Thrombolytic
Therapy of Pulmonary Edward
Genton BACKGROUND
of thrombolytic agents for of pulmonary thromboembolism is an attractive and rational concept based on a number of considerations. The process of pulmonary embolism involves compromise of the cross-sectional area of the pulmonary circulation by embolization of thrombotic material composed primarily of red cells enmeshed in a fibrin lattice. Damage to the pulmonary parenchyma results from the compromised circulation distal to the embolic material, and the hemodynamic alterations are due to the increased pulmonary resistance and its adverse effect on the right ventricle caused by the obliteration of the pulmonary bed. Removal of the embolic material immediately reverses the hemodynamic consequences, and probably also the effect on the pulmonary parenchyma, and in most instances restores the involved branches of the pulmonary artery to the state of normalcy that existed prior to the embolization. Recent emboli are favorable to lyse if exposed to plasmin because the embolic material is from freshly formed thrombi, usually no more than a few days old, and because there is often fragmentation of the thrombus as it embolizes, which exposes the inner aspects of thrombus. Thus, the administration of agents that greatly enhance fibrinolytic activity in plasma should lead to accelerated resolution of the embolic material. While spontaneous embolus resolution is the rule rather than the exception, the time required for this physiologic process is usually measured in days or weeks rather than in hours. More rapid reversal of the adverse consequences of an embolic episode may be desirble, especially in the patient who has marked hemodynamic effects of embolization. In such patients, deterioration of cardiopulmonary function is rapid after embolism, and prompt rapid restoration of normal blood flow may be important and, in fact, life saving. Theoretically, an additional benefit would be reduced likelihood of recurrent pulmonary embolism by inducing lyses of thrombi present in the veins in the lower extremities. These and other considerations have encouraged the evaluation of thrombolytic agents in acute pulmonary embolism.
E MPLOYMENT the treatment
Progress in Cardiovascular
Diseases, Vol. XXI,
No. 5 (March/April),
Thromboembolism
INFORMATION
Early animal studies with thrombolytic agents involved the embolization of freshly clotted blood into the lung of animals, followed by treatment with thrombolytic agents, with observation of dissolution of the emboli.1~2 Later studies embolized thrombi of various ages that had been formed in vivo3*4and provided further documentation that both streptokinase and urokinase produced rapid and marked degrees of lysis of the embolized material, with degrees of lytic activity that were easily achieved and readily sustained. For example, it was demonstrated that a 12-hr infusion of urokinase resulted in 95% lysis of 7-day-old thrombi embolized into the lungs of dogs, compared to only 23% lysis of similar emboli in control animals.4 Thrombolytic agents were administered in patients with pulmonary embolism by the late 1950s when preparations of plasmin were used, but little in the way of objective criteria was presented for diagnosis or documentation of the magnitude of the embolic involvment or quantifying the fibrinolytic state produced.5-7Plasminogen activators of the type and purity currently available were first used in the early 1960s by a number of investigators.E-‘3 The results of these studies were quite consistent and indicated that with as little as 6 hr of intravenous administration of amounts of streptokinase or urokinase that were quite well tolerated even by seriously ill patients, cases of acute massive embolization were associated with persuasive evidence to suggest thrombolysis had been produced (Table 1). The results of these studies were sufficiently encourging as to stimulate the conduct of several large controlled trials designed to compare conventional treatment with heparin with varying therapeutic regimens of streptokinase or urokinase.“16 These studies also allowed, along with others, the description
From McMaster University, Hamilton. Ontario, Canada. Reprint requests should be addressed to Edward Genton. M.D.. M&faster University, Hamilton. Ontario. Canada. 01979 by Grune & Stratton. Inc. 00334620/79/2105MOO3%02.00/0
1979
333
EDWARD
334
Table
1. Thrombolytic
Therapy
in Pulmonary
Embolism:
Uncontrolled
Studies Ar>gloyrdphy
Autho,
Sasahara
Agent
Treatmecd
UK UK
8 6-8
UK UK
8 8 12
et al
Tow et al Sawer et al Genton et al Miller et al Hirsh et al
SK SK
36 24-72
Total UK, urokmase.
PZiWi7fb
Improved
8 13 10
GENTON
or Scar,
No Change
7 7
1 5
0 1
13 9 24
8 9
2 4
0 0
6 20
3 3
0 1
77
57 (74%)
18
2
SK, streptokmase
of the natural history of pulmonary embolism associated with heparin treatment. The largest and most informative clinical trials have been the NIH-sponsored projects that compared conventional heparin treatment with a 12-hr infusion of urokinase. 12 hr of treatment with urokinase with 24-hr treatment of urokinase, and 24-hr urokinase with an equal period of streptokinase infusion. These were cooperative, multicenter studies using a modified double-blind protocol. with objective methods consisting of angiography, serial lung scans, and hemodynamic measurements as endpoints. In total, 327 patients were randomized into the studies, and both the design and the execution of these projects appeared excellent. Results from the various clinical trials have provided much information concerning the changes produced when thrombolytic agents are administered to patients with pulmonary embolism. This has clarified many of the questions pertaining to the use of these agents in therapeutics. However, the crucial question is where in the therapy of pulmonary embolism the drugs would be indicated. The answer to this must consider the effect of alternate approaches to therapy. Essentially, these would include no antithrombotic therapy or heparin. Although limited in amount, and certainly imprecise because of the unreliable methods used for diagnosis, the available information that bears on the natural history of untreated pulmonary embolus is persuasive that the failure to treat symptomatic pulmonary emboli is associated with a high incidence of recurrence, probably exceeding 40%, and a risk of fatal outcome from recurrent embolism, which approximates 25%.17-20 In contrast, the outlook for patients treated with heparin is excellent, as has been shown in a number of studies “~2’--23( Table 2). The incidence of recurrence is less than 5% in most series, and
fatal recurrence is very uncommon. In the National Heart and Lung Institute (NHL.1) thrombolytic therapy study. 78 patients received heparin for a period of at least 5 days, followed by several months of prophylactic anticoagulants. Fifty-five percent of these patients had massive emboli and 45% had submassive emboli; 7%) were in shock. Seventy percent were treated within 72 hr of onset of symptoms. After 24 hr 01 heparin treatment, there was some, but only slight, improvement as determined by angiogram, lung scan, and hemodynamic data (Figs. I and 2). In the lung scan, this amounted to about a 10% reduction in the size of the initial defect. There was essentially no difference in the total pulmonary resistance or the arterial poz at 24 hr. The subsequent change in the perfusion defect. as measured by serial lung scans, indicated there was progressive resolution that had amounted to 55%’ of the mean initial defect by 14 days, and to 80%’ by the end of 3 mo (Fig. 2). Of numerous variables considered. several were apparently associated with the rate of improvement. This included the age of the embolus. with lesions considered by history to have been present more than 48 hr having slower resolution, and previous cardiopulmonary disease also associated with slightly slower rates of resolution. Long-term residual of the perfusion abnormality, exceeding IO%, persisted in 16%) of patients followed for I yr. This was more frequently seen in patients Table
2.
Pulmonary Embolism Recurrence During Heparin Therapy Recurrence
NO Coon
O’Sullwan UPSET Basu
PatW?“tS
TONI
639 100 78 110 927
5 4 19
wi Fatal
1 2 0
3
0
58
09
THROMBOLMIC
THERAPY
OF PULMONARY
z 0 tz a
Complete 4 Improvement
Marked 3 lmpravement
335
THROMBOEMBOLISM
12 hour Urokinase
12 hour
24 hO”r uroklnare
24 hour St rept Dkinase
Moieraie 2 Improvement Slight 1 lmprovemenl
loo 90 80
f z 5 Y 5 &
m 60 = 40 30
%
20 10
d!
0
Day
1
3
7
14
3 mos.
1 year
changes of original from Circulation.“)
defect.
POST-INFUSION Fig. 1. (Reproduced
Angiographic with permission
changes from
in severity ./AMA.“)
at
24
hr.
with prior embolism or underlying cardiopulmonary disease (in which case about 25% had residual defects) and in patients with larger defects. These observations are consistent with the data presented by other workers who report minimal or no resolution within the first 2 or 3 days.24*2SThereafter, there is a varying rate of dissolution, which in the occasional patient may be marked in as little as 24 hr, but in most cases requires in excess of 1 wk for substantial change to occur. Evidence from several authors indicate that patients with underlying cardiopulmonary disease, especially when associated with left heart failure, have delayed rate and amount of resolution, and some residual is the rule rather than the exception.2”28 Thereafter, there is progressive decrease in the perfusion defect that proceeds at varying rates, and in some patients, appears to continue past 6 mo. In general, the more massive embolization has resolved more slowly. Thus, the outlook for patients with pulmonary embolism treated with heparin is excellent for survival, although a slow improvement in vascular obliteration is noted. In contrast to the expectation with heparin treatment, the results with thrombolytic agents in controlled trials provides evidence for accelerated dissolution of embolic material. In the NHLI study, treatment with urokinase was administered in one group of patients for 12 hr, in another group for 24 hr, and a further group received 24-hr treatment with streptokinase. The drugs were administered by constant intravenous infusion into peripheral arm veins. The laboratory parameters indicated brisk lytic activity in more than 85% of cases. Patients had symptoms for 5 days or less, and in the majority of instances, less than 72 hr. The objective parameters all showed substantial and significant
Fig. 2. (Reproduced
Perfusion lung with permission
scan
evidence of improvement when the studies were repeated 24-36 hr after onset of therapy. The pulmonary angiogram for the total thrombolytic therapy group demonstrated a mean change exceeding 40% from baseline, contrasted with less than 5% difference in the patients having received heparin infusion (Fig. 1). In regard to the lung scan, after 24 hr there was a 22% reduction in perfusion defect in the patients receiving urokinase, compared to 7% with heparin (Fig. 2). In the hemodynamic parameters examined, significant differences occurred that favored urokinase in all pressure measurements, including pulmonary artery, right ventricular systolic and diastolic, and in total pulmonary resistance, and was borderline for po2 measurements. The all-important total pulmonary resistance, which considers both the mean pulmonary artery pressure and the cardiac output, was elevated prior to treatment to a similar extent in both groups. There was a marked fall toward normal after 24 hr in this measurement in the urokinase, but not in the heparin patients. Comparison between treatment with 12 hr of thrombolytic therapy with 24-hr infusion of either urokinase or streptokinase indicated no significant differences between the three treatment groups, with each showing more than a threefold greater increased improvement by angiogram, compared with the heparin-treated group (Fig. 1). As regards pulmonary perfusion changes, the degree of resolution following initiation of therapy was 9% for 12-hr urokinase, 12% with 24-hr urokinase, and 7% for 24-hr streptokinase. The suggested difference between the urokinase and streptokinase 24-hr infusions failed to achieve statistical significance. The hemodynamic parameters revealed no difference between the 12- and 24-hr
336
EDWARD
urokinase, and some, but not statistically significant, difference between 24-hr urokinase and 24-hr streptokinase. Thus, the data are persuasive to suggest that there is accelerated resolution of pulmonary emboli from treatment with either urokinase or streptokinase compared to heparin, as judged by several objective indicators, including hemodynamic parameters, lung scan (perfusion), and pulmonary angiograms. The follow-up observations, consisting of serial lung scans performed frequently for 2 wk, after 3 mo, and at I yr, illustrated significant difference between the heparin and thrombolytic therapy patients only during the first week, and thereafter, there were no differences apparent (Fig. 2). In both groups, there was progressive improvement in perfusion of originally involved areas, which was maximum during the first week, but continued over at least a 3-mo period, following which there was a plateauing with minimal further evidence of improvement for the total group apparent after I2 mo. These findings are consistent with earlier studies previously referred to.‘(’ ” FACTORS INFLUENCING RESPONSE THROMBOLYTlC THERAPY
TO
Numerous factors that might potentially influence outcome, and would therefore have to be considered in selecting patients to receive thrombolytic therapy, have been examined. Age and Size of Enzbolus
Early work with thrombolytic agents produced evidence to suggestthat thrombi become progressively less responsive to the effects of thrombolytic agents as they age, presumably because of the organization that occurs on the surface with nonfibrin material. With experimental pulmonary emboli that had been aged in vivo for varying periods of time and histology documented, it was demonstrated that while very freshly formed thrombi are most susceptible, emboli 5-7 days old will undergo lysis during urokinase infusion. Emboli up to 2 wk old were less responsive, but underwent significant change during a brief infusion period compared to untreated animals. This is consistent with evidence presented that suggests that thrombi remain dynamic for long periods, making it likely that some recently deposited fibrin and cellular components are present even in “old”
GENTON
thrombi which could be lysed. Another point that has been made is that disruption or fragmentation of even an old thrombus that embolizes also is associatedwith increased thrombolysis, presumably because the interior of the thrombus with its fibrin laticework and lesser degree of organization causes the embolus to remain lysable.J In the human studies, the data suggestedthat while emboli estimated to be less than 72 hr were associatedwith the most impressive evidence of lysis, patients with lesionsup to 57 days old showed evidence of improvement. However, most patients with lesions that were judged to be older than 2 wk demonstrated littlc evidence of benefit from therapy. Casesin which the embolic lesionswere thought to be more than 6 wk old had no demonstrable change unless there wasevidence of coincidental recent embolization.” Patients who failed to show improvcment and died were found at autopsy to have embolic material that was organized? In the NIH study, only patients with emboli judged to be lessthan 5 days old were admitted. Analysis of results, based on estimated age of emboli, suggestedthat there was better response with thrombolytic therapy for emboli lessthan 48 hr old than with older lesions, in that there was 30X resolution in the less than 48-hr-old lesions and approximately half that when they were greater than 48 hr. This was not the same as with heparin where. if anything, there was more rapid resolution of the greater than 48hr-old lesions (Fig. 3). One must interpret this data with caution since. while all lesions were considered acute pulmonary emboli. it is quite likely that some patients had experienced more than one embolic episode, and the lesions observed were of varying age. As is known, the most rapid rate of change is over the first few days, and if the patient was first seen 2-3 days after the onset of symptoms, a substantial amount of lysis of the lesion might already have occurred and the rate of dissolution of remaining embolus would be expected to be slower. From the available information, it seemsreasonableto conclude that the fresher the embolus the more likely and more marked the response to lytic therapy. It appears that there is decreasing susceptibility to lysis, which is considerable after 557 days; and by the end of 2 wk, not much responseis to be expected. In addition to age of embolus, the location
THROMBOLMIC
THERAPY
m
OF PULMONARY
Heporin
DAY I
(N=35
DAY 3
DAY 3 Fig. 3. Perfusion lus at postinfusion (48 hr: W 248 Circu/etion.‘4)
THROMBOEMBOLISM
)
DAY 5
DAY 5
DAY 14
DAY 14
lung scan resolution by age of embodays 1, 3, 5, 14. (A) Age of embolus hr. (Reproduced with permission from
within a vessel is conceivably of importance. Thus, since thrombolysis depends on the exposure of the embolus to plasminogen activator, the lesion that is impacted in a vessel does not expose its surface except at the proximal end to elevated levels of lytic activator. Contact of the drug with other parts of the embolus would need occur through the vasa vasoro circulation or from retrograde filling of the obstructed vessel, or through percolation through the embolus. In some animal studies, it was suggested that impacted emboli lysed less rapidly than those that permitted laminar flow. However, this was not shown to be a significant factor in the response observed in the NIH studies. To the extent that impaction may be recognized angiographically, the data suggested that lysis was as effective in such lesions as those with filling defects. This is similar to the observations in other reports.26 In the majority of studies, treatment has been limited to patients with major compromise of the pulmonary bed from massive embolization. Small or submassive emboli that produce segmental or lobar-sized defects usually do not
337
produce sufficient symptoms to require treatment other than heparin. In the NIH study, patients with emboli of varying severity were included, and about 40% of the first study had submassive emboli. Results suggested that patients with the more massive emboli had a greater response than did those with submassive lesions, but the difference was not statistically significant. On the other hand, the patients who had massive emboli and were in shock, while only a small group, had an almost tenfold difference favoring the thrombolytic drug compared to heparin. This information suggests that patients with massive emboli may show rapid resolution of their defect, which is consistent with the results of all reported studies. It is more difficult to draw a conclusion concerning the effect of thrombolytic therapy with submassive emboli. Clearly there was substantial and significant reduction in embolus size in those with submassive lesions, but the quantification of this change in terms of lung scan and angiogram was difficult. Of importance is the fact that in most patients, whether with massive or submassive emboli, the resolution of the lesion was seldom complete at the end of either a 12- or 24-hr infusion period. With some residual lesion, there may be a discrepancy between the percentage lysis of the embolic material and the resultant effect on angiograms or lung scans. Thus, the lysis of 30% of a massive embolus, for example, might translate into very marked changes in perfusion, while a similar percentage lysis of an embolus in a segmental vessel might have less effect on the abnormalities in the diagnostic studies. There is no reason to suspect from available information that submassive emboli are any less responsive to lytic therapy, but the overall effects of treatment in terms of symptoms and diagnostic tests may be far less dramatic compared to those seen in patients with massive embolization. It is notable that the long-term outcome was not influenced significantly by the size of the initial defect, although there was some tendency for a greater absolute residual to be present in those patients with massive emboli. In that regard, lung scan information favored thrombolytic therapy in massive emboli in that residual perfusion defects were less in such patients who had been treated with urokinase as compared to heparin.
338
EDWARD
Effect of Underlying Cardiopulmonary Disease
As noted previously, several authors have drawn attention to the fact that patients with underlying cardiopulmonary diseasehave slower and less complete spontaneous resolution of pulmonary emboli and the resulting perfusion abnormalities. None of the thrombolytic therapy trials have indicated that the outlook is changed by the use of thrombolytic drugs. Thus. the response in patients with both massive and submassiveemboli. treated with either heparin or thrombolytic drugs, is the same basedon the presenceor absenceof cardiopulmonary disease. In all groups, it appears that there is slower resolution in the presence of cardiopulmonary disease.In addition, there is greater permanent residual, and this does not appear to be signihcantly altered by a short course of thrombolytic therapy during the acute phaseof the disease. Conditions of Treatment Infusion, etc.)
(Dose. Duration
of
Most of the clinical trials have employed similar and standard conditions. The drugs have been administered by constant infusion into a peripheral vein or directly into the pulmonary artery through a catheter left in place after angiography. Treatment has been continued for 12-72 hr with the occasional patient being treated for as long as 5 or 6 days. Both streptokinase and urokinase therapy was begun with a loading dose sufficient to produce immediate onset of a brisk fibrinolytic state, which was then sustained by continuous infusion. For streptokinase, the loading dose ranged between 250,000 and 600,000 U as a standard doseor determined by the streptokinase resistancetest. The sustaining dosewas usually 100,000-l 50.000 U/hr. For urokinase. a priming doseof approximately 2000 CTA U/lb body weight was followed by a similar dosageeach hour. Although it was frequently noted that clinical parameters improved, and in 2 studies that pulmonary artery pressure fell within 2 or 3 hr. most objective indicators of responsewere repeated only at the end of the infusion period. Only in the NIH trials was direct comparison made between infusion times of varying duration (Fig. 1). In the first of these studies, a 12-hr infusion with urokinase produced more than a threefold greater resolu-
GENTON
tion by angiography as compared with heparin. The I2-hr infusion with urokinase in the second phase gave nearly an identical result. In that study, the 12-hr infusion result was compared with a 24-hr infusion with either urokinase or streptokinase. Angiography results were equivulent for the three groups. Hemodynamic parameters, most importantly the total pulmonary resistance, showed slightly greater change in patients receiving 24-hr infusion compared to those treated for 12 hr. but this result did not approach statistical significance. The perfusion lung scan results demonstrated a somewhat greater improvement in patients receiving urokinasefor 24 hr ascompared to streptokinase. This was most impressive, and in fact, statistically significant for patients with massive embolization. The explanation for this ditrerencc is unclear, if in fact it is meaningful. Interestingly, the degree of thrombolysis observed was poorly correlated with the intensity of the tibrinolytic state produced as measured directly or indirectly by a variety of parameters. The significance of this is uncertain but might reflect the insensitivity of the available tests.lJ Ac mentioned previously, it was usual that some evidence of residual emboli was present even when improvement had been dramatic. In some patients in uncontrolled studies, thrombolytic therapy was resumed for varying times in an attempt to effect complete lysis. Evidence of further improvement in such instances was usually minimal and suggeststhat infusion periods past 72296 hr arc seldom indicated. Perhaps a more important question is the minimum time necessary to achieve significant clinical improvement. This question is not answerable from available literature and predictably would be influenced by a number ot factors. such as the extensiveness of embolization, age of emboli. etc. Interesting data have been reported that suggestvery short periods 01 thrombolytic therapy may be associated with substantial amounts of thrombolysis. One such report of 8 casestreated for 2 hr with moderate doses of urokinase delivered directly into the pulmonary artery, recorded impressive results.“’ In another study. injection of urokinase at 24 hr intervals produced improvement, including prompt fall in pulmonary artery pressure.” A somewhat different approach has beenevaluated that examines the effect of low dosestrep-
THROMBOLYTIC
THERAPY
OF PULMONARY
THROMBOEMBOLISM
tokinase in combination with full therapeutic doses of heparin. With this method, the usual loading dose is delivered over a 4-hr period and is followed by a sustaining dose approximately 10% of that usually given, which is continued for 48 hr. In 13 patients treated by this approach, 7 underwent follow-up angiography. Results indicated marked improvement, including 3 in whom normal pulmonary angiograms were obtained.32 Further information is necessary before the potential of this scheme can be determined, but it offers an exciting avenue for continued investigation. Presently, it is not possible to identify an optimal regimen for the thrombolytic drugs in terms of dosage and duration of treatment. With available information, it is reasonable to conclude that the dosage employed to date represents the maximum amount, and possibly a lower dosage might prove to be adequate. Complications
Hemorrhage is the only complication of major significance that has been encountered. In most studies it has occurred in 30%-50% of patients, and in many of these it was of severe proportions requiring termination of treatment and occasionally transfusion and in a few cases has caused death. In the trials comparing heparin and thrombolytic therapy, the bleeding incidence with the latter has been significantly greater. There has been no significant difference in bleeding incidence between urokinase and streptokinase treatment. Bleeding has most often been at cut-down sites of either arteries or veins, but also has occurred from the gastrointestinal or gastrourinary tracts and in some instances intracerebrally. Bleeding from cut-down sites has usually begun 6-8 hr after the onset of infusion and continued in spite of a variety of measures, such as pressure dressings, elevation, or local application of epsilon-amino caproic acid. The local bleeding usually stopped between 1 and 2 hr after termination of infusion and after that does not resume in most cases in spite of heparin treatment. The majority of instances of gastrointestinal bleeding have been recognized following completion of thrombolytic therapy and during heparin administration but might have begun earlier. There has been no clear-cut relationship of bleeding complications to the
339
patient’s age or sex or directly to the intensity of the lytic state that has been produced. On theoretical grounds, there was concern that a high incidence of recurrent pulmonary embolism would be observed in patients receiving thrombolytic therapy due to release of embolic material from thrombi in the leg veins. This fear has not been substantiated, and recurrent embolization during thrombolytic therapy has rarely occurred. The incidence of recurrent embolization over a IO-lbday period has varied considerably depending on the stringency of criteria for diagnosis. Overall, it has not exceeded 7% in most series when objective documentation is required. There has been no significant difference in the incidence of recurrence between heparin and thrombolytic treated patients.33 Mortality
The accumulated mortality in nearly 500 patients with pulmonary embolism treated with thrombolytic agents has been approximately 5%, with a similar incidence in patients receiving heparin in the same trials. In the urokinase study, the mortality at the end of 2 wk was 9% in both trials and with each of the treatment modalities. Even in the patients with massive pulmonary embolism and shock, the outlook would appear to be good for recovery when either thrombolytic agents or heparin have been used. It is perhaps not surprising that mortality is low and no different in patients treated with heparin or thrombolytic drugs. As previously noted, the outlook for patients with pulmonary embolism is excellent for rapid improvement and recovery once they are diagnosed and treatment, which arrests the thrombotic process, initiated. Unfortunately, patients who are destined to die from an embolic event do so rapidly, most within 1 hr from the onset of symptoms, before definitive diagnostic procedures can be carried out or usually before effective treatment can be instituted. These are not the cases that have been included in various trials of thrombolytic therapy and those who have been entered even with massive embolization would have a good prognosis. Thus, a very large number of cases would be necessary to demonstrate significant reduction in mortality by an agent more effective than heparin.
340
EDWARD
CONCLUSIONS
AND
RECOMMENDATIONS
The major objective of therapy for pulmonary embolism is to prevent mortality and secondarily to reduce the period of morbidity from obstruction of the pulmonary vascular bed. In most patients, these objectives are readily achieved with conventional heparin therapy. Substantial experience has now been gained with the use of the plasminogen activators, urokinase or streptokinase, in patients with acute pulmonary embolism. Persuasive evidence has been obtained that indicates that the rate of resolution of embolic material can be greatly accelerated by these agents, especially when the embolic episode was recent. Lysis of emboli probably begins rapidly with administration of these drugs, but several hours is usually required before objective evidence of their effects is demonstrable. Within 12 hr, dramatic effects are often seen, and in most instances treatment beyond that period of time is not associated with apparent additional improvement. In the majority of patients, lysis is not complete, and some residual perfusion abnormality persists that clears over ensuing days or weeks. The establishment and maintenance of “therapeutic” levels of fibrinolytic activity is readily achieved with standard regimens and is usually well tolerated even in severely ill patients. However, bleeding is a frequent and at times serious complication, and
GENTON
the likelihood of this complication increases with the duration of treatment. Thrombolytic therapy is contraindicated in patients particularly prone to bleeding complications, including those with recent surgery or trauma, recent stroke, severe hypertension, active peptic ulcer, malignant disease with metastasis, coagulation disorders or bleeding diathesis or pregnancy. Great care should be taken to decrease the likelihood of bleeding by keeping vascular invasion to a minimum and avoidance of all forms of trauma. Indications for thrombolytic therapy are not clearly established. It would be most useful in the small group of patients with massive pulmonary embolism who survive the initial hours following the onset of symptoms, especially it they have cardiac or pulmonary decompensation. Such patients may deteriorate rapidly from hypoxemia. arrhythmia, acidemia, or even a small recurrent embolism. Another group are patients with preexisting cardiopulmonary disease who have suffered a major insult from a pulmonary embolus. even though it may be 01 only moderate size. In both these groups, the rapid lysis of even a moderate amount of embolic material may serve as a useful alternative between pulmonary embolectomy and anticoaglant therapy to stabilize their condition and give them a greater margin of safety in terms of their immediate course.
REFERENCES I. Cahil
JM,
Byrne
JJ. White
RL:
Effect
of fibrinolytic
agents and anticoagulants on blood Surg Gynecol Obstet I 16:486, I963
clot
2. Hume M: Lysis of experimental embolus induced by streptokinase
radioactive pulmonary and streptokinase-acti-
vated plasmin. Thromb Diath Haemorrh 3. Browse NL, James DC: Streptokinase embolism. Lancet 2:1039, 1964 4. Genton lism: Effects
E, Wolf PS: of urokinase
Experimental therapy on
pulmonary
emboli.
I I :99, I964 and pulmonary pulmonary organizing
embothrombi.
J Lab Clin Med 70:3 I I, 1967 5. Moser KM: Clinical observation in thromboembolic disease treated with fibrinolysin. Angiology IO:3 19, I959 6. Sheffer AL, Israel HL: The treatment of pulmonary embolism with fibrinolysin. 7. Browse NL. James
Angiology lO:292, 1959 DC: Streptokinase and pulmonary
embolism. Lancet 2: 1039, I 964 8. Sasahara AA, Cannila JE, Belko JS, et al: Urokinase therapy in clinical pulmonary embolism. N Engl J Med 277:1168, 1967 9. Sautter nase for the
RD. Emanuel DA. treatment of acute
lism.
202:215.
JAMA
1967
Fletcher pulmonary
FW,
et al: Urokithromboembo-
IO l‘t,w DF. Wagner HN. Ilolmes pulmonary embolism. N Engl .I Med 277: I I Gcnton thromboembolism.
E. Wolf PS: Urokinase Am Heart .I 76:628.
RA Urokinasc I 16 I. 1967
therapy 1968
in pulmonary
12. Ilirsh .I, McDonald IG. llalc GS. Streptokinasc treatment of major pulmonary embolism. Expericncc twenty-live patients. Aust Ann Med I9 (Suppl I ):54. 11 Miller GAH. embolism. Clinical
Sutton and
GC:
Therapy of Pulmonary Edward
Genton BACKGROUND
of thrombolytic agents for of pulmonary thromboembolism is an attractive and rational concept based on a number of considerations. The process of pulmonary embolism involves compromise of the cross-sectional area of the pulmonary circulation by embolization of thrombotic material composed primarily of red cells enmeshed in a fibrin lattice. Damage to the pulmonary parenchyma results from the compromised circulation distal to the embolic material, and the hemodynamic alterations are due to the increased pulmonary resistance and its adverse effect on the right ventricle caused by the obliteration of the pulmonary bed. Removal of the embolic material immediately reverses the hemodynamic consequences, and probably also the effect on the pulmonary parenchyma, and in most instances restores the involved branches of the pulmonary artery to the state of normalcy that existed prior to the embolization. Recent emboli are favorable to lyse if exposed to plasmin because the embolic material is from freshly formed thrombi, usually no more than a few days old, and because there is often fragmentation of the thrombus as it embolizes, which exposes the inner aspects of thrombus. Thus, the administration of agents that greatly enhance fibrinolytic activity in plasma should lead to accelerated resolution of the embolic material. While spontaneous embolus resolution is the rule rather than the exception, the time required for this physiologic process is usually measured in days or weeks rather than in hours. More rapid reversal of the adverse consequences of an embolic episode may be desirble, especially in the patient who has marked hemodynamic effects of embolization. In such patients, deterioration of cardiopulmonary function is rapid after embolism, and prompt rapid restoration of normal blood flow may be important and, in fact, life saving. Theoretically, an additional benefit would be reduced likelihood of recurrent pulmonary embolism by inducing lyses of thrombi present in the veins in the lower extremities. These and other considerations have encouraged the evaluation of thrombolytic agents in acute pulmonary embolism.
E MPLOYMENT the treatment
Progress in Cardiovascular
Diseases, Vol. XXI,
No. 5 (March/April),
Thromboembolism
INFORMATION
Early animal studies with thrombolytic agents involved the embolization of freshly clotted blood into the lung of animals, followed by treatment with thrombolytic agents, with observation of dissolution of the emboli.1~2 Later studies embolized thrombi of various ages that had been formed in vivo3*4and provided further documentation that both streptokinase and urokinase produced rapid and marked degrees of lysis of the embolized material, with degrees of lytic activity that were easily achieved and readily sustained. For example, it was demonstrated that a 12-hr infusion of urokinase resulted in 95% lysis of 7-day-old thrombi embolized into the lungs of dogs, compared to only 23% lysis of similar emboli in control animals.4 Thrombolytic agents were administered in patients with pulmonary embolism by the late 1950s when preparations of plasmin were used, but little in the way of objective criteria was presented for diagnosis or documentation of the magnitude of the embolic involvment or quantifying the fibrinolytic state produced.5-7Plasminogen activators of the type and purity currently available were first used in the early 1960s by a number of investigators.E-‘3 The results of these studies were quite consistent and indicated that with as little as 6 hr of intravenous administration of amounts of streptokinase or urokinase that were quite well tolerated even by seriously ill patients, cases of acute massive embolization were associated with persuasive evidence to suggest thrombolysis had been produced (Table 1). The results of these studies were sufficiently encourging as to stimulate the conduct of several large controlled trials designed to compare conventional treatment with heparin with varying therapeutic regimens of streptokinase or urokinase.“16 These studies also allowed, along with others, the description
From McMaster University, Hamilton. Ontario, Canada. Reprint requests should be addressed to Edward Genton. M.D.. M&faster University, Hamilton. Ontario. Canada. 01979 by Grune & Stratton. Inc. 00334620/79/2105MOO3%02.00/0
1979
333
EDWARD
334
Table
1. Thrombolytic
Therapy
in Pulmonary
Embolism:
Uncontrolled
Studies Ar>gloyrdphy
Autho,
Sasahara
Agent
Treatmecd
UK UK
8 6-8
UK UK
8 8 12
et al
Tow et al Sawer et al Genton et al Miller et al Hirsh et al
SK SK
36 24-72
Total UK, urokmase.
PZiWi7fb
Improved
8 13 10
GENTON
or Scar,
No Change
7 7
1 5
0 1
13 9 24
8 9
2 4
0 0
6 20
3 3
0 1
77
57 (74%)
18
2
SK, streptokmase
of the natural history of pulmonary embolism associated with heparin treatment. The largest and most informative clinical trials have been the NIH-sponsored projects that compared conventional heparin treatment with a 12-hr infusion of urokinase. 12 hr of treatment with urokinase with 24-hr treatment of urokinase, and 24-hr urokinase with an equal period of streptokinase infusion. These were cooperative, multicenter studies using a modified double-blind protocol. with objective methods consisting of angiography, serial lung scans, and hemodynamic measurements as endpoints. In total, 327 patients were randomized into the studies, and both the design and the execution of these projects appeared excellent. Results from the various clinical trials have provided much information concerning the changes produced when thrombolytic agents are administered to patients with pulmonary embolism. This has clarified many of the questions pertaining to the use of these agents in therapeutics. However, the crucial question is where in the therapy of pulmonary embolism the drugs would be indicated. The answer to this must consider the effect of alternate approaches to therapy. Essentially, these would include no antithrombotic therapy or heparin. Although limited in amount, and certainly imprecise because of the unreliable methods used for diagnosis, the available information that bears on the natural history of untreated pulmonary embolus is persuasive that the failure to treat symptomatic pulmonary emboli is associated with a high incidence of recurrence, probably exceeding 40%, and a risk of fatal outcome from recurrent embolism, which approximates 25%.17-20 In contrast, the outlook for patients treated with heparin is excellent, as has been shown in a number of studies “~2’--23( Table 2). The incidence of recurrence is less than 5% in most series, and
fatal recurrence is very uncommon. In the National Heart and Lung Institute (NHL.1) thrombolytic therapy study. 78 patients received heparin for a period of at least 5 days, followed by several months of prophylactic anticoagulants. Fifty-five percent of these patients had massive emboli and 45% had submassive emboli; 7%) were in shock. Seventy percent were treated within 72 hr of onset of symptoms. After 24 hr 01 heparin treatment, there was some, but only slight, improvement as determined by angiogram, lung scan, and hemodynamic data (Figs. I and 2). In the lung scan, this amounted to about a 10% reduction in the size of the initial defect. There was essentially no difference in the total pulmonary resistance or the arterial poz at 24 hr. The subsequent change in the perfusion defect. as measured by serial lung scans, indicated there was progressive resolution that had amounted to 55%’ of the mean initial defect by 14 days, and to 80%’ by the end of 3 mo (Fig. 2). Of numerous variables considered. several were apparently associated with the rate of improvement. This included the age of the embolus. with lesions considered by history to have been present more than 48 hr having slower resolution, and previous cardiopulmonary disease also associated with slightly slower rates of resolution. Long-term residual of the perfusion abnormality, exceeding IO%, persisted in 16%) of patients followed for I yr. This was more frequently seen in patients Table
2.
Pulmonary Embolism Recurrence During Heparin Therapy Recurrence
NO Coon
O’Sullwan UPSET Basu
PatW?“tS
TONI
639 100 78 110 927
5 4 19
wi Fatal
1 2 0
3
0
58
09
THROMBOLMIC
THERAPY
OF PULMONARY
z 0 tz a
Complete 4 Improvement
Marked 3 lmpravement
335
THROMBOEMBOLISM
12 hour Urokinase
12 hour
24 hO”r uroklnare
24 hour St rept Dkinase
Moieraie 2 Improvement Slight 1 lmprovemenl
loo 90 80
f z 5 Y 5 &
m 60 = 40 30
%
20 10
d!
0
Day
1
3
7
14
3 mos.
1 year
changes of original from Circulation.“)
defect.
POST-INFUSION Fig. 1. (Reproduced
Angiographic with permission
changes from
in severity ./AMA.“)
at
24
hr.
with prior embolism or underlying cardiopulmonary disease (in which case about 25% had residual defects) and in patients with larger defects. These observations are consistent with the data presented by other workers who report minimal or no resolution within the first 2 or 3 days.24*2SThereafter, there is a varying rate of dissolution, which in the occasional patient may be marked in as little as 24 hr, but in most cases requires in excess of 1 wk for substantial change to occur. Evidence from several authors indicate that patients with underlying cardiopulmonary disease, especially when associated with left heart failure, have delayed rate and amount of resolution, and some residual is the rule rather than the exception.2”28 Thereafter, there is progressive decrease in the perfusion defect that proceeds at varying rates, and in some patients, appears to continue past 6 mo. In general, the more massive embolization has resolved more slowly. Thus, the outlook for patients with pulmonary embolism treated with heparin is excellent for survival, although a slow improvement in vascular obliteration is noted. In contrast to the expectation with heparin treatment, the results with thrombolytic agents in controlled trials provides evidence for accelerated dissolution of embolic material. In the NHLI study, treatment with urokinase was administered in one group of patients for 12 hr, in another group for 24 hr, and a further group received 24-hr treatment with streptokinase. The drugs were administered by constant intravenous infusion into peripheral arm veins. The laboratory parameters indicated brisk lytic activity in more than 85% of cases. Patients had symptoms for 5 days or less, and in the majority of instances, less than 72 hr. The objective parameters all showed substantial and significant
Fig. 2. (Reproduced
Perfusion lung with permission
scan
evidence of improvement when the studies were repeated 24-36 hr after onset of therapy. The pulmonary angiogram for the total thrombolytic therapy group demonstrated a mean change exceeding 40% from baseline, contrasted with less than 5% difference in the patients having received heparin infusion (Fig. 1). In regard to the lung scan, after 24 hr there was a 22% reduction in perfusion defect in the patients receiving urokinase, compared to 7% with heparin (Fig. 2). In the hemodynamic parameters examined, significant differences occurred that favored urokinase in all pressure measurements, including pulmonary artery, right ventricular systolic and diastolic, and in total pulmonary resistance, and was borderline for po2 measurements. The all-important total pulmonary resistance, which considers both the mean pulmonary artery pressure and the cardiac output, was elevated prior to treatment to a similar extent in both groups. There was a marked fall toward normal after 24 hr in this measurement in the urokinase, but not in the heparin patients. Comparison between treatment with 12 hr of thrombolytic therapy with 24-hr infusion of either urokinase or streptokinase indicated no significant differences between the three treatment groups, with each showing more than a threefold greater increased improvement by angiogram, compared with the heparin-treated group (Fig. 1). As regards pulmonary perfusion changes, the degree of resolution following initiation of therapy was 9% for 12-hr urokinase, 12% with 24-hr urokinase, and 7% for 24-hr streptokinase. The suggested difference between the urokinase and streptokinase 24-hr infusions failed to achieve statistical significance. The hemodynamic parameters revealed no difference between the 12- and 24-hr
336
EDWARD
urokinase, and some, but not statistically significant, difference between 24-hr urokinase and 24-hr streptokinase. Thus, the data are persuasive to suggest that there is accelerated resolution of pulmonary emboli from treatment with either urokinase or streptokinase compared to heparin, as judged by several objective indicators, including hemodynamic parameters, lung scan (perfusion), and pulmonary angiograms. The follow-up observations, consisting of serial lung scans performed frequently for 2 wk, after 3 mo, and at I yr, illustrated significant difference between the heparin and thrombolytic therapy patients only during the first week, and thereafter, there were no differences apparent (Fig. 2). In both groups, there was progressive improvement in perfusion of originally involved areas, which was maximum during the first week, but continued over at least a 3-mo period, following which there was a plateauing with minimal further evidence of improvement for the total group apparent after I2 mo. These findings are consistent with earlier studies previously referred to.‘(’ ” FACTORS INFLUENCING RESPONSE THROMBOLYTlC THERAPY
TO
Numerous factors that might potentially influence outcome, and would therefore have to be considered in selecting patients to receive thrombolytic therapy, have been examined. Age and Size of Enzbolus
Early work with thrombolytic agents produced evidence to suggestthat thrombi become progressively less responsive to the effects of thrombolytic agents as they age, presumably because of the organization that occurs on the surface with nonfibrin material. With experimental pulmonary emboli that had been aged in vivo for varying periods of time and histology documented, it was demonstrated that while very freshly formed thrombi are most susceptible, emboli 5-7 days old will undergo lysis during urokinase infusion. Emboli up to 2 wk old were less responsive, but underwent significant change during a brief infusion period compared to untreated animals. This is consistent with evidence presented that suggests that thrombi remain dynamic for long periods, making it likely that some recently deposited fibrin and cellular components are present even in “old”
GENTON
thrombi which could be lysed. Another point that has been made is that disruption or fragmentation of even an old thrombus that embolizes also is associatedwith increased thrombolysis, presumably because the interior of the thrombus with its fibrin laticework and lesser degree of organization causes the embolus to remain lysable.J In the human studies, the data suggestedthat while emboli estimated to be less than 72 hr were associatedwith the most impressive evidence of lysis, patients with lesionsup to 57 days old showed evidence of improvement. However, most patients with lesions that were judged to be older than 2 wk demonstrated littlc evidence of benefit from therapy. Casesin which the embolic lesionswere thought to be more than 6 wk old had no demonstrable change unless there wasevidence of coincidental recent embolization.” Patients who failed to show improvcment and died were found at autopsy to have embolic material that was organized? In the NIH study, only patients with emboli judged to be lessthan 5 days old were admitted. Analysis of results, based on estimated age of emboli, suggestedthat there was better response with thrombolytic therapy for emboli lessthan 48 hr old than with older lesions, in that there was 30X resolution in the less than 48-hr-old lesions and approximately half that when they were greater than 48 hr. This was not the same as with heparin where. if anything, there was more rapid resolution of the greater than 48hr-old lesions (Fig. 3). One must interpret this data with caution since. while all lesions were considered acute pulmonary emboli. it is quite likely that some patients had experienced more than one embolic episode, and the lesions observed were of varying age. As is known, the most rapid rate of change is over the first few days, and if the patient was first seen 2-3 days after the onset of symptoms, a substantial amount of lysis of the lesion might already have occurred and the rate of dissolution of remaining embolus would be expected to be slower. From the available information, it seemsreasonableto conclude that the fresher the embolus the more likely and more marked the response to lytic therapy. It appears that there is decreasing susceptibility to lysis, which is considerable after 557 days; and by the end of 2 wk, not much responseis to be expected. In addition to age of embolus, the location
THROMBOLMIC
THERAPY
m
OF PULMONARY
Heporin
DAY I
(N=35
DAY 3
DAY 3 Fig. 3. Perfusion lus at postinfusion (48 hr: W 248 Circu/etion.‘4)
THROMBOEMBOLISM
)
DAY 5
DAY 5
DAY 14
DAY 14
lung scan resolution by age of embodays 1, 3, 5, 14. (A) Age of embolus hr. (Reproduced with permission from
within a vessel is conceivably of importance. Thus, since thrombolysis depends on the exposure of the embolus to plasminogen activator, the lesion that is impacted in a vessel does not expose its surface except at the proximal end to elevated levels of lytic activator. Contact of the drug with other parts of the embolus would need occur through the vasa vasoro circulation or from retrograde filling of the obstructed vessel, or through percolation through the embolus. In some animal studies, it was suggested that impacted emboli lysed less rapidly than those that permitted laminar flow. However, this was not shown to be a significant factor in the response observed in the NIH studies. To the extent that impaction may be recognized angiographically, the data suggested that lysis was as effective in such lesions as those with filling defects. This is similar to the observations in other reports.26 In the majority of studies, treatment has been limited to patients with major compromise of the pulmonary bed from massive embolization. Small or submassive emboli that produce segmental or lobar-sized defects usually do not
337
produce sufficient symptoms to require treatment other than heparin. In the NIH study, patients with emboli of varying severity were included, and about 40% of the first study had submassive emboli. Results suggested that patients with the more massive emboli had a greater response than did those with submassive lesions, but the difference was not statistically significant. On the other hand, the patients who had massive emboli and were in shock, while only a small group, had an almost tenfold difference favoring the thrombolytic drug compared to heparin. This information suggests that patients with massive emboli may show rapid resolution of their defect, which is consistent with the results of all reported studies. It is more difficult to draw a conclusion concerning the effect of thrombolytic therapy with submassive emboli. Clearly there was substantial and significant reduction in embolus size in those with submassive lesions, but the quantification of this change in terms of lung scan and angiogram was difficult. Of importance is the fact that in most patients, whether with massive or submassive emboli, the resolution of the lesion was seldom complete at the end of either a 12- or 24-hr infusion period. With some residual lesion, there may be a discrepancy between the percentage lysis of the embolic material and the resultant effect on angiograms or lung scans. Thus, the lysis of 30% of a massive embolus, for example, might translate into very marked changes in perfusion, while a similar percentage lysis of an embolus in a segmental vessel might have less effect on the abnormalities in the diagnostic studies. There is no reason to suspect from available information that submassive emboli are any less responsive to lytic therapy, but the overall effects of treatment in terms of symptoms and diagnostic tests may be far less dramatic compared to those seen in patients with massive embolization. It is notable that the long-term outcome was not influenced significantly by the size of the initial defect, although there was some tendency for a greater absolute residual to be present in those patients with massive emboli. In that regard, lung scan information favored thrombolytic therapy in massive emboli in that residual perfusion defects were less in such patients who had been treated with urokinase as compared to heparin.
338
EDWARD
Effect of Underlying Cardiopulmonary Disease
As noted previously, several authors have drawn attention to the fact that patients with underlying cardiopulmonary diseasehave slower and less complete spontaneous resolution of pulmonary emboli and the resulting perfusion abnormalities. None of the thrombolytic therapy trials have indicated that the outlook is changed by the use of thrombolytic drugs. Thus. the response in patients with both massive and submassiveemboli. treated with either heparin or thrombolytic drugs, is the same basedon the presenceor absenceof cardiopulmonary disease. In all groups, it appears that there is slower resolution in the presence of cardiopulmonary disease.In addition, there is greater permanent residual, and this does not appear to be signihcantly altered by a short course of thrombolytic therapy during the acute phaseof the disease. Conditions of Treatment Infusion, etc.)
(Dose. Duration
of
Most of the clinical trials have employed similar and standard conditions. The drugs have been administered by constant infusion into a peripheral vein or directly into the pulmonary artery through a catheter left in place after angiography. Treatment has been continued for 12-72 hr with the occasional patient being treated for as long as 5 or 6 days. Both streptokinase and urokinase therapy was begun with a loading dose sufficient to produce immediate onset of a brisk fibrinolytic state, which was then sustained by continuous infusion. For streptokinase, the loading dose ranged between 250,000 and 600,000 U as a standard doseor determined by the streptokinase resistancetest. The sustaining dosewas usually 100,000-l 50.000 U/hr. For urokinase. a priming doseof approximately 2000 CTA U/lb body weight was followed by a similar dosageeach hour. Although it was frequently noted that clinical parameters improved, and in 2 studies that pulmonary artery pressure fell within 2 or 3 hr. most objective indicators of responsewere repeated only at the end of the infusion period. Only in the NIH trials was direct comparison made between infusion times of varying duration (Fig. 1). In the first of these studies, a 12-hr infusion with urokinase produced more than a threefold greater resolu-
GENTON
tion by angiography as compared with heparin. The I2-hr infusion with urokinase in the second phase gave nearly an identical result. In that study, the 12-hr infusion result was compared with a 24-hr infusion with either urokinase or streptokinase. Angiography results were equivulent for the three groups. Hemodynamic parameters, most importantly the total pulmonary resistance, showed slightly greater change in patients receiving 24-hr infusion compared to those treated for 12 hr. but this result did not approach statistical significance. The perfusion lung scan results demonstrated a somewhat greater improvement in patients receiving urokinasefor 24 hr ascompared to streptokinase. This was most impressive, and in fact, statistically significant for patients with massive embolization. The explanation for this ditrerencc is unclear, if in fact it is meaningful. Interestingly, the degree of thrombolysis observed was poorly correlated with the intensity of the tibrinolytic state produced as measured directly or indirectly by a variety of parameters. The significance of this is uncertain but might reflect the insensitivity of the available tests.lJ Ac mentioned previously, it was usual that some evidence of residual emboli was present even when improvement had been dramatic. In some patients in uncontrolled studies, thrombolytic therapy was resumed for varying times in an attempt to effect complete lysis. Evidence of further improvement in such instances was usually minimal and suggeststhat infusion periods past 72296 hr arc seldom indicated. Perhaps a more important question is the minimum time necessary to achieve significant clinical improvement. This question is not answerable from available literature and predictably would be influenced by a number ot factors. such as the extensiveness of embolization, age of emboli. etc. Interesting data have been reported that suggestvery short periods 01 thrombolytic therapy may be associated with substantial amounts of thrombolysis. One such report of 8 casestreated for 2 hr with moderate doses of urokinase delivered directly into the pulmonary artery, recorded impressive results.“’ In another study. injection of urokinase at 24 hr intervals produced improvement, including prompt fall in pulmonary artery pressure.” A somewhat different approach has beenevaluated that examines the effect of low dosestrep-
THROMBOLYTIC
THERAPY
OF PULMONARY
THROMBOEMBOLISM
tokinase in combination with full therapeutic doses of heparin. With this method, the usual loading dose is delivered over a 4-hr period and is followed by a sustaining dose approximately 10% of that usually given, which is continued for 48 hr. In 13 patients treated by this approach, 7 underwent follow-up angiography. Results indicated marked improvement, including 3 in whom normal pulmonary angiograms were obtained.32 Further information is necessary before the potential of this scheme can be determined, but it offers an exciting avenue for continued investigation. Presently, it is not possible to identify an optimal regimen for the thrombolytic drugs in terms of dosage and duration of treatment. With available information, it is reasonable to conclude that the dosage employed to date represents the maximum amount, and possibly a lower dosage might prove to be adequate. Complications
Hemorrhage is the only complication of major significance that has been encountered. In most studies it has occurred in 30%-50% of patients, and in many of these it was of severe proportions requiring termination of treatment and occasionally transfusion and in a few cases has caused death. In the trials comparing heparin and thrombolytic therapy, the bleeding incidence with the latter has been significantly greater. There has been no significant difference in bleeding incidence between urokinase and streptokinase treatment. Bleeding has most often been at cut-down sites of either arteries or veins, but also has occurred from the gastrointestinal or gastrourinary tracts and in some instances intracerebrally. Bleeding from cut-down sites has usually begun 6-8 hr after the onset of infusion and continued in spite of a variety of measures, such as pressure dressings, elevation, or local application of epsilon-amino caproic acid. The local bleeding usually stopped between 1 and 2 hr after termination of infusion and after that does not resume in most cases in spite of heparin treatment. The majority of instances of gastrointestinal bleeding have been recognized following completion of thrombolytic therapy and during heparin administration but might have begun earlier. There has been no clear-cut relationship of bleeding complications to the
339
patient’s age or sex or directly to the intensity of the lytic state that has been produced. On theoretical grounds, there was concern that a high incidence of recurrent pulmonary embolism would be observed in patients receiving thrombolytic therapy due to release of embolic material from thrombi in the leg veins. This fear has not been substantiated, and recurrent embolization during thrombolytic therapy has rarely occurred. The incidence of recurrent embolization over a IO-lbday period has varied considerably depending on the stringency of criteria for diagnosis. Overall, it has not exceeded 7% in most series when objective documentation is required. There has been no significant difference in the incidence of recurrence between heparin and thrombolytic treated patients.33 Mortality
The accumulated mortality in nearly 500 patients with pulmonary embolism treated with thrombolytic agents has been approximately 5%, with a similar incidence in patients receiving heparin in the same trials. In the urokinase study, the mortality at the end of 2 wk was 9% in both trials and with each of the treatment modalities. Even in the patients with massive pulmonary embolism and shock, the outlook would appear to be good for recovery when either thrombolytic agents or heparin have been used. It is perhaps not surprising that mortality is low and no different in patients treated with heparin or thrombolytic drugs. As previously noted, the outlook for patients with pulmonary embolism is excellent for rapid improvement and recovery once they are diagnosed and treatment, which arrests the thrombotic process, initiated. Unfortunately, patients who are destined to die from an embolic event do so rapidly, most within 1 hr from the onset of symptoms, before definitive diagnostic procedures can be carried out or usually before effective treatment can be instituted. These are not the cases that have been included in various trials of thrombolytic therapy and those who have been entered even with massive embolization would have a good prognosis. Thus, a very large number of cases would be necessary to demonstrate significant reduction in mortality by an agent more effective than heparin.
340
EDWARD
CONCLUSIONS
AND
RECOMMENDATIONS
The major objective of therapy for pulmonary embolism is to prevent mortality and secondarily to reduce the period of morbidity from obstruction of the pulmonary vascular bed. In most patients, these objectives are readily achieved with conventional heparin therapy. Substantial experience has now been gained with the use of the plasminogen activators, urokinase or streptokinase, in patients with acute pulmonary embolism. Persuasive evidence has been obtained that indicates that the rate of resolution of embolic material can be greatly accelerated by these agents, especially when the embolic episode was recent. Lysis of emboli probably begins rapidly with administration of these drugs, but several hours is usually required before objective evidence of their effects is demonstrable. Within 12 hr, dramatic effects are often seen, and in most instances treatment beyond that period of time is not associated with apparent additional improvement. In the majority of patients, lysis is not complete, and some residual perfusion abnormality persists that clears over ensuing days or weeks. The establishment and maintenance of “therapeutic” levels of fibrinolytic activity is readily achieved with standard regimens and is usually well tolerated even in severely ill patients. However, bleeding is a frequent and at times serious complication, and
GENTON
the likelihood of this complication increases with the duration of treatment. Thrombolytic therapy is contraindicated in patients particularly prone to bleeding complications, including those with recent surgery or trauma, recent stroke, severe hypertension, active peptic ulcer, malignant disease with metastasis, coagulation disorders or bleeding diathesis or pregnancy. Great care should be taken to decrease the likelihood of bleeding by keeping vascular invasion to a minimum and avoidance of all forms of trauma. Indications for thrombolytic therapy are not clearly established. It would be most useful in the small group of patients with massive pulmonary embolism who survive the initial hours following the onset of symptoms, especially it they have cardiac or pulmonary decompensation. Such patients may deteriorate rapidly from hypoxemia. arrhythmia, acidemia, or even a small recurrent embolism. Another group are patients with preexisting cardiopulmonary disease who have suffered a major insult from a pulmonary embolus. even though it may be 01 only moderate size. In both these groups, the rapid lysis of even a moderate amount of embolic material may serve as a useful alternative between pulmonary embolectomy and anticoaglant therapy to stabilize their condition and give them a greater margin of safety in terms of their immediate course.
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JJ. White
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