Berger AK, Schulman KA, Gersh BJ, Pirzada S, Breall JA, Johnson AE, Every NR. Primary Coronary Angioplasty vs Thrombolysis for the Management of
Acute Myocardial Infarction in Elderly Patients. JAMA. 1999;282(4):341-348. doi:10.1001/jama.282.4.341
Author Affiliations: Institute for Cardiovascular Sciences, Division of Cardiology (Drs Berger, Schulman, Gersh, and Breall), and the Clinical Economics Research Unit, Department of Medicine (Drs Berger, Schulman, and Johnson), Georgetown University Medical Center, Washington, DC; Delmarva Foundation for Medical Care Inc, Easton, Md (Dr Berger); and the Northwest Health Services Research and Development Field Program, Veterans Affairs Puget Sound Healthcare System and Cardiovascular Outcomes Research Center and the Division of Cardiology, University of Washington, Seattle (Drs Pirzada and Every). Dr Berger is currently a fellow in the Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Conn.
Context Despite evidence from randomized trials that, compared with early thrombolysis,
primary percutaneous transluminal coronary angioplasty (PTCA) after acute
myocardial infarction (AMI) reduces mortality in middle-aged adults, whether
elderly patients with AMI are more likely to benefit from PTCA or early thrombolysis
is not known.
Objective To determine survival after primary PTCA vs thrombolysis in elderly
Design The Cooperative Cardiovascular Project, a retrospective cohort study
using data from medical charts and administrative files.
Setting Acute care hospitals in the United States.
Patients A total of 20,683 Medicare beneficiaries, who arrived within 12 hours
of the onset of symptoms, were admitted between January 1994 and February
1996 with a principal discharge diagnosis of AMI, and were eligible for reperfusion
Main Outcome Measures Thirty-day and 1-year survival.
Results A total of 80,356 eligible patients had an AMI at hospital arrival and
met the inclusion criteria, of whom 23.2% received thrombolysis and 2.5% underwent
primary PTCA within 6 hours of hospital arrival. Patients undergoing primary
PTCA had lower 30-day (8.7% vs 11.9%, P=.001) and
1-year mortality (14.4% vs 17.6%, P=.001). After
adjusting for baseline cardiac risk factors and admission and hospital characteristics,
primary PTCA was associated with improved 30-day (hazard ratio [HR] of death,
0.74; 95% confidence interval [CI], 0.63-0.88) and 1-year (HR, 0.88; 95% CI,
0.73-0.94) survival. The benefits of primary coronary angioplasty persisted
when stratified by hospitals' AMI volume and the presence of on-site angiography.
In patients classified as ideal for reperfusion therapy, the mortality benefit
of primary PTCA was not significant at 1-year follow-up (HR, 0.92; 95% CI,
Conclusion In elderly patients who present with AMI, primary PTCA is associated
with modestly lower short- and long-term mortality rates. In the subgroup
of patients who were classified as ideal for reperfusion therapy, the observed
benefit of primary PTCA was no longer significant.
Acute myocardial infarction (AMI) is the leading cause of death in elderly
patients. The choice of an optimal management strategy for patients with AMI
has been addressed in multiple clinical trials and summarized in a meta-analysis
of trials comparing thrombolysis with placebo. The meta-analysis found a significant
benefit of thrombolysis in patients younger than 75 years, but only a trend
toward decrease in mortality rates in patients aged 75 years or older.1 Supporters of primary percutaneous transluminal coronary
angioplasty (PTCA) emphasize the procedure's higher early patency rate, lower
rates of death and recurrent reinfarction, and markedly reduced rate of stroke.
A recent meta-analysis of randomized clinical trials that compared thrombolytic
therapy with primary PTCA suggests that PTCA decreases short-term mortality
and the incidence of recurrent infarction.2
Observational studies in unselected patients have demonstrated similar outcomes
in patients undergoing primary PTCA compared with those receiving thrombolysis.3,4
The results of randomized clinical trials may be difficult to extrapolate
to elderly patients, who are more likely to have extensive coronary artery
disease, additional risk factors, and other comorbid conditions that may influence
decisions about the appropriate reperfusion strategy. In the absence of conclusive
evidence from randomized trials, data from observational studies may be used
to assess treatment outcomes in clinical practice. Observational studies reflect
general practice in the community and general community standards rather than
care provided in highly specialized centers. In light of these issues, we
compared the clinical outcomes of elderly patients with AMI who were treated
with either thrombolytic therapy or primary PTCA.
The Cooperative Cardiovascular Project (CCP) was initiated by the Health
Care Financing Administration as an ongoing national program to improve the
quality of care for Medicare beneficiaries with AMI.5,6
In this study, we used a database developed from the CCP that includes detailed
clinical data on patients with a principal discharge diagnosis of AMI (International Classification of Diseases, 9th Revision, Clinical
Modification code 410) between January 1994 and February 1996.
We restricted the study population to patients presenting within 12
hours of symptom onset with evidence of AMI at the time of hospital arrival.
We defined AMI as either an elevation of the creatine kinase-MB fraction level
(>5%), a 2-fold elevation in creatine kinase level, or diagnostic electrocardiogram
changes (ST elevation or new Q waves). Patients younger than 65 years were
excluded. Patients presenting with cardiogenic shock were excluded based on
the preferential use of primary PTCA in this high-risk population.7 We restricted the study group further to patients
without contraindications to thrombolysis (history of bleeding disorder, documentation
of prior internal bleeding, active bleeding on arrival, recent trauma or surgery,
and cardiopulmonary resuscitation on arrival).
The CCP data collection process focuses on patients' hospitalizations
and does not extract information from other institutions' records when a patient
is transferred. Therefore, transfers from other hospitals were excluded from
the primary analysis. Patients transferred to another facility were included
because their initial diagnostic and therapeutic strategy could be identified.
The analysis was further limited to the first AMI admission for any given
individual in the CCP cohort (Table 1).
The data elements we analyzed have been reported previously and included
140 clinical variables for each patient with AMI.8
Data abstraction included patient demographics, past cardiac and noncardiac
history, admission characteristics, diagnostic test results, and information
on in-hospital events and procedures. Documentation of PTCA required that
a coronary intervention was attempted; cardiac catheterizations without associated
coronary interventions were excluded. The time from onset of symptoms to hospital
arrival was categorized as fewer than 6 hours, 6 to 12 hours, or longer than
12 hours. In-hospital events, including when thrombolysis was initiated and
when PTCA was started, were obtained directly from the nursing and procedure
Hospital characteristics, including number of hospital beds, annual
volume of AMI cases, and the capability to perform on-site PTCA, were obtained
by linking the CCP data set with information obtained from the American Hospital
Association.9 We categorized each hospital
based on the annual number of AMI patients; a cutoff of 150 AMI admissions
per year (representing the 50th percentile) separated high– and low AMI–volume facilities. Similarly,
a cutoff of 250 beds (50th percentile) was used to separate large from small hospitals.
For missing data elements, we used indicator variables in our analysis.
Categorical variables, when undocumented, were considered to be absent from
the patient's history.
The primary clinical end points of the analysis were 30-day and 1-year
mortality rates, both of which were ascertained from the Medicare enrollment
database. Secondary end points included post-AMI angina, in-hospital reinfarction,
heart failure, hemorrhage (ie, gastrointestinal, genitourinary, and pulmonary
hemorrhage), intracerebral hemorrhage, ischemic or hemorrhagic stroke, and
performance of cardiac catheterization, coronary angioplasty, and coronary
artery bypass surgery.
The study sample was divided into 2 cohorts. The cohort receiving thrombolytic
therapy included patients who received tissue plasminogen activator or streptokinase
within 6 hours of arrival at the hospital. The cohort undergoing primary PTCA
consisted of patients who had not undergone prior thrombolysis and received
PTCA within 6 hours of hospital arrival. For the 1.5% of patients who underwent
both thrombolysis and PTCA, cohort assignment was based on the first strategy
initiated. The 6-hour cutoff was designed to select patients who would derive
the maximal benefit from either reperfusion strategy and to distinguish primary
PTCA cases from subsequent urgent or elective PTCAs.
Categorical characteristics were compared using the χ2
test and expressed as proportions. Differences in continuous variables were
compared using the t test. The use of the Medicare
enrollment database to establish the time of death has been validated in the
literature.10 Age-adjusted mortality rates
for both sexes were calculated by the direct method using 1990 census data.11
Overall survival was determined for each reperfusion strategy by the
Kaplan-Meier method.12 Homogeneity of the survival
curves was tested with both the log-rank test and the Wilcoxon rank sum test.
Multivariate correlates of 30-day survival were analyzed with a Cox
model.13 Candidate predictor variables for
the analysis were those variables shown to be important predictors of mortality
in published studies and those variables that differed between patients receiving
the 2 treatments: cardiac risk factors (age, sex, diabetes, hypertension,
and tobacco use), race, functional status (emphysema, impaired mobility, dementia,
and prior stroke), cardiac history (prior myocardial infarction, prior heart
failure, and prior PTCA or coronary artery bypass surgery), presenting features
(cardiac arrest, hypotension, bradycardia, and heart failure), electrocardiographic
features (Q wave, ST elevation, right and left bundle-branch block, atrial
fibrillation, and anterior location of infarction), admission serum creatinine
levels, coronary artery bypass surgery during the index hospitalization, and
hospital characteristics (number of beds, annual number of patients treated
with AMI, and capability to perform PTCA).14
All candidate predictor variables that were identified as important predictors
of mortality by univariate analysis (P<.10) were
included in the final multivariate Cox model.13
We report the hazard ratio (HR) and 95% confidence interval (CI) associated
with primary PTCA vs thrombolysis for the general CCP cohort at 30 days and
1 year. The HR and 95% CIs for the primary reperfusion strategy were then
stratified by patient category (older than 75 years, sex, presence of hypertension,
diabetes, or congestive heart failure on arrival, and the location of the
infarct) by means of the 30-day Cox models. The statistical analyses were
performed with the SAS 6.12 statistical analysis software package.15
Using institutional characteristics to stratify the population, we further
validated our findings by performing a series of subgroup analyses. We first
defined an ideal subgroup by restricting our cohort
to patients with either ST elevation or left bundle-branch block on arrival
and who presented to the hospital within 6 hours of symptom onset. To evaluate
the method of reperfusion in institutions with minimal and extensive experience
treating AMI, we repeated our analyses after classifying hospitals as either
low– or high AMI– volume facilities. In the final subgroup analysis,
we evaluated the effect of the treating hospital on the outcome of reperfusion
therapy. We stratified hospitals according to their capability to perform
PTCA and compared the mortality rates of institutions that made both reperfusion
Finally, we compared overall mortality rates between patients receiving
reperfusion therapy and those not receiving reperfusion therapy using the χ2 test.
From the CCP database, 80,356 patients had an AMI at the time of hospital
arrival and met the inclusion criteria of the study.
Table 1 shows the derivation of the study sample. In this cohort,
18,645 patients (23.2%) received thrombolysis and 2038 patients (2.5%) underwent
PTCA within the 6-hour time frame. Among the patients receiving thrombolysis,
76.5% received tissue plasminogen activator, 22.6% received streptokinase,
0.7% received anistreplase, and 0.2% received urokinase. The remaining 59,673
patients (74.2%) did not receive reperfusion therapy during the first 6 hours
after hospital arrival, and 54,989 (68.4%) did not receive PTCA or thrombolytic
therapy at any time.
Table 2 shows a comparison
of the baseline characteristics of patients who received early reperfusion
therapy by thrombolysis or PTCA group. The mean (SD) age of the cohort was
73.2 (6.0) years, and 42.1% of the patients were female. There was no significant
difference in the distribution of age, sex, or race between the 2 groups.
The prevalence of cardiac risk factors and noncardiac conditions was similar
between the 2 groups; however, prior PTCA, prior stroke, and prior coronary
artery bypass surgery were more prevalent among patients undergoing PTCA.
Patients undergoing primary PTCA presented longer after symptom onset
than patients receiving thrombolysis. Furthermore, more time lapsed before
initiation of treatment for patients undergoing primary PTCA (mean [SD], 142.6
 minutes; median, 129 minutes) than for patients receiving thrombolysis
(mean [SD], 68.3 [ 54.4] minutes; median, 52 minutes). Both groups had a similar
clinical presentation, although patients undergoing primary PTCA were less
likely to have evidence of congestive heart failure on examination. Fewer
patients undergoing primary PTCA had ST elevation (61.6% vs 68.0%, P=.001) and Q waves (23.5% vs 30.2%, P=.001).
Patients undergoing primary PTCA were more likely to have left bundle-branch
block, although the difference between the 2 groups was not clinically significant.
Table 3 displays the 30-day
and 1-year mortality rates for both groups. Compared with patients receiving
thrombolysis, patients undergoing primary PTCA had lower 30-day (8.7% vs 11.9%, P=.001) and 1-year mortality rates (14.4% vs 17.6%,P=.001).
shows 30-day and 1-year mortality rates, stratified by sex. After adjusting
for age, primary PTCA was associated with lower mortality rates for both sexes.
Kaplan-Meier survival curves for both reperfusion strategies are shown in
Figure 2. Mortality remained significantly
lower for patients undergoing primary PTCA for the follow-up period of 18
Patients undergoing primary PTCA had a lower prevalence of cerebral
hemorrhage and postinfarction angina and a higher prevalence of minor and
major bleeding events during hospitalization (Table 4). Of the 18,645 patients who were initially treated with
thrombolytic therapy, 39.2% eventually underwent cardiac catheterization and
12.4% underwent PTCA. A greater proportion of patients in the primary PTCA
group had coronary artery bypass surgery during hospitalization (10.4% vs
After adjustment for baseline characteristics (Table 2), the modality of reperfusion remained an independent predictor
of mortality. Compared with early thrombolysis, primary PTCA reduced 30-day
mortality (HR, 0.74; 95% CI, 0.63-0.88) (Figure 3) and 1-year mortality rates (HR, 0.88; 95% CI, 0.73-0.94).
Stratifying the groups by age, sex, hypertension, diabetes, prior heart failure,
and the location of myocardial injury did not change the observed difference
in mortality. The benefit of primary PTCA remained significant in each of
the subgroups except diabetic patients, patients with prior congestive heart
failure, and individuals without anterior location of injury.
Of the 80,356 patients eligible for reperfusion therapy, 28,955 presented
to the hospital within 6 hours of symptom onset and with ST elevation or left
bundle-branch block on the initial electrocardiogram. Among these "ideal"
patients, 12,941 (44.7%) received primary PTCA or thrombolysis within 6 hours
of hospital arrival. A strategy of primary PTCA was associated with a lower
30-day mortality rate than early thrombolysis, although the difference was
not statistically significant (10.1% vs 12.0%, P=.06).
In a Cox proportional hazard model, primary PTCA was associated with a lower
point estimate for 30-day mortality (HR, 0.84; 95% CI, 0.68-1.03). The difference
in survival between primary PTCA and thrombolysis diminished at 1 year (16.2%
vs 17.8%; P=.18; HR, 0.92; 95% CI, 0.78-1.08).
Because the volume of patients treated for AMI at an institution has
been associated with outcome, we performed a stratified analysis based on
whether a patient was treated at a low-volume hospital (<150 AMI cases
per year) or high-volume hospital (≥150 AMI cases per year) (Figure 4). In this analysis, primary PTCA continued to be associated
with lower short- and long-term mortality rates, regardless of the volume
of patients with AMI. In addition, patients treated at high-volume institutions
experienced lower 30-day and 1-year mortality.
In a stratified analysis comparing reperfusion therapies at hospitals
with and without on-site angiography, patients who received thrombolysis at
facilities that did not offer PTCA experienced the highest mortality rate;
patients who received thrombolysis at facilities that did offer PTCA had better
survival rates (Figure 5). Patients
treated with primary PTCA had lower 30-day and 1-year mortality rates than
either group treated with thrombolysis. Similar trends were noted in the "ideal"
subgroup of patients, although the differences in mortality rates were not
statistically significantly different (Figure
Finally, we compared mortality rates for patients receiving early reperfusion
therapy with those who received none. Patients not receiving therapy had higher
30-day (17.2% vs 11.8%, P=.001) and 1-year mortality
rates (33.1% vs 17.6%, P=.001).
Reperfusion therapy (primary PTCA or early thrombolysis) has been established
as a pivotal therapeutic strategy in the management of patients with AMI.16 Although randomized clinical trials have attempted
to identify the optimal reperfusion strategy, no single trial has had statistical
power to detect a difference in mortality between these 2 therapies, particularly
in elderly patients. A recent meta-analysis pooled data on 1290 patients from
10 randomized trials that compared primary PTCA with thrombolysis and demonstrated
a 34% risk reduction in short-term mortality with an interventional strategy
of PTCA.2 The homogeneity of the population
(resulting from exclusion of elderly patients in several trials) may prevent
the generalization of these results to older patients. The Primary Angioplasty
in Myocardial Infarction (PAMI) trial detected a trend toward a reduction
in short-term mortality (5.7% vs 15.0%, P=.07) among
patients older than 65 years who were treated with primary PTCA.17
The Global Use of Strategies to Open Occluded Coronary Arteries-IIB study
(GUSTO-IIB), the largest trial to date, also identified a trend toward lower
30-day mortality with primary PTCA compared with thrombolysis in patients
aged 70 years and older.18 No randomized clinical
trial to date has shown a statistically significant benefit of primary PTCA
over thrombolysis in the elderly.
Although data from randomized
clinical trials suggest a potential benefit of primary PTCA in the elderly,
it may not be appropriate to generalize these results to the community at
large. A comparison of primary PTCA with alteplase showed only a slightly
lower mortality rate in patients older than 75 years who were treated with
primary PTCA (14.4% vs 16.5%, P=.13).4
Institutions in which PTCA is performed less often have had worse mortality
rates in randomized clinical trials18 and in
In this study, we evaluated reperfusion strategies in elderly patients
who presented to hospitals with AMI as captured in the CCP database. The sample
of patients receiving reperfusion therapy in the CCP is larger than the combined
populations of patients older than 65 years from the previous randomized clinical
and community trials. Furthermore, in contrast to prior studies that evaluated
30-day survival rates, the Medicare enrollment database permits analysis of
long-term survival rates.
Patients who underwent primary PTCA,
in comparison to early thrombolysis, had lower 30-day and 1-year mortality
rates after adjustment for baseline characteristics. The lower mortality rates
associated with primary PTCA were observed in each of our subgroup analyses,
in both men and women, and independent of hospitals' volume of AMI cases,
a key indicator of hospital-level quality of care.21
Therefore, the survival advantage associated with primary PTCA was not solely
due to its performance in hospitals with experience in the management of AMI.
We further explored whether our study findings were biased by consideration
of contraindications to treatment in our primary analysis by assessing the
outcomes for patients who were considered ideal candidates for treatment.
Results in this subsample were in the same direction as our main analysis,
although the benefit of primary PTCA strategy was less and no longer significant.
Our findings support the subgroup analyses from the PAMI and
GUSTO-IIB randomized clinical trials and the Second National Registry of Myocardial
Infarction (NRMI-2) observational study. These analyses demonstrated a trend
toward decreased mortality in elderly patients who underwent primary PTCA.4,17,18 Furthermore, the data
suggest that elderly patients (a group with an inherently increased risk of
mortality) may achieve a greater benefit with coronary intervention compared
with the general population.
The observed lower mortality rate
in patients undergoing primary PTCA could be a reflection of the higher complication
rate observed in patients receiving thrombolytic therapy. Patients receiving
thrombolysis, in addition to having a higher prevalence of cerebral hemorrhage,
were more likely to develop postinfarction angina and congestive heart failure.
Bleeding from pulmonary and gastrointestinal sources may have also contributed
to the higher mortality rate among patients receiving thrombolysis.
The observed lower mortality rate in the PTCA group also could be due
to earlier presentation in patients treated with primary PTCA, but our data
indicate that a greater proportion of the patients who received thrombolysis
presented to the hospital within 6 hours of symptom onset. Furthermore, the
mean time to treatment after hospital arrival was 74.3 minutes shorter in
the thrombolysis group. The more rapid delivery of thrombolysis compared with
primary PTCA is consistent with published trials.2
Reperfusion therapy was used relatively infrequently among elderly patients
who experienced ST elevation or left bundle-branch block at the time of AMI.
Reperfusion therapy (primary PTCA or early thrombolysis) has been established
as a fundamental guideline in the management of patients with AMI.22 Less than half of the elderly patients ideal for
reperfusion therapy received primary PTCA or thrombolysis within 6 hours of
hospital arrival. While this likely reflects the high prevalence of contraindications
in the elderly population not ideal for reperfusion therapy, it may also signal
the underutilization of this important therapy.23
Compared with patients who received early reperfusion therapy, patients not
receiving therapy had higher 30-day and 1-year mortality rates. While an argument
can be made for primary PTCA over thrombolysis in the elderly, more attention
needs to be focused on the early recognition of AMI in this population and
the rapid delivery of either reperfusion therapy.
with AMI who present with ST segment elevation or bundle-branch block, the
choice of reperfusion strategies continues to be controversial because most
US hospitals do not have the facilities or staff to perform primary PTCA in
an expert fashion. Our findings argue that there may be a modest mortality
benefit from the use of primary PTCA in elderly patients with AMI. However,
because the mortality benefit at 1 year was small and further diminished in
the "ideal" subset of patients, we do not believe that our findings support
a policy of triage of the elderly to primary PTCA. Rather, these findings
are most consistent with the current American College of Cardiology/American
Heart Association guideline recommendation that suggests that "primary PTCA
should be used as an alternative to thrombolytic therapy only if performed
in a timely fashion by individuals skilled in the procedure and supported
by experienced personnel in high-volume centers."22
Because the overall rate of reperfusion in appropriate patients was low, efforts
would best be concentrated on increasing the proportion of eligible patients
treated with either form of reperfusion. Choice of reperfusion therapy should
be based on the expertise of an individual hospital. In elderly patients with
contraindications to thrombolytic therapy, a strategy of primary PTCA should
be considered if available on site or, for centers without on-site PTCA, the
use of transfer protocols may result in a greater proportion of eligible elderly
patients receiving reperfusion therapy.
There are several limitations
to our analysis. First, this was an observational study based on a retrospective
chart analysis and was, therefore, subject to missing data. Patients were
not assigned treatments at random, and unmeasured selection factors could
have influenced our findings. However, the large number of variables available
in the CCP allowed adjustment for many patient characteristics in multivariate
analysis and by stratification for volume of AMI cases at each hospital. Also,
our data were collected in a period when stents were infrequently used and
when glycoprotein IIB/IIIA inhibitors were unavailable. While the use of stents
has reduced the rates of restenosis and revascularization, there is no evidence
that the utilization of stents has reduced mortality, particularly in the
setting of an AMI.23 The advent of glycoprotein
IIB/IIIA inhibitors may have further improved outcomes in patients undergoing
primary PTCA. Finally, the observed benefit of primary PTCA cannot be generalized
to institutions without adequate institutional or operator volume to ensure
optimal primary PTCA results.
In summary, the use of primary PTCA
in elderly patients is associated with modestly lower short- and long-term
mortality rates compared with thrombolysis. The observed benefit of primary
PTCA was diminished in the subgroup of patients who were classified as ideal
for reperfusion therapy.