C a r d i o v a s c u l a r Drugs a n d T h e r a p y 4: 1337-1344, 1990 ,~', Kluwer Academic Publishers, Boston. P r i n t e d in U.S.A.

French Multicenter Trial of Anistreplase versus Heparin in Acute Myocardial Infarction* H. Lardoux,* Y. Louvard, D. de Vernejoul, C. Picot, M. Baudet, M. Hiltgen, M. Houplon, J. Ponsonnaille, M. Richard, R. Luccioni, R. Rocher, G. Hanania, P. Gaudeul, A. Cribier, B. Letac *Centre Hospitalier Gilles de Corbeil, CorbeiI-Essonnes, France

Summary. Eighty-four patients aged less than 71 years with less than 4-hour duration acute myocardial infarction (AM1) were randomized in a multicenter study to 30 U anistreplase or heparin (single injection of 6500 IU followed by 1000 IU/ hr). Early reperfusion was assessed from ECG changes (50~ of sum ST decrease 2 hours postdosing) and the CK release profile (CK peak < 16 hours after onset of symptoms, CK slope > 10~/hr). Reperfusion rates in patients meeting at least two criteria of reperfusion were 62.59~ on anistreplase versus 27.59~ on heparin. On delayed angiogram (13.7 +_ 3.4 days), patency rates were 66c~ with anistreplase versus 47cA (NS) with heparin in 76 patients. Global LVF was similar in both groups. With anistreplase, the mean lowest fibrinogen level was 0.43 _+ 0.55 g/I, plasminogen was 20 _+ 9~, and the highest F.D.P. was 1447 _+ 548 ~Lg/ml.All values recovered by hour 48. In-hospital and 1-year follow-up mortality was 7.2c/~ (three patients) with anistreplase versus 10.2c/~(four patients) with heparin. Bleeding occurred in 9.7c/~ and 5.1qr of the patients (NS), respectively. No intracranial hemorrhage occurred. Thus, with combined clinical criteria or reperfusion, anistreplase is twice as efficient as heparin, has a good tolerance, and is easy to use as a single injection.

Cardiovasc Drugs Ther 4:1337-1344, 1990 h'eg Words. anistreplase, clinical criteria of reperfusion, coronary angiography, clinical trial, heparin, myocardial infarction, fibronolytic agents

T h r o m b o l y t i c t h e r a p y has proved its efficiency in achieving coronary a r t e r y reperfusion and in improving left v e n t r i c u l a r function and survival [1]. A new generation of thrombolytic agents has recently appeared, including t P A and anistreplase, an anisoylated plasminogen streptokinase activator complex (APSAC). Anistreplase is a sustained-release formulation, as its low rate of deaeylation allows a 90-minute plasma clearance half-life and a sustained action at the site of the thrombus. It achieves a high rate of reperfusion after a single i n t r a v e n o u s injection and reduces mortality [2]. The F r e n c h E u r o p e a n E m i n a s e Mortality Study

(EMS) is a randomized noninvasive parallel gn-oup reperfusion study comparing anistreplase to heparin. The end points were a) reperfusion assessed with clinical criteria, b) evaluation of left ventrieular function (LVF), and c) safety of anistreplace in patients treated within the first four hours of an acute myocardial infarction (AMI).

Methods Patients, randomization, and thrombolysis Eight-four patients were included b e t w e e n J u n e 1985 and October 1986 in this prospective randomized study involving ten centers. P a t i e n t s were eligible if they had a) chest pain of duration -< 4 hours; b) STsegment elevation of at least 0.1 mV in two or more standard leads, or at least 0.2 mV in two or more precordial leads not relieved by nitrates; 3) were < 71 years of age; 4) had no contraindication to thrombol ~ i c therapy. P a t i e n t s having cardiogenic shock at admission, Killip class III or IV, a history of previous AMI, or coronary a r t e r y bypass gq'aft s u r g e r y were excluded. A n t e r i o r and inferior infarctions were prospeetively stratified. After informed consent had been obtained, patients were randomized to anistreplase or heparin. T r e a t m e n t was then given in a open-label fashion. F o r t y - t w o patients allocated to anistreplase received a single i n t r a v e n o u s injection of 30 U over 2 5 minutes. F o r t y - t w o patients allecated to heparin received a mean bolus of 6500 I U as soon as they were

Address for correspondenceand reprint requests: Dr. H. Lardoux, Service de Cardiologie, Centre Hospitalier de Corbeil, 59 bd Henri Dunamt, 91108 Corbeil-Essmmes,France.

A~tistreplase is the generic name of Emi,ase, a registered trademark of Beecham Pharmaceuticals. *This paper was presented, in part, at the 3rd CardiovascularPharmacotherapy International Symposium,October 15-19, 1989, Kyoto, Japan.

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randomized. In both gn'oups the infusion of stud), medication was followed by a continuous infusion of heparin at the mean rate of 1000 IU/hr. It was delayed 4-6 hours in the anistreplase gn-oup. The heparin infusion rate was then adapted to provide an activated partial thrombin time (APTT) of at least twice that of the control. Concomitant medications were administered according to loeal habits and were recorded, as well as second thrombolysis, percutaneous transluminal coronary angioplasty (PTCA), or coronary artery bypass gq'aft surgery (CABG).

Clinical criteria of reperfusion Chest pain improvement was not taken into account because of its high subjectivity. Reperfusion was assessed fl'om ECG alterations and the CK release profile. Twelve-lead ECGs were recorded on admission; after sublingual administration of nitrates: 30 minutes postdosing; at 1, 2, 6, and 24 hours postdosing; and at 7 and 21 days postdosing. The sum of ST-segment elevation 0.04 seconds after the J point in all leads except aVr was measured in millivolts above the isoelectric line on the pretreatment and hour 2 ECGs. ST-segment depression was not measured. ECGs with complete left bundle branch block were excluded fl'om the measurement of the ST-segment elevation. The criterion of reperfusion was a decrease of at least 509~ of the sum ST [3,4] between the two (on admission and hour 2) recordings. Serial measurements of serum creatine phosphokinase (CK) were performed just before treatment; 1 hour postdosing every 3 hours between 3 and 30 hours; and at 36, 48, and 60 hours after dosing. The delay of CK peaking from the onset of symptoms was used to separate reperfused and nonreperfused patients. CK peaking at less than 16 hours was considered as a reperfusion criterion [3-6]. The upward CK slope was further calculated according to Lewis [7] and expressed as the relative rate of increase during the first hours of thrombolytic treatment. A relative rate of increase of more than 10%/hr was chosen as the criterion of reperfusion. On the basis of clinical objective criteria assessment, the patients were considered to be reperfused if they met at least two of the three following criteria: a) sum of ST-segment elevation decrease of at least 50~ between p r e t r e a t m e n t and hour 2, b) CK peaking before the 16th hour, and e) CK upward slope above 10%/hr. The reperfusion arrhythmias that were taken into account, though not used to assess reperfusion, were only those recorded, together with ST-segment alter-

ations and the number of events noted. The following arrhythmias were registered: sinus bradycardia or tachyeardia, premature ventricular beats, ventrieular tachyeardia of fibrillation, atrioventricular bloeks, and aeeelerated idioventricular rhythms.

Angiographic analysis Patency rates (TIMI gTades 2-3) were assessed by coronary angiogTaphy between 7 and 21 days postdosing. The analysis of residual stenosis was made in a semiquantitative way (normal, stenosis < 50c~, 5090q~, and 91-99~ occlusion). Global left ventricular ejection fi'aetions were calculated with the area-length method. Angiogn'ams were read by two cardiologists, who were blind with respect to treatment.

Hematology Serial measurements of fibrinogen [8] and activated partial thrombin time (APTT) were recorded just before treatment: 1 hour postdosing; every 3 hours between 3 and 30 horn's; and at 36, 48, and 60 hours postdosing. Plasminogen levels were assessed with a chromogenic substrate and fibrin(ogen) degradation products (FDP) with the latex agglutination assay.

Adverse events Adverse events were reported by the physicians and dMded into cardiac events, death, cerebrovascular accidents, bleeding events (gastrointestinal, urinary, or requiring transfusion) and aller:a"ic reactions.

Statistical analysis Student's t test was used to test differences in a continuous variable between treatment groups. Fisher's exact test was used to compare the sex balance between the treatment gn'oups. The Mantel-Haenszel chi square was used to compare clinical reperfusion and residual stenosis.

Results Demography A total of 84 patients were randomized. The two g~'oups were well balanced in terms of demogral)hic criteria, and no difference between gToups was observed (Table 1). All patients were included for efficacy and safety analysis. Four patients had no ST-segnnent deviation (three heparin patients) or cardiac enzyme elevation (one anistreplase patient). All four had significant (>50~) coronary lesions. The mean time to treatment was 2.7 _+ 0.9 hours and 2.8 _+ 0.7 hours in each treatment gToup, respectively.

AMstreplase bt Acute Myocardial h~farctiot~

Table 1. Demography

The serum CK data (Figure 2) were assessable in 82 patients. Peak values (anistreplase 2107 -+ 2170 IU/1, heparin 1853 - 1108 IU/1, NS) occurred 6 hours earlier in the anistreplase group (13.4 -+ 0.7 hours) than in the heparin group (19.3 - 1.0 hours, p < 0.001). The mean upward slope was steeper in the anistreplase group (20.3 -+ 2.4%) than is the heparin D'oup (10.1 -+ 2.6%, p < 0.01). The percentage of reperfused patients (fulfilling at least 2 out of 3 previously defined criteria) was assessable in 80 patients. It was 62.5% (25 patients) in the anistreplase group versus 27.5% (11 patients) in the heparin group. The difference was highly significant (p < 0.001).

Treatment Groups Anistreplase Sex (N): Male Female Age (years) SD Anterior AMI Inferior AMI Mean time to treatment (hours) SD History of angina History of hypertension

Heparin 42)

(n = 4 2 )

(n =

41 1 54.0 11.0 20 22 2.7 0.9 16 9

40 2 54.2 10.4 20 22 2.8 0.7 15 11

Reperfusion

a ~ m l y s i s . Coronary angiogTaphy was assessable in 76 out of 84 patients. Eight angiograms were not available: Five patients died before angiography was performed, three patients had no angiography because of intervening adverse events (one CVA, one heart failure, one renal insufficiency). Fiftyfive percent of the angiograms were obtained between day 12 and day 14 (mean 13.7 _+ 3.4 days). The infarct-related artery was the left anterior descending artery in 23 patients (31.5%), the right coronary artery in 35 patients (48%), and the circumflex A~giographic

of repe~:f~sio~t. The sum of STsegment elevations was calculated in 82 patients. One of the remaining patients had a left bundle branch block. In the other one, ECG alterations were not assessable. The sum of the ST-segment elevation curves over time for both heparin and anistreplase are presented in Figure 1. The time to a 50% decrease in the sum of ST-segment elevations was significantly lower (p < 0.03) with anistreplase (5.1 • 1.3 hours) than in the heparin group (9.7 +- 1.6 hours). Cli~dcal

criteria

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No. of Hours after Treatment Fig. 1. S T sum elevation over time.

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Lardoux et al.

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Fig. 2. CK time to activity curve. - . . . . . . . . ~]. . . . . . . . . heparin,"

artery in 10 patients (13.7%). The infarct-related artery could not be identified in five patients (6.8%). Patency rates were 67% (13 of 39) with anistreplase versus 47% (7 of 36) with heparin (NS). Out of the 23 occluded patients, 39% (nine patients) were dosed with anistreplase versus 61% with heparin, regardless of the clinical criteria status in each group. There was no relationship between early clinical criteria of reperfusion and delayed coronary angiogn'aphy status. The global ejection fraction was 47.2% • 10.9 with anistreplase and 46.6% • 10.4 with heparin (NS). No difference was shown between anterior and inferior infarction. H e m a t o l o g y ( F i g u r e s 3 A a ~ d 3 B ) . In the anistreplase group, the mean plasma fibrinogen was 3.95 • 1.55 g/1 before treatment. It decreased to 0.43 • 0.55 g/1 12 hours after t r e a t m e n t until normalization occurred within 48 hours. Plasminogen levels decreased fl'om a mean 106 +- 11% to a lowest mean of 20 ___ 9% at hour 6; the mean F D P levels increased from normal values (