical trials and community settings, and the likelihood that
elderly patients in the community have more absolute or relative contraindications
and comorbidities than participants in randomized clinical trials, it is important
to study the appropriateness and outcomes of thrombolytic therapy in community
populations.
Because the rapid application of thrombolytic eligibility criteria for
elderly patients is challenging,23 it is possible
that some ineligible patients are receiving thrombolytic therapy, leading
to suboptimal outcomes, but few data exist to address this issue. Therefore,
we sought to answer the following specific questions using a large population-based
sample of elderly AMI patients in the community: (1) What proportion of eligible
and other patients (with absolute or relative contraindications) in community
settings receive thrombolytic therapy? (2) Controlling for baseline risk status,
demographic variables, and comorbidities, what is the association between
thrombolytic use and in-hospital mortality by age and among patients with
or without absolute or relative contraindications to thrombolytic treatment?
SUBJECTS AND METHODS
STUDY SAMPLE
The data for this study were drawn from medical records for a previous
study of patients admitted with AMI to 37 Minnesota hospitals during the periods
October 1, 1992, to July 31, 1993, and July 1, 1995, to April 30, 1996 (before
and after an educational intervention that did not affect thrombolytic use).14, 17-18,24 The
study hospitals represented more than 80% of all community hospital beds and
more than half of all AMI cases statewide. Only 2 of the hospitals were academic
centers, 17 were in rural communities, 19 had fewer than 100 beds, and 2 had
more than 500 beds.
The study population consisted of all elderly patients (65 years)
who were admitted with a diagnosis of AMI or suspected AMI and met at least
2 of the following criteria: (1) clinical symptoms typical of AMI (chest pain,
arm or shoulder pain, diaphoresis, dyspnea, nausea or vomiting, or neck and/or
jaw pain); (2) explicit medical record documentation by a physician that electrocardiographic
findings were considered compatible with AMI (ie, new Q wave or ST segment
depression or elevation 1 mm); and (3) elevated serum creatine kinase
and MB fractions.14, 24 Patients
were excluded if they died before admission, were transferred from a nonstudy
hospital, or had an AMI in the previous 2 weeks. We also excluded 229 patients
who received a revascularization procedure within 12 hours of admission, leaving
a total study sample of 2659.
DATA COLLECTION
As previously described,14, 17-18,24
trained nurses abstracted detailed medical record data on selected clinical
variables, including AMI inclusion and exclusion criteria; medical history;
admission data, including time to presentation; clinical and electrocardiographic
findings at presentation and during the first 24 hours of hospitalization,
and comorbidities at admission (based on the Greenfield Index of Coexistent
Disease)25; indications and absolute or relative
contraindications to thrombolytic therapy at presentation to the hospital,
based on national evidence-based guidelines (Table 1)26; drugs administered in
the first 48 hours, including during emergency transport and in the emergency
department; time from hospital presentation to thrombolytic administration;
complications during the first 72 hours, including significant bleeding (requiring
a blood transfusion or other procedure) and hemorrhagic stroke; and whether
discharged alive. Abstractors were required to demonstrate ongoing interrater
agreement of 95% or higher with the criterion reviewer. The reviewers audited
random samples of 10% of each abstractor's completed cases to ensure that
this standard was met. In addition, the interpretations of electrocardiographic
findings in the medical record correlated highly with the interpretations
of 2 cardiologists.24
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Table 1. Eligibility and Contraindications for Thrombolytic Therapy*
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As described in other studies,14, 17-18,24
we determined eligibility for thrombolytic therapy based on the 1990 American
College of Cardiology/American Heart Association guidelines26
in effect during the observation period. Eligible patients were defined as
having all indications for treatment and no absolute or relative contraindications
(Table 1). All other patients
had 1 or more absolute or relative contraindications.
PATIENT OUTCOMES AND INDEPENDENT VARIABLES
Our primary outcome of interest was short-term mortality, measured as
death due to any cause during the AMI hospitalization. Demographic variables
included age and female sex, which are associated with lower short-term survival
after AMI27 and reduced rates of thrombolytic
use,24 and race. We included relevant medical
history variables, time to presentation, and clinical characteristics at admission
(Table 1), which might predict
AMI outcomes.27 Also, we included variables
identifying anterior location of myocardial infarction and the presence of
a mild, moderate, or severe comorbidity (based on the Greenfield Index of
Coexistent Disease),25 both of which are associated
with poorer AMI outcomes.10 In addition, we
included variables identifying patients receiving selected treatments during
the first day of hospitalization (aspirin,  -blockers, and angiotensin-converting
enzyme inhibitors) and several provider characteristics that could influence
thrombolytic use or survival, such as the number of AMIs treated at the hospital28 and availability of cardiac catheterization.
STATISTICAL ANALYSIS
First, we compared the baseline demographic and clinical characteristics,
time to presentation, medical histories, drug management in the first 24 hours,
and provider characteristics of thrombolytic recipients vs nonrecipients using  2 statistics. Next, we conducted simple univariate comparisons of mortality
among thrombolytic recipients and nonrecipients stratified by age (65-74 years
vs 75 years).
We first calculated propensity scores29
to estimate the likelihood that a patient received thrombolytic therapy. These
propensity scores were then used as control variables in analyses of the effects
on mortality of actual use of thrombolytic therapy. Propensity scores are
used in observational studies to reduce selection-to-treatment bias and to
reduce to 1 value the differences in observed patient characteristics that
affect treatment selection. Propensity of exposure to a thrombolytic agent
was developed using logistic regression on all variables in Table 1 and interactions of these variables. To adjust maximally
for potential confounding, we included in the final propensity model all variables
associated with the likelihood of thrombolytic use with P<.30. A c statistic (area under a receiver
operating characteristic curve) and Hosmer-Lemeshow goodness-of-fit test indicated
that the propensity score model predicted thrombolytic use well.30-31
A logistic regression model, with patients' individual propensity scores
as a control variable, was used to test the effect of age and thrombolytic
use on mortality in all patients, while controlling for selection factors
leading to thrombolytic use. In a separate model, we added an interaction
term examining effect modification by age (continuous variable). In addition,
patients were stratified into those eligible for thrombolytic therapy and
all other patients with absolute or relative contraindications, and stratum-specific
estimates of the effect of thrombolytic use on mortality were obtained and
adjusted for propensity scores.
RESULTS
CHARACTERISTICS OF SAMPLE AND USE OF THROMBOLYTIC THERAPY
Of the 2659 elderly patients who met study criteria, 735 patients (27.6%)
received thrombolytic therapy. In general, patients receiving thrombolytic
therapy had fewer comorbidities and risk factors than patients who did not
receive a thrombolytic (Table 2). Patients who did not receive thrombolytic therapy were significantly more
likely to have medical histories of previous AMI, angina, revascularization
procedures, previous stroke, diabetes, and hypertension. Patients who did
not receive thrombolytic therapy were almost twice as likely to have heart
failure or pulmonary edema (31.5%) and a severe comorbidity (36.1%) at admission
compared with thrombolytic recipients. Thrombolytic recipients were more likely
to exhibit ST elevation and to have experienced anterior myocardial infarction.
As expected, more than twice as many patients who did not receive thrombolytic
therapy presented to the hospital more than 6 hours after symptoms (42.0%
vs 15.8% for thrombolytic recipients).
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Table 2. Baseline Demographic and Clinical Characteristics and Early
Treatments According to Receipt of Thrombolytic Therapy
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Thrombolytic therapy recipients were significantly more likely than
nonrecipients to have received aspirin or -blockers (89.4% vs 72.5%
and 60.3% vs 42.3%, respectively) but were somewhat less likely to receive
angiotensin-converting enzyme inhibitors (Table 2). In addition, those receiving thrombolytic therapy were
somewhat more likely to be cared for by a cardiologist or at a hospital with
a low volume of AMIs.
THROMBOLYTIC USE BY ELIGIBILITY
Among 719 patients who were eligible for thrombolytic therapy, 455 (63.3%)
received this treatment. However, among the remaining 1940 patients who had
1 or more absolute (n = 1709) or relative contraindications, 280 (14.4%) received
a thrombolytic.
Among 280 thrombolytic recipients with contraindications, 71.0% had
1 or more absolute contraindication to thrombolysis. The most frequent reasons
for ineligibility (Table 1) were
presence of 1 or more medical contraindications (43.3%), absence of an ST
segment elevation of 1 mm or more (25.3%), and delay greater than 12 hours
(23.9%).
UNADJUSTED MORTALITY AND HEMORRHAGIC STROKE
In the overall study population, 13.1% died during the AMI hospitalization.
The unadjusted mortality rate for thrombolytic recipients aged 65 to 74 years
was 7.2%, slightly below the rate of 7.6% observed for nonrecipients (nonsignificant).
However, among those 75 years or older, thrombolytic recipients experienced
a somewhat higher unadjusted mortality rate than nonrecipients (20.1% vs 16.6%, P = .15).
Overall, 0.6% of study patients experienced a fatal or nonfatal hemorrhagic
stroke; among younger thrombolytic recipients (age, <75 years), this rate
was 1.4% compared with 0.2% among nonrecipients (P
= .02); among patients 75 years and older, hemorrhagic stroke occurred in
2.4% of thrombolytic recipients compared with 0.2% of nonrecipients (P<.001).
MULTIVARIATE ANALYSES
Table 3 provides the results
of the multiple logistic regression analyses of the odds of death for thrombolytic
recipients vs nonrecipients for the entire sample and for subsets of the sample
stratified by thrombolytic eligibility. Propensity scores (probability of
receiving thrombolytic therapy) range between 0 and 1. As expected based on
the lower baseline risk status of thrombolytic recipients compared with nonrecipients,
the propensity score was strongly associated with a reduced odds of death
in the overall sample (odds ratio [OR], 0.42; 95% confidence interval [CI],
0.22-0.82; P = .01) and among those with absolute
or relative contraindications to thrombolytic therapy (OR, 0.23; 95% CI, 0.09-0.54; P = .001).
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Table 3. Multivariate Analysis of the Odds of In-Hospital Mortality*
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The odds of death associated with thrombolytic use in all patients (Table 3) was 1.53 (95% CI, 1.13-2.08; P = .006), but this was strongly influenced by the large
fraction (71.0%) of patients with 1 or more absolute or relative contraindication
for whom the adjusted odds of death among thrombolytic recipients was 1.57
(95% CI, 1.03-2.40; P = .04) compared with nonrecipients.
For patients eligible for thrombolytic treatment, the odds of death were not
significantly different between those patients receiving and not receiving
the drug in the model without an interaction term (OR, 0.96; 95% CI, 0.58-1.58; P = .86).
The significant interaction term for thrombolytic use with age for all
patients (Table 3) indicates that
the odds of death associated with thrombolytic use increased with age (OR,
1.04; 95% CI, 1.01-1.08; P = .03). This indicates
that there was a 4% increase in the odds of death for every 1-year increase
in age for all thrombolytic recipients compared with nonrecipients. Like the
overall cohort, mortality associated with thrombolytic use increased with
age (OR, 1.08; 95% CI, 1.02-1.14; P = .008) among
patients eligible for thrombolytic therapy. However, thrombolytic therapy
was associated with a survival benefit for eligible patients younger than
80 years. For all other patients with contraindications, the increased odds
of death associated with thrombolytic use did not change with age (Table 3).
Figure 1 shows the adjusted
odds of death for thrombolytic recipients vs nonrecipients by age for the
entire cohort, for eligible patients, and for all other patients with contraindications.
For the entire cohort (Figure 1A),
thrombolytic use for patients older than 70 years was associated with an increased
odds of mortality compared with younger patients. For eligible patients younger
than 80 years, thrombolytic use was associated with reduced mortality, but
thrombolytic recipients older than 80 years experienced higher mortality rates
than nonrecipients (predicted OR, 1.4 for patients aged 80-90 years). Age
did not significantly modify the association between thrombolytic use and
increased mortality among all other patients with absolute or relative contraindications
(Figure 1B).
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Predicted odds of in-hospital mortality for thrombolytic recipients
vs nonrecipients for different ages based on age interactions in multivariate
models and stratified by thrombolytic eligibility. The logistic regression
models controlled for age, propensity scores (to receive thrombolytic therapy),
and interactions between age and thrombolytic use (see Table 3). P values denote significance
of interaction of age and thrombolytic use as predictors of mortality.
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COMMENT
The findings of this observational study regarding the use of thrombolytic
agents in a large community population of AMI patients suggest that (1) in
general, thrombolytic recipients have fewer comorbidities and risk factors
than nonrecipients; (2) thrombolytic use is associated with reduced mortality
among eligible patients younger than 80 years but increased mortality among
the old-old; the oldest patients, even those without relative or absolute
contraindications to therapy, experienced an excess risk of mortality compared
with untreated patients (OR, 1.4 for thrombolytic recipients 80-90 years);
and (3) the manner in which thrombolytic therapy is used in the community
setting differs markedly from that observed in randomized clinical trials,
where patients are selected for treatment using explicit and consistent criteria
and agents are administered according to protocol. A substantial proportion
of thrombolytic recipients in the study (38.0%) had relative and absolute
contraindications to treatment, and this was strongly associated with an increased
risk of mortality compared with such patients who did not receive thrombolytic
therapy.
The current American College of Cardiology/American Heart Association
practice guidelines for AMI assign a class IIa designation to the recommendation
for use of thrombolytic therapy in persons older than 75 years, indicating
that while the weight of evidence and expert opinion is in favor of the usefulness
of treatment, there remains conflicting evidence or a divergence of opinion
about whether the treatment is beneficial, useful, and effective.11 While a large randomized trial focused exclusively
on elderly AMI patients would produce the most valid information regarding
the benefits vs risks of thrombolytic therapy, this approach has failed previously
because of ethical difficulties inherent in randomization of AMI patients
to placebo and in identifying and enrolling large enough numbers of patients
without contraindications to therapy.32 Analyses
of combined data from the largest trials of thrombolytic agents in AMI have
not demonstrated a significant survival benefit in patients older than 75
years. A systematic overview of 9 trials that randomized 58 600 patients
with suspected AMI between thrombolytic therapy and control included 5754
participants 75 years or older.10 Among this
group, the mortality during the first 35 days was 24.3% for those treated
with a thrombolytic agent compared with 25.3% for those who did not receive
treatment. These findings have been interpreted by many authorities to indicate
an absolute benefit of treatment of 10 lives saved per thousand patients treated
among those 75 years or older. However, the 95% CI around this estimate is
quite wide (-16.0 to 36.0), suggesting the potential for risk as well
as benefit. The relative risk of death for patients in this older age group
who received thrombolytic therapy compared with controls was 0.96 (95% CI,
0.88-1.05). Thus, the limited data derived from clinical trials of thrombolytic
therapy in elderly AMI patients suggest that the relative benefits from use
of thrombolytic therapy experienced by this group is marginal at best. Given
the low likelihood of mounting any new trials in the old-old, and a general
consensus that eligible elderly AMI patients should have access to all available
treatment modalities, it has become essential to examine the outcomes of these
therapies in observational studies of community populations, which may provide
more realistic information on effectiveness in a "real-world" setting.
The major challenge of this and other observational studies that attempt
to assess therapeutic effectiveness is to overcome confounding caused by treatment
decisions that are determined in a nonrandomized fashion.33
Even after extensive statistical adjustments, it is difficult to control for
the bias that elderly thrombolytic recipients have characteristics associated
with better prognosis before treatment relative to nonrecipients. While underadjusting
for this bias might lead to an exaggerated survival benefit in patients aged
65 to 74 years, it may also lead to an underestimation of the increased mortality
found among the oldest thrombolytic recipients. The validity of our findings
is further supported by the clear and predictable differences in survival
between eligible thrombolytic recipients and patients with relative and absolute
contraindications to therapy who received thrombolytic therapy.
There are additional limitations regarding the present study because
of its observational nature. In our study, all thrombolytic agents were combined
into a single category, and we did not assess issues relating to the specific
agent used, dosing, or the timing of drug administration in our analyses.
The rates of important adverse events of thrombolytic therapy, notably intracranial
hemorrhage, have been shown to vary across agents34-35;
however, agent-specific effects on mortality could not be examined in the
context of the present study owing to sample size limitations. Furthermore,
the dose at which the thrombolytic agent is administered can have an impact
on the occurrence of intracranial hemorrhage. Recent data from the National
Registry of Myocardial Infarction 2 have demonstrated that AMI patients who
received excessive tissue-type plasminogen activator doses, relative to the
recommended weight-adjusted doses, had a significantly increased risk of having
an intracranial hemorrhage.36-37
Another limitation of this study is the relatively small sample size
of AMI patients from a single state. However, the sample size was sufficient
to detect significant increases in the odds of dying among elderly thrombolytic
recipients. Furthermore, patterns of use of thrombolytic agents for elderly
AMI patients in Minnesota are similar to patterns observed in other studies.12, 16 Moreover, our findings of increased
mortality among eligible, elderly thrombolytic recipients are similar to those
of a recent study.22
In summary, the findings of this observational study confirm the benefits
of thrombolytic treatment in the community setting among younger patients
meeting eligibility criteria for treatment. However, our findings raise concerns
about the benefits of this treatment in the old-old, even those who might
be considered eligible for treatment according to current criteria. These
results require confirmation using data derived from other large observational
studies of AMI patients that include meaningful numbers of the old-old. For
the present, the findings of this study suggest a need to reassess our approach
to the use of thrombolytic therapy in the treatment of AMI patients older
than 75 years. Careful assessment for absolute and relative contraindications
to thrombolytic therapy is critical in this group of patients. When such patients
are considered eligible for treatment, the timing of treatment should be optimized,23 and the agent must be administered at the correct
dosage. The relative benefits of alternatives to thrombolytic therapy, such
as primary coronary angioplasty, in the old-old require further assessment.
Despite reservations about the true benefits of thrombolytic therapy in the
oldest AMI patients, this vulnerable group will clearly benefit from increased
adherence to guidelines regarding use of all available beneficial therapeutic
modalities.38-42
AUTHOR INFORMATION
Accepted for publication July 16, 2001.
This study was supported by grant AG14474 from the National Institute
on Aging, Bethesda, Md; by the Healthcare Education and Research Foundation,
St Paul, Minn; and by the Harvard Pilgrim Health Care Foundation, Boston,
Mass.
The views expressed in this article are those of the authors and do
not necessarily represent the views of the Department of Veterans Affairs.
This study was presented in part at the Annual Meeting of the Society
for General Internal Medicine, Boston, Mass, May 6, 2000, and the Association
for Health Services Research, Los Angeles, Calif, June 26, 2000.
We thank the participating hospitals in the Healthcare Education and
Research Foundation, St Paul, Minn; Xiaoming Gao, MA, for statistical support;
and Robert LeCates, MA, for the preparation of the manuscript and illustration.
Corresponding author and reprints: Stephen B. Soumerai, ScD, Department
of Ambulatory Care and Prevention, Harvard Medical School and Harvard Pilgrim
Health Care, 133 Brookline Ave, Sixth Floor, Boston, MA 02215 (e-mail: ssoumerai{at}hms.harvard.edu).
From the Department of Ambulatory Care and Prevention, Harvard Medical
School and Harvard Pilgrim Health Care, Boston, Mass (Drs Soumerai, McLaughlin,
and Ross-Degnan); the Boston University School of Public Health, Health Services
Department and Center for Health Quality, Outcomes, and Economic Research
at Veterans Affairs Health Services Research and Development, Bedford, Mass
(Dr Christiansen); and The Meyers Primary Care Institute, University of Massachusetts
Medical School, and the Fallon Healthcare System, Worcester (Dr Gurwitz).
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