Thrombolytic

Therapy

in Myocardial

Infarction

F. Duckert gen. The ‘151-fibrinogen was. however, injected between 5 and 145 hr after onset of the first symptoms of AMI. This delay could certainly have reduced the value of the findings. The radioactivity of thrombi was analyzed at necropsy in 12 cases. The pattern of labeling found was: in 5 cases, the thrombi were labeled throughout; in 3, the distal part only; in I the proximal end; and in I, both ends. Finally, in two cases receiving “‘I-fibrinogen 65 and I45 hr after the first symptoms occurred, the thrombus was not labeled at all. These results indicated that the entirely labeled thrombi were formed at the time of. or after, the injection of fibrinogen. that the partially labeled ones were partly formed at the time of injection, while the early formed thrombi were not labeled at all. It appeared, therefore, that in most cases fibrin is involved in the acute phase of myocardial infarction and that the administration of thrombolytic therapy is theoretically justified. The potentially beneficial action of thrombolysis may be mediated by several mechanisms. Thrombolysis may reopen coronary vessels occluded by small fresh thrombi. It may prevent secondary thrombotic occlusion, protect the microcirculation in the periphery of the infarcted area, slightly diminish the blood viscosity, improve hemodynamic conditions. improve oxygenation, decrease the tendency of platelets to aggregate through the action of the larger hbrinogen and fibrin-split products, and secondarily reduce the frequency of thromboembolic complications in the peripheral circulation. A very early initiation of thrombolytic therapy after the onset of the lirst symptoms may improve the coronary circulation and limit the extension of necrosis. Or, under the most favorable circumstances. it may prevent the necrosis through one of the above-mentioned mechanisms.

T

HE first attempt to use tibrinolysis in the treatment of acute myocardial infarction was made by Fletcher et al.’ in 1959. The value of this form of therapy remains speculative some 20 yr later. Since the activity of plasmin is quite specific, directed only towards fibrin, fibrinogen. and some other proteins not relevant in this context, and has no effect on atherosclerotic material, the theoretical basis for fibrinolytic therapy in acute infarction is, at least to some investigators, open to question. In this article, these questions and data previously collected on fibrinolytic therapy in acute infarction are reviewed. IS THROMBOLYSIS JUSTIFIED IN ACUTE MYOCARDIAL INFARCTION? The importance of coronary thrombosis in the pathogenesis of acute myocardial infarction (AMI) has been and is still a subject of controversy. Some investigators consider thrombosis the cause of myocardial infarction. while others believe it is the consequence. More importantly, in relationship to the time of thrombolytic treatment, one must consider the presence of fibrin, the frequency of coronary thrombosis just before, during, or immediately after the infarction, and its participation in the vessel occlusion. According to several authors,’ the frequency of coronary thrombosis in patients dying of AMI varies between 50%) and 96.5%‘. The thrombi always have an approximate spatial relationship to the infarcted area, being located in a proximal position in the artery or arteries supplying the infarcted myocardium. These observations support the concept that thrombi play a causal role in myocardial infarction, but do not exclude the possibility that the thrombi may bc secondary. The time relationship between infarction and thrombus formation is difficult to establish. Erhardt3 presented a new approach using the labeling of coronary thrombi with “‘I-fibrino-

DESIGN OF THE CLINICAL TRIALS From the Coagulation and Fibrinol.vsis Laboratories, Kantonsspital. Basle, Swit:erland. Reprint requests should be addressed to F. Duckert. Ph.D., Coagulation and Fibrino1.v.G Laboratories, Kantonsspital. 4031. Basle. Switzerland. 01979 by Grune & Stratton. Intrr

,156

An earlier rise of serum activity for aspartate aminotransferase (GOT), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) was noted in treated as compared to control groups in three studies.“,‘3.‘4 In another study,” similar data were obtained for GOT and LDH, but CPK time activity curves were identical in the treated and control groups. Other studies”,” demonstrated an earlier rise of CPK. In most studies the daily assay of the serum enzymes allowed neither a differentiation between the two patient groups, nor a valid comparison between the peak values. The urokinase trial’ showed no differ-

Follow

up

0 05

211

11014

10 62 116,114 23 I 294

NS NS NS

lOY,128 187211

NS NS

12 a27

6

0 01

142

150

NS

105

173

0 01

28 11

26 34 No difference

14 17

NS

No dlffere,>cr No difference CPK HBDH No dtflerenc~

143 214 2 13

0025

233222

NS

‘T. total number of patients. W. womer~ M. men The relative number of pat~ents I” the treated groups are gIveri for streptoklnase’cotltrui fvr plasmlil cor~tr”/. and for uroklnaw gwen according to the same scheme, mortaltty with SK’control. mortality with plasm~r~ PL cor~tr”l or m”rtality wth UK~cnntrol

the pilot nor in the double-blind study. The data indicate that the lowest level of fibrinogen after 3 hr was higher than 1 g/liter and apparently did not decrease later. It is not clear if such a decrease was sufficient to influence the blood viscosity as to markedly improve its rheologic properties. It is almost certain that in other studies using a standard streptokinase regimen the fibrinogen reached lower values.

i’

CPK

Scanty Infwmdtluri Mayor arrhythmias less frequent wth SK 005 Early start better Edtliet stronger Rise of heart rate cardaac output u>e for CPK

182/121

DUCKERT

control

The rn”rt&ty

I

ence, while more precise investigations with ;I determination every 4 hr on a small number of‘ patients” demonstrated a clear difference for lactate dchydrogenase, tu-hydroxybutyrate dehydrogenase (HBDH). aspartate aminotransfcrase, creatinc phosphokinase. and phosphohcxoscisomerase (PHI). The delay bctwecn the lirst symptoms of acute infarction and the peak activity was shortened, for example. from 39. I to 25.7 hr for HBDH and only from 12.2 to 16.X hr for PHI. This statistically signiticant difference may indicate that in the early phase of thrombolytic therapy, the microcirculation in the infarcted arca is protected or improved and that enrymcs are more rapidly and more effectively transported. This justifies the assumption that thrombolysis may have a protective effect on the myocardium. However, the data do not allow one to postulate a reduction in the mass of the necrotic zone.” Elrctrocardiogram

and

Cardiac

Function

Here again the information is quite variable. When differences are noted between the treated

THROMBOLYTIC

THERAPY

IN

MYOCARDIAL

347

INFARCTION

patients and the controls they indicate a faster regression of the signs of necrosis, which vary between slightly significant* or highly significanP after urokinase treatment and a faster normalization of ST elevation. However, the last differences were only sporadically significant.8 Under streptokinase, various effects were noted: the ST elevation and the R reduction were less than in the control group,6 the QRS complex was more rapidly normalized,‘7 and major arrhythmias were significantly less frequent (p < 0.05) in the treated patients than in the control group.” It must be stressed that in the other trials either data were not available or the differences were not significant. It was also observed that in the absence of any effect on cardiac performance, heart rate and cardiac output were elevated. This was attributed to a diminution of the resistance in the periphery associated with a decrease in blood viscosity.”

Au topsy Findings

Autopsies were not regularly performed. Nevertheless, available data indicate that bleeding was not a major problem as a cause of death, even though it was noted slightly more frequently than in the control group.9*‘8,46 In contrast, thrombi appeared more frequent in the control group.46 The rate of cardiac rupture was similar in both groups; some found it slightly lower in the streptokinase-treated patients,’ while others reported a slightly higher rate of this complication in the fibrinolytically treated patients.5,‘9 In general, there were no differences between the treated and the control patients. The often expressed fear of an adverse action of streptokinase or urokinase was not supported by the reports. Severe hemorrhage or rupture was not significantly different when fibrinolysis was compared to placebo or glucose or heparin infusion. Side Efects

Mortality

Table 3 reviews overall mortality figures from numerous studies. In several trials, mortality has been analyzed in great detail as a function of different parameters. The age, sex, site of infarct, or prognostic group did not influence mortality rate,7.‘s except for some trials in which the age and sex had a slight influence.’ As already mentioned, very early treatment with thrombolytic therapy should be more favorable. However, a clearly significant difference has never been demonstrated. Shock patients did not fare better with thrombolytic treatment.” Depending on the study, early death was possibly slightly reducedI or the rate of late death was decreased.7 In multicenter trials,9.‘8 the results between centers vary greatly. Trials performed exclusively in coronary care units (CCU) show no difference in mortality. In contrast, it has also been reported that the effectiveness of streptokinase treatment was identical in coronary care units and in genera1 wards,” but strangely, the study failed to show a mortality difference between the control groups of both the CCU and the general wards, and this mortality of 27.3% and 28.9%, respectively, was rather high. In another study, the lowest mortality was seen in the patients of coronary care units treated with streptokinase and the highest in the patients on the general wards who did not receive streptokinase.”

Minor side effects, such as fever and hemorrhage at puncture sites, were more frequent in the treated patients. Major side effects were comparable in both the control and the treated patients. However, bleeding sometimes required an early interruption of the streptokinase infusion, possibly because of overlooked contraindications, since in other studies on thrombolysis, excessive bleeding is in most cases a late event. Follow-up

In only four studies were the patients followed after hospital discharge. In two series, follow-up was for 1 yr, 8,20in another one for 6 mo,“’ and in the last for 3 mo.7 There were no differences after 1 yr between the treated group and the control patients as regards cardiac functional class or angina, dyspnea, or increase of ventricular size.” In one trial’ there were more late deaths after 3 wk in the control group, but the survivors showed the same incidence of heart failure and angina at 3 mo. Miscellaneous

Data

A certain number of references are to be noted that may add some complementary information about thrombolytic treatment of acute myocardial infarction. Feasibility studies,23*24 studies without randomized control groups25-28or without control groups at a1kz9 with variable treatment conditions3’ or experimental investigations”“* have been performed. Other investiga-

F. DUCKEAT

348

tions dealing with clinical states associated with myocardial infarction3’.““ or special groups of patients35,36 have been reported. A further report will be published soonl’ and the final evaluation of the European urokinase trial’ shall also become available. The Russian literature contains a number of early reports on fibrinolytic therapy in myocardial infarction,38 4’ but exact details were not available for this review. DISCUSSION

This review of thrombolytic treatment for acute myocardial infarction demonstrates that the role of this form of therapy remains unresolved. The gap between positive trials, which have led to excessive enthusiasm by some, and negative studies is significant. The various trials are extremely difficult to compare, and the disparity of results cannot be explained on the basis of available data. The number of variables is too high to be taken into consideration within a single trial. With so many variables and different types of acute infarction, the number of patients was never sufficient to make both the controls and the treated patients yualitatively identical in any given trial. Disparities between success and failure are not only seen between trials but have also been noticed from center to center in at least two multicenter trials.9.‘8 For the investigators, these remained unexplained, probably because the use of an identical protocol was thought to be a guarantee of intercenter homogeneity. Sometimes, however, even in well randomized trials, comparability of the two patient groups is borderline, and the differences may become larger as an increasing number of variables is included in the characterization of the patients. Frequently, specific variables have been neglected because there is no objective way to qualify or to quantify them or because their determination adds a considerable amount of laboratory work and also requires large venesections. For example, the determination of platelet aggregation revealed4’ a wide variation of response to ADP, indicating, besides the effect of the disease itself, the probable influence of patient’s own medication with unknown drugs. Even though the distribution of the various responses seems identical in the two groups of patients, the origin, drug, or disease resulting in abnormal behavior of the platelets, in this study, could not be analyzed and added to the disparity of the patient groups.

Assuming that all variables have been taken into consideration and that the number ot patients will be large enough to make specific analyses of well defined clinical subsets. the problem will still not be solved. Fibrinolytic treatment can be conducted under very different conditions. One can use a standard regimen at either high or low streptokinase dose with either a short but important hyperplasminemia or a moderate hyperplasminemia with a more or less extensive and more or less prolonged fibrinogen degradation. One can also infuse an individual titrated dose with possibly a more constant and reproducible lytic activity. The experience with thrombolysis in peripheral arterial occlusion has shown that the material to be lysed may be more sensitive to one or another scheme, depending on its intrinsic qualities.” The same dosage problem also exists with urokinase; however, there is ;I more direct relationship between dose and effect. It is, therefore, not only a question of selecting those patients who would be helped by thrombolysis but also a question of dose regimen, the best regimen being possibly different for an individual patient or subset of patients. The evaluation of the therapeutic action of thrombolysis in myocardial infarction is primarily based on relative mortality. Follow-up was organized in only three trials. In one,” the mortality is recorded only at 6 mo. In the two others, patients have been controlled over 12 mo*X.?Oand no difference has been found ax regards functional classX or angina, dyspnea. ventricular size, and electrocardiogram.‘” All these trials are more or less subject to justitied criticism, since all protocols were wanting in some aspect. All have been strongly criticized by Fletcher.jJ especially because they all use as final reference for success or failure the mortality rate and also because the thrombolytic or, more importantly, the therapeutic potential of the tibrinolytic agents streptokinasc and urokinase has not yet been judiciously exploited. Some investigators realized the difficulties inherent to the choice of the agent and to its dosage. The importance of dose regimen is well established, for example, in the fibrinolytic treatment of arterial occlusion.” Many agree on the advantages of urokinasc, which are real. Will they become apparent in the treatment of myocardial infarction? Fletcherj4 assumes that urokinase has a “higher ratio on thrombus plasminogen” and could lyse thrombi better or more specifically than streptokinase. However, in the

THROMBOLMlC

THERAPY

IN MYOCARDIAL

INFARCTION

349

treatment of myocardial infarction, the emphasis has rarely been on the lysis of coronary thrombi. It was expected that the fibrinolytic treatment may protect the microcirculation in the neighborhood of the infarcted area and limit the extension of necrosis. Therefore, one is not dealing in the first place with the problem of dissolving a thrombus but with the problem of improving blood flow at the periphery of the infarcted area by preventing the formation of fibrin and by decreasing the fibrinogen content of the blood, and possibly, during a short period, through reduction of the platelet aggregation by fibrinogen-split products. Therefore, the necessity of a decrease of the fibrinogen concentration determined the empirical but logical and reasonable choice of at least a few investigators. The successful investigators using a low dose of urokinase,16 a high dose of streptokinase,” or average doses of streptokinase4*g,22545will disagree about the best choice, but they will agree that any thrombolysis will do the job in these cases while disagreeing with the unsuccessful investigators using similar dose regimens. Fletcher44 suggested that evaluation criteria other than mortality would reduce the number of patients required for an unbiased judgment on the therapeutic value of fibrinolysis in AMI. I do not share his optimistic view, since we must replace a clear end-point with several less well defined criteria. The higher degree of interpretative variations will increase the number of patients to be investigated. In addition, it has not been demonstrated that an early improvement of objective measurements (ECG, enzymes, reduction of blood fibrinogen and viscosity, possibly elimination of fibrinogen-fibrin-monomer complexes, or others) is identical with a long-range

improvement of the patient’s health. At least it has not been demonstrated after fibrinolysis.s920 Thus, the objective of evaluation shall be different and better, but the difficulties shall remain the same. CONCLUSIONS

A substantial number of trials on thrombolytic treatment in acute myocardial infarction have been published. However, the situation today relative to this form of therapy remains quite confusing. Some trials are positive in respect to mortality reduction, others negative. The reasons for the discrepancy remains unknown. A faster regression or normalization of electrocardiographic signs has been demonstrated also in trials in which no effect on the mortality rate was observed. The enzyme behavior, characterized by a faster rise of activity in serum, can also be interpreted as a favorable effect, but not always related to the mortality rate. Conversely, a true deleterious effect of thrombolytic treatment has never been reported, and a significant difference in favor of the control group has never been reported. It is fair to conclude that today the value of thrombolytic treatment in AM1 has not been established. This form of therapy should be restricted to research protocols in very well controlled trials. Although the data presently available are insufficient to justify the application of fibrinolytic treatment in the routine treatment of acute myocardial infarction, the initiation of new trials in which a prolonged follow-up and a precise and multifaceted control protocol is obtained seems justified on both the basis of available incomplete data and theoretical considerations.

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