Observations in Anticoagulant and Thrombolytic Therapy in Pulmonary Embolism Edward Genton and Jack Hirsh

LL PATIENTS with clinically recognized pulmonary embolism have the constant threat of a recurrent episode which may prove fatal, making it imperative that treatment be give,n to prevent this development. In fact, autopsy studies indicate that in more than two-thirds of cases with fatal pulmonary embolism, evidence is found of prior emboli having occurred in the days or weeks preceding the fatal episode, and it has been suggested that untreated, more than one-third of patients will have recurrence. 1-3 Contrariwise, if recurrence is prevented, significant resolution of the pulmonary obstruction occurs over a period of weeks or months which returns the pulmonary circulation to preembolic condition in most cases. 4 Thus, in the majority of patients with pulmonary embolism, the primary objective of therapy is to prevent recurrence, and therefore, a course of anticoagulants is the only therapy indicated, and outlook for recovery is excellent. In a few cases, either because of the size or number of emboli, or presence of preexisting abnormality of the pulmonary circulation, there is severe compromises of cardiopulmonary dynamics which threaten survival. In such patients, it is desirable to accelerate removal of the obstruction of the pulmonary circulation as well as to prevent recurrence, and in those cases thrombolytic therapy may be of value.

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RATIONALE FOR ANTICOAGULANT THERAPY Pulmonary emboli arise from peripheral veins, in more than 75% of cases from deep veins of the lower extremities, occasionally from pelvic veins, and even less frequently from vessels of the upper extremities or right-heart chambers. It is currently felt from data obtained in 12sI fibrinogen scan

From the Department of Medicine, University of Colorado Medical Center, Denver, Colo., and the Department of Medicine and Pathology, McMaster University Medical Center, Hamilton, Ontario, Canada. Reprint requests should be addressed to Edward Genton, M.D., Professor of Medicine University of Colorado Medical Center, Denver, Colo. 80220. 9 1975 by Grune & Stratton, Inc.

studies, that calf veins seldom give rise to symptomatic pulmonary emboli and that major emboli arise from thrombi in the popliteal, femoral, or ileofemoral vessels, s Thus, the objective of therapy to prevent recurrence is to arrest the thrombotic process, prevent propagation proximally and embolization, allow thrombus attachment to the vessel wall, and organization. If this is accomplished, not only is the danger of embolization greatly minimized but resolution of thrombus in the vein, or embolus in the pulmonary circulation, occurs through action of the fibrinolytic system. The only therapeutic agent of proven value to achieve this objective is heparin. Although the oral anticoagulants reduce plasma levels of several clotting factors and may act as prophylactic agents, in this construct they are not predictably effective in arresting an active thrombotic state .6 Heparin is a heterogeneous, mucopolysaccharide molecule extracted commercially from the mast cells of many tissues, including liver, lung, and intestines. Heparin is a potent anticoagulant, and affects the coagulation mechanism at several points in the reaction sequence including inhibition of factor IX activation, inhibition of thrombin conversion of fibrinogen to fibrin, and perhaps most importantly, the inhibition of activated factor X, thereby preventing conversion of prothrombin to thrombin. In its inhibitor action on thrombin and activated factor X, heparin acts by enhancing the effect of an alpha2 globulin present in plasma which has been termed the heparin cofactor and appears to be identical to the molecule previously called antithrombin III. The heparin globulin complex is a more potent inhibitor of activated factor X than of thrombin. Since factor X occupies a central role in both the intrinsic and extrinsic thromboplastin pathways, and due to the cascading of the coagulation sequence, inhibition of small amounts of activated factor X blocks the formation of large amounts of later reactant products, including thrombin. A D M I N I S T R A T I O N OF HEPARIN Because it is not absorbed from the gastrointestinal tract, heparin must be administered par-

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enterally. Its action on coagulation is immediate and its effect may be measured by a variety of coagulation tests. The most frequently used test is the whole blood clotting time or Lee-White time. Although relatively insensitive, the test detects the effects of heparin and the prolongation of LeeWhite time essentially parallels the amount ofheparin present in blood. Other tests suitable for monitoring heparin effects are the plasma or whole blood activated partial thromboplastin time (PTT). However, care must be taken to insure that the test is sensitive to therapeutic amounts of heparin and produces a linear dose response curve. Partial thromboplastins vary in sensitivity to heparin, and these recommendations are based on the use of reagents which detect 0.05-0.1 units of heparin per ml plasma. The dose of heparin necessary to achieve the desired effect on the coagulation mechanism generally falls within a predictable range for the majority of patients, but must be individualized since extremes of sensitivity to the drug occur in approximately 10%-15% of patients and prolongation of an appropriately chosen clotting test is the only reliable way of documenting achievement of the desired effect. Further, the heparin requirement may change during the course of treatment with the most frequent change being a decreased requirement after the first two or three days of therapy, especially in patients who have had active thrombosis initially or in those with right heart failure. Some authors suggest that it is unnecessary to monitor heparin therapy and that levels of activity which create clotting times of infinity are welltolerated and indeed may be desirable. There is some indirect evidence in the literature that uncontrolled therapy is associated with a higher incidence of hemorrhage than if kept within "therapeutic" range. This is particularly true if treatment is to be continued for more than a few days. In addition to monitoring the coagulation studies, it is desirable to observe for evidence of bleeding with serial determination of the hematocrit in all patients during heparin therapy. The amount of heparin used clinically is based upon a number of experimental studies which have demonstrated that a dose of the drug sufficient to constantly maintain the whole blood clotting time or its equivalent to at least twice the normal control value prevents the formation of stasis thrombi in animals. Recently, studies using isotopically labeled fibrinogen have demonstrated that similar

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amounts of heparin prevent accretion of fibrin onto an embolus. Although earlier studies suggested that heparin may have a fibrinolytic effect, further observations have failed to confirm this effect but have rather indicated that the apparent fibrinolytic effect of heparin is due to the inhibition of deposition of fresh fibrin onto an established thrombus or embolus which facilitates the natural lysis and resolution of the original embolus, s Administration of heparin may be accomplished in several ways; the most widely used are the continuous intravenous infusion and the intermittent intravenous bolus or subcutaneous injection methods. 9'1~ To date, there have been no control studies which have conclusively established the superiority of one of these methods; however, in some circumstances, one approach may be more convenient for the physician or patient, or less hazardous. For example, the continuous intravenous method may be preferable in patients with high risk of bleeding in whom tight control of the degree of anticoagulation is desirable. Patients in the early postoperative period or those with local or generalized hemostatic defects would fit into this category. The subcutaneous route may be advantageous for selfadministered or outpatient therapy.

Continuous Intravenous 1nfusion of Heparin Treatment is usually started with an injection of a bolus of 5000 U and is continued with a continuous infusion of 25,000-30,000 U/24 hr. The partial thromboplastin time (PTT) or clotting time is measured before starting heparin treatment and 4-5 hr after the bolus injection and then daily during heparin treatment. The maintenance dose is 1 1 adjusted to keep the PTT between 13-23 times the control level or the whole blood clotting time between 2-3 times control level at all times. However, in patients who are at particular risk of bleeding because of a general hemostatic defect or a local lesion which is prone to bleed (e.g., surgery) and in patients with liver or renal disease who have reduced heparin clearance, smaller doses of heparin are recommended. For such patients, an appropriate regimen is to give a bolus of 2000-3000 U and a maintenance dose of 15,000-20,000 U/24 hr. These patients should be monitored more frequently (two to three times a day) aiming to maintain the PTT at the lower end of the recommended therapeutic range. The continuous infusion can be delivered with the

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aid of an infusion pump or through an IV drip, using a pediatric control volume set which allows isolation of 10-50 ml aliquots of the solution to prevent the inadvertent administration of excess quantities of the infusion. Because of the likelihood of varying flow rates when needles or catheters are in forearm veins, it is preferable when using this approach to infuse through a catheter placed above the antecubital fossa. This approach requires close surveillance unless a mechanical pump is employed.

Intermittent Intravenous Injection of Heparin When heparin is given by intermittent intravenous injection, the doses used are between 5000 and 7000 U every 4 hr or 7000 and 10000 U every 6 hr. It is convenient to use a so-called heparin lock placed in a peripheral vein. This consists of a small caliber, thin-walled winged scalpel vein needle connected to a short tubing, the end of which is sealed with a rubber resealable diaphragm through which a small needle may be inserted to deliver the intermittent injection. The advantages of this means of heparin administration are that it is easy since the drug can be administered by the nursing staff, is reliable and restricts the patients minimally, and may even be satisfactory for outpatient therapy on a short-term basis in carefully chosen cases. A potential difficulty is that the clotting time is prolonged to infinity for an hour or more after the bolus injection which may increase the likelihood of bleeding complications, especially in patients with large wounds or major trauma such as following hip fracture or hip surgery or in patients with local bleeding sites such as a peptic ulcer.

Intermittent Subcutaneous Injection of Heparin The subcutaneous route of administration involves the injection of concentrated aqueous heparin (20,000 to 40,000 U/ml) through a small 25-26 gauge needle into the subcutaneous fat of the abdominal wall. Using proper technique which emphasizes the production of minimal trauma to tissue, wiping the needle clean of heparin, and holding an ice cube over the injection site several minutes before and several minutes following the injection, pain and hematoma can usually be avoided. With this method, therapeutic levels of heparin are absorbed within 1-2 hr, and if more rapid anticoagulation is desired it is of course necessary to initiate therapy with an intravenous bolus. Thereafter, ef-

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fective anticoagulation can be maintained by repeat injections given every 8-12 hr. Advantages of this method of administration include the prolonged duration of action which is obtained and the potential for long-term use in ambulatory, nonhospitalized patients. DURATION OF HEPARIN THERAPY

The objective of therapy is to arrest the thrombotic process and prevent the propagation or embolization of existing thrombi. The risk of continuing thrombosis remains until there has been organization of the thrombus and probably until collateralization or recanahzation around and through the thrombus restores reasonably normal flow. Tile time for this to occur will vary depending on local fibrinolytic activity and on the extensiveness of the thrombus. In general, heparin treatment should be continued through 7-10 days which is the time required for experimental thrombi to become adherent to the vessel wall and endothelialized. At that point, the objective of therapy switches from arresting an active thrombotic state to prevention of its recurrence. Full-dose heparin is not required and when necessary, therapy may be switched to the oral anticoagulants or possibly to low-dose, subcutaneous heparin. The former agents, through their effect as vitamin K antagonists, inhibit one of the final stages in the synthesis by the liver of the vitamin K dependent clotting factors II, VII, 1X and X. Through this action, there is sufficient retardation of the response of the coagulation mechanism to prevent the development of thrombosis in the presence of mild to moderate provocation. The reduction of the levels of clotting factors in plasma following initiation of oral anticoagulant therapy occurs at a rate reflecting the circulating half-time of these proteins and it requires 3-5 days for sufficient reduction in circulating levels to occur in factors IX and X, which are the key factors for the antithrombotic effect, n Thus, heparin should be continued for that period of time after initiation of oral therapy, following which heparin may be rapidly discontinued without need for tapering. RESULTS OF HEPARIN THERAPY

Heparin therapy has been used in venous thromboembolism for nearly half a century and there are few drugs which have proven as remarkably successful for so long a time, and even now the drug

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maintains its position as the mainstay of antithrombotic therapy. Swedish and Canadian workers in the late 1930s reported the first successes with this form of treatment b u t it was not until 1960 that Barritt and Jordan reported their now classic study which was the first randomized trial of heparin therapy in venous thromboembolism. 3 In this study, although the groups were small, there was a striking reduction in fatal and nonfatal recurrences of embolization. Subsequently, there have been numerous reports confirming the benefits of anticoagulation in venous thromboembolism. In general, the results have been uniformly good when heparin has been given in amounts sufficient to achieve the levels of anticoagulation prevously described. There is some difficulty in quantifying the magnitude of effectiveness of heparin because reliable data has been difficult to obtain which bears upon the incidence in untreated patients of pulmonary embolism in deep vein thrombosis, of recurrence of pulmonary embolism in patients following an initial embolization and of fatal outcome from recurrence. The previously mentioned study of Barritt and Jordan observed a 26% mortality in 19 control patients not given heparin and an equal incidence of nonfatal recurrence. Other studies include that of Zilliacus which reported a 32% fatality rate in 214 patients, and of Barker who observed an incidence of 18%. ~2'1a These older studies probably underestimated the true incidence of recurrence in light of our current knowledge as regards the difficulty of recognizing a recurrent episode) 4 There are now a number of studies which have evaluated the results of treatment in patients who received heparin in adequate amounts as previously defined. '5-23 In these studies the recurrence rate has been between 2~% to 5%, although higher rates have occasionally been reported. 4 Fatal pulmonary emboli during adequate heparin treatment is very u n c o m m o n and most recurrences are well-tolerated by the patient, suggesting they are of small size. Recurrence is most likely when inadequate amounts of heparin have been given or after heparin has been stopped and has been replaced by oral anticoagulants, especially when the latter treatment is less than optimum. Late recurrences are reduced not only by an adequate course of heparin but also by continuing anticoagulant prophylaxis for an appropriate period of time. The total duration of prophy-

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laxis is difficult to define and probably should vary with different types of patients. Data has been presented to suggest that a minimum of 6 wk is desirable and logically a much longer period of treatment may be necessary in patients with continued provocation to recurrence such as those with heart failure, immobility or previous recurrence. 19 Also important is that patients who survive an embolus and are protected from recurrence have an excellent outlook for total recovery. This has been shown in several studies, the most recent being the Urokinase/Pulmonary Embolism Trial. 4 There is complete or nearly complete resolution of the perfusion defect in most patients. In that study, the heparin-treated control patients had a 55% average resolution of the perfusion defect as measured by lung scan after 2 wk, which by 6 too, had reached 80% resolution and was complete in many cases. Notably, this was the same as for the group of patients who had received thrombolytic therapy with Urokinase. COMPLICATIONS OF HEPARIN THERAPY

The only significant complication to short-term heparin therapy is hemorrhage. In most series, bleeding has occurred in approximately 10% of patients and in about one-half of those, it has been of severe proportions requiring blood transfusions or cessation of the heparin. In the Urokinase/Pulmonary Embolism Trial, it is notable that the incidence of hemorrhage in the heparin-treated group was 27% with the site of bleeding from cutaneous sites usually in areas of invasion for catheterization or similar procedures and from the GI tract or retroperitoneal space. It is not uncommon that patients have a fall in hematocrit of significant amounts over a several-day period without an apparent bleeding site being determined. In a number of studies, it was observed that the risk of bleeding during heparin increased in those patients with very prolonged clotting times, giving some significance to the concept of keeping the patient's clotting time in a controlled range and avoiding total inhibition of the clotting mechanism. 4' ~s,l~ It has also been pointed out that females, especially elderly ones, tend to have a higher i n c i d e n c e of bleeding complications with heparin and this has led some workers to recommend that the dosage be reduced in those patients and the control kept tighterY, 24

ANTICOAGULANT AND THROMBOLYTIC THERAPY

INDICATIONS FOR HEPARIN THERAPY

The foregoing information makes it apparent that a course of heparin therapy, followed in most instances by prophylactic anticoagulants for an appropriate length of time, is indicated in all patients with pulmonary embolism. The heparin should be initiated at the time that the diagnosis is suspected rather than delayed while diagnostic studies are in process, since recurrence is a constant and the most dangerous threat. There are few absolute contraindications to heparin therapy when pulmonary emboli exist. The drug should only be withheld if its use would be life-threatening, as might exist in the case of uncontrollable bleeding of severe proportions or bleeding into a closed space such as intracranially; because to withhold heparin is, in fact, to expose the patient to a life-threatening risk of some magnitude. A course of heparin can often be accomplished even in postoperative patients with bleeding into the wound site or in patients with mild GI or genitourinary (GU) bleeding if the continuous intervenous method is used and clotting times are kept in the 15-20 min range, although suboptimal is preferable to no heparin. If bleeding begins during heparin treatment, it is often possible to complete the desired course by withholding the drug until bleeding ceases and resuming therapy by continuous infusion and at lesser amount. If bleeding complicates the prophylactic phase of treatment with oral anticoagulants, administration of lowdose subcutaneous heparin can be used and in fact, is a preferable initial choice in some patients such as those at high risk of bleeding for whom necessary laboratory facilities to monitor oral drugs are inaccessible. THROMBOLYTIC THERAPY

The concept of effecting the dissolution of pulmonary emboli germinated in the minds of investigators in the late 1950s following the successes of Tiller and Johnson in inducing lysis of thrombi in the ear veins of rabbits; and Johnson and McCarty who achieved similar results on thrombi induced in the forearm veins of human volunteersY '26 In the 1960s, several investigators presented evidence that experimental emboli to the pulmonary circulation could be lysed with available thrombolytic agents. Initially, blood freshly clotted in vitro was era-

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bolized to the lung but later studies utilized thrombi formed in vivo which histologically resembled those seen in man. 27'28 Later, thrombi were formed in donor dogs and aged as long as 14 days before they were embolized to the pulmonary circulation of recipient animals. Thrombolytic therapy with Urokinase in amounts known to be tolerated by man effected lysis of both 1- and 2owk old thrombi, thus suggesting that in man where thrombi may age for several days in the lower extremities before embolization that thrombolytic therapy may accelerate their dissolution in the lung. 29 Simultaneous with these developments, much progress was being made in developing potent, standardized, highly purified thrombolytic agents in the form of the plasminogen activators, Streptokinase and Urokinase. These agents stimulate lysis of thrombi by activating in plasma and on the surface and possibly in the interstices of the thrombus, the conversion of the proenzyme plasminogen to the fibrin digesting enzyme plasmin. The plasminogen activators are considered superior to other proteolytic enzymes as thrombolytic agents, a~ Pulmonary embolism was a particularly attractive model for the study of thrombolytic therapy for a number of reasons: (1) Embolic material in the lung is predominantly red thrombus in contrast to arterial thrombi and therefore would theoretically be susceptible to lysis. (2) Pulmonary emboli are likely to have derived from reasonably fresh thrombi and therefore be susceptible to the action of plasminogen activators. (3) The vessels into which pulmonary emboli pass are essentially normal and removal of the embolic material would restore the vessel with little likelihood of rethrombosis. (4) The importance of pulmonary embolism as a cause of morbidity and mortality has been well established. Finally, and of considerable importance is that objective methods are available to quantify the significance of obstruction before treatment and to document the change produced by treatment. These methods include the lung scan, pulmonary angiography and hemodynamic measurements. On the other hand, it is known that most patients seen with a pulmonary embolus, will have one or more earlier embolic episodes, making it difficult to reliably distinguish new from old emboli.

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The initial studies of thrombolytic therapy with plasminogen activators in patients were performed by several investigators to document the feasibility of thrombolytic therapy in severely ill patients and to gain objective evidence of embolus lysis, al'a6 In these studies, impressive evidence of improvement was observed by angiography and lung scan but seldom was there complete resolution of the erabolus. Patients with histories to suggest recent emboli demonstrated regular evidence of lysis contrasted to those with subacute or chronic symptoms in whom there was little or no evidence of benefit. The data from these investigations estabblished the feasibility of creating and sustaining for prolonged periods of time, a brisk and controllable lytic state and of employing thrombolytic therapy in major pulmonary embolism and suggested that such therapy in patients with recent emboli would conceivably be of value. The efficacy of such therapy could not be established from these studies due to lack of adequate controlled observations. However, the demonstrated rate of resolution was in marked variation to the data available on the resolution rate of emboli during heparin treatment which suggested that minimal lysis of emboli occurs in the initial 3-6 day postembolization periodfl 7'as Based upon these encouraging preliminary resuits, a controlled trial of the effects of thrombolytic therapy in pulmonary embolism was launched in 1968 in the United States under the sponsorship of the National Heart and Lung Institute. Detailed reports of this study have been published. 4 This cooperative effort was conducted in 14 institutions with the objective to determine whether abnormalities resulting from pulmonary embolism, as demonstrated by lung scan, pulmonary angiography, and hemodynamic measurements, resolved more rapidly following thrombolytic therapy with Urokinase than following heparin alone. This study was therefore a physiologic experiment rather than a trial with morbidity or mortality as primary endpoints, since it was thought that mortality would be low in patients surviving to reach hospital and morbidity very difficult to quantify. Patients admitted to this study were those with angiographically confirmed emboli and symptoms for 5 days or less prior to the initiation of treatment. Actually, 50% of the patients had symptoms for less than 48 hr and in 70%, the duration was

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less than 72 hr. Prestratification was based on anatomic circumstance; that is, whether emboli was massive or submassive and also physiologically as to whether the patient was or was not in shock. To avoid interpretive bias, all objective data including lung scans, angiograms, and hemodynamic data were evaluated by a central panel of experts blinded to the type of therapy that the patient had received. Treatment consisted of infusion for 12 hr with either heparin or Urokinase in standard amounts based upon body weight. Upon completion of the 12-hr infusion, all patients received heparin in therapeutic amounts for at least 5 days. In total, 160 patients were randomized to the TriaI-78 in the heparin and 82 in the Urokinase group. In all, 90 patients had massive and 70 submassive embolization, as defined by the severity of the perfusion abnormality which existed. The desired level of drug effect was achieved in both the heparin- and Urokinase-treated patients and in all but two cases, the 12-hr course of treatment was successfully completed. The objective studies obtained demonstrated significantly better results in the Urokinase-treated patient than in those receiving heparin. One-third of those given Urokinase had large objective improvement contrasted to none with equivalent degree of response in the heparin grofip. In the hemodynamic parameters examined, significant differences occurred which 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. Only cardiac index and arteriovenous (AV) oxygen differences failed to show significance but these were not abnormal prior to therapy. The all4mportant total pulmonary resistance, a calculation which considers both the mean pulmonary artery pressure and the cardiac output, was elevated prior to treatment to a similar extent in both groups. The Urokinase, but not the heparin patients, had a marked fall toward normal after 24 hr in this measurement. Pulmonary angiograms were comparable before treatment in the two groups and after treatment, the Urokinase but not the heparin patients demonstrated a significant decrease in the severity of angiographic involvement. Of interest is that the greatest improvement, angiographically, was observed in patients with massive embolism, while those with submassive emboli improved to a significant but less impres-

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sire degree. Similarly, patients in shock at the time treatment was begun, had an eightfold greater improvement in their angiograms than did patients receiving heparin. The lung scans before treatment revealed dose correlation between the two groups as regards the severity of perfusion defect, and the mean defect for both groups was approximately 25% of the total lung area. Following treatment, the absolute resolution was significantly greater for the Urokinase group and the difference was threefold greater than for the heparin group. The difference in lung scans between the two groups lessened during the period of observation being greatest after 24 hr, and was no longer significant at 14 days indicating that spontaneous resolution of emboli in the heparin-treated group while slower, ultimately was the same. Of interest is that 50% of the initial defect remained at 14 days and even after 1 yr, 15% of patients had prominent residual equaling 10% or more of the initial defect. Of the many variables which were examined, only the age of the embolus appeared to influence this rate of resolution, and emboli judged to be less than 48-hr old had strikingly greater resolution than did older lesions. Mortality during the 2-wk observation period was quite low in both groups, occurring in 9% of the heparin-treated and 7% of the Urokinase-treated patients. Of the seven heparin patients who died, four were judged to have expired from the effects of the embolus. In contrast, only one of six Urokinase deaths resulted from effects of the embolus. On the other hand, two and possibly three deaths in the Urokinase group resulted from bleeding, whereas none expired from this complication in those receiving heparin. At the end o f a year of followup, there were no differences in mortality between the two groups. Hemorrhage was the only significant complication of thrombolytic therapy and ot,curred in 45% of patients receiving Urokinase contrasted to 27% in the heparin-treated group and was of severe amount in about one-half of these. In the majority of patients, bleeding occurred from cutdown sites and appeared to be venous rather than arterial in nature. It is of interest that the embolus resolution rate proved to be independent of the intensity of the lyric state created. In fact, no correlation was observed between any of the parameters of improvement with the parameters of lyric activity.

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Unanswered by this study was whether a more prolonged period of thromb01ytic therapy than the 12-hr employed would increase the amount of lysis achieved since few patients in this study demonstrated complete dearance of the perfusion abnormality. Further, it was desirable to examine comparability of effectiveness of Streptokinase with Urokinase, since the former drug has the advantages of greater availability and less cost compared to Urokinase and experiences reported from Europe and Australia were very encouraging. Therefore, a second multicenter study was carried out under the sponsorship of the National Institutes of Health, which compared a I2-hr with a 24-hr infusion of Urokinase and of Streptokinase 39

The protocol employed was nearly identical to that of the first study as regards the dosage and pre and postinfusion observations. A total of 167 patients with angiographically demonstrated pulmonary emboli were equally divided among the three treatment groups. More than one-half the patients had massive embolization and 7% were in shock. As in the earlier study, a brisk lytic state was produced as measured by a fall in the plasma fibrinogen and plasminogen levels and in the euglobulin lysis time. Treatment was well tolerated by even the severely ill patients and adverse reactions during the thrombolytic therapy was limited to mild fever, most often with Streptokinase and three instances of allergic reaction, also with Streptokinase. Significant improvement in angiograms, hemodynamic parameters, and lung scans were observed to the same extent as in the first study. Notably, there was no significant increase in the amount of improvement after a 24-hr infusion o f Urokinase or Streptokinase compared to 12 hr of Urokinase. The patients with massive emboli had the greatest percent change of the demonstrated abnormality by each objective parameter and the improvement was significantly increased in the Urokinase patients compared to those treated with Streptokinase. Significant bleeding occurred in more than onethird of the patients, which was severe and requiring transfusion in a total of 14%of cases. ROLE OF THROMBOLYTIC THERAPY

The available data are persuasive that thrombolytic therapy with plasminogen activators pro-

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duces a predictable, controllable and intense increase in fibrinolytic activity. Further it appears clear that such therapy accelerates the dissolution rate o f pulmonary emboli, especially when administered within 3-5 days o f the r event. Apparently the effectiveness of the two agents, Urokinase and Streptokinase, is essentially similar and at the dosage which has been used, the achievable lysis is accomplished with less than 24 hr of treatment. Whether a lesser dosage than that employed would be equally effective is an important question and yet to be conclusively answered. Reduced dosage, if effective, would have great appeal because o f the lesser expense and possibly reduced incidence o f bleeding. Preliminary data has been presented to suggest that "minidose" Streptokinase with simultaneous heparin may be effective in dissolving experimental emboli. 4~ The role o f thrombolytic therapy in the management o f patients with pulmonary embolism remains to be established. Most with embolization tolerate the insult well and the only necessary

therapy is anticoagulation to prevent recurrence, as has been discussed. A n o t h e r group o f patients develop cardiopulmonary decompensation after embolization, either because o f the size or number of emboli, o r d u e to the preexisting disease o f the pulmonary circulation, Unfortunately, m a n y such patients die rapidly before needed resources can be mobilized for their care and it is likely that in such cases, surgical embolectomy is o f greatest value. This leaves an intermediate group, small in number, who following massive embolization, compensate but remain precarious and in danger of deterioration from infection, arrhythmia or even small, recurrent embolization. In such patients, rapid removal o f a majority o f embolic material may be o f great value by improving their condition and providing them with a greater reserve and hopefully, reduce the likelihood o f recurrence by removing thrombus from the veins, giving rise to emboli. It is in this group that thrombolytic therapy would offer the greatest promise.

REFERENCES

1. Smith GT, Dexter L, Dammin GJ: Postmortem quantitative studies in pulmonary embolism, in Sasahara AA, Stein MM (eds): Pulmonary Embolic Disease. New York, Grune & Stratton, 1965, p 120 2. Barker NW: Anticoagulant therapy in thrombosis and embolism. Postgrad Med 1:265, 1957 3. Barritt DW, Jordan SC: Anticoagulant drugs in the treatment of pulmonary embolism: A controlled trial. Lancet I:1309, 1960 4. A National Cooperative Study. The Urokinase/Pulmonary Embolism Trial. Circulation 47: Suppl II, 1973 5. Kakkar VV: The diagnosis of deep venous thrombosis using the 12sI-fibrinogen test. Arch Surg 104:152, 1972 6. Deykin D, Wessler S, Reimer SM: Evidence for an antithrombotic effect of dicumarol. Am J Physiol 199: 1161, 1960 7. Wessler S, Yin ET: Theory and practice of minidose heparin in surgical patients. Circulation 47:671,1973 8. Wessler S, Morris LE: Studies on intravascular coagulation IV. The effect of heparin and dicumarol on serum induced venous thrombosis. Circulation 12:553, 1955 9. Genton E: Guidelines for heparin therapy. Ann Intern Med 80:77, 1974 10. Hirsh J, GaUus AS: The use of anticoagulants for the prevention and treatment of venous thromboembolism. Postgrad Med (in press) 11. Deykin D: Warfarin therapy. N Engl J Med 283: 691, 1970 12. Zilliacus H: On specific treatment of thrombosis and pulmonary embolism with anticoagulants with particular reference to post thrombotic sequelae. Results of 5

yr of treatment of thrombosis and pulmonary embolism at series of Swedish Hospitals, 1940-1945 13. Barker NW, Nygaard KK, Waiters W, et al: A statistical study of postoperative venous thrombosis and pulmonary embolism: IV Location of thrombosis: Relation of thrombosis and embolism. Proc Mayo Clin 16:33, 1941 14. Genton E: Recognizing and reacting to recurrent pulmonary embolism. Geriatrics 28:84, 1973 15. O'Sullivan EF, Hirsh J, McCarthy RA, et al: Heparin in the treatment of venous thromboembolic disease: Administration control, and results. Med J Austr 2:153, 1968 16. Crane C: Deep venous thrombosis and pulmonary embolism. N Engl J Med 257:147, 1957 17. Murray G: Anticoagulants in venous thrombosis and the prevention of pulmonary embolism. Surg Gynec Obstet 84:665, 1947 18. Bauer G: Clinical experiences of a surgeon in the use of heparin. Am J Card 14:29, 1964 19. Coon WW, Willis PW, Symons MJ: Assessment of anticoagulant treatment of venous thromboembolism. Ann Surg 170:559, 1969 20. Jorpes JE: Anticoagulant therapy in thrombosis. Surg Gynec Obstet 84:677, 1947 21. Lange KF, Schatz IJ: Prevention of recurrent pulmonary emboli with anticoagulants. Dis Chest 54:18, 1968 22. Basu D, GaUus A, Hirsh J, et al: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 287:324, 1972 23. Kernahan RJ, Todd C: Heparin therapy in thromboembolic disease. Lancet I:621, 1966

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