Results from the few trials of thrombolytic therapy that enrolled relatively large numbers of elderly patients suggest that for such patients, treatment beneficially affects short-term mortality associated with acute myocardial infarction [5-9]. Although a larger proportionate reduction in mortality is seen with thrombolytic treatment for younger patients, older patients have a higher absolute risk for dying of acute myocardial infarction. As a result, the absolute mortality reductions (net number of lives saved per 1000 patients treated) are similar for younger and older patients [10]. Furthermore, the findings of a decision analytic model have suggested that thrombolytic therapy is a cost-effective intervention for elderly patients suspected of having had acute myocardial infarction [11]. In summary, a consensus has emerged that patient age should not be a factor in the decision to use thrombolytic therapy for acute myocardial infarction [12, 13].

Despite the favorable effects of thrombolytic agents on mortality in older patients, several studies have shown that with increasing patient age, these drugs are used much less frequently for acute myocardial infarction [3, 14-16]. A beneficial effect of thrombolysis on mortality from acute myocardial infarction in elderly patients depends on the willingness of physicians to use this therapy in eligible patients [17]. Survey data have indicated that cardiovascular specialists are more reluctant to use thrombolytic therapy in elderly patients who have had acute myocardial infarction [18]. One explanation for the limited use of thrombolytic agents in the elderly, even among patients with no contraindications to therapy, is physicians' desire to avoid an iatrogenic hemorrhagic stroke, the risk for which increases with advancing patient age [19]. In the Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries (GUSTO) trial [20], 0.42% of patients aged 75 years or younger treated with streptokinase and 0.52% of those treated with accelerated tissue plasminogen activator (tPA) had a hemorrhagic stroke. Among patients older than age 75 years, these percentages were 1.23% and 2.08%, respectively.

We examined recent trends in the use of thrombolytic therapy in elderly patients who have had acute myocardial infarction and determined whether failure to meet time-to-hospital presentation and electrocardiographic criteria might explain age-related differences in the use of thrombolytic therapy. We examined data from the National Registry of Myocardial Infarction, a large registry of patients who have had acute myocardial infarctions and who were treated at selected U.S. hospitals.

Methods

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Data Sources

The National Registry of Myocardial Infarction included patients who had an acute myocardial infarction at selected U.S. hospitals from 1 July 1990 to 30 September 1994. The data collection process at each site and quality control features of the registry have been previously described [21].

By the close of the registry, 1249 U.S. hospitals were participating (19.6% of all U.S. hospitals). Participation in the registry was voluntary; each hospital received a small fee for each patient enrolled in the registry as reimbursement for the costs of data collection. Registry hospitals were significantly larger than nonparticipating hospitals (25% compared with 10% of the hospitals that have more than 400 beds). Registry hospitals were also more likely to be certified by the Joint Commission on Accreditation of Health Care Organizations (94% compared with 68%); more likely to be affiliated with a medical school (28% compared with 12%); and more likely to have an emergency department (99% compared with 74%), a coronary care unit (72% compared with 22%), a cardiac catheterization laboratory (61% compared with 16%), and a cardiac surgery program (38% compared with 9%).

Registry hospitals were encouraged to enter consecutive patients who had had acute myocardial infarction, regardless of treatment or outcome. However, hospitals participating in both the registry and the GUSTO trial were requested not to enter trial participants into the registry during the study period (27 December 1990 to 22 February 1993) so that the registry would more closely reflect actual clinical practice than treatment mandated by the GUSTO trial protocol.

Study Patients

Patients included in the registry had an acute myocardial infarction documented according to local hospital criteria, usually by cardiac enzyme levels or results of electrocardiography or coronary angiography. The diagnosis of acute myocardial infarction was not independently validated. Patients could have initially presented to a registry hospital or could have been transferred to a registry hospital from another acute-care facility.

Study Definitions

The method of diagnosis of acute myocardial infarction was characterized according to the following categories, which were not mutually exclusive: 1) initial electrocardiogram, 2) initial creatine kinase level, 3) subsequent electrocardiogram, and 4) serial creatine kinase determinations. On the basis of electrocardiographic findings, infarctions were characterized according to the following categories, which were also not mutually exclusive: anterior, inferior, posterior, lateral, subendocardial, nondiagnostic electrocardiogram (such as "nonspecific" ST-T wave abnormalities or no electrocardiographic evidence of acute myocardial infarction), and other [such as septal, right ventricular, or left bundle-branch block pattern]. We characterized infarction description according to the following hierarchical categories based on electrocardiographic findings: 1) anterior [may include any other specified category]; 2) inferior or posterior [may include any other specified category except anterior]; and 3) lateral (may include any other specified category except anterior, inferior, or posterior). Infarctions that did not fall into these categories were characterized as subendocardial (no location specified), nondiagnostic electrocardiogram, and other.

We characterized patients according to the use of the following medications at any time during hospitalization for the acute infarction: thrombolytic agents, aspirin, intravenous heparin, intravenous nitroglycerin, intravenous or oral ß-blocker therapy, calcium channel blockers, and inotropic agents. Procedures of interest included coronary arteriography, coronary angioplasty, and coronary artery bypass surgery.

We defined the time to hospital presentation as the interval between the time acute symptoms suggestive of acute myocardial infarction intensified or became prolonged to such an extent that the patient decided to seek treatment and the time the patient arrived at the registry hospital (or referral hospital if that was earlier).

Data Analysis

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We stratified patients into five age groups: younger than age 55 years, 55 to 64 years, 65 to 74 years, 75 to 84 years, and 85 years and older. Analyses were done for the entire study population and separately for men and women. We used chi-square tests for discrete variables to examine the statistical significance of differences in selected characteristics across patients in these five age groups.

We did logistic regression analyses to examine the independent association between patient age and the use of thrombolytic therapy [22]. In these models, patients younger than 55 years of age were the reference category (odds ratio, 1.0). In these models, we simultaneously controlled for the following variables: sex, diagnosis by initial electrocardiogram (compared with alternative method of diagnosis), infarction description, time to hospital presentation ( 6 hours compared with less than 6 hours), and period of the acute myocardial infarction event (1 July 1990 to 30 June 1991, 1 July 1991 to 30 June 1992, 1 July 1992 to 30 June 1993, and 1 July 1993 to 30 September 1994). All tests of statistical significance were two-tailed. We considered P values less than 0.05 to be statistically significant.

Results

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Patient Characteristics

The registry consisted of 350 755 patients who had had acute myocardial infarction: Fourteen percent had an infarction from 1 July 1990 to 30 June 1991; 21.3%, from 1 July 1991 to 30 June 1992; 28.8%, from 1 July 1992 to 30 June 1993; and 35.5%, from 1 July 1993 to 30 September 1994. These proportions reflect the involvement of an increasing number of hospitals over the study period. Information on age was available for 347 276 patients (99%); 22.8% were younger than age 55 years, 22.3% were aged 55 to 64 years, 28.3% were aged 64 to 74 years, 20.4% were aged 75 to 84 years, and 6.2% were aged 85 years or older. As shown in Table 1, older patients were significantly less likely to be male (P < 0.001). Older patients were less likely to be diagnosed on the basis of the initial electrocardiogram and were more likely to have a nondiagnostic electrocardiogram, a non-Q-wave infarction (with no location specified), or an electrocardiogram characterized as "other," a category that included left bundle-branch block (P < 0.001). These age-related differences in patient characteristics were consistent within groups stratified by sex Table 2 and Table 3.

Use of Medications and Invasive Procedures according to Age

Use of thrombolytic therapy decreased substantially with increasing patient age from 50.7% among patients younger than age 55 years to 7.4% among those aged 85 years or older (Table 1). Older patients were also less likely to receive aspirin, intravenous heparin, intravenous nitroglycerin, and oral and intravenous ß-blocker therapy. Use of calcium channel blockers was similar across the age groups. Older patients were more likely to receive an inotropic agent than were younger patients.

The use of invasive cardiac procedures also decreased substantially with increasing age. For example, coronary arteriography, coronary angioplasty, and bypass surgery were done in 72.5%, 31.2%, and 11.1%, respectively, of patients younger than age 55 years compared with 9.8%, 3.6%, and 1.4% of those aged 85 years or older.

We noted similar differences in the use of medications and invasive procedures among the five age groups in both men and women Table 2 and Table 3.

In-Hospital Case-Fatality Rates

In-hospital case-fatality rates increased from 2.7% among patients younger than age 55 years to 26.5% among those aged 85 years or older (Table 1). The relation between age and the short-term case-fatality rate was similar for men and women. The case-fatality rate increased from 2.2% for men younger than age 55 years to 26.2% for those aged 85 years or older (Table 2). The case-fatality rate increased from 4.4% for women younger than age 55 years to 26.6% for those aged 85 years or older (Table 3).

Temporal Trends in the Use of Thrombolytic Therapy

Increases in the use of thrombolytic therapy over time were greatest for patients in the oldest age groups (Table 4). For 1 July 1990 to 30 June 1991, 16.0% (1546 of 9662) of patients aged 75 to 84 years received a thrombolytic agent compared with 21.4% (5480 of 25 607) from 1 July 1993 to 30 September 1994, a 34% relative increase in use. Of the patients 85 years of age or older, 5.3% (147 of 2774) received a thrombolytic agent from 1 July 1990 to 30 June 1991; this percentage increased to 9.1% (769 of 8451) from 1 July 1993 to 30 September 1994, a 71.7% relative increase in use. We did not find similar relative increases in the use of thrombolytic therapy over time in the younger age groups. For example, among patients younger than 55 years of age, 52.2% (6095 of 11 676) received thrombolytic therapy during the first period compared with 50.6% (14 205 of 28 073) during the final period.

Older women had the greatest relative increases in the use of thrombolytic therapy over time. Of women aged 75 to 84 years, 14% (698 of 4916) received a thrombolytic agent from 1 July 1990 to 30 June 1991; this percentage increased to 20% (2557 of 12 785) from 1 July 1993 to 30 September 1994, a 40.9% relative increase in use. Of women 85 years of age or older, 4.2% (73 of 1738) received a thrombolytic agent from 1 July 1990 to 30 June 1991; this percentage increased to 8.8% (473 of 5375) from 1 July 1993 to 30 September 1994, a 109.5% relative increase in use.

We wanted to determine whether these differential increases in thrombolytic use by age and sex resulted from the fact that hospitals that began to participate in the registry in later years had higher rates of thrombolytic use in elderly patients than hospitals that began to participate earlier. We therefore did an analysis limited to a core group of 135 hospitals that began to participate during the first year (July 1990 to June 1991) and consistently enrolled at least 6 patients every 6 months until the close of the registry. From this core group of hospitals, data were available for 24 421 patients younger than age 55 years, 23 534 patients aged 55 to 64 years, 29 351 patients aged 65 to 74 years, 20 314 patients aged 75 to 84 years, and 6194 patients aged 85 years or older. Temporal trends in thrombolytic use by age and sex for these patients were similar to those for all patients.

Time to Hospital Presentation and Thrombolytic Use

The time from symptom onset to hospital presentation was reported for 74% of patients (n = 259 542). The proportion of patients for whom this information was available was inversely related to increasing patient age: for patients younger than age 55 years, 81%; for those aged 55 to 64 years, 77%; for those aged 65 to 74 years, 73%; for those aged 75 to 84 years, 68%; and for those aged 85 years or older, 63%. The mean time from symptom onset to hospital presentation increased with increasing patient age: 4.6 ± 7.0 hours for patients younger than age 55 years; 4.9 ± 7.2 hours for those aged 55 to 64 years; 5.3 ± 7.5 hours for those aged 65 to 74 years; 5.7 ± 7.8 hours for those aged 75 to 84 years; and 5.9 ± 7.9 hours for those aged 85 years or older.

As shown in Figure 1, top, the proportion of patients within each age group who presented to the hospital less than 6 hours after symptom onset decreased from 80% of those younger than age 55 years to 72% of those 85 years of age or older. Among patients presenting within 6 hours of acute symptom onset, thrombolytic use decreased from 63% of those younger than age 55 years to 12% of those aged 85 years or younger (Figure 1, top). Among patients who delayed hospital presentation for 6 hours or longer, thrombolytic use decreased from 26% of those younger than age 55 years to 4% of those aged 85 years or older (Figure 1, bottom). The relation between age and time to hospital presentation and thrombolytic use was similar for men and women.

View larger version (23K): [in this window] [in a new window]   Figure 1. Top. The proportions of all patients in each age group who had acute myocardial infarction and came to the hospital within 6 hours of symptom onset. Bottom. The proportions of all patients in each age group who had acute myocardial infarction and came to the hospital 6 or more hours after symptom onset. The percentages shown above the solid area of each bar represent the proportion of parents who received a thrombolytic agent.

Use of Thrombolytic Therapy and Patient Age

As shown in Table 5, the odds of receiving thrombolytic therapy were significantly reduced for all older age groups compared with patients younger than age 55 years; the odds ratio decreased to 0.23 (95% CI, 0.22 to 0.24) for those aged 75 to 84 years and 0.08 (CI, 0.07 to 0.09) for those aged 85 years or older. After adjustment for sex, diagnosis by initial electrocardiogram, infarction description, time to hospital presentation from symptom onset, and period of acute myocardial infarction, the odds ratios for each age group remained similar to the unadjusted estimates. The relation between age group and receipt of a thrombolytic agent was similar within groups stratified by sex (Table 5).

Discussion

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Our results are consistent with those of previous studies showing that thrombolytic therapy is far less likely to be used to manage older patients who have had acute myocardial infarction [14-16]. However, during our study period, proportionately greater increases were seen in the use of thrombolytic therapy among older patients compared with younger patients; this finding indicates an increased willingness to use these agents in the care of selected elderly patients who have had acute myocardial infarction. These increases were most prominent for older women, possibly reflecting the increased attention the medical community has given cardiovascular health in women [23, 24].

One proposed explanation for decreased use of thrombolytic therapy in older patients is that fewer elderly patients who present with acute myocardial infarction are eligible to receive it [25]. The time from the onset of symptoms suggestive of acute myocardial infarction to the administration of thrombolytic therapy appears to be the most critical factor with respect to the benefits of treatment. Thrombolytic therapy has been shown to be most beneficial when used in patients who present within 6 hours of symptom onset and with ST-segment elevation seen on electrocardiogram [10]. The 1990 American Heart Association and the American College of Cardiology guidelines on the early management of patients who have had acute myocardial infarction advise that thrombolytic therapy is acceptable for treating patients older than age 75 years, but only those who present within 6 hours of the onset of pain and with ST-segment elevation seen on electrocardiogram [26, 27]. As with patients of all ages, eligibility for therapy and the decision to use treatment in the elderly patient must be determined as early as possible in the course of infarction.

Using data derived from the Multicenter Chest Pain Study on 1584 patients who presented to hospital emergency departments with acute myocardial infarction between January 1984 and November 1986, Krumholz and colleagues [17] examined the relation between age and the proportion of patients who met conventional electrocardiographic and time-to-hospital presentation criteria for thrombolytic therapy. The proportion of these patients who arrived within 6 hours of the onset of pain and had ST-segment elevation or pathologic Q-waves not known to be old decreased significantly with increasing age, from 34% of patients younger than age 65 years to 18% of those aged 75 years and older. The major limitation of data from the Multicenter Chest Pain Study is that most events occurred before the "thrombolytic era" of acute myocardial infarction management.

We examined treatment patterns since 1990, and our findings similarly suggest that older patients are less likely to meet timing and electrocardiographic criteria for treatment than are younger patients. The availability of information on time from symptom onset to hospital presentation decreased with increasing patient age. Because the trigger for using thrombolytic therapy hinges so closely on an accurate determination of the time from onset of acute coronary symptoms, patients who have asymptomatic or atypical myocardial infarctions are essentially excluded from receiving this therapy. The proportion of events in this category tends to increase with advancing age [28-30]. Data from the Bronx Aging Study [31], a prospective study of community-based patients aged 75 years and older, indicate that more than 40% of myocardial infarctions in these patients are asymptomatic [31]. These observations suggest that even considering the use of thrombolytic therapy may not be possible in many older patients who have had acute myocardial infarction.

Among the patients in our study for whom information on the time from symptom onset was available, delay to hospital presentation was significantly greater for older patients. Furthermore, the initial electrocardiogram was less likely to suggest the diagnosis of acute myocardial infarction in older patients, implying increased difficulty in meeting electrocardiographic eligibility criteria and further extending the time from symptom onset to potential treatment with a thrombolytic agent. The more frequent electrocardiogram descriptions in older patients as "nondiagnostic" or "other" also suggest that ST-segment elevation may have appeared less commonly on the electrocardiograms of elderly patients who had had acute myocardial infarction. However, our findings also suggest that the increased frequency of ineligibility for thrombolytic therapy among older patients may not fully explain the differences in thrombolytic use that we saw across the age groups.

When we stratified patients by the time to hospital presentation, the proportion of patients receiving thrombolytic therapy decreased significantly with age, even among those presenting within 6 hours of symptom onset. We also explored the effect of various potential confounding variables on the relation between patient age and the use of thrombolytic therapy, including sex, method of diagnosing acute myocardial infarction, infarction description, period of the event, and the time from symptom onset to hospital presentation. Simultaneous adjustment for these factors did little to alter the negative effect of increasing patient age on the use of a thrombolytic agent. Recently published data from the Health Care Financing Administration's Health Care Quality Improvement Initiative on acute myocardial infarction are consistent with our findings of underuse of thrombolytic therapy in older patients [32, 33]. On the basis of a review of 16 124 hospitalizations for acute myocardial infarction, Ellerbeck and colleagues [33] reported that although many older patients may not be ideal candidates for thrombolytic therapy, this treatment is inadequately used even when no discernible contraindications are present.

We also noted that the use of other potentially beneficial therapies, including aspirin and ß-blockers, substantially decreased with advancing patient age. Although we did not fully assess patient eligibility for such treatments, these observations are consistent with those made in other population-based studies [34, 35]. Our findings indicate that age-related variation in the approach to the management of acute myocardial infarction is not unique to thrombolytic therapy. In view of the high short-term case-fatality rates in older patients who have had acute myocardial infarction, these data suggest that the overall approach to current patterns of management in this population should be thoroughly reassessed.

The limitations of the National Registry of Myocardial Infarction have been previously described [21]. Although more than 1000 hospitals from 49 U.S. states participated in the registry, these facilities tended to be larger and more procedure-oriented than hospitals not in the registry. Clinical data obtained on each patient were limited; no specific data were available on absolute and relative contraindications to the use of thrombolytic therapy, cardiovascular risk factors, indicators of infarction size, and the patient's comorbid conditions and functional status before myocardial infarction. Only limited qualitative electrocardiographic information was provided, and ST-segment elevation was not specifically characterized. Each site was individually responsible for identifying cases and collecting data. Nonconsecutive patient enrollment was possible, and data were not independently validated. Despite these limitations, the characteristics of this large study population (such as age, sex, time from symptom onset to hospital presentation, and case-fatality rates) compare favorably with recent findings from a large community-based study of acute myocardial infarction [3, 36].

In summary, recent data derived from the National Registry of Myocardial Infarction show trends toward the expanded use of thrombolytic therapy in elderly patients who have had acute myocardial infarction. However, substantial differences persist in the proportions of older and younger patients receiving treatment. Our findings suggest that these differences may not be completely explained by the degree to which older patients do not meet conventional electrocardiographic and time-to-presentation criteria for thrombolytic therapy. Although greater efforts are necessary to reduce the duration of prehospital delay and to expedite the diagnosis of acute myocardial infarction in older patients at hospital presentation, factors involved in the decision to administer thrombolytic therapy extend beyond the list of currently accepted eligibility criteria for treatment. Physicians' knowledge, beliefs, and attitudes about the benefits and risks of thrombolytic therapy should be assessed and correlated with current practice patterns so that a better understanding is achieved on the extent to which the use of these agents can be expanded beyond current levels in the geriatric population [37].

Drs. Gore and Goldberg: Department of Medicine, University of Massachusetts Medical Center, 55 Lake Avenue North, Worcester, MA 01655.

Dr. Rubison: Clin Trials Research, Inc., 2365 Harrodsburg Road, Suite A-290, Lexington, KY 40504.

Dr. Chandra: Johns Hopkins Bayview Medical Center, Division of Cardiology, 4940 Eastern Avenue, Baltimore, MD 21224-2780. Dr. Rogers: The University of Alabama at Birmingham, 334 Lyons-Harrison Research Building, 701 South 19th Street, Birmingham, AL 35294-0007.