Coronary Thrombolysis with Intravenous Urokinase in Patients with Acute Myocardial lnfardtion

DETLEF G. MATHEY, M.D. JOACHIM SCHOFER, M.D. Hamburg, Federal Republic of Germany

FLORENCE H. SHEEHAN, M.D. Seattle, Washington

From the Department of Cardiology, University Hospital Eppendorf, Hamburg, Federal Republic of Germany, and Cardiovascular Research and Train- ing Center, University of Washington, Seattle, Washington. Requests for reprints should be ad- dressed to Dr. Detlef G. Mathey, Department of Cardiology, University Hospital Eppendorf, Mar- tinistrasse 52,200O Hamburg 20, Federal Republic of Germany.

Regional left ventricular wall motion, about two to three weeks after acute myocardial infarction (Ml), is perhaps the best clinical mea- sure of myocardial salvage and limitation of infarct size by thrombo- lytic therapy. Normal or only slightly depressed wall motion at the site of infarction indicates significant limitation of infarct size, whereas markedly abnormal wall motion indicates irreversible myo- cardial damage. Early studles found significant improvement in re- gional wall motion in only 40 percent of patients undergoing suc- cessful intracoronary thrombolytic therapy after the onset of symp- toms of acute MI. Why only 40 percent of these reperfused patients demonstrated salvage of ischemic myocardlum could not be an- swered at that time. Animal experiments show that the duration of coronary occlusion is an important factor in determining myocardial salvage after reperfusion. To study whether this time dependency also exists under clinical circumstances in patients with coronary artery disease, the relationship between regional wall motion (as an index of Infarct size) and the time to thrombolytic therapy after the onset of symptoms (as an index of duration of coronary occlusion) was examined. After showing that such time dependency does in- deed exist in patients with acute MI, the efficacy and safety of intra- venous bolus injections of uroklnase were then demonstrated.

lntracoronary Thrombolytic Therapy. Between 1979 and 1983, 211 patients admitted to the hospital within three hours after the onset of symptoms of acute myocardial infarction (MI) received intracoronary thrombolytic therapy according to the protocol previously described [l].

Repet-fusion was achieved in 82 percent of these patients. Reinfarction within the first few days after thrombolytic therapy occurred in 12 percent, however, and was more likely in those patients who had very tight resid- ual stenosis after thrombolytic therapy.

Patients underwent left ventricular angiography during the acute infarc- tion and approximately two weeks later, to determine whether thrombo- lytic therapy reduced infarct size and improved left ventricular function. Surprisingly, there was no significant difference in global left ventricular ejection fraction at the follow-up study between patients in whom reperfu- sion was successful as compared with those in whom it was not success- ful. This unexpected finding could have been explained by either the inef- fectiveness of thrombolytic therapy or the inaccuracy of global left ejec- tion fraction as a measure of thrombolytic benefits.

Further evaluation indicated that the latter was true. The patient in Fig- ure 1, for example, had a normal global left ventricular ejection fraction of

26 August 24, 1987 The American Journal of Medicine Volume 63 (ruppl 2A)

SYMPOSIUM ON THROMBOLYTIC THERAPY-MATHEY ET AL

acute

EF = 0.65

Figure 1. In this patient with acute infe- rior MI, the global ejection fraction re- mains normal because of hyperkinesis in the opposite, non-ischemic wall. At follow-up, the ejection fraction is un- changed despite improvement in inferior wall hypokinesis because hyperkinesis has decreased. I

follow - UD

Figure 2. Centerline method. A and 6, Between the end-diastolic and end- systolic contours of the leff ventricle per- pendicular to a centerline, 100 chords are constructed representing regional wall motion. C, Regional wall motion is related to normal wall motion. 0, Wall motion is expressed as standard devia- tions from normal. Negative values indi- cate hypokinesis; positive values indicate hyperkinesis. Reprinted with permission from [6].

EF = 0.63

NORMALIZED WALL MOTION

-1 0 t 10 : 20 : 30 : 40 :- 50 : 60 : 70 : 00 i a0 ; i

STP_NDARD DEVIATION

0 10 20 30 40 w 80 70 80 a0 loo CHORD NUMBER

65 percent both at the time of MI and at follow-up evalua- tion. Although the patient had an inferior wall infarction with hypokinesia of that wall, his ejection fraction re- mained normal because of hyperkinesia of the opposite wall. Although there was marked improvement in inferior wall motion at follow-up examination, the ejection fraction remained unchanged because of a reduction in the hyper- kinesia of the opposite wall.

Therefore, regional wall motion was calculated by the area-length method described by Sheehan and col- leagues [2]. Wall motion was measured along 100 chords constructed perpendicular to a centerline drawn midway between the end-diastolic and end-systolic contours (Fig- ure 2) and normalized by the end-diastolic perimeter.

Regional wall motion was calculated as the mean motion of chords lying in the most hypokinetic 50 percent of the infarct artery territory, and expressed in standard devia- tions per chord from the mean wall motion of normal pa- tients. Hypokinesia is indicated by negative values and hyperkinesia by positive values. Normal wall motion is characterized by a value of 0; mild hypokinesia by a stan- dard deviation of less than -2; and severe hypokinesia by a standard deviation of greater than -2.

We found significant improvement in regional wall mo- tion (defined as improvement in wall motion greater than one standard deviation) in 40 percent of patients who had been reperfused, but in no patients in whom reperfusion failed. It was unclear at first why only 40 percent of the

August 24, 1987 The American Journal of Medlclne Volume 83 (suppl2A) 27

SYMPOSIUM ON THROMBOLYTIC THERAPY-MATHEY ET AL

Salvageable ischemic myocardium % 100

80

60

40

20

0 40min 3 h 6h

Duration of occlusion

Figure 3. Relationship between myocardial salvage and duration of coronary artery occlusion in dogs. Reproduced with permission of the American Heart Association from 151.

follow-up hypokinesis (SD/Chord) 1 , 1

normal 0 1

0 1 2 3 4 5 time to i.c. streptokinase (hrs)

igure 4. Relationship between follow-up wall motion and time to thrombolytic treatment. In about 80 percent of the patients treated within two hours, follow-up wall motion is in the normal range. Reprinted with permission from [S].

reperfused patients had improvement in wall motion and limitation of infarct size. However, data from animal stud- ies shed light on the question.

Our initial study involved 50 patients with acute Ml [7]. Twenty-five of these had anterior infarctions with left ante- rior descending coronary artery thrombosis; the other 25 had inferior infarctions, 15 with thrombosis in the right cor- onary artery and 10 with thrombosis in the dominant cir- cumflex. Patients received an intravenous bolus injection of 2 million units of urokinase, followed by an intravenous infusion of heparin in a dose of 200 U/kg per 12 hours.

Animal studies show a significant relationship between The bolus injection of urokinase was given to all of the infarct size and duration of coronary artery occlusion [3,4]. patients immediately after they entered the hospital and In dog experiments, Reimer and colleagues [5] found the within three hours after the onset of their symptoms of amount of time a coronary artery is occluded to be a major acute Ml. Coronary angiography was performed approxi- determinant of the amount of salvaged myocardium (Fig- mately one hour after urokinase was administered and ure 3). The longer a coronary artery is occluded, the less revealed a patent infarct artery in 30 (60 percent) of these myocardium can be salvaged. After 40 minutes of acute patients. (Spontaneous reperfusion may account for 20

occlusion, reperfusion leads to salvage of 64 percent of the jeopardized myocardium, whereas after three hours of occlusion, only IO percent is salvaged. Although the curve of myocardial salvage falls steeply in the first two hours after occlusion, it flattens with time, indicating that the time to reperfusion is a major determinant of myocardial sal- vage early after acute MI.

To determine whether this time dependency of myocar- dial salvage is also present in patients with coronary ar- tery disease, we studied the relationship between regional wall motional abnormalities at follow-up and time to thrombolytic therapy [6]. Regional hypokinesia is an index of myocardial damage and infarct size, and the time from onset of symptoms to the administration of thrombolytic therapy is a measure of the duration of coronary artery occlusion. Figure 4 demonstrates such a relationship. In patients successfully reperfused within two hours after the onset of chest pain, the likelihood of only mild hypokinesia or even normal wall motion at the time of follow-up evalua- tion is very high. If therapy is instituted between two to four hours after the onset of symptoms, however, the likeli- hood of normal wall motion at follow-up is less than 40 percent. Some patients clearly do show some benefit from thrombolytic therapy begun during the two- to four-hour period after their symptoms begin; but we do not know how to identify these individuals prior to treatment. Intravenous Urokinase in MI. Since the duration of cor- onary occlusion is a crucial factor in myocardial salvage, and two hours seems to be a critical time interval in the majority of patients who are experiencing a Ml, therapy has to be simple, safe, easy to administer, and should possibly start before the patient is even admitted to the hospital. These conditions can usually only be fulfilled by administering thrombolytic agents intravenously. We have used urokinase for this purpose because it has several advantages: in contrast to streptokinase, urokinase is non-antigenic and can be given repeatedly to the same patient; it can also be given as an intravenous bolus injec- tion since, unlike streptokinase, it does not cause hypo- tension when administered rapidly.

28 August 24, 1987 The American Journal of Medicine Volume 83 (suppl2A)

SYMPOSIUM ON THROMBOLYTIC THERAPY-MATHEY ET AL

percent of the patent arteries.) The patency rate did not differ significantly among the three major coronary ar- teries. Clinically significant limitation of infarct size was seen in those patients who were treated within two hours after the onset of their symptoms.

maxCK 4 WI) !jow _ I- P a.01 -1

.

4099 - .

Peak serum creatinine kinase levels were lower in ear- lier-treated reperfused patients compared with later- treated reperfused patients or those in whom reperfusion was not accomplished (Figure 5).

3000 - . .

2999 - 0

1. - :

At follow-up evaluation, wall motion measured by con- trast ventriculography was significantly better only in pa- tients who received an intravenous bolus injection of uro- kinase within two hours of the onset of symptoms, com- pared with patients in whom reperfusion was not achieved (Figure 6). Interestingly, patients who underwent acute angioplasty because there was no response to intrave- nous urokinase also did not show improvement in wall motion. In fact, there was no difference in their wall motion compared with that of other patients in whom reperfusion could not be achieved.

1099 - T

i i l

.

0 I ! 1

Time to umkinase <2h 2-4h No

Infarct artery patent reperfurion I

Figure 5. Peak serum creatinine levels in patients reper- fused within two hours, those reperfused after two to four hours, and those in whom reperfusion was not accom- plished. Reprinted with permission from [7].

Approximately two weeks after reperfusion, angiogra- phy showed that the arteries in 23 of 24 patients (96 per- cent), whose arteries were initially patent, stayed open.

The urokinase bolus injection was well tolerated by all patients. There were no hypotensive, allergic, or anaphy- lactic reactions, nor were there any serious bleeding com- plications, although all patients underwent acute coronary angiography. Two patients who underwent coronary ar- tery bypass surgery within 24 hours of their acute Ml re- ceived fibrinogen. One patient experienced ventricular fi- brillation after receiving a urokinase bolus at another hos- pital but was resuscitated successfully. Since he contin- ued to have significant ST-segment elevation, his arrhyth- mia was probably caused by occlusion rather than by re- perfusion. Only one patient, whose angiogram showed that he had a re-opened artery after urokinase bolus ther- apy, had reocclusion at follow-up.

Hypokinesisf (SD/Chord)

2- - P<O.W -1

1

t

0

0 l

-1

-2

i

;

-3

-A 0

l

l

t

:

+

i iime to umkinei

<2h 2-4h Infarct artery patent

No reperfusion

Figure 6. Follow-up wall motion in the infarct region in pa-

There are no studies evaluating the effects of an intra- venous bolus injection of urokinase on the coagulation and fibrinolytic systems. The arbitrary dose of 2 million units used in this study caused profound changes in these systems. Fibrinolysis after bolus urokinase injection was comparable to that achieved by intravenous infusion of streptokinase. Fibrinogen levels dropped to about 100 mg/percent immediately after infusion, and returned to within the normal range slowly over the next 24 hours. Plasmin activity increased rapidly, peaking 15 minutes after the bolus injection of urokinase, and remained ele- vated for up to six hours.

tients reperfused within two hours, those reperfused after two to four hours, and those in whom reperfusion was not accomplished. Reprinted with permission from p].

acute Ml even before they are hospitalized-the time when salvage of myocardium is most likely to occur.

We conclude that intravenous bolus injection of 2 million units of urokinase is safe, effective, and at least compara- ble to intravenous streptokinase infusion in reperfusion efficacy. Not only is intravenous bolus injection of uroki- nase a useful alternative to streptokinase infusion, it may be particularly helpful to attain reperfusion in patients with

Currently, my colleagues and I are performing a con- trolled study on the effects of the use of intravenous bolus infusions of thrombolytic agents prior to hospitalization. Patients who are reached by ambulance or physician within four hours of the onset of chest pain, and in whom the diagnosis of acute Ml is confirmed by a 1Plead elec- trocardiograph, are divided into two treatment groups: One group receives urokinase before hospital admission; the other group receives urokinase upon hospitalization. Contrast left ventricular angiograms are taken two to three weeks after thrombolytic therapy to determine left ventric- ular wall motion as an index of myocardial salvage.

August 24, 1907 The American Journal of Medicine Volume 93 (suppl PA) 29

SYMPOSIUM ON THROMBOLYTIC THERAPY-MATHEY ET AL

REFERENCES

1. Mathey DG, Kuck K-H, Tilsner V, et al: Nonsurgical coronary ar- tery recanalization in acute transmural myocardial infarction. Circulation 1981; 63: 489-497.

2. Sheehan FH, Mathey DG, Schafer J, Krebber HJ, Dodge HT: Effect of interventions in salvaging left ventricular function in acute myocardial infarction: a study of intracoronary streptoki- nase. Am J Cardiol 1983; 52: 431-438.

3. Lang TW, Corday E, Gold H, et al: Consequences of reperfusion after coronary occlusion: effects on hemodynamic and regional myocardial metabolic function. Am J Cardiol 1974; 33: 69- 81.

4. Geary GG, Smith GT, McNamara JJ: Quantitative effect of early coronary artery reperfusion in baboons: extent of salvage of the perfusion bed of an occluded artery. Circulation 1982; 66: 391-396.

5. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB: The wave- front phenomenon of ischemic cell death. I. Myocardial infarct size vs. duration of coronary occlusion in dogs, Circulation 1977; 56: 786-794.

6. Mathey DG, Sheehan FH, Schafer J, et al: Time from onset of symptoms to thrombolytic therapy: a major determinant of myocardial salvage in patients with acute transmural infarction. J Am Coil Cardiol 1985; 6: 518-525.

7. Mathey DG, Schafer J, Sheehan FH, et al: Intravenous urokinase in acute myocardial infarction. Am J Cardiol 1985; 55: 878- 882.

8. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB: The wave- front phenomenon of ischemic cell death. I. Myocardial infarct size vs. duration of coronary occlusion in dogs. Circulation 1977; 56.

30 August 24, 1987 The American Journal of Medicine Volume 83 (suppl 2A)