Complications of fibrinolytic therapy in relation to age. Numbers above bars are numbers of patients.
Adjusted probability of death or cerebral bleeding in relation to fibrinolytic therapy in patients with ST-segment–elevation myocardial infarction who were 75 years or older (n = 6891) by multiple Cox regression analysis at the mean of all covariates; relative risk, 0.87; 95% confidence interval, 0.80 to 0.94; P = .001. Adjusted probability of death or cerebral bleeding in patients receiving and not receiving fibrinolytic therapy at 30 days was 23% and 26% and at 1 year was 32% and 36%, respectively.
Stenestrand U, Wallentin L, for the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA). Fibrinolytic Therapy in Patients 75 Years and Older With ST-Segment–Elevation Myocardial InfarctionOne-Year Follow-up of a Large Prospective Cohort. Arch Intern Med. 2003;163(8):965–971. doi:10.1001/archinte.163.8.965
Fibrinolytic therapy reportedly may not be beneficial in acute ST-segment–elevation myocardial infarction (STEMI) in patients who are 75 years and older.
The association between fibrinolytic therapy and 1-year mortality and bleeding complications in an unselected large cohort of patients with STEMI was evaluated by means of propensity and Cox regression analysis adjusting for multiple factors known to influence fibrinolytic therapy as well as survival. The Register of Information and Knowledge About Swedish Heart Intensive Care Admissions recorded every patient admitted to a coronary care unit in 64 hospitals during 1995 through 1999. One-year mortality was obtained by merging with the National Cause of Death Register.
A total of 6891 patients 75 years and older with first registry-recorded STEMI were included, of whom 3897 received fibrinolytic therapy and 2994 received no such treatment. Fibrinolytic therapy was associated with a 13% adjusted relative reduction in the composite of mortality and cerebral bleeding complications after 1 year (95% confidence interval, 0.80-0.94; P = .001). This effect seemed homogeneous among all subgroups based on age, sex, coronary risk factors, and previous disease manifestations.
Fibrinolytic therapy in patients with STEMI who are 75 years and older is associated with a reduction in the composite of mortality and cerebral bleedings after 1 year. These results from an unselected coronary care unit population support the use of fibrinolytic therapy in elderly patients.
SINCE THE LATE 1980s, reperfusion has been the standard treatment for ST-segment–elevation myocardial infarction (STEMI). In randomized trials of fibrinolytic therapy, the numbers of elderly patients have been small, although patients older than 75 years constitute about 30% of patients who have a myocardial infarction (MI) in the United States1 and 49% of those in Sweden.2 In the Fibrinolytic Therapy Trialists' Collaborative Group meta-analysis of all available data regarding placebo-controlled randomized trials of fibrinolysis in MI, 5754 of the patients were 75 years and older. In this elderly subgroup, there was only a nonsignificant trend toward benefit from fibrinolytic therapy.3 Thereafter, some reports support the benefit of fibrinolytic therapy in the elderly,4- 6 while others claim no benefit or even harmful effects in elderly patients.7,8 Recently, a registry study from the United States stated that fibrinolytic therapy in elderly patients with STEMI was associated with worse outcome than no fibrinolysis because of an increased risk of fatal bleedings not compensated for by a reduction in cardiac mortality.9 Therefore, we investigated the effects on 1-year mortality and severe bleeding complications of fibrinolytic therapy in a large cohort of unselected patients with acute STEMI at 75 years or older who were admitted to the coronary care units of Swedish hospitals during 1995 through 1999.
The Register of Information and Knowledge About Swedish Heart Intensive Care Admissions (RIKS-HIA) registers all patients admitted to the coronary care units of all participating hospitals. Information is reported on case record forms including 100 variables and has been described elsewhere.10 Briefly, the register includes information on age, sex, smoking status, hypertension, diabetes mellitus, hyperlipidemia, previous angina pectoris, previous MI, previous coronary revascularization, previous medications (previous refers to events occurring or medication started before the current admission), symptoms, electrocardiogram changes at entry, biochemical markers, echocardiography, reperfusion treatment, pharmacologic treatment, interventional procedures, major complications, and outcomes during the hospital stay; risk assessment with stress test, coronary angiography, and revascularization procedures; and medications at discharge. The ST segment was recorded as the first choice of which of the following alternatives accurately described the ST segment of the electrocardiogram: 1, normal; 2, left bundle-branch block or pacemaker; 3, ST-segment elevation; 4, ST-segment depression; 5, T-wave inversion; and 6, other changes. Bleeding complications were predefined in the protocol as follows: 1, fatal bleeding; 2, nonfatal cerebral bleeding; and 3, other major bleedings that demanded transfusion or surgery. (The full protocol is available at http://www.riks-hia.c.se.)
Source data were continuously verified by comparison of the registry information with the hospital's patient records in 50 randomly selected patients in 10 hospitals every year by an external monitor. In the first 1004 computer forms from 21 hospitals comprising 92 368 variables, there was 94% agreement overall between the registered information and the source data in the patient records.
One-year mortality data were obtained by merging the RIKS-HIA database with the National Cause of Death Register, which includes the vital status of all Swedish citizens in 1995 through 2000. At the time of our analyses, for the year 2000 only the death dates were available and not the causes, resulting in 38 cases (1.0%) in the fibrinolysis group and 54 cases (1.8%) in the no-reperfusion group that were missing data regarding cause of death. Previous history of stroke, dementia, renal failure, congestive heart failure, chronic pulmonary disease, or cancer were obtained by merging with the National Patient Register, which includes diagnoses on all patients hospitalized in Sweden from 1987 and forward. All patients for whom data were entered into the RIKS-HIA were informed of their participation in the registry (patients could request to be excluded from the registry) and the long-term follow-up. The registry and the merging with registries were approved by the National Board of Health and Welfare and the Swedish Data Inspection Board.
We included all patients admitted with ST-segment elevation on the electrocardiogram at entry and with acute MI as the final diagnosis. The criteria for the diagnosis of acute MI were standardized and identical for all participating hospitals, using the World Health Organization criteria.11 The biochemical criterion was at least 1 measurement indicating twice the upper limit of normal of an appropriate biochemical marker (usually creatine kinase MB protein concentration).
Different patient strata were compared by χ2 tests for categorical variables and by the t test for continuous variables. Multiple covariate Cox regression analyses were used to identify any variable with a significant influence on the combined end point of 1-year mortality or cerebral bleeding. For each patient, a propensity score12,13 indicating the likelihood of fibrinolytic therapy was calculated by forward logistic regression analysis including 22 covariates: age, sex, previous MI, history of diabetes mellitus, history of stroke, congestive heart failure, renal failure, chronic pulmonary disease, dementia, cancer within 3 years, history of hypertension, medications before study entry (including angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, anticoagulants, calcium-channel blockers, digitalis, diuretics, long-acting nitrates, and lipid-lowering drugs), circulatory arrest at arrival, hospital size (number of acute MI admissions per year <100, 100-199, 200-399, or ≥400), hospital access to catheterization laboratory, and admission year. Patients of all ages in the registry with their first diagnosis of MI and ST-segment elevation were included in the propensity score analysis. Goodness of fit of the propensity score was evaluated by the c statistic and the Hosmer-Lemeshow test. Smoking status, previous percutaneous coronary intervention or coronary artery bypass graft surgery, aspirin use, or β-blocker use before study entry had no significant influence on whether fibrinolytic therapy was performed and were not included in the propensity score analysis, but were part of the Cox regression survival analysis. All of the above variables, together with the individual propensity scores, congestive heart failure in the hospital, and atrial fibrillation, a total of 29 covariates, were forced into the multiple covariate Cox regression analyses evaluating the association of fibrinolytic therapy with the 30-day and 1-year outcome of all-cause mortality or cerebral bleeding. The same model, with 29 covariates, was also used in subgroups based on dichotomized risk factors, and analyses were also performed regarding cardiovascular mortality only. To ensure that coronary interventions after fibrinolysis and discharge medication did not alter the results, a Cox regression analysis was also performed concerning the same outcome in survivors at discharge, also including the covariates percutaneous coronary intervention or coronary artery bypass graft surgery while in the hospital, discharge medication (including angiotensin-converting enzyme inhibitor, intravenous or subcutaneous anticoagulants, oral anticoagulants, aspirin, β-blockers, calcium-channel blockers, digitalis, diuretics, long-acting nitrates, and statins) plus the previous 29 covariates, a total of 40 covariates. A separate backward logistic regression analysis, including the same 22 variables as in the propensity score, calculated the association between these variables and bleeding complications. All statistical analyses were performed with the SPSS Version 11.0 software (SPSS Inc, Chicago, Ill).
Nineteen hospitals participated in the registry in 1995, which increased gradually to 65 of all 81 Swedish hospitals in 1999. Data for this study were collected between 1995 and 1999, when a total of 50 779 admissions for acute MI to the 65 coronary care units were recorded with complete data. Of these, 19 052 were patients with their first recorded admission for STEMI during the registration period, which was considered the index event for follow-up in this study. The frequency of reperfusion treatment (fibrinolysis, acute percutaneous coronary intervention, or acute coronary artery bypass graft surgery) among the hospitals ranged from 61% to 88% (mean, 74%) for patients with STEMI who were younger than 75 years, and from 38% to 82% (mean, 57%) for those 75 years and older. The 3% of the elderly (≥75 years) patients with STEMI who were treated with primary acute percutaneous coronary intervention (n = 175) or acute coronary artery bypass graft surgery (n = 5) were not included in the present analyses, since the aim of this study was to evaluate pharmacologic vs no reperfusion treatment. The remaining 6891 patients older than 74 years with STEMI who were included in the registry for the first time constituted the study cohort.
The baseline characteristics of these patients with or without fibrinolytic therapy are shown in Table 1. Patients given fibrinolytic therapy were younger, more often men, and less likely to have diabetes mellitus, history of stroke, renal failure, congestive heart failure, dementia, cancer, hypertension, or previous MI. They also had fewer medications indicative of heart failure (angiotensin-converting enzyme inhibitors, digitalis, or diuretics) or previous coronary heart disease (aspirin, warfarin, or nitrates) at entry. The fibrinolytic-treated patients were more often treated with intravenous β-blockers and intravenous nitroglycerin, while there was no difference in the use of intravenous or subcutaneous anticoagulants. During hospital stay, atrial fibrillation was less prevalent, whereas reinfarction was more common among the fibrinolytic-treated patients (Table 2). Risk stratification by stress test, echocardiography, or coronary angiography and revascularization were performed more often after fibrinolysis. Among the hospital survivors, discharge prescriptions of β-blockers, aspirin, angiotensin-converting enzyme inhibitors, anticoagulants, and statins were more common in fibrinolytic-treated patients, whereas calcium-channel blockers, digitalis, diuretics, and long-acting nitrates were less often used.
Among the elderly patients with STEMI not treated with reperfusion, the unadjusted all-cause mortality was 24.1% (n = 723) at 14 days, 28.2% (n = 845) at 30 days, and 41.8% (n = 1251) at 1 year, compared with 21.2% (n = 828), 23.9% (n = 933), and 31.4% (n = 1225), respectively, in the fibrinolytic-treated patients. When the nonfatal cerebral bleedings were added to the mortality for the fibrinolytic therapy group, the figures were 21.4% (n = 833) at 14 days, 24.1% (n = 938) at 30 days, and 31.5% (n = 1228) at 1 year. Bleeding complications among fibrinolytic-treated patients older than 74 years were no different from those of the group aged 65 to 74 years. However, patients younger than 65 years had a lower bleeding rate (Figure 1). Lethal bleeding complications in the oldest age group were twice as prevalent in the group treated with alteplase, reteplase, or tenecteplase (1.0%) as compared with streptokinase (0.4%), while nonfatal cerebral bleeding had similar incidences (both 0.4%), as did other major bleeding (both 1.0%). The causes of deaths within 1 year after the acute MI differed significantly between the 2 groups, with a lower incidence of all causes in the fibrinolytic therapy group, except for stroke, the incidence of which was about the same in both groups (Table 3).
When the propensity score analysis for the likelihood of fibrinolytic therapy was calculated in patients with STEMI, age was the factor with the strongest influence on the use of this treatment. Thus, for every additional year of age there was a 2% lower likelihood of fibrinolytic therapy (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.98-0.99; P<.001). The second most important variable was the use of oral anticoagulants before inclusion, which reduced the likelihood of fibrinolytic therapy by 64% (OR, 0.36; 95% CI, 0.31-0.43; P<.001). History of stroke reduced the likelihood of fibrinolytic therapy by 40% (OR, 0.60; 95% CI, 0.55-0.66; P<.001). Hospitals with catheterization laboratories in house were less likely to use fibrinolytic therapy in the elderly (OR, 0.74; 95% CI, 0.68-0.79; P<.001). The remaining variables significantly related to no fibrinolytic therapy were (in descending strength of association) hospital size, circulatory arrest on arrival, congestive heart failure, renal failure, use of diuretics before inclusion, diabetes mellitus, cancer within 3 years, use of an angiotensin-converting enzyme inhibitor before inclusion, and previous MI. The goodness of fit of the propensity score was evaluated by the c statistic (area under the receiver operating characteristic curve, 0.66) and the Hosmer-Lemeshow test (χ2 = 20.94; P = .007). This indicates an acceptable level, but still there were things influencing the decision for fibrinolytic therapy not covered by our 22 variables. In the elderly patients the propensity score itself was associated with improved outcome (P<.001), and, hence, an increasing score identified patients with lower risk. Stratifying the patients older than 74 years into quartiles based on individual propensity scores produced similar means and SDs of the scores in the compared groups within all strata (Table 4). In the backward logistic regression analysis, the association between bleeding complications was significantly correlated to history of stroke (relative risk [RR], 6.56; 95% CI, 4.81-8.97; P<.001) and increasing age (RR, 1.08; 95% CI, 1.01-1.15; P = .03).
In Cox regression analysis, adjusting for the 29 covariates including the propensity score for fibrinolysis, the treatment was associated with a reduction in the combined variable of 1-year mortality and nonfatal cerebral bleeding among the elderly patients with STEMI (32% vs 36%; RR, 0.87; 95% CI, 0.80-0.94; P = .001) (Figure 2, Table 5). Exclusion of the propensity score variable from the analysis made no difference in the result. Adjusting for the propensity score only, fibrinolytic therapy was associated with improved 1-year outcome (RR, 0.82; 95% CI, 0.76-0.89; P<.001) in patients older than 74 years. In the individual propensity score quartiles, the adjusted RR for the combined outcome was between 0.83 and 0.92, although it did not reach statistical significance in all subgroups. Also, if only patients between 75 and 85 years of age were analyzed, the results were the same (RR, 0.86; 95% CI, 0.78-0.94; P = .001). However, in patients older than 85 years there tended to be less benefit from fibrinolytic therapy (RR, 0.94; 95% CI, 0.81-1.09; P = .4). In patients taking oral anticoagulants on inclusion, the fibrinolytic therapy did not appear to improve outcome (RR, 0.98; 95% CI, 0.61-1.59; P = .9). The overall benefit associated with fibrinolytic therapy was supported by the results of the Cox regression analyses in subgroups based on the most important factors related to mortality (Table 6). Thus, there were no indications of a heterogeneous response to fibrinolytic therapy with respect to sex, diabetes mellitus, previous MI, or congestive heart failure. The benefit associated with fibrinolytic therapy in the elderly was also supported by the results of the Cox regression analyses in hospital survivors (n = 5333) adding discharge medication, complications, and interventions in hospital to the list of covariates (RR, 0.69; 95% CI, 0.60-0.79; P<.001). This indicated that the higher proportion of β-blockers and antiplatelet therapy among fibrinolytic-treated patients did not cause the difference in long-term survival. Already at 30 days, a benefit from fibrinolytic therapy was evident for the combination of mortality and cerebral bleeding complications in patients aged 75 years and older (RR, 0.88; 95% CI, 0.79-0.98; P = .02). Also, when only cardiovascular deaths, fatal stroke, and nonfatal cerebral bleeding complications within 1 year were used as the combined end point in the Cox regression analyses, the result remained unchanged (RR, 0.92; 95% CI, 0.84-1.00; P = .04).
The method used by the current Swedish national registry for cardiac intensive care started in 1991 and has become a reliable source of information on consecutive patients admitted to participating units. It features an automated software control of data at data entry and a regular source data verification of random samples of patients at each center, ensuring an average 94% correctness of all entered variables and thus a high validity of the data used in the present analyses.
In this analysis of the effects of fibrinolytic therapy in patients with STEMI who were older than 74 years, the Cox regression analysis including a propensity score adjusting for the likelihood of treatment demonstrated a significant improvement in survival without intracranial hemorrhage. In accordance with the randomized trials,3,14,15 the difference appeared in the first month and then was sustained without further gain during long-term follow-up. The differences in basic characteristics between the fibrinolytic therapy and no-reperfusion groups were important to take into consideration, and this was emphasized by the fact that the propensity score variable in itself was associated with a significant relative risk reduction for death and cerebral hemorrhage (P<.001). This clearly demonstrated that patients treated with fibrinolysis were at a lower risk already at admission. By including the propensity score and 27 other covariates, we adjusted for all available factors that influenced the likelihood of fibrinolytic treatment as well as those that were related to survival. The credibility of our analysis was supported by the lack of heterogeneity between the quartiles of propensity score, although statistical significance was not reached in all groups. The validity of the results was further strengthened by the subgroup analyses. Thus, a homogeneous benefit from fibrinolytic therapy was observed among most subgroups in concordance with previous randomized trials.3,14,15 In agreement with results of randomized trials,16- 18 patients with a history of hypertension seemed to have less net benefit from thrombolytic therapy. Also in accordance with previous findings,19 the small number of patients taking oral anticoagulants at inclusion had less benefit from fibrinolytic treatment. These findings confirm that both history of hypertension and oral anticoagulant treatment should remain relative contraindications to fibrinolytic therapy.20 It is noteworthy that in patients older than 85 years there was no conclusive evidence of any benefit of fibrinolytic therapy in our study. However, neither was there any significant heterogeneity in the response even in the oldest patients.
The Fibrinolytic Therapy Trialists' study3 showed a nonsignificant benefit from fibrinolysis on 35-day mortality (24.3% compared with 25.3%) in patients 75 years and older, similar to our adjusted 30-day results of 23% and 26%. In the 2 Cooperative Cardiovascular Project studies,6,9 however, there was no survival benefit at 30 days. The intriguing thing is that the same Cooperative Cardiovascular Project population gave conflicting 1-year results, as Berger et al6 (n = 5754) showed survival benefit, whereas Thiemann et al9 (n = 2673) restricted the study to centers without invasive facilities and showed increased mortality from fibrinolysis in patients older than 75 years. This emphasizes how important the selection of patients is, and that is why we chose to include all patients in our study to avoid selection bias. In our analysis, not only mortality but also nonfatal intracranial bleeding was included in the end point, in contrast to the CCP studies. Even so, in our study both 30-day and 1-year outcomes were better for patients who received fibrinolytic therapy, although the overall event rate was slightly higher in our study. The higher event rate might have contributed to the benefit from fibrinolysis in our study, as the effect of any intervention tends to be more effective in patients at higher risk. In the Cooperative Cardiovascular Project studies, more exclusion criteria were applied and the early revascularization rates were considerably higher (32.5% and 20.4%, compared with 3.4% and 2.5% in our study), probably contributing to the better long-term outcome. On the other hand, the present study evaluated the effect of fibrinolytic therapy in an unselected population with almost no early revascularization, which is very similar to the strategy used in the placebo-controlled trials of fibrinolytic agents.3,14,15
Regarding severe complications of fibrinolysis, there was, in the present study, a higher incidence among patients 75 years and older compared with patients younger than 65 years. However, in comparison with patients aged 65 to 74 years, there was no significant difference. Since this was not a randomized trial, physician selection could have contributed to the low incidence of bleeding complications among patients 75 years and older. History of stroke increased the risk of bleeding complications more than 6 times, an even stronger relationship than in previous reports,16 and next to age it was also the second-strongest variable associated with no fibrinolytic therapy in patients with STEMI. Still, the subgroup of patients with a history of stroke did not experience any worse 1-year outcome when treated with fibrinolysis compared with patients who received no reperfusion. These findings indicate that, when used in accordance with the current guidelines, fibrinolytic therapy does not need to be a hazardous treatment even in elderly patients.
The most important limitations of this study are the nonrandomized assignment of treatment strategy and the possibility that unknown differences in the background characteristics between the groups contributed to the result. To address this concern, we used several multivariate methods to minimize the problems of bias inherent to observational studies.12,13 On the other hand, this study has the strength that no patient was excluded because of certain inclusion or exclusion criteria, which is always the case in controlled randomized trials. Thus, the present results reflect all the patients admitted in routine care for intensive coronary care. Evaluations of cause-specific mortality indicated no selection bias due to any specific diagnosis. Thus, when the analysis was confined to include only cardiovascular deaths or bleeding complications, the improved long-term outcome in the patients who received fibrinolytic therapy was further supported. Another limitation of this nationwide study is that cause of death is a clinical diagnosis in most cases, and that in only about 25% of these patients is an autopsy performed.
The main message from this large-scale registry study is that, in the majority of elderly patients, fibrinolytic therapy is associated with better outcome in the combined end point of 1-year mortality and bleeding complications. Until results from randomized trials on fibrinolytic therapy in this age group become available, there is no reason to withhold this treatment from the elderly because of age, at least not before the age of 85 years. On the contrary, our study, in an unselected STEMI population, indicates that fibrinolytic therapy might be lifesaving also in patients who are 75 years and older.
Corresponding author and reprints: Ulf Stenestrand, MD, Department of Cardiology, University Hospital of Linköping, SE 581 85 Linköping, Sweden (e-mail: firstname.lastname@example.org).
Accepted for publication July 29, 2002.
This study was supported by grants from the National Board of Health and Welfare, Stockholm, Sweden, the Federation of County Councils, Stockholm, and the Swedish Heart-Lung Foundation, Stockholm.
We thank all of the participating hospitals in Sweden for their help and cooperation in contributing data to RIKS-HIA. We also acknowledge Max Köster at the National Board of Health and Welfare for his support in merging the databases, and Lisa Wernroth at Statisticon, Uppsala, Sweden, for her statistical advice.
Alingsås, Avesta, Bollnäs, Borås, Eksjö, Enköping, Eskilstuna, Fagersta, Falun, Finspång, Gävle, Halmstad, Helsingborg, Huddinge, Hässleholm, Jönköping, Kalix, Kalmar, Karlshamn, Karlskoga, Karlskrona, Karlstad, Karolinska Hospital Stockholm, Katrineholm, Kristianstad, Kungälv, Köping, Lidköping, Lindesberg, Linköping, Ljungby, Ludvika, Lund, Lycksele, Malmö, Motala, Mölndal, Nacka, Norrköping, Norrtälje, Nyköping, Sahlgrenska Hospital Göteborg, Sala, Sandviken, Simrishamn, Skellefteå, Skene, Skövde, Sollefteå, St Görans Hospital Stockholm, Säffle, Södersjukhuset Stockholm, Trelleborg, Trollhättan, Uddevalla, Umeå, Uppsala, Varberg, Visby, Värnamo, Västervik, Västerås, Ängelholm, Örebro, and Östersund.