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Reperfusion therapy in elderly patients with acute myocardial infarction
Journal of the American College of Cardiology © 2002 by the American College of Cardiology Foundation Published by Elsevier Science Inc.
Vol. 39, No. 11, 2002 ISSN 0735-1097/02/$22.00 PII S0735-1097(02)01878-8
Reperfusion Therapy in Elderly Patients With Acute Myocardial Infarction A Randomized Comparison of Primary Angioplasty and Thrombolytic Therapy Menko-Jan de Boer, MD, Jan-Paul Ottervanger, MD, Arnoud W. J. van’t Hof, MD, Jan C. A. Hoorntje, MD, Harry Suryapranata, MD, Felix Zijlstra, MD, on behalf of the Zwolle Myocardial Infarction Study Group Zwolle, the Netherlands This study sought to determine the short- and long-term outcome of primary coronary angioplasty and thrombolytic therapy for acute myocardial infarction (AMI) in patients older than 75 years of age. BACKGROUND The benefit of reperfusion therapy in elderly patients with AMI is uncertain, although elderly people account for a large proportion of deaths. METHODS We randomly assigned a total of 87 patients with an AMI who were older than 75 years to treatment with angioplasty or intravenous (IV) streptokinase. Clinical outcome was measured by taking the end points of death and the combination of death, reinfarction or stroke during follow-up. RESULTS The primary end point, a composite of death, reinfarction or stroke, at 30 days had occurred in 4 (9%) patients in the angioplasty group as compared with 12 (29%) in the thrombolysis group (p ⫽ 0.01, relative risk [RR]: 4.3, 95% confidence interval [CI]: 1.2 to 20.0). At one year the corresponding figures were 6 (13%) and 18 (44%), respectively (p ⫽ 0.001, RR: 5.2, 95% CI: 1.7 to 18.1). CONCLUSIONS In this series of patients with AMI who were older than 75 years, primary coronary angioplasty had a significant clinical benefit when compared with IV streptokinase therapy. (J Am Coll Cardiol 2002;39:1723– 8) © 2002 by the American College of Cardiology Foundation OBJECTIVES
Mortality among older patients with acute myocardial infarction (AMI) is higher than for patients of younger age (1–5). Reperfusion therapy may improve survival, but the effectiveness of thrombolytic therapy in elderly patients has recently been questioned (6 – 8). Primary coronary angioplasty is an alternative tool to accomplish reperfusion of the infarct-related vessel (IRV) with at least equal or greater clinical benefit, and with a lower risk of intracerebral hemorrhage, when compared with thrombolytic therapy (9 –12). On the other hand, percutaneous coronary interventions carry an increased procedural risk in older patients when compared with those of younger age (13). An analysis See page 1729 of data from the Primary Angioplasty for Myocardial Infarction (PAMI), the Zwolle and the Mayo Clinic studies suggests a stronger benefit of primary angioplasty over thrombolytic therapy with increasing age (14). However, the place of primary coronary angioplasty in elderly patients with AMI has not yet been determined in a randomized comparison, as most studies recruited only few elderly patients. We performed a prospective randomized trial From the Department of Cardiology, Isala Clinics location “de Weezenlanden,” Zwolle, the Netherlands. Manuscript received July 12, 2001; revised manuscript received March 4, 2002, accepted March 13, 2002.
comparing primary coronary angioplasty with intravenous (IV) streptokinase therapy in patients with AMI and 76 years or older and no contraindications for thrombolytic therapy. We chose streptokinase as the thrombolytic drug in our study because the risk of stroke is lower with this agent, and it is still the most widely used pharmacologic reperfusion therapy in the Netherlands (15).
METHODS From March 1996 until April 1999, 87 patients of 76 years or older referred to our hospital directly with AMI and without contraindications for thrombolytic therapy were randomly assigned to treatment with IV streptokinase or immediate angiography and, if possible, subsequent angioplasty. All patients admitted to our coronary care unit with the diagnosis of AMI who were 76 years or older, but not fulfilling the study inclusion criteria, were registered in a separate database. Inclusion criteria were as follows: symptoms of AMI that persisted for more than 30 min accompanied by an elevation of more than 1 mm (0.1 mV) in the ST segment in two or more contiguous electrocardiographic leads; and presentation within 6 h after the onset of symptoms (or between 6 h and 24 h, if there was evidence of continuing ischemia). Contraindication to thrombolytic therapy was defined as previous stroke or other known intracranial disease, recent trauma or surgery, refractory hypertension (systolic
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Abbreviations and Acronyms AMI ⫽ acute myocardial infarction CI ⫽ confidence interval ECG ⫽ electrocardiogram IRV ⫽ infarct-related vessel IV ⫽ intravenous LDH ⫽ lactate dehydrogenase PAMI ⫽ Primary Angioplasty for Myocardial Infarction study RR ⫽ relative risk TIMI ⫽ Thrombolysis In Myocardial Infarction
ⱖ 180 mm Hg, diastolic ⱖ 110 mm Hg), active bleeding or prolonged cardiopulmonary resuscitation. Before randomization we recorded each patient’s age, gender, Killip class on admission (16), electrocardiographic site of infarction, history of previous infarction, heart rate, time of onset of symptoms and time of hospital admission. The catheterization laboratory and the dedicated house staff were available 24 h, 7 days a week. All patients received 450 mg of aspirin intravenously, followed by 80 mg of aspirin per day orally and IV nitroglycerin in a dose designed to maintain a systolic blood pressure of 110 mm Hg. Intravenous heparin was given in a dose designed to maintain the activated partial thromboplastin time between two and three times the normal value for at least two days. This partial thromboplastin time was measured twice a day. Patients assigned to streptokinase received 1.5 million U intravenously over a period of 1 h. In patients assigned to angioplasty treatment, coronary angiography was performed as soon as possible. Both coronary arteries were visualized; left ventriculography was not performed routinely. Coronary angioplasty was performed at the investigator’s discretion using any approved techniques and devices. Patients who received a stent were treated with ticlopidine, 250 mg, twice a day for two weeks. All cineangiograms were reviewed by two experienced investigators not involved in other parts of the study. Flow through the IRV was scored according to the Thrombolysis In Myocardial Infarction (TIMI) flow grading, before and after the angioplasty procedure (17). Agreement on flow and extent of coronary artery disease was reached in all cases. The time from admission to the initiation of therapy was calculated as the time to the start of the streptokinase infusion or the first balloon inflation. Recurrent AMI was defined as chest pain, changes in the ST-T segment and a second increase in the creatine kinase level to more than two times the upper limit of normal or an increase of ⬎200 U/l over the previous value if the level had not dropped below the upper limit of normal. The primary end point was the composite of death, reinfarction or stroke at 30 days after randomization. The secondary end points were: 1. The composite of death, reinfarction and stroke at one year.
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2. Enzymatic infarct size as was calculated from lactate dehydrogenase (LDH) release in the plasma during the first 72 h after symptom onset. This method is equal to estimation of infarct size from a-hydroxybutyrate dehydrogenase and has previously been described in detail (18). Cumulative enzyme release from five to seven serial measurements up to 72 h after symptom onset was calculated with blinding to all data other than hospital registration number and date of birth. 3. Left ventricular ejection fraction, as was measured before discharge by radionuclide ventriculography using the multiple gated equilibrium method following the labelling of red blood cells of the patient with 99mTcpertechnetate. A General Electric 300 gamma camera with a low-energy all-purpose parallel-hole collimator was used. Global ejection fraction was calculated by a General Electric Star View (Milwaukee, Wisconsin) computer using the fully automatic PAGE program. The use of this software program protects against operator bias. This technique has been validated by us before (18). The study protocol was approved by the institutional ethics committee, and all patients gave oral informed consent. Before randomization it was ascertained that a catheterization laboratory was immediately available for coronary intervention. Randomization was performed using a telephone randomization service and was stopped early (April 1999) because a significant difference in the primary end point was found. Follow-up data were collected in March 2000. All clinical and outpatient records were reviewed, and general practitioners were contacted by telephone. Statistical analysis. All end points were analyzed according to the principle of intention-to-treat. A chi-square statistic was calculated to test differences between proportions with calculations of relative risks (RR) and exact 95% confidence intervals (CIs). Fisher exact test was used if there was an expected cell value of ⬍5. The Student t test or the Mann-Whitney U test was used to compare continuous values. Survival and survival without recurrent infarction or stroke were calculated by the Kaplan-Meier product-limit method (19). Survival analysis over the total follow-up period was also performed by fitting Cox proportional hazards model (20). Because of the small sample size, this was not used as a multivariate model but enabled us to calculate hazard ratios, which may be interpreted as RRs, with 95% CIs. Continuous variables are summarized by using medians (with 25th, 75th percentiles) unless otherwise indicated; discrete variables are represented as frequencies and percentages. A p value of ⱕ0.05 was considered to indicate statistical significance. The sample size was estimated on the basis of the following assumption: the 30-day incidence of death, reinfarction or stroke in the thrombolysis group would be 30%, whereas this incidence in the angioplasty group would be 15% (14,21). At alpha-level 5% and beta-level 20%, the
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Table 1. Baseline and Clinical Characteristics of the Two Patient Groups
Age, yrs Male gender, n (%) Systemic hypertension, n (%) Diabetes mellitus, n (%) Previous AMI, n (%) Anterior AMI, n (%) Previous CABG, n (%) Killip class III or IV, n (%) Heart rate on admission, beats/min Systolic blood pressure, mm Hg Time onset–admission, min (range) Multivessel disease, n (%) Initial TIMI flow grade IRV, n (%) 0 1 2 3
Angioplasty (n ⴝ 46)
p Value
Streptokinase (n ⴝ 41)
80 (77–84) 22 (48) 12 (27) 11 (24) 6 (13) 23 (50) 3 (7) 6 (13) 69 (55–78) 120 (100–145) 207 (60–1,020) 39 (87)
0.17 0.31 0.86 0.60 0.82 0.89 0.47 0.74 0.74 0.34 0.62 —
81 (78–84) 25 (61) 10 (24) 7 (17) 7 (17) 19 (46) 4 (10) 4 (10) 65 (50–80) 120 (100–140) 212 (25–700) —
30 (67) 4 (9) 6 (13) 5 (11)
Values presented are as median and 25th and 75th percentiles or number (%), unless stated otherwise. AMI ⫽ acute myocardial infarction; CABG ⫽ coronary artery bypass grafting; IRV ⫽ infarct-related vessel; TIMI ⫽ Thrombolysis In Myocardial Infarction.
number of patients required was 266, with 133 patients in each group.
RESULTS During the study period, a total number of 164 patients older than 75 years and with the diagnosis of AMI were admitted to our hospital. Of these patients, 87 fulfilled the criteria for inclusion in our study. Of the patients randomized, 46 were assigned to primary angioplasty treatment and 41 patients were assigned to treatment with streptokinase. The baseline characteristics are summarized in Table 1, and the two patient groups were well balanced with regard to the most important determinants of mortality and morbidity. Six patients in the group assigned to angioplasty and four in the streptokinase group were randomized more than 6 h after symptom onset (p ⫽ 0.7). Patients were followed for a mean of 20 ⫾ 6 months, and no patient was lost to follow-up. The clinical results are given in Table 2. The mean time from hospital admission to start of streptokinase infusion was 31 ⫾ 15 min. Of the patients randomized to invasive treatment, 45 underwent coronary angiography, and 41 actually underwent angioplasty with a procedural success rate of 90% (37 of 41), defined as a residual stenosis of the culprit lesion of ⬍50% and TIMI 3 flow through the IRV. One patient died before angiography could be performed. Two patients were referred for bypass surgery, and in two patients a conservative treatment was chosen. Four strokes occurred, one in the angioplasty group (one week after treatment with an intra-aortic balloon pump) and three in the streptokinase group (all on the day of treatment), of whom one died. Of the patients treated with angioplasty, 51% (21 of 41) did receive a stent, whereas the remaining patients underwent balloon angioplasty only. None of the study patients received glycoprotein IIb/IIIa inhibitors during the study period. The mean time from hospital admis-
sion to first balloon inflation was 59 ⫾ 19 min (range: 33 to 120 min). One patient in each group was treated with an intra-aortic balloon counterpulsation device in the immediate postinfarction period. After 30 days, three patients (7%) in the angioplasty group died, compared with nine patients (22%) in the thrombolysis group (p ⫽ 0.04), resulting in an RR for patients treated with thrombolysis of 4.0 (95% CI: 0.9 to 24.6) compared with patients treated with primary angioplasty. The composite predefined end point of death, recurrent infarction and stroke at 30 days occurred in 4 (9%) Table 2. Clinical Course of the Two Patient Groups Angioplasty (n ⴝ 46) Mortality in-hospital, 3 (7) n (%) Stroke, n (%) 1 (2) Recurrent AMI, n (%) 1 (2) Bleeding (noncerebral) 5 (11) Maximum CK 829 (422–1,425) LDH Q72 1,442 (781–2,022) Days on CCU 2 (1–3) Total days in hospital 5 (3–10) Number of readmissions 13 Ejection fraction %, 43 ⫾ 10 mean ⫾ SD Additional CABG/PTCA, 2 (4) n (%) Death during follow-up, 7 (15) n (%) Combined clinical end 9 (20) point during follow-up, (death, stroke or reinfarction), n (%)
p Value
Streptokinase (n ⴝ 41)
0.07
8 (20)
0.34 3 (7) 0.01 6 (15) 0.72 3 (7) 0.71 997 (448–1,568) 0.10 1,772 (996–2,672) 0.003 2 (2–3) 0.95 5 (3–10) 0.29 9 0.34 44 ⫾ 11 0.41
4 (10)
0.04
13 (32)
0.01
18 (44)
Values presented are as median and 25th and 75th percentiles or number (%), unless stated otherwise. AMI ⫽ acute myocardial infarction; CABG ⫽ coronary artery bypass grafting surgery; CCU ⫽ Coronary Care Unit; CK ⫽ creatine kinase; LDH Q72 ⫽ lactate dehydrogenase release in the plasma during the first 72 h after symptom onset; PTCA ⫽ percutaneous transluminal coronary angioplasty.
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JACC Vol. 39, No. 11, 2002 June 5, 2002:1723–8 Table 3. Characteristics and In-Hospital Outcome of the Study and the Registry Patients
Age, yrs, median (25–75 p) Male gender, n (%) Systemic hypertension, n (%) Diabetes mellitus, n (%) Previous AMI, n (%) Anterior AMI, n (%) Previous CABG, n (%) Killip class III or IV, n (%) In-hospital mortality In-hospital reinfarction Stroke Figure 1. The Kaplan-Meier curve compares the overall survival for patients randomized for angioplasty treatment (solid line) and thrombolysis treatment (dashed line) during 24 ⫾ 6 months of follow-up (p ⫽ 0.04, relative risk: 2.5, 95% confidence interval: 1.0 to 6.2).
patients in the angioplasty treated patients versus 12 (29%) in the thrombolysis group (p ⫽ 0.01, RR: 4.3, 95% CI: 1.2 to 20.0). Survival and survival without the combined clinical end point curves are depicted in Figures 1 and 2. Follow-up was complete in all patients. After one year, 5 patients (11%) in the angioplasty group and 12 patients (29%) in the thrombolysis group had died (p ⫽ 0.03), resulting in an RR for patients treated with thrombolysis of 3.4 (95% CI: 1.0 to 13.5) compared with patients treated with primary angioplasty. The corresponding figures for the composite end point after one year were 6 (13%) and 18 (44%), respectively (p ⫽ 0.001, RR: 5.2, 95% CI: 1.7 to 18.1). The significant difference in reaching the primary end point between the two groups was the reason to end the study before the anticipated number of patients was included. During the total follow-up period (mean: 24 months),
Randomized (n ⴝ 87)
p Value
Excluded Registry (n ⴝ 77)
80 (78–84) 47 (54) 22 (25) 18 (21) 13 (15) 42 (48) 7 (8) 10 (11) 11 (13) 7 (8) 4 (5)
0.02 0.78 0.23 0.24 0.008 0.89 0.77 0.07 0.23 0.14 1.0
78 (77–82) 39 (51) 15 (19) 10 (13) 26 (34) 35 (51)* 5 (6) 14 (18) 16 (21) 13 (17) 3 (4)
*In eight patients the localization of the infarct was not possible. AMI ⫽ acute myocardial infarction; CABG ⫽ coronary artery bypass grafting surgery.
there were 20 deaths: 7 (15%) in the angioplasty group and 13 (32%) in the streptokinase group (p ⫽ 0.04, RR: 2.5, 95% CI: 1.0 to 6.2). The corresponding figures for the composite end point were 9 (20%) and 18 (44%), respectively (p ⫽ 0.003, RR: 3.1, 95% CI: 1.4 to 7.0). The Kaplan-Meier curves are depicted in Figures 1 and 2. The in-hospital mortality of the 77 patients not included in our study was 21%, and their baseline characteristics are given in Table 3. They were compared with baseline characteristics and in-hospital outcome of the study patients. Six patients retrospectively fulfilled the criteria for study entry but were not randomized. The reasons for not including patients in the study were: not fulfilling the electrocardiogram (ECG) criteria, 27 patients; contraindications for thrombolysis, 23 patients; beyond the study time window, 11 patients; referral from other hospitals for rescue angioplasty, 5 patients; already participating in other study, 3 patients; and subacute stent thrombosis, 2 patients.
DISCUSSION
Figure 2. The Kaplan-Meier curve compares the overall survival free of recurrent infarction or stroke for patients randomized for angioplasty treatment (solid line) and thrombolysis treatment (dashed line) during 24 ⫾ 6 months of follow-up (p ⫽ 0.003, relative risk: 3.1, 95% confidence interval: 1.4 to 7.0).
We conducted a randomized trial in elderly patients, comparing thrombolytic therapy and primary coronary angioplasty for the treatment of AMI. The benefit with regard to 30-day survival did reach statistical significance (p ⫽ 0.04, RR: 4.0, 95% CI: 0.9 to 24.6), and the incidence of the predefined composite end point of death, recurrent infarction and stroke after 30 days was significantly lower in the angioplasty treated patient group (p ⫽ 0.01, RR: 4.3, 95% CI: 1.2 to 20.0). This was the reason why the study was halted prematurely. The long-term follow-up data showed a statistically significant benefit with regard to survival after one year (p ⫽ 0.03, RR: 3.4, 95% CI: 1.0 to 13.5) and the combined clinical end point of death, recurrent AMI or stroke (p ⫽ 0.001, RR: 5.2, 95% CI: 1.7 to 18.1) of angioplasty treatment over thrombolytic therapy. In the initial phase after the index infarction, infarct size, as was estimated from cumulative LDH release in the
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plasma, was lower in the angioplasty treated patients, although this did not reach the level of significance. There was no difference in mean ejection fraction measured with radionuclide techniques between the two groups. This apparent lack of benefit with regard to direct myocardial salvage may be a similar finding as was observed when comparing thrombolytic therapy with placebo treatment (22). In our experience with angioplasty, we did not encounter specific age-related problems with performing angioplasty in old patients as was reflected in the short time from hospital admission to first balloon inflation. All noncerebral bleedings in the angioplasty group were related to the arterial puncture site, and this occurs more frequently in the elderly (13). The main reason for excluding patients from our study was the high incidence of nonconclusive ECGs, and the number of patients with previous AMI in this group was significantly higher. Other studies. Recently, the benefits of thrombolytic therapy in the elderly were questioned based on data from the Medicare Cooperative Cardiovascular Project registry (8). This observational survey concerned 7,864 patients age 76 to 86 years from a retrospective cohort study but does not represent randomized data. Although older patients from the same registry, who received thrombolytic therapy or primary angioplasty, had a lower mortality at one year compared with those who did not receive a reperfusion strategy, only those treated with primary angioplasty had better survival at 30 days (23,24). The number of elderly patients with symptomatic coronary artery disease and the relative number of older patients being treated in Western society is steadily increasing (25–27). Approximately 30% of all patients presenting with AMI are ⬎75 years old (27). However, in most studies of reperfusion therapy in AMI, elderly people are excluded or represent a very small minority of the study population. In a pooled analysis of three randomized studies of primary angioplasty versus thrombolysis in elderly patients (⬎70 years), angioplasty was more effective (14). Furthermore, the high incidence of comorbidity and contraindications for thrombolytic therapy makes primary angioplasty an attractive reperfusion modality in this patient group. On the other hand, data from a recently published pooled analysis of the PAMI study group indicate that elderly patients still remain at an increased risk of death, bleeding, stroke and other complications despite treatment with primary angioplasty (28). Some limitations of our study should be noted. In contrast with multicenter trials that have included large numbers of patients undergoing reperfusion therapy for AMI, our study included only 87 patients from a single institution. A trial comparing angioplasty with pharmacologic reperfusion therapy cannot be blinded. Furthermore, the high success rates associated with primary angioplasty and subsequent clinical outcome are directly related to
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technical skills and experience of operators in high volume interventional centers (29 –31). Conclusions. In this series of patients with AMI who were older than 75 years, primary coronary angioplasty had a significant clinical benefit when compared with IV streptokinase therapy. Our data stress the need for a large community-based multicenter trial to confirm our conclusion that primary coronary angioplasty may be the reperfusion therapy of choice in elderly patients. Acknowledgments The authors are indebted to the many general practitioners in our region for their speedy referral of patients with AMI and for their superb assistance in obtaining follow-up information. Reprint requests and correspondence: Dr. Menko-Jan de Boer, Department of Cardiology, Isala Klinieken lokatie “de Weezenlanden,” Groot Wezenland 20, 8011 JW, Zwolle, the Netherlands. E-mail: [email protected].
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12. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1,000 patients. Lancet 1994;343:311–22. 13. Batchelor WB, Anstrom KJ, Muhlbaier LH, et al., for the National Cardiovascular Network Collaboration. Contemporary outcome trends in the elderly undergoing percutaneous coronary interventions: results in 7,472 octogenarians. J Am Coll Cardiol 2000;36:723–30. 14. O’Neill WW, de Boer MJ, Gibbons RJ, et al. Lessons from the pooled outcome of the PAMI, Zwolle and Mayo clinic randomized trials of primary angioplasty versus thrombolytic therapy of acute myocardial infarction. J Invasive Cardiol 1998;10:4 –10. 15. White HD. Selecting a thrombolytic agent. Cardiol Clin 1995;13: 347–54. 16. Killip T III, Kimball JT. Treatment of myocardial infarction in a coronary care unit: a two year experience with 250 patients. Am J Cardiol 1967;20:457–64. 17. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis In Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation 1987;76:142–54. 18. de Boer MJ, Suryapranata H, Hoorntje JCA, et al. Limitation of infarct size and preservation of left ventricular function after primary coronary angioplasty compared with intravenous streptokinase in acute myocardial infarction. Circulation 1994;90:753–61. 19. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–80. 20. Cox DR. Regression models and life tables. J R Stat Society 1972;34: 187–220. 21. Bueno H, Vidan MT, Almazan A, Lopez-Sendon JL, Delcan JL. The influence of sex on the short-term outcome of elderly patients with a first myocardial infarction. Circulation 1995;92:1133–40.
JACC Vol. 39, No. 11, 2002 June 5, 2002:1723–8 22. van de Werf F. Discrepancies between the effects of coronary reperfusion on survival and left ventricular function. Lancet 1989;1:1367–8. 23. White HD. Thrombolytic therapy in the elderly. Lancet 2000;356: 2028 –30. 24. Berger AK, Radford MJ, Wang Y, Krumholz HM. Thrombolytic therapy in older patients. J Am Coll Cardiol 2000;36:366 –74. 25. Dalstra JAA, Reitsma JB. Coronary Artery Disease and Atherosclerosis in the Netherlands, 1997. Data on Morbidity and Mortality. The Hague, the Netherlands: The Netherlands Heart Foundation, 1997. 26. Thompson RC, Holmes DR. Percutaneous transluminal coronary angioplasty in the elderly. Clin Geriatr Med 1996;12:181–94. 27. Goldberg RJ, McCormick D, Gurwtz JH, et al. Age-related trends in short- and long-term survival after myocardial infarction: a 20-year population-based perspective (1975–1995). Am J Cardiol 1998;82: 1311–7. 28. DeGeare VS, Stone GW, Grines L, et al. Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the Primary Angioplasty in Myocardial Infarction trials). Am J Cardiol 2000;86:30 –4. 29. Jollis JG, Peterson ED, DeLong ER, et al. The relation between the volume of coronary angioplasty procedures at hospitals treating medicare beneficiaries and short-term mortality. N Engl J Med 1994;331: 1625–9. 30. Canto JG, Every NR, Magid DJ, et al., for the National Registry of Myocardial Infarction-2 Investigators. The volume of primary angioplasty procedures and survival after acute myocardial infarction. N Engl J Med 2000;342:1573–80. 31. Vakili BA, Kaplan R, Brown DL. Volume-outcome relation for physicians and hospitals performing angioplasty for acute myocardial infarction in New York state. Circulation 2001;104:2171–6.
Vol. 39, No. 11, 2002 ISSN 0735-1097/02/$22.00 PII S0735-1097(02)01878-8
Reperfusion Therapy in Elderly Patients With Acute Myocardial Infarction A Randomized Comparison of Primary Angioplasty and Thrombolytic Therapy Menko-Jan de Boer, MD, Jan-Paul Ottervanger, MD, Arnoud W. J. van’t Hof, MD, Jan C. A. Hoorntje, MD, Harry Suryapranata, MD, Felix Zijlstra, MD, on behalf of the Zwolle Myocardial Infarction Study Group Zwolle, the Netherlands This study sought to determine the short- and long-term outcome of primary coronary angioplasty and thrombolytic therapy for acute myocardial infarction (AMI) in patients older than 75 years of age. BACKGROUND The benefit of reperfusion therapy in elderly patients with AMI is uncertain, although elderly people account for a large proportion of deaths. METHODS We randomly assigned a total of 87 patients with an AMI who were older than 75 years to treatment with angioplasty or intravenous (IV) streptokinase. Clinical outcome was measured by taking the end points of death and the combination of death, reinfarction or stroke during follow-up. RESULTS The primary end point, a composite of death, reinfarction or stroke, at 30 days had occurred in 4 (9%) patients in the angioplasty group as compared with 12 (29%) in the thrombolysis group (p ⫽ 0.01, relative risk [RR]: 4.3, 95% confidence interval [CI]: 1.2 to 20.0). At one year the corresponding figures were 6 (13%) and 18 (44%), respectively (p ⫽ 0.001, RR: 5.2, 95% CI: 1.7 to 18.1). CONCLUSIONS In this series of patients with AMI who were older than 75 years, primary coronary angioplasty had a significant clinical benefit when compared with IV streptokinase therapy. (J Am Coll Cardiol 2002;39:1723– 8) © 2002 by the American College of Cardiology Foundation OBJECTIVES
Mortality among older patients with acute myocardial infarction (AMI) is higher than for patients of younger age (1–5). Reperfusion therapy may improve survival, but the effectiveness of thrombolytic therapy in elderly patients has recently been questioned (6 – 8). Primary coronary angioplasty is an alternative tool to accomplish reperfusion of the infarct-related vessel (IRV) with at least equal or greater clinical benefit, and with a lower risk of intracerebral hemorrhage, when compared with thrombolytic therapy (9 –12). On the other hand, percutaneous coronary interventions carry an increased procedural risk in older patients when compared with those of younger age (13). An analysis See page 1729 of data from the Primary Angioplasty for Myocardial Infarction (PAMI), the Zwolle and the Mayo Clinic studies suggests a stronger benefit of primary angioplasty over thrombolytic therapy with increasing age (14). However, the place of primary coronary angioplasty in elderly patients with AMI has not yet been determined in a randomized comparison, as most studies recruited only few elderly patients. We performed a prospective randomized trial From the Department of Cardiology, Isala Clinics location “de Weezenlanden,” Zwolle, the Netherlands. Manuscript received July 12, 2001; revised manuscript received March 4, 2002, accepted March 13, 2002.
comparing primary coronary angioplasty with intravenous (IV) streptokinase therapy in patients with AMI and 76 years or older and no contraindications for thrombolytic therapy. We chose streptokinase as the thrombolytic drug in our study because the risk of stroke is lower with this agent, and it is still the most widely used pharmacologic reperfusion therapy in the Netherlands (15).
METHODS From March 1996 until April 1999, 87 patients of 76 years or older referred to our hospital directly with AMI and without contraindications for thrombolytic therapy were randomly assigned to treatment with IV streptokinase or immediate angiography and, if possible, subsequent angioplasty. All patients admitted to our coronary care unit with the diagnosis of AMI who were 76 years or older, but not fulfilling the study inclusion criteria, were registered in a separate database. Inclusion criteria were as follows: symptoms of AMI that persisted for more than 30 min accompanied by an elevation of more than 1 mm (0.1 mV) in the ST segment in two or more contiguous electrocardiographic leads; and presentation within 6 h after the onset of symptoms (or between 6 h and 24 h, if there was evidence of continuing ischemia). Contraindication to thrombolytic therapy was defined as previous stroke or other known intracranial disease, recent trauma or surgery, refractory hypertension (systolic
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Abbreviations and Acronyms AMI ⫽ acute myocardial infarction CI ⫽ confidence interval ECG ⫽ electrocardiogram IRV ⫽ infarct-related vessel IV ⫽ intravenous LDH ⫽ lactate dehydrogenase PAMI ⫽ Primary Angioplasty for Myocardial Infarction study RR ⫽ relative risk TIMI ⫽ Thrombolysis In Myocardial Infarction
ⱖ 180 mm Hg, diastolic ⱖ 110 mm Hg), active bleeding or prolonged cardiopulmonary resuscitation. Before randomization we recorded each patient’s age, gender, Killip class on admission (16), electrocardiographic site of infarction, history of previous infarction, heart rate, time of onset of symptoms and time of hospital admission. The catheterization laboratory and the dedicated house staff were available 24 h, 7 days a week. All patients received 450 mg of aspirin intravenously, followed by 80 mg of aspirin per day orally and IV nitroglycerin in a dose designed to maintain a systolic blood pressure of 110 mm Hg. Intravenous heparin was given in a dose designed to maintain the activated partial thromboplastin time between two and three times the normal value for at least two days. This partial thromboplastin time was measured twice a day. Patients assigned to streptokinase received 1.5 million U intravenously over a period of 1 h. In patients assigned to angioplasty treatment, coronary angiography was performed as soon as possible. Both coronary arteries were visualized; left ventriculography was not performed routinely. Coronary angioplasty was performed at the investigator’s discretion using any approved techniques and devices. Patients who received a stent were treated with ticlopidine, 250 mg, twice a day for two weeks. All cineangiograms were reviewed by two experienced investigators not involved in other parts of the study. Flow through the IRV was scored according to the Thrombolysis In Myocardial Infarction (TIMI) flow grading, before and after the angioplasty procedure (17). Agreement on flow and extent of coronary artery disease was reached in all cases. The time from admission to the initiation of therapy was calculated as the time to the start of the streptokinase infusion or the first balloon inflation. Recurrent AMI was defined as chest pain, changes in the ST-T segment and a second increase in the creatine kinase level to more than two times the upper limit of normal or an increase of ⬎200 U/l over the previous value if the level had not dropped below the upper limit of normal. The primary end point was the composite of death, reinfarction or stroke at 30 days after randomization. The secondary end points were: 1. The composite of death, reinfarction and stroke at one year.
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2. Enzymatic infarct size as was calculated from lactate dehydrogenase (LDH) release in the plasma during the first 72 h after symptom onset. This method is equal to estimation of infarct size from a-hydroxybutyrate dehydrogenase and has previously been described in detail (18). Cumulative enzyme release from five to seven serial measurements up to 72 h after symptom onset was calculated with blinding to all data other than hospital registration number and date of birth. 3. Left ventricular ejection fraction, as was measured before discharge by radionuclide ventriculography using the multiple gated equilibrium method following the labelling of red blood cells of the patient with 99mTcpertechnetate. A General Electric 300 gamma camera with a low-energy all-purpose parallel-hole collimator was used. Global ejection fraction was calculated by a General Electric Star View (Milwaukee, Wisconsin) computer using the fully automatic PAGE program. The use of this software program protects against operator bias. This technique has been validated by us before (18). The study protocol was approved by the institutional ethics committee, and all patients gave oral informed consent. Before randomization it was ascertained that a catheterization laboratory was immediately available for coronary intervention. Randomization was performed using a telephone randomization service and was stopped early (April 1999) because a significant difference in the primary end point was found. Follow-up data were collected in March 2000. All clinical and outpatient records were reviewed, and general practitioners were contacted by telephone. Statistical analysis. All end points were analyzed according to the principle of intention-to-treat. A chi-square statistic was calculated to test differences between proportions with calculations of relative risks (RR) and exact 95% confidence intervals (CIs). Fisher exact test was used if there was an expected cell value of ⬍5. The Student t test or the Mann-Whitney U test was used to compare continuous values. Survival and survival without recurrent infarction or stroke were calculated by the Kaplan-Meier product-limit method (19). Survival analysis over the total follow-up period was also performed by fitting Cox proportional hazards model (20). Because of the small sample size, this was not used as a multivariate model but enabled us to calculate hazard ratios, which may be interpreted as RRs, with 95% CIs. Continuous variables are summarized by using medians (with 25th, 75th percentiles) unless otherwise indicated; discrete variables are represented as frequencies and percentages. A p value of ⱕ0.05 was considered to indicate statistical significance. The sample size was estimated on the basis of the following assumption: the 30-day incidence of death, reinfarction or stroke in the thrombolysis group would be 30%, whereas this incidence in the angioplasty group would be 15% (14,21). At alpha-level 5% and beta-level 20%, the
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Table 1. Baseline and Clinical Characteristics of the Two Patient Groups
Age, yrs Male gender, n (%) Systemic hypertension, n (%) Diabetes mellitus, n (%) Previous AMI, n (%) Anterior AMI, n (%) Previous CABG, n (%) Killip class III or IV, n (%) Heart rate on admission, beats/min Systolic blood pressure, mm Hg Time onset–admission, min (range) Multivessel disease, n (%) Initial TIMI flow grade IRV, n (%) 0 1 2 3
Angioplasty (n ⴝ 46)
p Value
Streptokinase (n ⴝ 41)
80 (77–84) 22 (48) 12 (27) 11 (24) 6 (13) 23 (50) 3 (7) 6 (13) 69 (55–78) 120 (100–145) 207 (60–1,020) 39 (87)
0.17 0.31 0.86 0.60 0.82 0.89 0.47 0.74 0.74 0.34 0.62 —
81 (78–84) 25 (61) 10 (24) 7 (17) 7 (17) 19 (46) 4 (10) 4 (10) 65 (50–80) 120 (100–140) 212 (25–700) —
30 (67) 4 (9) 6 (13) 5 (11)
Values presented are as median and 25th and 75th percentiles or number (%), unless stated otherwise. AMI ⫽ acute myocardial infarction; CABG ⫽ coronary artery bypass grafting; IRV ⫽ infarct-related vessel; TIMI ⫽ Thrombolysis In Myocardial Infarction.
number of patients required was 266, with 133 patients in each group.
RESULTS During the study period, a total number of 164 patients older than 75 years and with the diagnosis of AMI were admitted to our hospital. Of these patients, 87 fulfilled the criteria for inclusion in our study. Of the patients randomized, 46 were assigned to primary angioplasty treatment and 41 patients were assigned to treatment with streptokinase. The baseline characteristics are summarized in Table 1, and the two patient groups were well balanced with regard to the most important determinants of mortality and morbidity. Six patients in the group assigned to angioplasty and four in the streptokinase group were randomized more than 6 h after symptom onset (p ⫽ 0.7). Patients were followed for a mean of 20 ⫾ 6 months, and no patient was lost to follow-up. The clinical results are given in Table 2. The mean time from hospital admission to start of streptokinase infusion was 31 ⫾ 15 min. Of the patients randomized to invasive treatment, 45 underwent coronary angiography, and 41 actually underwent angioplasty with a procedural success rate of 90% (37 of 41), defined as a residual stenosis of the culprit lesion of ⬍50% and TIMI 3 flow through the IRV. One patient died before angiography could be performed. Two patients were referred for bypass surgery, and in two patients a conservative treatment was chosen. Four strokes occurred, one in the angioplasty group (one week after treatment with an intra-aortic balloon pump) and three in the streptokinase group (all on the day of treatment), of whom one died. Of the patients treated with angioplasty, 51% (21 of 41) did receive a stent, whereas the remaining patients underwent balloon angioplasty only. None of the study patients received glycoprotein IIb/IIIa inhibitors during the study period. The mean time from hospital admis-
sion to first balloon inflation was 59 ⫾ 19 min (range: 33 to 120 min). One patient in each group was treated with an intra-aortic balloon counterpulsation device in the immediate postinfarction period. After 30 days, three patients (7%) in the angioplasty group died, compared with nine patients (22%) in the thrombolysis group (p ⫽ 0.04), resulting in an RR for patients treated with thrombolysis of 4.0 (95% CI: 0.9 to 24.6) compared with patients treated with primary angioplasty. The composite predefined end point of death, recurrent infarction and stroke at 30 days occurred in 4 (9%) Table 2. Clinical Course of the Two Patient Groups Angioplasty (n ⴝ 46) Mortality in-hospital, 3 (7) n (%) Stroke, n (%) 1 (2) Recurrent AMI, n (%) 1 (2) Bleeding (noncerebral) 5 (11) Maximum CK 829 (422–1,425) LDH Q72 1,442 (781–2,022) Days on CCU 2 (1–3) Total days in hospital 5 (3–10) Number of readmissions 13 Ejection fraction %, 43 ⫾ 10 mean ⫾ SD Additional CABG/PTCA, 2 (4) n (%) Death during follow-up, 7 (15) n (%) Combined clinical end 9 (20) point during follow-up, (death, stroke or reinfarction), n (%)
p Value
Streptokinase (n ⴝ 41)
0.07
8 (20)
0.34 3 (7) 0.01 6 (15) 0.72 3 (7) 0.71 997 (448–1,568) 0.10 1,772 (996–2,672) 0.003 2 (2–3) 0.95 5 (3–10) 0.29 9 0.34 44 ⫾ 11 0.41
4 (10)
0.04
13 (32)
0.01
18 (44)
Values presented are as median and 25th and 75th percentiles or number (%), unless stated otherwise. AMI ⫽ acute myocardial infarction; CABG ⫽ coronary artery bypass grafting surgery; CCU ⫽ Coronary Care Unit; CK ⫽ creatine kinase; LDH Q72 ⫽ lactate dehydrogenase release in the plasma during the first 72 h after symptom onset; PTCA ⫽ percutaneous transluminal coronary angioplasty.
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JACC Vol. 39, No. 11, 2002 June 5, 2002:1723–8 Table 3. Characteristics and In-Hospital Outcome of the Study and the Registry Patients
Age, yrs, median (25–75 p) Male gender, n (%) Systemic hypertension, n (%) Diabetes mellitus, n (%) Previous AMI, n (%) Anterior AMI, n (%) Previous CABG, n (%) Killip class III or IV, n (%) In-hospital mortality In-hospital reinfarction Stroke Figure 1. The Kaplan-Meier curve compares the overall survival for patients randomized for angioplasty treatment (solid line) and thrombolysis treatment (dashed line) during 24 ⫾ 6 months of follow-up (p ⫽ 0.04, relative risk: 2.5, 95% confidence interval: 1.0 to 6.2).
patients in the angioplasty treated patients versus 12 (29%) in the thrombolysis group (p ⫽ 0.01, RR: 4.3, 95% CI: 1.2 to 20.0). Survival and survival without the combined clinical end point curves are depicted in Figures 1 and 2. Follow-up was complete in all patients. After one year, 5 patients (11%) in the angioplasty group and 12 patients (29%) in the thrombolysis group had died (p ⫽ 0.03), resulting in an RR for patients treated with thrombolysis of 3.4 (95% CI: 1.0 to 13.5) compared with patients treated with primary angioplasty. The corresponding figures for the composite end point after one year were 6 (13%) and 18 (44%), respectively (p ⫽ 0.001, RR: 5.2, 95% CI: 1.7 to 18.1). The significant difference in reaching the primary end point between the two groups was the reason to end the study before the anticipated number of patients was included. During the total follow-up period (mean: 24 months),
Randomized (n ⴝ 87)
p Value
Excluded Registry (n ⴝ 77)
80 (78–84) 47 (54) 22 (25) 18 (21) 13 (15) 42 (48) 7 (8) 10 (11) 11 (13) 7 (8) 4 (5)
0.02 0.78 0.23 0.24 0.008 0.89 0.77 0.07 0.23 0.14 1.0
78 (77–82) 39 (51) 15 (19) 10 (13) 26 (34) 35 (51)* 5 (6) 14 (18) 16 (21) 13 (17) 3 (4)
*In eight patients the localization of the infarct was not possible. AMI ⫽ acute myocardial infarction; CABG ⫽ coronary artery bypass grafting surgery.
there were 20 deaths: 7 (15%) in the angioplasty group and 13 (32%) in the streptokinase group (p ⫽ 0.04, RR: 2.5, 95% CI: 1.0 to 6.2). The corresponding figures for the composite end point were 9 (20%) and 18 (44%), respectively (p ⫽ 0.003, RR: 3.1, 95% CI: 1.4 to 7.0). The Kaplan-Meier curves are depicted in Figures 1 and 2. The in-hospital mortality of the 77 patients not included in our study was 21%, and their baseline characteristics are given in Table 3. They were compared with baseline characteristics and in-hospital outcome of the study patients. Six patients retrospectively fulfilled the criteria for study entry but were not randomized. The reasons for not including patients in the study were: not fulfilling the electrocardiogram (ECG) criteria, 27 patients; contraindications for thrombolysis, 23 patients; beyond the study time window, 11 patients; referral from other hospitals for rescue angioplasty, 5 patients; already participating in other study, 3 patients; and subacute stent thrombosis, 2 patients.
DISCUSSION
Figure 2. The Kaplan-Meier curve compares the overall survival free of recurrent infarction or stroke for patients randomized for angioplasty treatment (solid line) and thrombolysis treatment (dashed line) during 24 ⫾ 6 months of follow-up (p ⫽ 0.003, relative risk: 3.1, 95% confidence interval: 1.4 to 7.0).
We conducted a randomized trial in elderly patients, comparing thrombolytic therapy and primary coronary angioplasty for the treatment of AMI. The benefit with regard to 30-day survival did reach statistical significance (p ⫽ 0.04, RR: 4.0, 95% CI: 0.9 to 24.6), and the incidence of the predefined composite end point of death, recurrent infarction and stroke after 30 days was significantly lower in the angioplasty treated patient group (p ⫽ 0.01, RR: 4.3, 95% CI: 1.2 to 20.0). This was the reason why the study was halted prematurely. The long-term follow-up data showed a statistically significant benefit with regard to survival after one year (p ⫽ 0.03, RR: 3.4, 95% CI: 1.0 to 13.5) and the combined clinical end point of death, recurrent AMI or stroke (p ⫽ 0.001, RR: 5.2, 95% CI: 1.7 to 18.1) of angioplasty treatment over thrombolytic therapy. In the initial phase after the index infarction, infarct size, as was estimated from cumulative LDH release in the
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plasma, was lower in the angioplasty treated patients, although this did not reach the level of significance. There was no difference in mean ejection fraction measured with radionuclide techniques between the two groups. This apparent lack of benefit with regard to direct myocardial salvage may be a similar finding as was observed when comparing thrombolytic therapy with placebo treatment (22). In our experience with angioplasty, we did not encounter specific age-related problems with performing angioplasty in old patients as was reflected in the short time from hospital admission to first balloon inflation. All noncerebral bleedings in the angioplasty group were related to the arterial puncture site, and this occurs more frequently in the elderly (13). The main reason for excluding patients from our study was the high incidence of nonconclusive ECGs, and the number of patients with previous AMI in this group was significantly higher. Other studies. Recently, the benefits of thrombolytic therapy in the elderly were questioned based on data from the Medicare Cooperative Cardiovascular Project registry (8). This observational survey concerned 7,864 patients age 76 to 86 years from a retrospective cohort study but does not represent randomized data. Although older patients from the same registry, who received thrombolytic therapy or primary angioplasty, had a lower mortality at one year compared with those who did not receive a reperfusion strategy, only those treated with primary angioplasty had better survival at 30 days (23,24). The number of elderly patients with symptomatic coronary artery disease and the relative number of older patients being treated in Western society is steadily increasing (25–27). Approximately 30% of all patients presenting with AMI are ⬎75 years old (27). However, in most studies of reperfusion therapy in AMI, elderly people are excluded or represent a very small minority of the study population. In a pooled analysis of three randomized studies of primary angioplasty versus thrombolysis in elderly patients (⬎70 years), angioplasty was more effective (14). Furthermore, the high incidence of comorbidity and contraindications for thrombolytic therapy makes primary angioplasty an attractive reperfusion modality in this patient group. On the other hand, data from a recently published pooled analysis of the PAMI study group indicate that elderly patients still remain at an increased risk of death, bleeding, stroke and other complications despite treatment with primary angioplasty (28). Some limitations of our study should be noted. In contrast with multicenter trials that have included large numbers of patients undergoing reperfusion therapy for AMI, our study included only 87 patients from a single institution. A trial comparing angioplasty with pharmacologic reperfusion therapy cannot be blinded. Furthermore, the high success rates associated with primary angioplasty and subsequent clinical outcome are directly related to
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technical skills and experience of operators in high volume interventional centers (29 –31). Conclusions. In this series of patients with AMI who were older than 75 years, primary coronary angioplasty had a significant clinical benefit when compared with IV streptokinase therapy. Our data stress the need for a large community-based multicenter trial to confirm our conclusion that primary coronary angioplasty may be the reperfusion therapy of choice in elderly patients. Acknowledgments The authors are indebted to the many general practitioners in our region for their speedy referral of patients with AMI and for their superb assistance in obtaining follow-up information. Reprint requests and correspondence: Dr. Menko-Jan de Boer, Department of Cardiology, Isala Klinieken lokatie “de Weezenlanden,” Groot Wezenland 20, 8011 JW, Zwolle, the Netherlands. E-mail: [email protected].
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