Primary angioplasty with routine stenting compared with thrombolytic therapy in elderly patients with acute myocardial infarction

Primary angioplasty with routine stenting compared with thrombolytic therapy in elderly patients with acute myocardial infarction Ilan Goldenberg, MD,a Shlomi Matetzky, MD,a Amir Halkin, MD,b Arie Roth, MD,b Elio Di Segni, MD,a Dov Freimark, MD,a Dan Elian, MD,a Oren Agranat, MD,a Yedael Har Zahav, MD,a Victor Guetta, MD,a and Hanoch Hod, MDa Tel Hashomer and Tel Aviv, Israel

Background

Prior studies have yielded conflicting data on the advantage of primary angioplasty compared with thrombolysis in elderly patients with acute myocardial infarction (AMI). These studies, however, were performed before the contemporary widespread use of intracoronary stents and glycoprotien IIb/IIIa antagonists.

Methods

We prospectively compared the outcome of 130 consecutive elderly patients (aged ⱖ70 years) with STelevation AMI who were admitted to 2 similar neighboring medical centers. Patients were assigned to receive either thrombolytic therapy with accelerated tissue-type plasminogen activator (center I) or primary angioplasty with routine stenting (center II).

Results Of the patients assigned to receive primary angioplasty, 91% underwent stenting. At 6 months, patients treated with primary angioplasty, compared with those treated with thrombolytic therapy, had a lower incidence of reinfarction (2% vs 14%, P ⫽ .053) and revascularization for recurrent ischemia (9% vs 61%, P ⬍ .001) and a significant reduction in the prespecified combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P ⬍ .01). Primary angioplasty remained an independent predictor of the triple combined end point after controlling for potential covariables (relative risk 0.63, 95% CI 0.38 – 0.84). Major bleeding complications were also significantly reduced in the primary angioplasty group (0% vs 17%, P ⫽ .03). Conclusions Compared with thrombolysis, primary angioplasty with routine stenting in elderly patients with AMI is associated with better clinical outcomes and a lower risk of bleeding complications.(Am Heart J 2003;145:862-7.) Advanced age is a major determinant of mortality in patients with acute myocardial infarction (AMI).1,2 The administration of thrombolytics to older patients with AMI is often limited by delays in seeking medical care, a higher incidence of atypical presentations, concomitant illnesses and contraindications to thrombolytic therapy.3–7 In addition, intracranial hemorrhage, the most feared complication of thrombolytics, is more common with increasing age.8 Therefore, primary angioplasty might be more beneficial than thrombolysis, particularly in this age group. Although a growing amount of recently acquired data suggest beneficial effects of primary angioplasty compared with thromboFrom the aHeart Institute, Sheba Medical Center, Tel Hashomer, and the bHeart Institute, Soraski Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Submitted May 22, 2002; accepted Aug 29, 2002. Reprint requests: Hanoch Hod, MD, Director of the Cardiac Intensive Care Unit, Heart Institute, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel. E-mail: [email protected] © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(02)94709-5

lytic therapy,9 –11 trials in the elderly remain controversial and include a low rate of stent implantation.12,13 Current techniques of primary angioplasty in AMI, which use routine stent implantation and intensive antiplatelet therapy, might disclose the unrevealed benefit of primary angioplasty, while at the same time they might confer a potential bleeding hazard in elderly patients. In this study, we prospectively compared accelerated tissue-type plasminogen activator (t-PA) with primary angioplasty with the routine use of coronary stents and intensive antiplatelet therapy in elderly patients with AMI.

Methods Patient population This study is a prospective analysis of 130 consecutive patients ⱖ70 years of age from the greater Tel-Aviv area with ST-elevation AMI. Patients were admitted to the intensive coronary care units (ICCUs) of 2 local medical centers (Soraski Medical Center and Sheba Medical Center, both affiliated with the Tel Aviv University Sackler School of Medicine) between February 1998 and November 1999. Each patient en-

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tered the emergency department of the medical center in the vicinity, with similar transport times to both centers. Both ICCUs have 8 beds and an admission rate of approximately 1000 patients per year and are staffed with similar medical personnel who have similar training and expertise. On-site coronary bypass grafting facilities are available in both medical centers, although each medical center used a different reperfusion strategy for patients with AMI at the time of the study. The routine treatment at center I (Soraski Medical Center) was thrombolysis, whereas primary angioplasty with stenting was routinely used at center II (Sheba Medical Center). Eligibility for inclusion in the study required that patients come to the center within 12 hours after the onset of symptoms, with pain lasting for at least 20 minutes, ST-segment elevations of ⱖ0.1 mV in ⱖ2 contiguous limb leads or ⱖ0.2 mV in precordial chest leads. Patients with contraindications for thrombolytic therapy according to the American College of Cardiology/American Heart Association guidelines14 were excluded from the study.

Treatment protocol The thrombolysis regimen consisted of accelerated tissuetype plasminogen activator ([rt-PA] 15-mg bolus followed by 0.75 mg/kg for 30 min, not to exceed 50 mg, then 0.5 mg/kg for 60 min, not to exceed 35 mg, for a maximum total of 100 mg). In the thrombolytic group, cardiac catheterization was performed because of unsuccessful thrombolysis necessitating rescue angioplasty and spontaneous postinfarction angina during hospitalization. All other patients underwent a predischarge stress test and were referred for catheterization when the test results were positive for ischemia. Postdischarge patients were referred for catheterization on the basis of clinical events. In the primary angioplasty group, the infarction-related artery was the only target in all patients, except for patients who had hemodynamic deterioration despite restoration of patency in the infarction-related artery. Placement of coronary stents was routinely employed unless Thrombolysis In Myocardial Infarction (TIMI) III flow was achieved with residual stenosis ⬍20%, without dissection or residual thrombus. During the intervention, patients received an additional dose of heparin to yield a clotting time of 250 ms. Abciximab (ReoPro, Lilly Deutschland, Bad Homburg, Germany), given as a bolus of 0.25 mg per kilogram, followed by continuous infusion at a rate of 10 ␮g per minute for 12 hours, was commenced during the angioplasty procedure according to the discretion of the interventional cardiologist. Postinterventional antithrombotic therapy included the routine administration of aspirin. In patients who received coronary stents, 250 mg of ticlopidine twice daily for 4 weeks was added. At both medical centers, adjunctive medications were given according to the individual patient’s clinical status, in accordance with the American College of Cardiology/American Heart Association guidelines for the treatment of AMI.14 Follow-up observation and therapy were performed in the cardiac outpatient clinics at both centers.

Data collection The following inhospital events were recorded: death, recurrent MI (defined as clinical symptoms and new electrocar-

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diographic changes with a new creatine kinase MB elevation of at least twice that of the last value), recurrent cardiac ischemia (defined as ischemic-type chest discomfort accompanied by ST-segment deviation, T-wave changes on the electrocardiogram, or both), revascularization procedures, arrhythmias (atrial fibrillation, high degree artrioventricular block, sustained ventricular tachycardia/ventricular fibrillation), major bleeding (defined as an intracranial bleed or bleeding that causes hemodynamic compromise requiring blood or fluid replacement, inotropic support, surgical repair, or bleeding resulting in death), minor bleeding (any type of bleeding not classified as major bleeding), or disabling stroke. The primary end point was a composite of death, recurrent MI, and the need for revascularization procedures for recurrent ischemia, either spontaneously or on stress test at 6 months. Follow-up data were obtained by direct interviews at the cardiac outpatient clinics of each medical center or by telephone contact with the patients, their families, and/or their referring physicians. The following specific data were assessed: cardiac events requiring hospitalization, recurrent ischemic events, reinfarction, new or worsening congestive heart failure, revascularization procedures (coronary angioplasty or coronary bypass graft surgery), noncardiac events requiring hospitalization, and mortality during the 6 months after the index MI. Mortality data during the 6-month follow-up period were also obtained from the Israeli Ministry of the Interior.

Statistical analysis Continuous variables are presented as the mean ⫾ SD when normally distributed and as median and interquartile range when not normally distributed. Comparisons between groups were made by unpaired t tests for normally distributed continuous variables and the Wilcoxon test when the variables were not normally distributed. Parametric variables were presented as percentages and were compared by the ␹2 with Yates correction or with the 2-tail Fisher exact test. Multivariate logistic regression was applied to determine the independent predictors of the 6-month composite end point. The following variables were used in the final model: the initial reperfusion regimen, admission Killip class (Killip class I vs Killip class ⱖ2), sex, history of hypertension, and diabetes mellitus.

Results Of the 130 patients who comprised the study population, 86 (66%) were admitted to center I and 44 (34%) were admitted to center II. Of the 86 patients who were treated with thrombolytic therapy, 41 (48%) were catheterized during hospitalization because of unsuccessful thrombolysis requiring rescue angioplasty (n ⫽ 4), recurrent spontaneous ischemia (n ⫽ 30), positive stress test results (n ⫽ 6), and after a diagnosis of a ventricular septal defect (n ⫽ 1). Coronary angioplasty was performed in 37 patients, and a stent was implanted in 31 of these patients (84%). Four patients were referred for coronary artery bypass graft surgery (2 patients because of 3-vessel coronary artery

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864 Goldenberg et al

Table I. Baseline characteristics of the study patients Thrombolysis (n ⴝ 86) Age (y) (mean ⫾ SD) Males (%) Risk factors (%) Smoking Hypercholesteronemia Hypertension Diabetes mellitus Family history Prior MI Prior revascularization Killip class (%) I II III IV MI location (%) Anterior Inferior/posterior Undetermined (CLBBB) Time to treatment (min)*† Peak CPK (IU)*

Primary angioplasty (n ⴝ 44)

P

76 ⫾ 5 35 (41)

77 ⫾ 5 18 (41)

.84 .98

22 (26) 36 (42) 44 (51) 20 (23) 9 (10) 15 (17) 8 (9)

12 (27) 14 (32) 25 (57) 11 (25) 3 (7) 11 (25) 5 (11)

.85 .26 .54 .82 .75 .3 .76 .18

48 (56) 24 (28) 10 (12) 3 (3)

21 (48) 9 (20) 11 (25) 3 (7) .93

40 (46.5) 42 (49) 4 (4.5) 180 (120-300) 926 (155-7667)

22 (50) 20 (45.5) 2 (4.5) 240 (200-310) 955 (146-4770)

⬍.001 .33

*Numbers are medians (range). †Time to treatment is defined as time from symptom onset to needle time in the thrombolysis group, and time from symptom onset to balloon time in the primary angioplasty group.

Table II. Medical therapy during hospitalization Thrombolysis ␤-Blockers (%) ACE inhibitors (%) Nitrates (%) Diuretics (%) Aspirin (%)

57 (66) 54 (63) 83 (97) 31 (36) 86 (100)

Primary angioplasty

P

30 (68) 33 (75) 38 (84) 23 (52) 44 (100)

.82 .16 .03 .07 1

disease and 2 patients because of significant left main coronary artery disease). All 44 patients in center II were catheterized on admission, and 43 of these patients (98%) underwent primary angioplasty; of these 43 patients, 39 (91%) underwent stent implantation. One patient was referred for urgent coronary artery bypass graft surgery for diffuse and severe 3-vessel coronary artery disease. Abciximab was administered to 23 of the 43 patients (53%) who underwent primary percutaneous interventions (PCIs) and to 6 patients (15%) who underwent cardiac catheterization after thrombolytic therapy. Baseline characteristics of patients and medical treatment during hospitalization. There was no significant difference between the 2 groups in demographic data, risk factors, cardiac history, MI location, Killip class on admission, or peak creatine phosphoki-

nase levels. The time that elapsed from symptom onset to initiation of thrombolytic therapy (center I) was significantly shorter than the mean time from symptom onset to first balloon inflation (center II) (Table I). Throughout hospitalization and at discharge, medical management with aspirin, ␤-blockers, and angiotensinconverting enzyme inhibitors was similar in the 2 groups, whereas nitrates were prescribed more frequently to patients who received thrombolytic therapy (Table II). Inhospital outcome. Patients treated with thrombolytic therapy were more likely to sustain recurrent ischemia (31% vs 2%, P ⫽ .006). This difference largely accounted for a significantly higher rate of subsequent revascularization procedures after the first assigned reperfusion therapy during the hospital stay in patients treated with thrombolysis (48% vs 5%, P ⬍ .001) and the prevalence of the aforementioned composite triple end point of mortality, reinfarction, and/or revascularization for recurrent ischemia (64% vs 21%, P ⬍ .001). Although there was no significant difference in the rate of inhospital mortality or nonfatal recurrent infarction in the entire study population, the inhospital mortality rate among patients with Killip class III and IV only tended to be lower in the primary angioplasty group, not the thrombolytic group (29% vs 45%, respectively, P ⫽ .08). Thrombolytic therapy was also associated with a significantly higher rate of inhospital hemorrahagic complications. Fifteen patients

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Table III. Inhospital events Thrombolysis Inhospital mortality (%) Recurrent cardiac ischemia (%) Recurrent MI (%) Revascularization procedures* (%) Composite end point† (%) High-degree AV block (%) Sustained VT or VF (%) Atrial fibrillation (%) Major bleeding (%) Ischemic stroke/TIA (%) Hospital duration (mean days)

10 (12) 27 (31) 4 (5) 41 (48) 55 (64) 4 (5) 5 (6) 14 (16) 15 (17) 1 (1) 12 ⫾ 4.7

Primary angioplasty

P

6 (14) 1 (2) 1 (2) 2 (5) 9 (21) 3 (7) 2 (5) 3 (7) 0 (0) 1 (2) 9.1 ⫾ 3.9

.59 .006 .66 ⬍.001 ⬍.001 .67 1 .22 .03 1 .11

*Revascularization procedures include percutaneous coronary interventions and coronary bypass procedures which were performed due to reinfarction or postinfarction angina. †Includes death, recurrent MI, or the need for revascularization procedures.

(17%) in the thrombolysis group had an episode of major bleeding, compared with no patients in the primary angioplasty group (P ⬍ .05). Of the 15 patients who were treated with thrombolytic therapy and sustained major bleeding, 4 patients (27%) had gastrointestinal bleeding, 2 patients (13%) had genitourinary bleeding, and 3 patients (20%) had oropharyngeal/pulmonary hemorrhage. Large hematomas were the cause of major bleeding in 4 patients (27%), and there were other causes in 2 patients (13%). There were no cases of intracranial bleeding in the study group. Minor bleeding occurred in 14 patients (16%) in the thrombolysis group (including venous puncture hematomas in 11 patients and oropharyngeal/epistaxis in 3 patients) and in 9 patients (20%) in the primary angioplasty group (including groin hematomas in 6 patients, gingival bleeding in 2 patients, and epistaxis in 1 patient). The higher incidence of major bleeding during the hospitalization of patients treated with thrombolysis substantially contributed to the observed trend toward a longer hospitalization period in this group (12 ⫾ 4.7 vs 9.1 ⫾ 3.9 days, P ⫽ .11) (Table III). Six-month outcome. Six-month outcomes are shown in Table IV. The rate of recurrent MIs was higher in the thrombolysis group than in the primary angioplasty group (14% and 2%, respectively, P ⫽ .053). There was also a significantly higher number of revascularization procedures performed in patients receiving thrombolytic therapy than in the primary angioplasty group of patients (61% vs 9%, respectively, P ⬍ .001). Although there was no significant difference in mortality, the 6-month composite triple end point of mortality, recurrent MI, and revascularization procedures was significantly lower in patients treated with primary angioplasty than in patients treated with intravenous thrombolysis (29% vs 93%, respectively, P ⬍

Table IV. Six-month mortality and recurrent cardiac events Primary angioplasty

P

17 (20) 11 (14) 47 (61)

8 (18) 1 (2) 4 (9)

.83 .053 .001

72 (93)

13 (29)

.001

Thrombolysis Six-month mortality (%) Recurrent MI* (%) Revascularization procedures*† (%) Composite endpoint*‡ (%)

*Data were available for 77 (90%) patients in the thrombolysis group and for all patients in the primary angioplasty group. †Revascularization procedures include percutaneous coronary interventions and coronary bypass procedures which were performed during the 6-month follow-up period. ‡Includes death, recurrent MI, or the need for revascularization procedures.

Table V. Multivariate predictors of the triple end point*

Primary angioplasty Males Hypertension Killip ⱖ2 *

Relative risk inhospital (95% CI)

Relative risk 6 months (95% CI)

0.79 (0.24-0.95) 0.53 (0.17-1.66) 3.08 (0.88-10.78) 11.34 (2.42-53.14)

0.63 (0.38-0.84) 0.76 (0.30-1.93) 1.73 (0.67-4.52) 5.13 (1.87-14.04)

Includes death, recurrent MI, or the need for revascularization procedures.

.01). In multivariate analysis (Table V) , there was a significant reduction in the risk of triple outcome in the primary angioplasty group at 6 months (relative risk 0.63, 95% CI 0.38 – 0.84).

Discussion Although elderly patients, who comprise as much as 80% of all patients with AMI, have a substantially worse short- and long-term prognosis, acute treatment

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866 Goldenberg et al

is usually less vigorous in older patients than younger patients.5 Thrombolytic therapy is often withheld from elderly patients because of the fear of bleeding complications, particularly intracerebral hemorrhage, and the contradictory data on the efficacy of this therapy in the older age group.2–5,15–20 Thus, safer and more effective reperfusion therapy is needed to reduce shortand long-term morbidity and mortality rates in the older age group. We prospectively compared, in consecutive patients aged ⱖ70 years, thrombolytic therapy with accelerated t-PA to primary angioplasty with the routine use of stents. Our results indicate a reduction in the incidence of reinfarction and in the need for repeat revascularization because of recurrent ischemia, with a significantly lower incidence of major bleeding complications in patients treated with primary angioplasty with routine stenting, compared with thrombolytic therapy, in elderly patients. Previous studies have yielded limited and conflicting data on the advantage of primary angioplasty compared with thrombolytic therapy in elderly patients with AMI.12,13,21–30 Earlier trials have suggested that high-risk patients with evolving infarction, associated with a high mortality rate, such as advanced age (⬎70 years), anterior infarction, persistent tachycardia, or cardiogenic shock, are most likely to benefit from immediate angioplasty.21,22 A meta-analysis from the Primary Angioplasty for Myocardial Infarction (PAMI), Zwolle, and Mayo Clinic studies also suggested increased benefit from primary angioplasty compared with thrombolytic therapy in the aging patient.12 In contrast, analysis of the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) study demonstrated that advanced age did not change the incremental risk of thrombolytixc therapy compared with primary angioplasty.13 Several recent observational studies have been performed to assess treatment outcome in elderly patients in clinical practice.28,29 However, the results of these studies are also conflicting. Although data from the Second National Registry of Myocardial Infarction (NRMI-2) suggest that primary angioplasty and thrombolytic therapy offer similar efficacy,28 data from the Cooperative Cardiovascular Project (CCP) demonstrate a significant reduction in mortality rate with primary angioplasty compared with thrombolysis in elderly patients.29 Moreover, analysis of the CCP data has indicated that thrombolytic therapy may even be harmful in patients aged ⱖ75 years.15 Recently, a randomized comparison of primary angioplasty and thrombolytic therapy in 87 elderly patients (⬎75 years) demonstrated a significant clinical benefit with primary PCI when compared with intravenous streptokinase therapy.30 However, stent implantation was performed in

only 51% of study patients treated with angioplasty, and none of the patients received glycoprotein IIb/IIIa inhibitors. In this study, primary angioplasty was performed with more contemporary techniques than in former comparative trials, as evidenced by the routine use of intracoronary stent implantations and the use of IIb/IIIa antagonists in more than half the patients who underwent primary PCI. We have shown that aggressive antiplatelet therapy in elderly patients is safe and results in an improved clinical outcome. This study, however, may have several limitations. Patients from the 2 study groups, those receiving thrombolytic therapy and those with primary PCI, were treated in 2 neighboring medical centers, and this might have potential effects on the results. However, the strikingly similar demographic baseline characteristics of the 2 groups and a similar medical therapy policy used by both local medical centers facilitated the comparison of the effect of reperfusion strategy on the outcome of the 2 groups of patients. There were more patients in the primary angioplasty group with an admission Killip class of III or IV (32% in the primary angioplasty group vs 13% in the thrombolysis group, P ⫽ .028). This difference may carry a potential bias, but because it favors those patients treated with thrombolytic therapy, the study results are not weakened. Despite this difference, we believe that there was no major shunting of more critical patients to the more aggressive center, because patients who come to the emergency department with AMI are usually not aware of reperfusion policies. Moreover, approximately 60% of patients were transferred to the 2 hospitals by mobile ICCU, the team of which was instructed to transport the patient to the medical center closest to the patient’s home. In addition, it should be emphasized that the results of treatment with primary angioplasty in our study apply only to a center that specializes in this reperfusion technique and is equipped and staffed with personnel prepared to offer immediate therapy 24 hours a day. In conclusion, we have demonstrated that primary angioplasty, with coronary stenting and intensive antiplatelet therapy, improved clinical outcomes compared with thrombolytic therapy, mainly in a reduced reinfarction rate and the need for ischemia-related revascularization at 6 months. In addition, this mode of therapy may be performed safely in elderly patients because the risk of major bleeding is lowered.

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