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The feasibility of urokinase therapy in acute myocardial infarction
Reports on Therapy
The Feasibility of Urokinase Therapy in Acute Myocardial Infarction
GEORGE RUSSELL NANETTE Atlanta,
I. LITMAN, MD B. SMILEY, Jr., KASS WENGER,
MD MD,
FACC
Georgia
From the Department of Medicine (Cardiology), Emory University School of Medicine and the Medical Service, Grady Memorial Hospital, Atlanta, Ga. This study was supported in part by U. S. Public Health Service Grant HE-5653. Manuscript received June 16, 1970, accepted September 10, 1970. Address for reprints: Nanette K. Wenger, MD, Emory University School of Medicine, 69 Butler St., SE., Atlanta, Ga. 30303.
636
Seventeen patients with early acute myocardial infarction were treated with urokinase to determine the feasibility of administration of this drug to acutely ill patients. Before the institution of urokinase therapy, 15 patients had complications of myocardial infarction, including arrhythmia, congestive heart failure, intractable pain, shock and cardiac arrest. Hemorrhage was the only significant complication of urokinase therapy; it occurred in 3 patients but necessitated the discontinuation of urokinase administration in only 1. It was feasible to administer urokinase to acutely ill patients with myocardial infarction without compromising the usual care given these patients.
Coronary artery thrombosis is the major etiologic factor in acute myocardial infarction.‘J The use of thrombolytic therapy in acute myocardial infarction might prove beneficial by restoring blood flow and salvaging tissue that would otherwise become necrotic. In addition, prevention of microthrombus formation or lysis of microthrombi in the marginal zone around the infarcted area could improve the blood supply to this ischemic area and might reduce the incidence of arrhythmias due to electrical instability of the heart. A third possible benefit would be the prevention or lysis of mural thrombi.S This study was designed to evaluate the feasibility of thrombolytic therapy with urokinase in patients with acute myocardial infarction. The thrombolytic agent urokinase is a naturally occurring plasminogen activator of human origin. This single chain polypeptide with a molecular weight of 53,000 is capable of hydrolyzing arginine and lysine bonds. It acts to split one or more peptide bonds of plasminogen and to open the active enzyme center of plasmin. Plasmin, a proteolytic enzyme, digests fibrin and produces thrombolysis.4 Urokinase is nontoxic and nonantigenic ; it has a high fibrinolytic/fibrinogenolytic activity ratio, and its administration on a dose per body weight basis produces a predictable change in plasma thrombolytic activity, plasma fibrinogen, plasminogen and other coagulation factors. Urokinase produces an intense sustained state of enhanced plasma thrombolytic activity in man.” Prior studies with urokinase have shown lysis of arterial and venous thrombi and the resolution of acute pulmonary emboli.5-10 The therapeutic results in pulmonary embolism were sufficiently promising to warrant establishment of a National Cooperative Urokinase Pulmonary Embolism Trial. To our knowledge, the present study is the first to utilize purified urokinase in the treatment of acute myocardial infarction.
The
American
Journal
of
CARDIOLOGY
UROKINASE
THERAPY
IN ACUTE MYOCARDIAL
INFARCTION
TABLE I
Methods and Materials The criteria required for the admission of a patient to the study were as follows: (1) classic history of acute myocardial infarction; (2) diagnostic electrocardiographic criteria for acute myocardial infarction, including Q waves and S-T segment elevation or T wave inversion, or both; (3) patient age of less than 65 to initiate urokinase treatment years ; (4) ability within 14 hours of the onset of chest pain. Urokinase therapy was considered contraindicated in patients with the following: risk of hemorrhage from a recent surgical procedure; recent diagnosis of peptic ulcer or other bleeding gastrointestinal lesion ; recent cerebrovascular accident (10 to 14 days) ; severe uncontrolled hypertension ; nonsurgical hematuria ; severe hepatic disease; or blood dyscrasia or coagulation disorder. Laboratory determinations obtained before the institution of urokinase therapy included hematocrit ; white blood cell count and differential ; blood urea nitrogen ; blood sugar ; urinalysis ; stool examination for occult blood ; prothrombin time and euglobulin clot lysis time. The prothrombin time was determined by the Quick l-stage method and the euglobulin clot lysis time by the method of Buckel1.l’ Dosage : Urokinase” was administered by a continuous infusion pump (Harvard Instrument Co.) through a polyethylene catheter in a forearm vein. A priming dose of 1,650 CTAt units/lb of body weight was given over 10 minutes, followed by a sustaining infusion of 1,650 CTA units/lb of body weight/hour for 8 hours.5 All patients were in a coronary care unit, with a physician investigator in attendance during the infusion. During the urokinase infusion plasma fibrinolytic activity and alterations in the coagulation mechanism were monitored by determination of euglobulin clot lysis time and prothrombin time at 10 minutes and 2, 4, 6 and 8 hours after institution of the infusion. Hematocrit levels were also determined at these intervals. On the day after infusion, euglobulin clot lysis time, prothrombin time, hematocrit, white blood count, serum glutamic oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH) were determined, and urinalysis was performed. Hematocrit values were determined serially during the hospitalization.
Patients Studied
Age00
Site of
no.
& Sex
Infarct
1 2 3 4 5 6
54F 64M 62F 48F 49M 26F 47M 40M 52M 48M 59M 49M 55M 44M 43M 46M 41M
Case
7 8 9 10 11 12 13 14 15 16 17
Anterior Inferior Inferior Anteroseptal Anterolateral Inferior Inferior Inferior Inferior Inferior
Inferior Inferior Anteroseptal Inferior Inferior Inferior Inferior
Mortality Survived Survived Died Survived Survived Died Died Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived
for 13 patients ; 4 patients had electrocardiographic evidence of a prior myocardial infarction in addition to the acute infarction. Two patients had a prior radiographically documented duodenal ulcer without hemorrhage, and 1 patient had had a hemigastrectomy for bleeding gastric ulcer 2 years previously without recurrence of symptoms or of bleeding. Chronic alcoholism was reported by 3 patients. Thirteen of the 1’7 patients had electrocardiographic evidence of acute inferior myocardial infarction, and 4 had acute anterior infarction (Table I). Prior angina pectoris was described by 7 patients, and a questionable history of angina was obtained from an additional patient. Three patients had diabetes mellitus, 3 had essential hypertension, and 2 had a strong family history of coronary atherosclerotic heart disease. An elevated level of blood cholesterol had been documented in 2 patients on a routine examination before the myocardial infarction. One patient with angina pectoris also had moderately severe rheumatic mitral stenosis. One patient had had a cerebral vascular accident 1 year before the acute myocardial infarction, but had no residual neurologic deficit.
Case Material Seventeen patients were studied, 13 men and 4 women, ranging in age from 26 to 64 years (Table I). Enzyme confirmation (SGOT and LDH)12v1” of myocardial infarction was obtained in all patients except 1 whose blood specimens were lost in the laboratory. This was the initial episode of myocardial infarction
* Sterling-Winthrop Research Institute. Urokinase by the National Blood Resource Program of the Heart and Lung Institute, Bethesda, Maryland. t The CTA (Committee standard urokinase unit mittee on Thrombolytic Lung Institute.
VOLUME
27, JUNE
1971
supplied National
on Thrombolytic Agents) unit is the of activity established by the ComAgents of the National Heart and
Results Clinical course : Thirty-six complications of myocardial infarction were documented in 15 of the 17 patients before the institution of urokinase therapy (Table II). Only 2 patients had a completely uncomplicated clinical course; 13 had congestive heart failure and 12 had concomitant cardiac arrhythmias. These arrhythmias included sinus tachycardia, sinus bradycardia, slow idioventricular rhythm, multiple premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, first, second and third degree atrioventricular (A-V) block, A-V dissociation and atria1 fibrillation.
637
LITMAN
ET AL.
TABLE
II
Complications
of Acute Myocardial
Infarction
Before Treatment Intractable Pain
Cardiac Arrest
+
0
0
0 0 0 0 0 0 0 0
+ 0
0
0
+
+
0
0
0
...
0
0
0
0 0
Arrhythmia, Arrhythmia,
+
0
Case no.
CHF
Arrhythmia
Shock
0 +
1 2 3 4 5 6 7 8 9
+ + + + + + + + 0
10 11 12
+ + 0
+ -t
0
13
+
+
+
-I+ + + +
0
0
0
0
0
...
+
0
Shock, bilateral
0
pulmonary Arrhythmia ... ...
+
.
0
0 0
0
16 17
+ 0
* Pacemaker inserted prior to urokinase therapy. BBB = bundle branch block; CHF = congestive
aneurysm
pericardial
rub
BBB, emboli
CHF,
embolism
arrhythmia,
pacemaker,
recurrent
heart failure.
Four patients had cardiogenic shock before the urokinase infusion ; this was manifested by peripheral cyanosis, a blood pressure of less than 80/60 mm Hg, low urinary output, and the like ; all 4 patients survived to leave the hospital. Three patients with cardiac arrest were successfully resuscitated and survived to leave the hospital. Severe recurrent chest pain occurred in 4 patients before and during the urokinase infusion. One patient required a bipolar transvenous catheter pacemaker before infusion. Nine patients had continued complications of myocardial infarction after infusion (Table II). Arrhythmias either persisted or developed in 9 patients, and a bipolar catheter pacemaker was inserted in 4. Severe congestive heart failure persisted in 4 patients, and clinical shock persisted in 1 of the 4 patients after completion of the urokinase infusion. Two patients had pulmonary embolization ; a pericardial friction rub developed in 2 patients, in 1 on the day after urokinase infusion and in 1 on the sixth day after infusion. Only 1 patient had recurrent angina pectoris in the hospital. Fourteen patients survived to be discharged from the hospital (Table I). A ventricular aneurysm was demonstrated by fluoroscopy just prior to discharge in 1 patient. Fibrinolytic activity: Adequate plasma fibrinolytic activity as measured by a euglobulin clot lysis time of 1 to 6 minutes was demonstrated in all patients during the urokinase infusion. In all patients the euglobulin clot lysis time had returned
638
ventricular
... CHF, arrhythmia, pulmonary Arrhythmia, CHF
+
0
+ +
pacemaker, CHF
0
0
0 0
+ 0
Arrhythmia Recurrent pain Arrhythmia, pacemaker Arrhythmia, pacemaker, ...
+* +
+
14 15
0
After Treatment
to normal 24 hours after termination of the infusion. There was no major alteration in the prothrombin time during infusion. Bleeding : Eight patients had a decrease in hematocrit which ranged from 1 to 5 percent over a 6 day period. We found no associated symptoms or clinical evidence of bleeding except as later discussed. This fall in hematocrit may have represented rehydration, blood loss from venipunctures for blood tests, or both. Bleeding occurred during the urokinase infusion in 3 patients. One patient bled from a 2 day old femoral arterial catheterization site in the sixth hour of infusion; the bleeding was readily controlled by local pressure and the infusion was completed. In a second patient a hematoma developed with continued bleeding at a site of attempted subclavian venous catheterization ; the urokinase infusion was discontinued at 6 hours, 45 minutes because of fear of intrathoracic hemorrhage. The third patient bled from an antecubital venipuncture site; again, the bleeding was easily controlled by local pressure and the infusion was completed. No toxic, pyrogenic or antigenic reactions were noted in any patient. Postmortem examinations were perDeaths: formed on 2 of the 3 patients who died. One patient died on the fifth hospital day, and we found a recent thrombosis of the circumflex branch of the left coronary artery with recent left ventricular lateral wall infarction. Microscopic examination demonstrated no organization of the clot in the
The American
Journal
of CARDIOLOGY
UROKINASE
left circumflex artery. The age of the infarction was consistent with the clinical history. The second patient died on the twelfth hospital day. A recent myocardial infarction involved the posterior walls of both the left and right ventricles and the posterosuperior portion of the intraventricular septum; at autopsy, estimation of the age of the infarction was 15 days. A recent thrombotic occlusion of the right coronary artery was found 3 to 3.5 cm from its origin from the aorta. The anterior descending branch of the left coronary artery was narrowed to approximately 20 percent of its original lumen by atherosclerotic changes. The circumflex artery was also moderately narrowed. In neither case was there unusual hemorrhage or any specific lesion which could be attributed to the urokinase infusion.
Discussion The success of thrombolytic therapy in acute myocardial infarction depends on several variables. First, the etiologic process must be thrombosis. In myocardial infarction caused by hemorrhage into a subintimal plaque, or by vasoconstriction or hypotension, fibrinolytic therapy would be of no value. Second, even if the etiologic process is thrombosis, thrombolytic therapy should be initiated soon after thrombus formation since thrombolytic therapy is probably ineffective once endothelialization and fibrosis occur.14J5 Third, the perfusion to the involved artery is critical, in that the thrombolytic agent must be brought into contact with the thrombus. Finally, the most effective duration and schedule of dosage have yet to be determined, Previous studies: Feasibility studies have been reported for several thrombolytic agents in acute myocardial infarction. In a controlled study, Fletcher et al.lB administered streptokinase to patients with acute myocardial infarction. Thrombolytic activity was maintained for 30 hours in 19 patients with early acutae myocardial infarction ; all survived the acute phase, although 1 patient died 3 weeks later. The results with streptokinase therapy were not statistically different from those for the control group; however, this study demonstrated that the infarcted myocardium could tolerate an inten,se thrombolytic state. Schmutzler et a1.l’ administered streptokinase to 297 patients with acute myocardial infarction; anticoagulant agents (heparin followed by phenprocoumon) were given to a control group of 261 patients with acute myocardial infarction. A significantly lower mortality was r,eported for the patients treated with streptokinase than for those receiving anticoagulant therapy. Fibrinolytic therapy was well tolerated by all patients with the exception of 1 who bled from an unsuspected carcinoma of the stomach.
VOLUME
27. JUNE
1971
THERAPY
IN ACUTE MYOCARDIAL
INFARCTION
In a double-blind trial Lippschutz et a1.18utilized urokinase-activated human plasmin to treat 84 patients with acute myocardial infarction and concluded that the plasmin treatment was safe for such patients. This series was too small to permit evaluation of survival statistics. Interestingly, among their pati,ents classified as severely ill with a poor prognosi.s, 47 percent of the control subjects died compared with 24 percent of those treated with urokinase-activated plasmin. Clinical problems : All of our patients were treated with urokinase within 14 hours of the onset of symptoms of acute myocardial infarction; in most instances, the infusion was initiated within 8 hours. Only 2 of the 17 patients were considered to have uncomplicated myocardial infarction before the initiation of urokinase therapy. All patients were carefully monitored in a coronary care unit, and the majority had a central venous catheter inserted. The 8 hour urokinase infusion did not curtail the usual care given these acutely ill patients, interfere with therapy for arrhythmias, congestive heart failure or shock, or disturb the usual cardiovascular monitoring. The major complication of urokinase therapy is hemorrhage. Although bleeding from venipuncture or cutdown sites is generally readily controlled by local pressure, the inability to control intense bleeding requires discontinuation of the infusion. In 1 patient, a hematoma and active bleeding occurred at the site of an attempted pacemaker insertion through a subclavian vein before initiation of urokinase therapy. The bleeding occurred 6 hours, 45 minutes after the start of infusion, which was then terminated for fear of intrathoracic hemorrhage. No intrathoracic bleeding occurred, and the external hemorrhage was easily controlled by pressure ; shortly after discontinuation of the infusion, all coagulation studies showed normal results. Two patients had had documented duodenal ulcers in the past ; 2 others had required surgery for bleeding gastrointestinal lesions. None had recent symptoms of an ulcer ‘or a history of recent bleeding. No hemorrhage occurred in these patients during or after urokinase therapy. The thrombolytic state rapidly disappears after termination of the urokinase infusion”; in all patients the euglobulin clot lysis time had returned to normal within 24 hours. Our experience suggests that treatment with urokinase may be contraindicated in patients who have had active cardiopulmonary resuscitation measures with multiple intravascular and intracardiac punctures. Patients with known gastrointestinal lesions, especially those with a history of bleeding, should be evaluated individually for urokinase therapy. A significant decrease in hematocrit has been reported in patients treated with urokinase. This
639
LITMAN
ET AL.
decrease has usually been associated with excessive bleeding from wound or cutdown sites, induced by the thrombolytic state. In a few patients the drop in hematocrit has remained unexplained ; this complication of urokinase administration awaits clarification.” Nine of our patients had a decrease in hematocrit, but none of serious proportion. Clinical evaluation in these patients did not reveal a bleeding site; no extensive hematologic studies were undertaken. The initial level of hematocrit in these patients may have been spuriously elevated, since patients with acute myocardial infarction may have elevation of the hematocrit or hemoconcentration, or both.‘” A drop in plasma volume may occur after acute myocardial infarction, as a result of fluid loss from vomiting or decreased fluid intake during the first day after acute infarction.20 Therefore, the decrease in hematocrit in our patients might result from subsequent rehydration and return to a more normal state.
There were no febrile reactions that could not be attributed to the myocardial infarction. We did not observe allergic or hypotensive reactions from urokinase therapy. Clinical evidence of pulmonary embolism developed in 1 patient 6 days after urokinase therapy; however, the chest roentgenographic findings were negative and no lung radioisotope scan or pulmonary angiogram was performed. This patient had been extremely ill, was confined to bed for the prior 6 days and had not r,eceived anticoagulant therapy, Anticoagulant therapy was begun, he recovered and is presently well. Postmortem studies on 2 of the 3 patients who died revealed poorly organized thrombi in the coronary arteries and findings consistent with the clinical history and age of the acute infarction. No conclusions can be drawn from these findings. There was no evidence that urokinase caused added damage to myocardial tissue in these 2 patients.
References Colloquium uber 1. Fritze E, Vandeioo J, Kovemeier H: Koronar-thrombose and Myocardi-infarkt, Bochum, 1964 (abstr). Deutsch Med Wschr 90:933-936, 1965 2. Parkinson J, Bedford DE: Cardiac infarction and coronary thrombosis. Lancet 1,4-11, 1928 3. Sherry S: Fibrinolytic agents. DM May, 1969. 1968 4. Sherry S: Fibrinolysis. Ann Rev Med 19:247-268, 5. Fletcher AP, Alkjaersig N, Sherry S, et al: The development of urokinase as a thrombolytic agent. Maintenance of a sustained thrombolytic state in man by its intravenous infusion. J Lab Clin Med 65:713-731, 1965 6. Johnson AJ, McCarthy WR, Newman J: Proceedings of the Ninth Congress of the European Society of Hematology, Lisbon 1963, p 1389-1393 7. Sautter RD. Emanuel DA. Fletcher FW. et al: U?okinase in the treatment of acute pulmonary thromboembolism. JAMA 202:215-218, 1967 8. Tow DE, Wagner HN Jr, Holmes RA: Urokinase in pulmonary embolism. New Eng J Med 277:1161-1167, 1967 Urokinase 9. Sasahera HA, Cannili JF, Belks JS, et al: therapy in clinical pulmonary embolism. New Eng J Med 277:1168-l 173, 1967 Urokinase therapy in pulmonary 10. Genton E, Wolf PS: thromboembolism. Amer Heart J 76:628-637, 1968 11. Buckell M: The effect of citrate on euglobulin methods of estimating fibrinolytic activity. J Clin Path 11:403405,19!% 12. LaDue JS, Wroblewski F: The significance of the serum glutamic oxaloacetic transaminase activity following
640
13.
14.
15.
16.
17.
18
19.
20,
acute myocardial infarction. Circulation 11:871-877, 1955 Wroblewski F: Serum enzymes and isoenzyme alteration in myocardial infarction. Progr Cardiovasc Dis 6:63-83, 1963 Back N, Ambrus TL, Simpson CL, et al: Study on the effect of streptokinase activated plasmin (fibrinolysin) on clots in various stages of organization. J Clin Invest 37:864-871, 1958 Ambrus JL, Ambrus CM, Back N, et al: Clinical and experimental studies on fibrinolytic enzymes. Ann N Y Acad Sci 68:97-137, 1957 Fletcher AP, Sherry S, Alkjaersig N, et al: The maintenance of a sustained thrombolytic state in man. 2. Clinical observation on patients with myocardial infarction and other thromboembolic disorders. J Clin Invest 38:1111-1119, 1959 Schmutzler R, Heckner F, Kortge P, et al: Thrombolytic therapy of recent myocardial infarction. 1. Introduction, plan of trial, general clinical results. German Med Monthly 11:308--314, 1966 Lippshutz EJ, Ambrus JL, Ambrus CM, et al: Controlled study of the treatment of coronary occlusion with urokinase-activated human plasmin. Amer J Cardiol 16: 93-98, 1965 Stables DP, Rubenstein AH, Metz J, et al: The possible role of hemoconcentration in myocardial infarction. Amer Heat-t J 73:155-159, 1967 Hematocrit after acute myocardial infarcGilbert RP: tion. (letter to editor). Amer Heart J 77:713, 1969
The American
Journal
of CARDIOLOGY
The Feasibility of Urokinase Therapy in Acute Myocardial Infarction
GEORGE RUSSELL NANETTE Atlanta,
I. LITMAN, MD B. SMILEY, Jr., KASS WENGER,
MD MD,
FACC
Georgia
From the Department of Medicine (Cardiology), Emory University School of Medicine and the Medical Service, Grady Memorial Hospital, Atlanta, Ga. This study was supported in part by U. S. Public Health Service Grant HE-5653. Manuscript received June 16, 1970, accepted September 10, 1970. Address for reprints: Nanette K. Wenger, MD, Emory University School of Medicine, 69 Butler St., SE., Atlanta, Ga. 30303.
636
Seventeen patients with early acute myocardial infarction were treated with urokinase to determine the feasibility of administration of this drug to acutely ill patients. Before the institution of urokinase therapy, 15 patients had complications of myocardial infarction, including arrhythmia, congestive heart failure, intractable pain, shock and cardiac arrest. Hemorrhage was the only significant complication of urokinase therapy; it occurred in 3 patients but necessitated the discontinuation of urokinase administration in only 1. It was feasible to administer urokinase to acutely ill patients with myocardial infarction without compromising the usual care given these patients.
Coronary artery thrombosis is the major etiologic factor in acute myocardial infarction.‘J The use of thrombolytic therapy in acute myocardial infarction might prove beneficial by restoring blood flow and salvaging tissue that would otherwise become necrotic. In addition, prevention of microthrombus formation or lysis of microthrombi in the marginal zone around the infarcted area could improve the blood supply to this ischemic area and might reduce the incidence of arrhythmias due to electrical instability of the heart. A third possible benefit would be the prevention or lysis of mural thrombi.S This study was designed to evaluate the feasibility of thrombolytic therapy with urokinase in patients with acute myocardial infarction. The thrombolytic agent urokinase is a naturally occurring plasminogen activator of human origin. This single chain polypeptide with a molecular weight of 53,000 is capable of hydrolyzing arginine and lysine bonds. It acts to split one or more peptide bonds of plasminogen and to open the active enzyme center of plasmin. Plasmin, a proteolytic enzyme, digests fibrin and produces thrombolysis.4 Urokinase is nontoxic and nonantigenic ; it has a high fibrinolytic/fibrinogenolytic activity ratio, and its administration on a dose per body weight basis produces a predictable change in plasma thrombolytic activity, plasma fibrinogen, plasminogen and other coagulation factors. Urokinase produces an intense sustained state of enhanced plasma thrombolytic activity in man.” Prior studies with urokinase have shown lysis of arterial and venous thrombi and the resolution of acute pulmonary emboli.5-10 The therapeutic results in pulmonary embolism were sufficiently promising to warrant establishment of a National Cooperative Urokinase Pulmonary Embolism Trial. To our knowledge, the present study is the first to utilize purified urokinase in the treatment of acute myocardial infarction.
The
American
Journal
of
CARDIOLOGY
UROKINASE
THERAPY
IN ACUTE MYOCARDIAL
INFARCTION
TABLE I
Methods and Materials The criteria required for the admission of a patient to the study were as follows: (1) classic history of acute myocardial infarction; (2) diagnostic electrocardiographic criteria for acute myocardial infarction, including Q waves and S-T segment elevation or T wave inversion, or both; (3) patient age of less than 65 to initiate urokinase treatment years ; (4) ability within 14 hours of the onset of chest pain. Urokinase therapy was considered contraindicated in patients with the following: risk of hemorrhage from a recent surgical procedure; recent diagnosis of peptic ulcer or other bleeding gastrointestinal lesion ; recent cerebrovascular accident (10 to 14 days) ; severe uncontrolled hypertension ; nonsurgical hematuria ; severe hepatic disease; or blood dyscrasia or coagulation disorder. Laboratory determinations obtained before the institution of urokinase therapy included hematocrit ; white blood cell count and differential ; blood urea nitrogen ; blood sugar ; urinalysis ; stool examination for occult blood ; prothrombin time and euglobulin clot lysis time. The prothrombin time was determined by the Quick l-stage method and the euglobulin clot lysis time by the method of Buckel1.l’ Dosage : Urokinase” was administered by a continuous infusion pump (Harvard Instrument Co.) through a polyethylene catheter in a forearm vein. A priming dose of 1,650 CTAt units/lb of body weight was given over 10 minutes, followed by a sustaining infusion of 1,650 CTA units/lb of body weight/hour for 8 hours.5 All patients were in a coronary care unit, with a physician investigator in attendance during the infusion. During the urokinase infusion plasma fibrinolytic activity and alterations in the coagulation mechanism were monitored by determination of euglobulin clot lysis time and prothrombin time at 10 minutes and 2, 4, 6 and 8 hours after institution of the infusion. Hematocrit levels were also determined at these intervals. On the day after infusion, euglobulin clot lysis time, prothrombin time, hematocrit, white blood count, serum glutamic oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH) were determined, and urinalysis was performed. Hematocrit values were determined serially during the hospitalization.
Patients Studied
Age00
Site of
no.
& Sex
Infarct
1 2 3 4 5 6
54F 64M 62F 48F 49M 26F 47M 40M 52M 48M 59M 49M 55M 44M 43M 46M 41M
Case
7 8 9 10 11 12 13 14 15 16 17
Anterior Inferior Inferior Anteroseptal Anterolateral Inferior Inferior Inferior Inferior Inferior
Inferior Inferior Anteroseptal Inferior Inferior Inferior Inferior
Mortality Survived Survived Died Survived Survived Died Died Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived
for 13 patients ; 4 patients had electrocardiographic evidence of a prior myocardial infarction in addition to the acute infarction. Two patients had a prior radiographically documented duodenal ulcer without hemorrhage, and 1 patient had had a hemigastrectomy for bleeding gastric ulcer 2 years previously without recurrence of symptoms or of bleeding. Chronic alcoholism was reported by 3 patients. Thirteen of the 1’7 patients had electrocardiographic evidence of acute inferior myocardial infarction, and 4 had acute anterior infarction (Table I). Prior angina pectoris was described by 7 patients, and a questionable history of angina was obtained from an additional patient. Three patients had diabetes mellitus, 3 had essential hypertension, and 2 had a strong family history of coronary atherosclerotic heart disease. An elevated level of blood cholesterol had been documented in 2 patients on a routine examination before the myocardial infarction. One patient with angina pectoris also had moderately severe rheumatic mitral stenosis. One patient had had a cerebral vascular accident 1 year before the acute myocardial infarction, but had no residual neurologic deficit.
Case Material Seventeen patients were studied, 13 men and 4 women, ranging in age from 26 to 64 years (Table I). Enzyme confirmation (SGOT and LDH)12v1” of myocardial infarction was obtained in all patients except 1 whose blood specimens were lost in the laboratory. This was the initial episode of myocardial infarction
* Sterling-Winthrop Research Institute. Urokinase by the National Blood Resource Program of the Heart and Lung Institute, Bethesda, Maryland. t The CTA (Committee standard urokinase unit mittee on Thrombolytic Lung Institute.
VOLUME
27, JUNE
1971
supplied National
on Thrombolytic Agents) unit is the of activity established by the ComAgents of the National Heart and
Results Clinical course : Thirty-six complications of myocardial infarction were documented in 15 of the 17 patients before the institution of urokinase therapy (Table II). Only 2 patients had a completely uncomplicated clinical course; 13 had congestive heart failure and 12 had concomitant cardiac arrhythmias. These arrhythmias included sinus tachycardia, sinus bradycardia, slow idioventricular rhythm, multiple premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, first, second and third degree atrioventricular (A-V) block, A-V dissociation and atria1 fibrillation.
637
LITMAN
ET AL.
TABLE
II
Complications
of Acute Myocardial
Infarction
Before Treatment Intractable Pain
Cardiac Arrest
+
0
0
0 0 0 0 0 0 0 0
+ 0
0
0
+
+
0
0
0
...
0
0
0
0 0
Arrhythmia, Arrhythmia,
+
0
Case no.
CHF
Arrhythmia
Shock
0 +
1 2 3 4 5 6 7 8 9
+ + + + + + + + 0
10 11 12
+ + 0
+ -t
0
13
+
+
+
-I+ + + +
0
0
0
0
0
...
+
0
Shock, bilateral
0
pulmonary Arrhythmia ... ...
+
.
0
0 0
0
16 17
+ 0
* Pacemaker inserted prior to urokinase therapy. BBB = bundle branch block; CHF = congestive
aneurysm
pericardial
rub
BBB, emboli
CHF,
embolism
arrhythmia,
pacemaker,
recurrent
heart failure.
Four patients had cardiogenic shock before the urokinase infusion ; this was manifested by peripheral cyanosis, a blood pressure of less than 80/60 mm Hg, low urinary output, and the like ; all 4 patients survived to leave the hospital. Three patients with cardiac arrest were successfully resuscitated and survived to leave the hospital. Severe recurrent chest pain occurred in 4 patients before and during the urokinase infusion. One patient required a bipolar transvenous catheter pacemaker before infusion. Nine patients had continued complications of myocardial infarction after infusion (Table II). Arrhythmias either persisted or developed in 9 patients, and a bipolar catheter pacemaker was inserted in 4. Severe congestive heart failure persisted in 4 patients, and clinical shock persisted in 1 of the 4 patients after completion of the urokinase infusion. Two patients had pulmonary embolization ; a pericardial friction rub developed in 2 patients, in 1 on the day after urokinase infusion and in 1 on the sixth day after infusion. Only 1 patient had recurrent angina pectoris in the hospital. Fourteen patients survived to be discharged from the hospital (Table I). A ventricular aneurysm was demonstrated by fluoroscopy just prior to discharge in 1 patient. Fibrinolytic activity: Adequate plasma fibrinolytic activity as measured by a euglobulin clot lysis time of 1 to 6 minutes was demonstrated in all patients during the urokinase infusion. In all patients the euglobulin clot lysis time had returned
638
ventricular
... CHF, arrhythmia, pulmonary Arrhythmia, CHF
+
0
+ +
pacemaker, CHF
0
0
0 0
+ 0
Arrhythmia Recurrent pain Arrhythmia, pacemaker Arrhythmia, pacemaker, ...
+* +
+
14 15
0
After Treatment
to normal 24 hours after termination of the infusion. There was no major alteration in the prothrombin time during infusion. Bleeding : Eight patients had a decrease in hematocrit which ranged from 1 to 5 percent over a 6 day period. We found no associated symptoms or clinical evidence of bleeding except as later discussed. This fall in hematocrit may have represented rehydration, blood loss from venipunctures for blood tests, or both. Bleeding occurred during the urokinase infusion in 3 patients. One patient bled from a 2 day old femoral arterial catheterization site in the sixth hour of infusion; the bleeding was readily controlled by local pressure and the infusion was completed. In a second patient a hematoma developed with continued bleeding at a site of attempted subclavian venous catheterization ; the urokinase infusion was discontinued at 6 hours, 45 minutes because of fear of intrathoracic hemorrhage. The third patient bled from an antecubital venipuncture site; again, the bleeding was easily controlled by local pressure and the infusion was completed. No toxic, pyrogenic or antigenic reactions were noted in any patient. Postmortem examinations were perDeaths: formed on 2 of the 3 patients who died. One patient died on the fifth hospital day, and we found a recent thrombosis of the circumflex branch of the left coronary artery with recent left ventricular lateral wall infarction. Microscopic examination demonstrated no organization of the clot in the
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left circumflex artery. The age of the infarction was consistent with the clinical history. The second patient died on the twelfth hospital day. A recent myocardial infarction involved the posterior walls of both the left and right ventricles and the posterosuperior portion of the intraventricular septum; at autopsy, estimation of the age of the infarction was 15 days. A recent thrombotic occlusion of the right coronary artery was found 3 to 3.5 cm from its origin from the aorta. The anterior descending branch of the left coronary artery was narrowed to approximately 20 percent of its original lumen by atherosclerotic changes. The circumflex artery was also moderately narrowed. In neither case was there unusual hemorrhage or any specific lesion which could be attributed to the urokinase infusion.
Discussion The success of thrombolytic therapy in acute myocardial infarction depends on several variables. First, the etiologic process must be thrombosis. In myocardial infarction caused by hemorrhage into a subintimal plaque, or by vasoconstriction or hypotension, fibrinolytic therapy would be of no value. Second, even if the etiologic process is thrombosis, thrombolytic therapy should be initiated soon after thrombus formation since thrombolytic therapy is probably ineffective once endothelialization and fibrosis occur.14J5 Third, the perfusion to the involved artery is critical, in that the thrombolytic agent must be brought into contact with the thrombus. Finally, the most effective duration and schedule of dosage have yet to be determined, Previous studies: Feasibility studies have been reported for several thrombolytic agents in acute myocardial infarction. In a controlled study, Fletcher et al.lB administered streptokinase to patients with acute myocardial infarction. Thrombolytic activity was maintained for 30 hours in 19 patients with early acutae myocardial infarction ; all survived the acute phase, although 1 patient died 3 weeks later. The results with streptokinase therapy were not statistically different from those for the control group; however, this study demonstrated that the infarcted myocardium could tolerate an inten,se thrombolytic state. Schmutzler et a1.l’ administered streptokinase to 297 patients with acute myocardial infarction; anticoagulant agents (heparin followed by phenprocoumon) were given to a control group of 261 patients with acute myocardial infarction. A significantly lower mortality was r,eported for the patients treated with streptokinase than for those receiving anticoagulant therapy. Fibrinolytic therapy was well tolerated by all patients with the exception of 1 who bled from an unsuspected carcinoma of the stomach.
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1971
THERAPY
IN ACUTE MYOCARDIAL
INFARCTION
In a double-blind trial Lippschutz et a1.18utilized urokinase-activated human plasmin to treat 84 patients with acute myocardial infarction and concluded that the plasmin treatment was safe for such patients. This series was too small to permit evaluation of survival statistics. Interestingly, among their pati,ents classified as severely ill with a poor prognosi.s, 47 percent of the control subjects died compared with 24 percent of those treated with urokinase-activated plasmin. Clinical problems : All of our patients were treated with urokinase within 14 hours of the onset of symptoms of acute myocardial infarction; in most instances, the infusion was initiated within 8 hours. Only 2 of the 17 patients were considered to have uncomplicated myocardial infarction before the initiation of urokinase therapy. All patients were carefully monitored in a coronary care unit, and the majority had a central venous catheter inserted. The 8 hour urokinase infusion did not curtail the usual care given these acutely ill patients, interfere with therapy for arrhythmias, congestive heart failure or shock, or disturb the usual cardiovascular monitoring. The major complication of urokinase therapy is hemorrhage. Although bleeding from venipuncture or cutdown sites is generally readily controlled by local pressure, the inability to control intense bleeding requires discontinuation of the infusion. In 1 patient, a hematoma and active bleeding occurred at the site of an attempted pacemaker insertion through a subclavian vein before initiation of urokinase therapy. The bleeding occurred 6 hours, 45 minutes after the start of infusion, which was then terminated for fear of intrathoracic hemorrhage. No intrathoracic bleeding occurred, and the external hemorrhage was easily controlled by pressure ; shortly after discontinuation of the infusion, all coagulation studies showed normal results. Two patients had had documented duodenal ulcers in the past ; 2 others had required surgery for bleeding gastrointestinal lesions. None had recent symptoms of an ulcer ‘or a history of recent bleeding. No hemorrhage occurred in these patients during or after urokinase therapy. The thrombolytic state rapidly disappears after termination of the urokinase infusion”; in all patients the euglobulin clot lysis time had returned to normal within 24 hours. Our experience suggests that treatment with urokinase may be contraindicated in patients who have had active cardiopulmonary resuscitation measures with multiple intravascular and intracardiac punctures. Patients with known gastrointestinal lesions, especially those with a history of bleeding, should be evaluated individually for urokinase therapy. A significant decrease in hematocrit has been reported in patients treated with urokinase. This
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decrease has usually been associated with excessive bleeding from wound or cutdown sites, induced by the thrombolytic state. In a few patients the drop in hematocrit has remained unexplained ; this complication of urokinase administration awaits clarification.” Nine of our patients had a decrease in hematocrit, but none of serious proportion. Clinical evaluation in these patients did not reveal a bleeding site; no extensive hematologic studies were undertaken. The initial level of hematocrit in these patients may have been spuriously elevated, since patients with acute myocardial infarction may have elevation of the hematocrit or hemoconcentration, or both.‘” A drop in plasma volume may occur after acute myocardial infarction, as a result of fluid loss from vomiting or decreased fluid intake during the first day after acute infarction.20 Therefore, the decrease in hematocrit in our patients might result from subsequent rehydration and return to a more normal state.
There were no febrile reactions that could not be attributed to the myocardial infarction. We did not observe allergic or hypotensive reactions from urokinase therapy. Clinical evidence of pulmonary embolism developed in 1 patient 6 days after urokinase therapy; however, the chest roentgenographic findings were negative and no lung radioisotope scan or pulmonary angiogram was performed. This patient had been extremely ill, was confined to bed for the prior 6 days and had not r,eceived anticoagulant therapy, Anticoagulant therapy was begun, he recovered and is presently well. Postmortem studies on 2 of the 3 patients who died revealed poorly organized thrombi in the coronary arteries and findings consistent with the clinical history and age of the acute infarction. No conclusions can be drawn from these findings. There was no evidence that urokinase caused added damage to myocardial tissue in these 2 patients.
References Colloquium uber 1. Fritze E, Vandeioo J, Kovemeier H: Koronar-thrombose and Myocardi-infarkt, Bochum, 1964 (abstr). Deutsch Med Wschr 90:933-936, 1965 2. Parkinson J, Bedford DE: Cardiac infarction and coronary thrombosis. Lancet 1,4-11, 1928 3. Sherry S: Fibrinolytic agents. DM May, 1969. 1968 4. Sherry S: Fibrinolysis. Ann Rev Med 19:247-268, 5. Fletcher AP, Alkjaersig N, Sherry S, et al: The development of urokinase as a thrombolytic agent. Maintenance of a sustained thrombolytic state in man by its intravenous infusion. J Lab Clin Med 65:713-731, 1965 6. Johnson AJ, McCarthy WR, Newman J: Proceedings of the Ninth Congress of the European Society of Hematology, Lisbon 1963, p 1389-1393 7. Sautter RD. Emanuel DA. Fletcher FW. et al: U?okinase in the treatment of acute pulmonary thromboembolism. JAMA 202:215-218, 1967 8. Tow DE, Wagner HN Jr, Holmes RA: Urokinase in pulmonary embolism. New Eng J Med 277:1161-1167, 1967 Urokinase 9. Sasahera HA, Cannili JF, Belks JS, et al: therapy in clinical pulmonary embolism. New Eng J Med 277:1168-l 173, 1967 Urokinase therapy in pulmonary 10. Genton E, Wolf PS: thromboembolism. Amer Heart J 76:628-637, 1968 11. Buckell M: The effect of citrate on euglobulin methods of estimating fibrinolytic activity. J Clin Path 11:403405,19!% 12. LaDue JS, Wroblewski F: The significance of the serum glutamic oxaloacetic transaminase activity following
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acute myocardial infarction. Circulation 11:871-877, 1955 Wroblewski F: Serum enzymes and isoenzyme alteration in myocardial infarction. Progr Cardiovasc Dis 6:63-83, 1963 Back N, Ambrus TL, Simpson CL, et al: Study on the effect of streptokinase activated plasmin (fibrinolysin) on clots in various stages of organization. J Clin Invest 37:864-871, 1958 Ambrus JL, Ambrus CM, Back N, et al: Clinical and experimental studies on fibrinolytic enzymes. Ann N Y Acad Sci 68:97-137, 1957 Fletcher AP, Sherry S, Alkjaersig N, et al: The maintenance of a sustained thrombolytic state in man. 2. Clinical observation on patients with myocardial infarction and other thromboembolic disorders. J Clin Invest 38:1111-1119, 1959 Schmutzler R, Heckner F, Kortge P, et al: Thrombolytic therapy of recent myocardial infarction. 1. Introduction, plan of trial, general clinical results. German Med Monthly 11:308--314, 1966 Lippshutz EJ, Ambrus JL, Ambrus CM, et al: Controlled study of the treatment of coronary occlusion with urokinase-activated human plasmin. Amer J Cardiol 16: 93-98, 1965 Stables DP, Rubenstein AH, Metz J, et al: The possible role of hemoconcentration in myocardial infarction. Amer Heat-t J 73:155-159, 1967 Hematocrit after acute myocardial infarcGilbert RP: tion. (letter to editor). Amer Heart J 77:713, 1969
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