Summary. Thrombolysis reduces mortality in patients with acute myocardial infarction (AMI) who are hospitalized within 6 hours from the onset of symptoms.
Cardiovascular Drugs and Therapy 2000;14:83–89 © 2000 Kluwer Academic Publishers. Manufactured in The Netherlands.
Ef~cacy of Rescue Thrombolysis in Patients with Acute Myocardial Infarction: Preliminary Findings Rescue Thrombolysis Sarullo in AMI et al.
Filippo Maria Sarullo,1 Luigi Americo,1 Pietro Di Pasquale,2 Antonio Castello,1 and Francesco Mauri3 1
Division of Cardiology, Buccheri La Ferla Fatebenefratelli Hospital, Palermo, Italy; 2Division of Cardiology “Paolo Borsellino,” G.F. Ingrassia Hospital, Palermo, Italy; 3Division of Cardiology, L. Mandic Hospital, Merate, Italy.
Summary. Thrombolysis reduces mortality in patients with acute myocardial infarction (AMI) who are hospitalized within 6 hours from the onset of symptoms. AMIs involving a small area of myocardium show a lower mortality in comparison with AMI involving a large area. The present study was aimed at evaluating the safety and ef~cacy of rescue thrombolysis in patients with large AMI who had failed thrombolysis. Ninety patients (69 Males and 21 Females), mean age 56.7 ⴞ 9 years, hospitalized for suspected AMI within 4 hours from the onset of symptoms, suitable for thrombolysis (First episode), and showing pain and persistent ST segment elevation 120 minutes after starting thrombolysis, were randomized (double-blind) into two groups. Group A (45 patients: 10 females and 35 males) received an additional thrombolytic treatment (rTPA 50 mg), 10 mg as bolus plus 40 mg in 60 minutes. Group B (45 patients: 11 females and 34 males) received placebo. Positive noninvasive markers were de~ned as follows: (1) resolution of chest pain, (2) ⱖ50% reduction in ST segment elevation, (3) double marker of creatine kinase (CK) and CK-MB activity 2 hours after the start of thrombolysis, and (4) occurrence of reperfusion arrhythmias within the ~rst 120 minutes of thrombolytic therapy. Blood pressure, heart rate, and ECG were continuously monitored. An echocardiogram was carried out at entry, and before discharge, to control ejection fraction and segmentary kinetics. Adverse events such as death, re-AMI, recurrent angina, incidence of major and minor bleeding, and emergency CABG/ PTCA were checked. The groups were similar in terms of age, sex, diabetes, smoking habits, hypertension, and adjuvant therapy (betablockers). No signi~cant difference was observed between the two groups regarding the time elapsed from the onset of symptoms to thrombolysis and AMI localization. Thirty-~ve patients (77.7%) showed reperfusion (10–50 minutes) after commencement of additional rTPA. Of the patients receiving placebo, 12 (26.6%) showed reperfusion within 35–85 minutes. Group A showed an earlier and lower CK and CK-MB peak than the control group, (respectively, p ⴝ 0.0001–0.009 and 0.002). Mortality (17.7%, 16 patients) was higher in group B than in the additional rTPA group, i.e., 6.6% (3 patients) in group A versus 28.8% (13 patients) in Group B (p ⴝ 0.041). Seven patients from group A showed nonfatal re-AMI. Angina was observed in 18 patients (40%) from group A and 3 (6.6%) from group B (p ⴝ 0.006). Ten of these patients underwent urgent PTCA (9
from group A and 1 from group B), and 3 from group A underwent urgent CABG. Minor bleeding was higher in group A than in group B (44.4% versus 15.5%, p ⴝ 0.047). Major bleeding was observed in group A (nonfatal stroke). At predischarge, the echocardiogram ejection fraction was higher in group A than in group B (46 ⴞ 8% versus 38 ⴞ 7%, p ⴝ 0.0001). Our data suggest that an additional dose of thrombolytic drug in patients with unsuccessful thrombolysis is feasible and also that the bleeding increase is an acceptable risk in comparison with the advantages obtained in reducing AMI extension. Rescue thrombolysis can allow a gain in time to perform mechanical revascularization in patients admitted to hospital without an interventionist cardiology laboratory or in those who have to be referred to another hospital for urgent CABG. Cardiovasc Drugs Ther 2000;14:83–89 Key Words. acute myocardial infarction, rescue thrombolysis, thrombolysis
In the last years, the treatment of acute myocardial infarction (AMI) has undergone a considerable change. This change was determined by the important trials GISSI, ISAM, AIMS, ISIS-2, GISSI-2, ISIS-3, and GUSTO [1–7], which have demonstrated the feasibility of using thrombolytic treatment in AMI, and a reduction of mortality (30% to 6.3%) in patients thrombolysed within 6 hours from onset of symptoms [7]. Unfortunately, the AMIs involving a small area of myocardium show a lower mortality in comparison with AMIs involving a large area (2–4% and 20–25%, respectively) [8]. These patients with high risk of mortality appear to receive a greater bene~t by an aggressive Address for correspondence: Pietro Di Pasquale, M.D., Division of Cardiology, “Paolo Borsellino,” G.F. Ingrassia Hospital, Via Val Platani, 3, 90144 Palermo, Italy.
Received 14 May 1999; receipt/review time 53 days; accepted 23 September 1999 83
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treatment by primary or rescue percutaneous transluminal coronary angioplasty (PTCA) [9,10] when thrombolysis is unsuccessful. Unfortunately, interventional cardiology laboratories are not available in all hospitals, and often, when they are available, they are not open 24 hours a day. Rescue thrombolysis may be an alternative treatment in patients with AMI and unsuccessful thrombolysis (persistence of pain and ST segment elevation). To evaluate the safety and ef~cacy of an additional dose of thrombolytic drugs in patients with unsuccessful thrombolysis and the effects on incidence of mortality, reinfarction, recurrent ischemia, major and minor bleeding, urgent PTCA and coronary artery bypass grafting (CABG), a randomized double-blind study in patients with a large AMI was carried out.
hours of thrombolysis, a CK, CK-MB level greater than twice normal values 120 minutes after starting thrombolysis, early ventricular arrhythmias (VAs) within 2 hours of the start of thrombolysis, and bradycardia with hypotension. A CK peak within 12 hours and a CK-MB level greater than twice normal value 120 minutes after starting thrombolysis were considered mandatory, associated with one or the other reperfusion criteria [12–21].
AMI classi~cation AMIs were classi~ed as anterior, inferior, and lateral according to the localization of the alterations of the ST segment in the standard 12-lead ECG ⫹ V3R-V4R lead performed at entry before thrombolysis.
AMI treatment
Materials and Methods Population From January 1995 to December 1997, 887 patients were admitted consecutively to the hospital for suspected AMI; 559 of them (63%) were suitable for thrombolysis.
Eligibility criteria Patients had to have a ~rst episode of AMI, age ⬍70 years, to be admitted to the hospital and thrombolysed within 4 hours of the onset of AMI symptoms (pain), Killip class I–II, plus an acceptable echocardiographic window to allow echocardiographic images of adequate technical quality. On the electrocardiogram (ECG), there had to be an ST elevation of ⬎1 mm in the peripheral leads and/or 2 mm in pericardial leads, involving more than four leads, with concomitant alterations of the segmentary kinetics in the echocardiogram performed at entry [11]. The basal creatine kinase (CK, CK-MB before thrombolysis) had to be within the normal range. Pain and ST segment elevation showed lack of response to thrombolysis 120 minutes after starting treatment. The study protocol was approved by the ethical committee of our hospital. Informed consent was obtained from all patients.
Exclusion criteria Patients who were not suitable for thrombolysis or who had left bundle branch block on the admission ECG, a history of cardiomyopathy, or heart failure were excluded from the study. Patients receiving betablockers were also excluded from the study. Patients who showed no enzymatic alterations after thrombolysis were classi~ed as having unstable angina and were excluded from the study.
Reperfusion criteria Reperfusion criteria included evidence of typical behavior of the ST segment, rapid (50%) reduction, rapid regression of pain, an enzymatic peak (CK) within 12
All patients received our standard treatment: nitrates 20–100 U/min, heparin 5000 IU bolus followed by 25000 IU/d, aspirin 160 mg/d, and where possible, metoprolol i.v. 5 mg ⫻ 3. The thrombolytic drug used was the accelerated rTPA (100 mg) [7]. A continuously adjusted maintenance infusion of heparin was administered to keep the activated partial thromboplastin time (aPTT) at 1.5 to 2.5 times laboratory control values (45s). The aPTT was determined within 4 hours after heparinization on the ~rst day and every 12 hours the next 4 days.
Study protocol (Fig. 1) All patients suitable for thrombolysis received thrombolytic treatment (rTPA 100 mg). Randomization (double blind) was carried out by sequentially numbered boxes and was determined when the thrombolysed patients showed persistent pain and ST segment elevation 120 minutes after starting thrombolytic treatment. Patients were randomized (double blind) into two groups. Group A (45 patients: 10 female and 35 male) received an additional thrombolytic treatment (rTPA) administered as a 10-mg bolus followed by 40 mg in 60 minutes. Group B (45 patients: 11 female and 34 male) received placebo. All patients continued our standard treatment. Blood pressure, heart rate, and ECG were monitored continuously (H.P. System), recorded on tape (~rst 6 hours), and then analyzed to check any rhythm disturbance, with attention focused on the time of pain cessation and regression of ST segment alteration. Ventricular tachycardia (VT) and ventricular ~brillation (VF) were counted. Blood CK levels were measured every 2 hours during the ~rst 24 hours and then every 6 hours until normalization in order to determine the enzymatic peak (12 hours). Before discharge, the surviving patients underwent a 24hour Holter monitoring to evaluate late ventricular arrhythmias, taking into account only those in Lown’s class ⬎2, as well as a symptom-limited exercise test. All the patients admitted into the study underwent a hemodynamic study 7–10 days after admission. PTCA
Rescue Thrombolysis in AMI
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Fig. 1. Protocol of the study.
or CABG was performed according to angiographic ~ndings and left ventricular function. Patients enrolled in the study after discharge were regularly followed up as outpatients. Echocardiography was carried out according to a standard procedure at entry (just after randomization) and before discharge. Patients lay in the left lateral position during the examination; echocardiographic recordings were obtained at the end of the expiratory phase during normal breathing, and an apical ~vechamber and two-chamber view was used. The analysis of segmentary motion was obtained by the subdivision of the left ventricle chamber into 16 segments according to American Society of Echocardiography [22]. The ejection fraction (EF) and the segmentary kinetics were measured at the end of the T wave, by the area–length method. The mean of three measurements was used. The interobserver and intraobserver coef~cients of variation were 4% and 3%, respectively. Systolic thickening and motion of the left ventricular walls were classi~ed as normal, iperkinetic, ipokinetic, and akinetic. The physicians who performed an echocardiogram as part of the hemodynamic study were unaware of the patients’ clinical and analytic data. Dur-
ing hospitalization, major adverse events (death, reAMI, recurrent angina at rest), incidence of major and minor bleeding, and emergency CABG/PTCA were checked.
Statistical analysis Results are expressed as the mean ⫾ standard deviation (SD). Data were analyzed by the two-tailed T-test to identify differences between the groups. Nominal data were analyzed by the chi-square test or Fisher’s test. P ⬍ 0.05 was assumed as statistically signi~cant.
Results Ninety patients met the entry criteria and continued the study in accordance with the study protocol. The patients who had proven reperfused AMI and late coronarography had an infarct-related artery (IRA) patency corresponding to the classi~cation of reperfusion based on noninvasive diagnosis; unreperfused patients showed occluded IRA. The groups were similar as to age, sex, diabetes, smoking habits, hypertension, and adjuvant therapy (beta-blockers). Table 1 shows the clinical data of all patients admit-
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Table 1. Clinical data of patients with proven unreperfused acute myocardial infarction Total Patient no. Sex F/M Age years Onset of symptoms (min) Anterior AMI Lateral ⫹ inferior AMI Anterior ⫹ inferior AMI Beta-blockers Hypertension Diabetes Hypercholesterol Smokers
90 21/69 56.7 ⫾ 9 112 ⫾ 55 50
Group A
Group B
p
45 10/35 56 ⫾ 9
45 11/34 57 ⫾ 8
ns ns ns
107 ⫾ 53 26
116 ⫾ 54 24
ns ns
21
10
11
ns
19 28 53 28 31 54
9 18 30 15 18 30
10 20 23 13 13 24
ns ns ns ns ns ns
F ⫽ female; M ⫽ male; ns ⫽ not signi~cant.
ted into the study with proven unreperfused and reperfused AMI. No signi~cant difference was observed between the two groups regarding the time lapse from the onset of symptoms to thrombolysis and localization of AMI. Table 2 shows the results obtained in the 90 thrombolysed patients. Thirty-~ve patients (77.7%) receiving
additional rTPA (50 mg) showed a rapid reduction of pain and ST elevation 10–50 minutes after the start of additional rTPA administration. Twenty-six of these patients (74.3%) showed noninvasive signs of reperfusion within 20 minutes after the start of additional thrombolysis, the other patients within 50 minutes. In contrast among patients receiving placebo as an additional thrombolytic, only 12 (26.6%) showed successful reperfusion 35–85 minutes (mean 55 minutes) after standard thrombolysis. In addition, the patients receiving an additional thrombolytic drug showed an earlier and lower CK and CK-MB peak in comparison with patients receiving placebo (p ⫽ 0.0001, 0.009, and 0.002, respectively). Table 3 shows intrahospital data. Overall mortality was 17.7% (16 patients). Mortality was higher in patients receiving placebo than in those receiving additional rTPA (28.8% versus 6.6% p ⫽ 0.041). In group A, 3 patients died, 2 for irreversible heart failure and 1 for fatal reinfarction; in group B (placebo), 13 patients died, 10 for irreversible heart failure and 3 for reinfarction. Seven patients from group A (additional rTPA) showed nonfatal reinfarction 4 ⫾ 2 days after admission. In addition, 2 of these 7 patients received a further administration of thrombolytic drug before emergency PTCA was performed (TIMI 1 _ow). A new episode of angina was observed in 21 patients, 18 from group A and 3 from group B. Ten of these patients underwent urgent PTCA (9 from group A and 1 from group B) (TIMI 2
Table 2. Effects of thrombolysis
Total Patient no. Reperfused Unreperfused CK peak max (IU/l) CK peak time (min) CK-MB peak (ng/mL)
90 47 (52.2%) 43 (47.8%)
rTPA 100 ⫹ 50 mg
rTPA ⫹ placebo
45 35 (77.7%) 10 (22.3%) 1701 ⫾ 931 586 ⫾ 168 278 ⫾ 200
45 12 (26.6%) 33 (73.4%) 3137 ⫾ 1090 1076 ⫾ 618 610 ⫾ 381
p ns 0.01 0.006 0.002 0.0001 0.009
CK ⫽ creatine kinase; ns ⫽ not signi~cant.
Table 3. Results during hospitalization period
Patients no. Mortality Nonfatal re-AMI Recurrent angina Major bleeding Minor bleeding Urgent PTCA Urgent CABG
Total
Group A
Group B
p
90 16 (17.7%) 7 (7.8%) 21 (23.3%) 1 (1.1%) 27 (30%) 12 (13.3%) 3 (3.3%)
45 3 (6.6%) 7 (15.5%) 18 (40%) 1 (2.2%) 20 (44.4%) 11 (24.4%) 3 (6.6%)
45 13 (28.8%) 0 3 (6.6%) 0 7 (15.5%) 1 (2.2%) 0
ns 0.041 0.014 0.006 ns 0.047 0.016 0.24
AMI ⫽ acute myocardial infarction; PTCA ⫽ percutaneous transluminal coronary angioplasty; CABG ⫽ coronary artery bypass graft; ns ⫽ not signi~cant.
Rescue Thrombolysis in AMI
Table 4. Angiographic data
Patient no. Patency No patency 1 Vessel 2 Vessels 3 Vessels No cr. st.
Total
Group A
Group B
70 45 (64.3%) 25 (35.7%) 40 (57.1%) 18 (25.7%) 10 (14.3%) 2 (2.8%)
39 33 (84.6%) 6 (15.4%) 21 (53.8%) 11 (28.2%) 6 (15.3%) 1 (2.5%)
31 12 (28.7%) 19 (61.3%) 18 (58%) 8 (25.8%) 4 (12.9%) 1 (2.2%)
No cr. st. ⫽ Noncritical stenosis.
_ow). Three patients from group A underwent urgent CABG (three-vessel disease). None of these patients showed important bleeding during surgery and the postsurgery period. Table 4 shows angiographic data. Seventy patients underwent coronarography (39 from group A and 31 from group B); 16 patients died before angiography was performed, due to irreversible due to heart failure and fatal reinfarction (13 from group B and 3 from group A); 2 patients refused treatment (group A); and 2 were excluded for other reasons (1 patient in both groups). Coronarography showed the following results: one-vessel disease, 57.1%; two-vessel disease, 25.7%; threevessel disease, 14.3%. The IRA in patients was as follows: anterior descending coronary artery, 46 (65.7%); right coronary artery, 12 (17.1%); and circum_ex coronary artery, 12 (17.1%). No patency of IRA was observed in patients without noninvasive signs of reperfusion (TIMI 0–1 _ow), while in patients with reperfusion, clinical data showed patency and critical stenosis of IRA (TIMI 2–3 _ow). Only 2 patients (1 patient in both groups) showed coronary stenosis ⬍ 50% in the IRA (2.8%). Table 3 also shows the incidence of bleeding in the patients admitted into the study. Minor bleeding was higher in patients from group A in comparison with group B (p ⫽ 0.047) and occurred at the site of vascular punctures (patients receiving emergency PTCA, urgent PTCA, and urgent CABG). A single case of major bleeding was observed in group A (1 nonfatal stroke). Three patients from group A needed blood transfusion. One patient developed retroperitoneal bleeding (two blood transfusions), and two patients showed gross hematuria (one blood transfusion in both patients). Fiftynine patients at predischarge (28 from group A and 31 from group B) underwent echocardiographic examination. The patients who underwent urgent CABG/PTCA did not have an echocardiogram, since they were sent to other hospitals to receive CABG/PTCA. The ejection fraction was higher in group A than in group B (46 ⫾ 8% versus 38 ⫾ 7%, p ⫽ 0.0001). No patients discharged from hospital presented with events in the ~rst 30 days. The hospitalization stay was not possible to measure, because 15 patients were sent to other hospitals for
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CABG/PTCA, and hospitalization was continued there (from 3 to 10 days).
Discussion Thrombolysis is able to determine about 75–90% of coronary patency in patients with AMI [23]. In cases of unsuccessful thrombolysis, PTCA is usually performed to obtain coronary patency [10]. Several studies have shown that patency of IRA confers a bene~cial effect on survival in post-AMI patients [24]. Patients who survive AMI with patency of IRA within 90 minutes after treatment show a better prognosis in the long term than those with occluded IRA who have similar left ventricular function [25,26]. For this reason, in cases of failed thrombolysis, PTCA of IRA is performed to determine early patency of IRA and to save damaged but vital myocardium. Unfortunately, PTCA is not technically feasible in 20% of patients due to the localization and characteristics of coronary lesions [27]. In addition, the success of PTCA in these patients is about 80% [27], and the lack of optimal coronary _ow determines a bad prognosis [27–29]. In fact, the TAMI trial reported a 5.9% hospital mortality in patients with successful PTCA and a 39.1% mortality in patients with failed PTCA [27]. In addition, 8% of patients who underwent rescue PTCA required urgent CABG. However, many hospital hemodynamic laboratories do not have the ability to offer follow-up services for whatever reason (e.g., economics, experience, and standby surgery). Rescue thrombolysis could be an alternative treatment in case of failed thrombolysis. An earlier study showed that in patients with persistent ST segment elevation after thrombolysis with streptokinase (1.5 MU i.v. over 60 minutes) who received additional alteplase (10 mg as a slow bolus injection followed by 50 mg over 1 hour and then an infusion of 20 mg/h over the next 2 hours), the infarct size was smaller and ejection fraction was higher in comparison with patients receiving additional placebo [30]. This study had a small sample of patients and was not able to show a difference in mortality between groups. In addition, the authors used two different thrombolytic drugs, different doses, and different administration protocols. Unsuccessful thrombolysis is due to many factors, including atherosclerotic plaque complexity, intraintimal bleeding and/or spontaneous dissections, and high platelet deposition intrathrombus (with subsequent increase of thrombolysis resistance). Another interesting possibility to explain thrombolysis resistance may be early reocclusion: ~brin thrombus could be removed (by lysis) and replaced by a new platelet-rich thrombus, which is more resistant to thrombolytic drugs. These data suggest that the use of an additional dose of thrombolytic drug, as previously reported in the TIMI II trial [31], results in a higher incidence of IRA patency. The incidence of major bleeding (intracranial bleeding) was higher in the TIMI II trial than in our
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study. The differing results are probably due to the following reasons. In the TIMI II trial, all patients received 150 mg of rTPA, while in our study only patients without indirect signs of reperfusion received an additional 50 mg of rTPA. In addition, our patients were thrombolysed within 4 hours from the onset of symptoms and were ⬍70 years old. These inclusion criteria probably reduced major bleeding risks. The data from this study show a higher incidence of minor bleedings (44%) in comparison with other studies (20%) [32,33], and three patients needed blood transfusions. Most probably, the increased bleedings observed in our patients are dose and/or duration related; our patients received 150 mg of rTPA, and for a longer time (2 hours ⫹ 1 hour). It is important to compare the side effects of thrombolysis with the bene~cial clinical effects in high-risk patients. In fact, in agreement with other studies [32–35], an additional dose of rTPA, when stable reperfusion was not obtained and mechanical revascularization was indicated, was able to effect a hemodynamic stabilization of patients during AMI, i.e., a reduction of myocardial damage, as evidenced by faster CK peak in group A than group B (586 ⫾ 168 minutes versus 1076 ⫾ 618 minutes, p ⬍ 0.0001). Patients receiving additional thrombolytic drug showed an earlier and lower CK and CK-MB peak than patients receiving placebo (p ⫽ 0.0001–0.009 and 0.002, respectively). Additional thrombolysis determined a signi~cantly higher EF in comparison with placebo (p ⬍ 0.0001) and a signi~cant reduction of mortality (p ⫽ 0.041). A second bolus of rTPA is not able to effect stable myocardial perfusion: 55.5% of patients receiving additional thrombolytic drug showed recurrent angina (7 nonfatal re-AMI and 18 myocardial angina). Since our hospital does not have a hemodynamic laboratory, we were not able to perform angiographic control immediately before and after rescue thrombolysis. Subsequent coronary angiography was performed in other hospitals. Our data suggest that an additional dose of thrombolytic drug in patients with persistent clinical signs of ischemia is feasible and also that an increase in bleeding is an acceptable risk for reduction of the AMI area. When possible, rescue thrombolysis could be used to gain time to perform mechanical revascularization. In fact, our data show that the rescue tPA group became an unstable population, with a high rate of recurrent ischemia and reinfarction, necessitating a more aggressive strategy. The fact that the outcomes of rescue PTCA are likely to be enhanced, given the advent of stents and glycoprotein IIb/IIIa inhibitors, makes an acute invasive strategy more attractive for high-risk patients. Our study was performed before the utilization of glycoprotein IIb/IIIa inhibitors [36]. Current investigations using reduced-dose thrombolytics and fulldose glycoprotein IIb/IIIa inhibitors, which achieve higher patency rates at 60 and 90 minutes in comparison with full thrombolytics, could in_uence in the near fu-
ture the recommendation of retreatment with thrombolytic drugs [37,38]. In addition, rescue thrombolysis in the contemporary era of glycoprotein IIb/IIIa inhibitors might be reconsidered. The potential reduction of reinfarction, recurrent ischemia, and the need for urgent revascularization through the use of glycoprotein IIb/IIIa inhibitors in a facility with an interventional laboratory could enable clinicians to avoid thrombolytic retreatment. Patients receiving low-dose thrombolytics with glycoprotein IIb/IIIa inhibitors could receive additional thrombolysis in the event of failure to resolve either pain or ST segment, when an acute invasive strategy is not possible in the short term. However, rescue thrombolysis remains a viable strategy at hospitals without invasive facilities or in patients who have to be referred to hospitals with a cardiac surgery facility. The major limitation of this study was the small number of patients.
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