Anisoylated plasminogen streptokinase activator complex in acute myocardial infarction: A placebo-controlled arteriographic coronary recanalization study

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REPORTS ON THERAPY

Anisoylated Plasminogen Streptokinase Activator Complex in Acute Myocardial Infarction: A Placebo-Controlled Arteriographic Coronary Recanalization Study ADAM D. TIMMIS, MD, MRCP, BRIAN GRIFFIN, MB, MRCPI, JONATHAN C. P. CRICK, DPHIL, MRCP, EDGAR SOWTON, MD, FACC London, England

Anisoylated plasminogen streptokinase activator complex (APSAC) is a new thrombolytic agent that is of Interest because of its ease of administration as an intravenous bolus injection. This report describes the first double-blind, placebo-controlled evaluation of intravenous APSAC tor coronary recanalization in acute myocardial infarction. Unequivocal documentation of recanalization was provided by coronary arteriography before and after the drug intervention. Forty patients with acute myocardial infarction underwent coronary arteriography 3.1 ± 1.2 hours after the onset of symptoms. This demonstrated occlusion of the infarct-related coronary artery in 29 patients who were then randomized to treatment with intravenous APSAC, 30 mg (n = 16), and placebo (n = 13) 3.3 ± 1.3 hours after the onset of symptoms. Repeat arteriography 90 minutes later demonstrated recanalization of the infarct-related coronary artery in nine patients who had received APSAC compared with

Myocardial infarction is usually the result of thrombotic occlusion of an atherosclerotic coronaty artery. The full extent of myocardial damage, however, may not be established for 26 hours, providing the rationale for early intervention with thrombolytic agents to recanalize the occluded artery and reduce eventual infarct size (I). Streptokinase is now widely used for this purpose, but because this drug induces a systemic fibrinolytic state its use is associated with a significant risk of hemorrhagic complications (2). Moreover, its short plasma half-life of only 18 minutes demands that it be administered by continuous intravenous infusion (3). From the Department of Cardiology, Guy's Hospital. London, England. Manuscript received October 20, 1986; revised manuscript received January 14, 1987, accepted January 26, 1987. Address for reprints: Adam D. Timmis Mb, Department of Cardiology. Guy's Hospital, St. Thomas' Street, London SE1 9RT, England. © 1987 by the American College of Cardiology

only one patient who had received placebo (56 versus 8%, p < 0.05). The 95% confidence limits for this 48% difference between the groups are 20 to 76%. Arteriography at 3 days showed persistent patency of all recanalized coronary arteries except one (APSAC group) and also showed late recanalization in another four patients, three of whom had received APSAC. In the patients who had a patent infarct-related coronary artery at the initial arteriographic study, patency was maintained throughout the study period regardless of whether the patient was randomized to APSAC (n = 4) or placebo (n = 7). Complications related to APSAC therapy were excessive bruising at the catheterization site in seven patients and minor sensitivity reactions in three. These data confirm the thrombolytic efficacy of APSAC in acute myocardial infarction, and indicate that the drug may be used safely by the intravenous route with a 56% early recanalization rate. (J Am Coli Cardiol1987;JO:20S-JO)

Anisoylated plasminogen streptokinase activator complex (APSAC, previously called BRL 26921) has theoretical advantages over streptokinase, although these are only partially fulfilled in practice. The active serine site within the streptokinase-plasminogen complex has been acylated with p-anisoic acid. Acylation renders the complex catalytically inert and prohibits its reaction with circulating plasminogen and plasma inhibitors (4). Fibrin binding at the site of recent thrombosis, however, is unaffected and after hydrolytic deacylation (T1J2 = 40 minutes) activation of the plasminogen moiety to plasmin initiates the fibrinolytic cascade (5). Depending on the extent to which these novel properties of APSAC are realized, two theoretical advantages will emerge. First the consumption of circulating fibrinogen will be limited, reducing the risk of hemorrhagic complications. Second, delay in plasma inhibition will prolong the plasma halflife, allowing the drug to be administered as a single intravenous bolus injection. 0735-1097/87/$3.50

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Despite the theoretical advantages of APSAC over streptokinase, the thrombolytic efficacy of this new agent after intravenous administration has not been subjected to the same rigorous testing involving pre- and postdosing coronary arteriography to document drug-induced recanalization of the occluded infarct-related coronary artery (6-11). Our study was designed to examine the thrombolytic efficacy of intravenous APSAC in acute myocardial infarction using strict arteriographic criteria and double-blind placebo control.

Methods Study patients. Forty patients (35 men and 5 women) aged :::::70 years (average 56 ± 9, range 27 to 70) were included in this study of anisoylated plasminogen streptokinase activator complex (APSAC) over a period of 18 months. Criteria for inclusion in the study were the recent onset of cardiac chest pain (:::::6 hours before randomization to APSAC or placebo) associated with ST segment elevation >0.1 mV in a standard electrophysiologic (ECG) lead or 0.2 mV in a precordial lead. In all cases these ECG indexes of acute infarction (anterior in 21, inferior in 19) were demonstrated to persist despite treatment with sublingual or intravenous nitrates. Exclusion criteria included a history of cerebrovascular accident, surgery or active peptic ulceration within the previous 3 months. Patients with severe hypertension (blood pressure > 200/120 mm Hg) or heart failure and those who had had external cardiac massage were also excluded. All patients gave informed verbal consent for inclusion in the study, which had been approved by the hospital ethical committee. Protocol. Patients who fulfilled inclusion criteria for the study underwent immediate coronary arteriography to identify the degree of patency of the infarct-related coronary artery. Patients were then randomized to treatment with APSAC, 30 mg intravenously, or with placebo. Coronary arteriography was repeated 90 minutes later to determine any change in the degree of patency of the infarct-related coronary artery. Four hours after treatment with APSAC or placebo, intravenous heparin, 1,000 units hourly, was started. Heparin therapy continued until the final coronary arteriographic study approximately 3 days later (range 25 to 139 hours), although in 18 patients the dose was either reduced or subcutaneous heparin, 5,000 units every 8 hours, was substituted. During the study period, drugs routinely used for the management of myocardial infarction were not withheld. Coronary arteriography. The predosing coronary arteriograms were performed in a side room attached to the coronary care unit. The coronary arteries were imaged in tum, starting with the (predicted) noninfarct-related vessel, using a modified Judkins technique. After insertion of a short sheath in the right femoral artery, the catheter was

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positioned in the coronary ostium under fluoroscopic control. Arteriography was performed using 5 to 8 ml of Urografin-370 solution, and the images were recorded on videotape. Single views in the posteroanterior projection were used in all cases, but when difficulties were encountered identifying the branches of the left coronary artery, the left lateral projection was also used. After the predosing coronary arteriograms were obtained, the femoral sheath was left in position and patency was maintained with a slow infusion of normal saline solution. The 90 minute postdosing coronary arteriograms were performed in exactly the same manner, except that injection was made only into the infarctrelated coronary artery. The arterial sheath was not removed until at least 24 hours afterward. The sole purpose of the pre- and postdosing arteriographic studies was to identify and determine the patency of the infarct-related coronary artery. In every case, the arteriograms recorded on videotape were adequate for this purpose. The coronary arteriograms performed 3 days after treatment, however, had the additional purpose of guiding further management. For this reason, they were performed in the cardiac catheterization laboratory using multiple radiographic projections recorded on cine film. Randomization. Patients were randomized to intravenous treatment with APSAC, 30 mg in 5 ml of water (n = 20), or an identical preparation of placebo (n = 20). The placebo consisted of freeze-dried human albumin in lysinemannitol, which was the base for the active preparation. Randomization was double-blind. The drugs were injected through a cannula in a peripheral vein over a period of 2 to 5 minutes. After drug administration, no further venipuncture was performed for 12 hours. During this period all blood samples were obtained from the femoral arterial sheath. Analysis of arteriographic data. In one patient with a persistently occluded coronary artery, equipment failure prevented recording of the pre- and postdosing coronary arteriograms on videotape. In four other patients, coronary arteriography at 3 days was not performed because of clinical deterioration or death in three and the request of the referring physician in one. The remainder of the arteriographic recordings were complete and were reported by a cardiologist not included in the authorship of this paper who was provided with no clinical details and was unaware of the randomization sequence. Coronary patency was graded according to the criteria of the TIMI study group (12). For the purpose of our study, coronary recanalization required positive demonstration of a change from TIMI grade 0 or I at the predosing arteriogram to TIMI grade 2 or 3 at subsequent arteriograms. Statistical analysis. Chi-square testing was used to evaluate differences between the incidence of coronary recanalization in the APSAC and placebo groups. All averaged values were expressed as mean ± I SO.

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TlMMIS ET AL. APSAC IN ACUTE MYOCARDIAL INFARCTION

PATIENTS

N;40

PRE-DOSING ARTERIOGRAM

OCCLUDED IRCA

I

29

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Figure 1. Effects of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) versus placebo on coronary patency in the 29 patients with an occluded infarct-related coronary artery (lRCA),

RANDOMIZATION

90' POST-DOSING ARTERIOGRAM

3 DAY ARTERIOGRAM

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APSAC 16

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PERSISTENTL Y PATENT IRCA 8

LATE RECANALIZA TlON 3

Results The major results of the thrombolytic efficacy of anisoylated plasminogen streptokinase activator complex (APSAC) in 29 patients with an occluded infarct-related coronary artery are summarized in Figure I, Predosing coronary arteriogram. The predosing coronary arteriogram was performed 3, I ± 1,2 hours (range 0,75 to 5,75) after the onset of chest pain, In 29 patients (group A), a TIMI grade 0 or I occlusion was identified in the infarct-related coronary artery. The occluded vessels were the left anterior descending coronary artery in 14 patients, the right coronary artery in 14 and the circumflex coronary artery in I. In 11 patients (group B), the infarctrelated coronary artery already showed TIMI grade 22 patency involving the left anterior descending coronary artery in 7 patients and the right coronary artery in 4, The time from the onset of chest pain to the predosing coronary arteriogram was similar in groups A (3, I ± 1,2 hours) and B (3.0 ± 1.4 hours). Randomization. Randomization to APSAC, 30 mg intravenously, or placebo was performed 3.3 ± I. 3 hours (range 1.0 to 6.0) after the onset of chest pain. Of the 29 patients in group A, 16 received APSAC and 11 received placebo. Of the 11 patients in group B, 4 received APSAC and 7 received placebo. Postdosing coronary arteriogram. Ninety minutes after dosing, repeat coronary arteriography was performed. In group A this demonstrated TIMI grade 22 recanalization of the infarct-related coronary artery in 9 (56%) of the 16 patients who received APSAC compared with only I of the 13 patients who received placebo (p < 0.05). Recanalization occurred in the right coronary artery in three patients, the left anterior descending coronary artery in six and the circumflex coronary artery in one. These differences were not significant. In group B, persistent patency of the infarctrelated coronary artery was demonstrated in all I I patients 90 minutes after dosing, regardless of treatment.

PLACEBO 13

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PERSISTENTL Y PATENT IRCA 1

LATE RECANALIZA TlON 1

Diagnostic coronary arteriography. Approximately 3 days after randomization to APSAC or placebo, coronary arteriography was repeated. In group A this showed persistent patency of all but one recanalized infarct-related coronary artery (a patient treated with APSAC whose right coronary artery had reoccluded). Late recanalization of the infarct-related coronary artery was demonstrated in four patients (three of whom had received APSAC), although clinical benefit in terms of myocardial salvage is unlikely to have been significant. Thus, at 3 days, recanalization was established in 69% of patients treated with intravenous AP· SAC compared with 15% of those who received placebo (p < 0.05). In group B, coronary arteriography at 3 days showed persistent patency of the infarct-related coronary artery in all cases. Procedural and drug-related complications. Complications of coronary arteriography included two episodes of ventricular fibrillation that occurred during the predosing procedure and responded rapidly to electrical cardioversion. One patient developed severe but ultimately reversible ischemia of the leg, probably due to embolization from the catheterization site. There were no side effects related to the administration of placebo, but two patients developed mild diaphoresis and dyspnea shortly after the APSAC injection. In both cases this resolved spontaneously within a period of 10 minutes. One other patient developed asymptomatic hypotension (90/60 mm Hg) for 15 minutes after the APSAC injection. Bleeding complications were limited to bruising around the femoral artery catheterization site, although in no case was this severe enough to warrant blood transfusion. Nevertheless in eight patients, seven of whom received APSAC, bruising was more pronounced than would normally be expected after cardiac catheterization and was attributed to the effects of thrombolytic (ASPAC) and anticoagulant (heparin) therapy. Clinical course. All patients except one (group B) developed completed myocardial infarction by cardiac enzy-

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matic criteria with peak plasma creatine kinase exceeding twice the upper reference limit for our laboratory(200 IV/liter). Three patients (two of whom received APSAC) died 3 to 5 days after admission because of intractable left ventricular failure in each case. In none of these patients was death attributable to APSAC therapy.

Discussion Laffel and Braunwald (13) pointed out that many patients who have undergone successful pharmacologically mediated thrombolysis would have had early spontaneous thrombolysis even if they had not received a thrombolytic agent. For this reason, they emphasized the need for well designed prospective randomized clinical trials to test the efficacy of thrombolytic agents in acute myocardial infarction. The purpose of our study was to define the thrombolytic efficacy of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) versus placebo in acute myocardial infarction by arteriographic documentation of the coronary anatomy before and after treatment. This information is essential to define the potential of this new agent for recanalization of the infarct-related coronary artery after thrombotic occlusion. No attempt was made to evaluate the effects of treatment on the evolution of myocardial infarction because the study was not primarily designed for this purpose. The findings demonstrate that intravenous APSAC is significantly more effective than placebo for thrombolysis in acute myocardial infarction and leads to early recanalization of the infarct-related coronary artery in 56% of cases. Importantly, none of our patients developed severe hemorrhagic complications related to APSAC therapy. Previous experience with APSAC. Previous studies (14-18) in which APSAC was delivered by the intracoronary route have consistently demonstrated recanalization of the infarct-related coronary artery in> 70% of cases. Similar recanalization rates have been reported after intravenous administration of the drug, particularly in studies (19-24) in which "recanalization" was inferred from arteriographic demonstration of coronary patency after treatment was given. These studies, however, have almost certainly overestimated the true drug-induced recanalization rate because in a significant proportion of cases with recent myocardial infarction, the infarct-related coronary artery is already patent at the time of hospital admission. Thus, our own predosing arteriographic findings demonstrated patency of the infarct-related coronary artery in 11 (28%) of the 40 patients, all of whom required exclusion from the analysis of the thrombolytic efficacy of APSAC. Had these patients been included and the thrombolytic efficacy of APSAC been assessed on the postdosing arteriograms, we would have reported a 70% recanalization rate rising to 80% at 3 days. Certainly, therefore, the 100% APSAC-induced recanalization rate reported by Doenecke et al. (22) and based on

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postdosing arteriographic findings at 48 hours must be interpreted cautiously. Marder et al. (25) provided preliminary pre- and postdosing arteriographic data in patients with acute myocardial infarction treated with 30 mg of intravenous APSAC. Their finding of a 60% recanalization rate agrees with our own, and is likely to provide a more realistic measure of the thrombolytic efficacy of this new agent. Interestingly, this is similar to the 57% recanalization rate after intravenous streptokinase that Schroder (26) reported in his review of pooled data from six studies in which pre- and postdosing coronary arteriography were performed in acute myocardial infarction. Indeed, there is probably no reason why the thrombolytic efficacy of APSAC should be significantly different from that of streptokinase, because streptokinase is the active component of the APSAC complex. Spontaneous thrombolysis. Accurate assessment of the efficacy of new thrombolytic agents in acute myocardial infarction requires not only pre- and postdosing arteriography, but also a placebo group to control for spontaneous thrombolysis leading to recanalization of the infarct-related coronary artery (27). Thus, spontaneous thrombolysis probably accounted for the high incidence of patency of the infarct-related coronary artery at the predosing arteriogram and for the recanalization that was demonstrated in the control group at the postdosing arteriogram (8%) and at the diagnostic arteriogram after 3 days (15%). Been et al. (21) included a placebo group in their randomized study of 32 patients given intravenous APSAC, 30 mg, early after the onset of myocardial infarction. Although they did not obtain predosing arteriograms, their findings, like our own, clearly demonstrate that early patency of the infarct-related coronary artery occurs significantly more often in patients treated with APSAC than in patients treated with placebo. Other randomized studies (28,29) using noninvasive functional markers of recanalization lend support to this conclusion. Thrombolytic therapy in patients with a patent infarct-related coronary artery. Patency of the infarct-related coronary artery is a commonly observed phenomenon in angiographic studies of acute myocardial infarction (30), and was demonstrated in 28% of our patients at the predosing investigation. It has been suggested (31,32) that the natural history of coronary occlusion in atherosclerotic arteries involves a dynamic interaction of thrombosis, endogenous thrombolysis and alterations in arterial tone. Because thrombolytic agents have the potential to influence this dynamic process favorably, treatment of this type might theoretically be helpful even in patients with patent infarctrelated coronary arteries. Nevertheless, our own findings suggest that in patients who present with a patent infarctrelated coronary artery, patency is maintained regardless of thrombolytic therapy. This conclusion must be interpreted cautiously, however, because our numbers were small and all of our patients received vasodilators and heparin, which

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are likely to have had an independent influence on coronary patency separate from the effects of thrombolytic therapy. Advantages of APSAC versus streptokinase. Our study indicates that the thrombolytic efficacy of intravenous APSAC is similar to that of streptokinase. APSAC has the theoretical advantage, however, of producing less systemic fibrinolysis (4). Nevertheless, although hemorrhagic complications in our study were relatively trivial, other investigators have reported more serious complications including gastrointestinal and intracranial bleeding with dosage regimens similar to our own (23,24). Indeed, measurements of circulating fibrinogen after intravenous APSAC, 30 mg, have shown profound hypofibrinogenemia (19,23,24), which in one study was comparable with that observed after administration of 1.5 million units of streptokinase or 2 million units of urokinase. It is clear, therefore, that whereas low doses of APSAC (5 to 20 mg) may have a relatively attenuated effect on systemic coagulation variables (17), the effect is considerably more pronounced with higher doses. This undoubtedly exposes the patient to the risk of hemorrhagic complications, but at the same time may contribute to successful and permanent reperfusion (33). The minor sensitivity reactions that occurred in three patients after APSAC were similar to those that occasionally complicate streptokinase therapy and were presumably due to the antigenicity of the complex (34). In this respect, therefore, APSAC appears to offer no advantage over streptokinase. Larger studies are necessary to determine the prevalance and potential severity of APSAC-induced hypersensitivity before recommendations for prophylactic corticosteroid therapy can be made. Other potential advantages ofAPSAC over streptokinase relate to its sustained thrombolytic action, which continues for up to 8 hours after administration and may reduce the incidence of reocclusion after initial recanalization (35). Nevertheless, as Hillis and Hornung (36) commented in a recent review, .'The major advantage of APSAC is its rate of administration as a single bolus injection over five minutes which may allow its application to use in the community by the primary care doctor, the hospital emergency department or the coronary care setting." The benefits of APSAC in the coronary care setting have now been substantiated by Ikram et al. (29) in a randomized study of 149 patients. They found that in patients randomized to APSAC within 150 minutes of the onset of symptoms, confirmed infarction (by enzymatic criteria) developed less commonly than in those treated conventionally (84 versus 100%, p < 0.05). This indicates that APSAC may play an important role in the coronary care unit for the early management of myocardial infarction. Our own data suggest that up to 56% of patients may benefit from treatment of this type. Limitation of study. The principal limitation of our study is the small number of patients randomized. Thus, although the best estimate of the difference between treat-

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ment groups for patients showing early coronary recanalization is 48%, the 95% confidence limits range from 20 to 76%. Importantly, however, even at the lowest limit of confidence there is an appreciable advantage of APSAC over placebo. The small number of patients studied also places constraints on the analysis of complications. A more meaningful assessment of the clinical safety of APSAC would require studies on a much larger scale. An additional limitation of the present study relates to the image quality of the videotape recordings of the acute phase coronary arteriograms, which was inevitably inferior to that of the cine recordings obtained at 3 days in the catheterization laboratory. In no case, however, did the image quality preclude identification of the infarct-related coronary artery. Moreover, because our criteria for recanalization discounted subtle (TIMI grade I) penetration of the occlusion and required instead full opacification of the distal vessel (TIMI grade 2 or 3), it is unlikely that our assessment of the thrombolytic efficacy of APSAC represented a significant underestimate. We acknowledge the help of Dr. David de Bono, Department of Cardiology, Royal Infirmary of Edinburgh, who reported on all the coronaty arteriograms obtained in this study. The technical assistance of Ms. Elizabeth Joyce. Department of Radiology, Guy's Hospital, London, is also gratefully acknowledged.

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