Lung (1990) Suppl:841-848

Modem Treatment of Pulmonary Embolism Craig M. Kessler Division of Hematology-Oncology, The George Washington University Medical Center, Washington, D.C., USA

Abstract. Pulmonary embolism is diagnosed over 100,000 times yearly in the United States and is the recognized primary cause of death in at least 10,000 cases. Thrombolytic therapy has been successful in reducing clot burden substantially; however, clinical data are lacking to indicate that thrombolytic therapy improves mortality rates in patients with pulmonary emboli or that the pharmacologic removal of clot will improve future quality of life. The use of thrombolytic agents has been limited by the potential for producing hemorrhagic complications. This paper discusses the pharmacology of numerous thrombolytic agents and their clinical use in research studies intended to determine the safest and most efficacious regimens. Recombinant t-PA infusions appear quite safe and produce very rapid lyses of pulmonary emboli. Innovative administration regimens of urokinase also appear promising. The availability of extremely safe and efficacious treatment regimens should allow for large epidemiologic studies to be conducted to determine whether thrombolytic therapy will improve the morbidity and mortality of pulmonary embolism. Key words: Pulmonary embolism--Thrombolytic therapy--Recombinant tissue plasminogen activator--Urokinase. The diagnosis of pulmonary embolism is responsible for over 100,000 hospital admissions yearly in the United States and is the recognized primary cause of death in at least 10,000 cases [1]. Numerous autopsy studies have indicated that pulmonary embolism is considerably underdiagnosed, perhaps because of its insidious occurrence and the difficulty associated with establishing its presence. There is abundant evidence that the immediate and subsequent intended Offprint requests to: Dr. C. M. Kessler, Division of Hematology-Oncology, The George Washington University Medical Center, 2150 Pennsylvania Avenue N.W., Washington, D.C. 20037, USA.

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institution of anticoagulation in patients with acute pulmonary emboli significantly reduces the associated morbidity and mortality [2, 3]; however, over the past decade, the fatality rates for pulmonary embolism have not diminished despite the introduction of never therapeutic modalities [4]. In fact, the use of thrombolytic therapy, which has been enthusiastically espoused by cardiologists to treat acute myocardial infarction, is rarely considered for the treatment of even massive acute pulmonary embolism despite the cautious endorsement for its more widespread use by the 1980 National Institutes of Health Consensus Conference [5]. This paper will discuss the results of clinical trials which have investigated the use of recombinant human tissue type plasminogen activator (rt-PA) and novel dosing regimens of urokinase in patients with acute pulmonary embolism and will suggest that improved safety and efficacy can be achieved when compared to various traditional therapeutic approaches. These recent observations may stimulate the use of thrombolytic agents and increase appreciation of their potential advantages in treatment of pulmonary emboli. There has also been substantial improvement in mechanical treatment modalities for the treatment and prophylaxis of recurrent pulmonary emboli in patients who are either resistant to anticoagulation or in whom anticoagulants are contraindicated. Of greatest importance is the recent introduction of a nonferromagnetic vena cava filter device which does not preclude the future use of diagnostic magnetic resonance imaging procedures. The therapeutic goals of interruption filters are necessarily narrow and their use is usually reserved for special high risk situations characterized by an unfavorable risk : benefit ratio for thrombolytic agents and anticoagulants. Thrombolytic therapy activates the fibrinolytic system in vivo through the pharmacologic conversion of the zymogen plasminogen to plasmin, the active enzyme (Fig. 1). Plasmin proteolyzes the fibrin clot and generates characteristic, cross-linked degradation products. Fibrin is not an exclusive substrate for plasmin; the nonspecific degradation of fibrinogen, Von Willebrand factor protein, and coagulation factors V and VIII by plasmin may exacerbate the hemorrhagic tendency of thrombolytic therapy. On the other hand, there is laboratory evidence suggesting that plasmin may induce platelet aggregation and possibly may contribute to the rethrombosis occasionally observed following the successful pharmacologic lysis of intracoronary thrombosis [6]. Plasmin is specifically and rapidly inhibited by complexing with alphaz-antiplasmin. The activation of fibrin-bound plasmfiaogen by thrombolytic agents minimizes the activation of freely circulating plasminogen, increases fibrinolytic efficacy, and subsequently reduces the hemorrhagic potential produced by the nonspecific proteolytic effects of plasmin. Relative fibrin-specific thrombolysis has been produced in human and animal models by the second generation thrombolytic agents, r-tpa [7-9] and recombinant single-chain urokinase-type plasmin0gen activator (pro-UK) [ 10-12], which interact with fibrin and/or fibrin-bound plasminogen at high affinity binding sites [13, I4]. In contrast, the first generation thrombolytic agents, streptokinase and urokinase, possess little fibrin specificity and their activation of free and fibrin bound plasminogen proceeds with no substrate specificity. Urokinase and tissue plasminogen activator exist as in

843

Modern Treatment of Pulmonary Embolism Protein C I thrombin tissue injury Xll

",,,,

Xlla

\

/,oac,::oa;o:o;;a,o,

Release of tissue 0tasminogen activator (tPA) from vascular endothelium

Plasma Plasminogen Activator

activated Protein C --Protein S

Plasminogen

l + ) U K , SK

J

Plasmin

fibrin clot

fibrin degradation products (including fibrin-specific D-dimers and B/3 1-42/B/3 15-42 peptides)

Fig. 1. As in the coagulation cascade, fibrinolysis may be divided into intrinsic and extrinsic systems. Activators intrinsic to plasma include thrombin and activated factor XII (Xlla) that activate plasma plasminogen activator. Activators extrinsic to plasma include stimuli that culminate in release of tissue plasminogen activator. ~2AP = alphaz-antiplasrnins; EACA = epsilon amino caproic acid; U K = urokinase; SK = streptokinase. (Reproduced with permission: The Basic Science of Vascular Surgery, Giordano JM, Trout HH, De Palma RG, eds. Mount Kisko, NY: Futura Publishing Co. Inc., 1988, Ch. 14, pp. 477).

vivo physiologic activators of the fibrinolytic mechanism. Urokinase and its inert zymogen pro-UK circulate in plasma and are attracted to sites of fibrin formation. Tissue plasminogen activator is synthesized, stored, and released from endothelial cells adjacent to thrombi to initiate fibrinolysis. The activities of tissue plasminogen activator and urokinase are modulated by the specific plasminogen activator inhibitor, PAI-1 (endothelial type plasminogen activator inhibitor) [15]. PAI-1, in turn, is inhibited by activated protein C complexed to protein S (Fig. 1), both of which are vitamin K dependent proteins synthesized by the liver. Proteins S and C also participate in the modulation of the coagulation cascade by inactivating activated factors V and VIII. Urokinase can also be inhibited through a heparin-dependent mechanism mediated by PAI-3, which is immunologically identical to the specific inhibitor of activated protein C (PCI) [16, 17]. The physiologic significance of plasminogen activation via the intrinsic coagulation pathway and factor XII (Fig. 1) remains to be elucidated. Interestingly, the first individual diagnosed with severe factor XII deficiency died following a pulmonary embolus. Tissue plasminogen activator (or rt-PA) and urokinase activate plasminogen by direct cleavage at the Arg 561 Vat 562 site. This process is significantly more efficient than with streptokinase, which activates fibrinolysis only after complexing with circulating plasminogen. The streptokinase-plasminogen com-

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Table 1. Exclusion criteria and major contraindications for rt-PA administration Significant internal bleeding within the previous 6 months Intracranial disease or intraspinal surgery within the past year Internal surgery or organ biopsy within 10 days Occult blood on stool examination Severe impairment of kidney and/or fiver function Severe uncontrolled arterial hypertension, left heart thrombus, subacute bacterial endocarditis, or diabetic hemorrhagic retinopathy Pregnancy or lactation Inability to tolerate or complete the initial diagnostic pulmonary angiographic procedure

plex subsequently cleaves residual free or fibrin-bound plasminogen to form plasmin. Clinical streptokinase resistance may, therefore, result from a severe deficiency of circulating plasminogen caused by thrombus consumption and is compounded by streptokinase-plasminogen complex formation. Recently, the pharmacologic manipulation of the streptokinase(human)-plasmin(ogen) activator complex has yielded an anisoylated derivative (APSAC) with a significantly extended active circulating half-life, enhanced protection from inhibitors, and, theoretically, increased fibrin specificity [18]. These properties are conducive to bolus infusion regimens which have been shown to be safe and effective in the treatment of coronary thrombosis [19, 20], pulmonary emboli, and deep venous thrombosis [21]. In collaboration with Dr. Samuel Goldhaber, Boston, Massachusetts, we have been evaluating the safety and efficacy of rt-PA (Activase, Genentech, S. San Francisco, CA) for the treatment of pulmonary emboli. Our initial open label study [22] examined the clot lysis in 47 patients with angiographically documented pulmonary emboli in a segmental or more proximal pulmonary artery and with symptoms of no more than 5 days duration. The exclusion criteria for this and subsequent trials are listed in Table 1 and include many of the major contraindications which should be considered before administering any thrombolytic agent or anticoagulant. Immediately following the peripheral venous infusion of rt-PA (25 rag/h) over 2 h, a repeat pulmonary angiogram was performed and if no significant clot lysis was evident an additional 40 mg rt-PA was administered (10 mg/h) over the next 4 h prior to a third angiogram. If substantial lysis occurred at the 2 h study point, no further thrombolytic therapy was used and continuous intravenous heparin anticoagulation was initiated without a preceding bolus dose at the physician's discretion. Evidence of thrombolysis was demonstrated by 44/47 patients; marked lysis was observed in 62%, moderate in 27%, and slight in 11%. Major hemorrhagic complications, occurring in 2 patients, consisted of mediastinal tamponade and bleeding from an occult pelvic tumor. Minor bleeding problems were seen most frequently at the groin catheterization sites and prompted premature termination of the intended rt-PA infusion dose in 7 patients. Nonspecific fibrinogenolysis was apparent with a 33% decrease in fibrinogen concentration from baseline values. The effect of rt-PA infusions on right ventricular function was examined in

Modem Treatment of Pulmonary Embolism rt-PA

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UK

Fig. 2. Angiographic lysis within 2 h of therapy (N = 45): rt-PA vs Urokinase. (Reproduced with permission from [9].)

a subset of this study population [23]. Thrombolytic treatment was associated with significant and rapid reversal of baseline right ventricular dilatation, tricuspid regurgitation, and right ventricular wall hypokinesis. These encouraging results prompted an extended multi-institutional randomized controlled trial to compare the safety and efficacy of rt-PA with a widely accepted and utilized urokinase regimen [24]. Patient entry criteria were similar to the initial study except that the symptoms of pulmonary embolism could have been present for up to I4 days and patients with previous pulmonary emboli were allowed to participate. In this trial, patients received either peripheral infusions of rt-PA 50 mg/h for 2 h or urokinase 4400 U/Kg as a bolus dose followed by 4400 U/Kg/h for 2 h. Pulmonary angiography was then repeated. If no significant clot lysis was observed in the urokinase recipients, additional urokinase 4400 U/Kg/h was administered for 22 h. rt-PA subjects received no further thrombolytic treatment after the 2 h angiogram, in contrast to the first study. All patients were evaluated with baseline and 24 h posttreatment lung scans. Of the 22 rt-PA treated patients, 18 (12%) had angiographic evidence of clot lysis at 2 h compared to the urokinase group in whom only 10/23 (48%) experienced improvement (Fig. 2) (p = 0.008). Moderate or marked clot lysis occurred much more frequently after rt-PA than with U K (p = 0.002) (Fig. 2) and a substantial 39% of urokinase recipients had no evidence of lysis at 2 h. Mean pulmonary artery pressures decreased following rt-PA (p = 0.28) but remained essentially unchanged after 2 h of urokinase. Nevertheless, there were no differences in the degree of improvement between the two treatment arms when the 24 h perfusion lung scans were analyzed. This suggests that both therapies might be equally effective in nonurgent clinical situations but that the increased rapidity of thrombolysis achieved by rt-PA could be especially suitable for critical and emergency situations with significant cardiopulmonary instability and large clot burden. This study revealed important differences in the safety profiles of these two thrombolytic regimens, which obviously will influence patient and physician preference and acceptance. Six patients experienced allergic reactions during urokinase infusions compared to 1 rt-PA patient who developed wheezing at the end of his treatment. Urokinase infusions were terminated prematurely in one patient with an allergic reaction and in 8 others because of intolerable bleeding complications. The majority of these problems occurred after 12 h of

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Table 2. Thrombolysis: new therapeutic strategies

Synergistic combination of activated protein C and UK or pro-UK Specific antifibrin antibody-rt-PA complexes for fibrin directed therapy Antiplatelet antibody-urokinase conjugates Chimeric proteins consisting of the functional domains of pro-UK (single chain urokinase-type plasminogen activator) (scu-PA) and rt-PA Chemical conjugates of scu-PA and monoclonal antifibrin antibody Targeting thrombolytics to thrombi by magnetic force Laser ablation of thrombolytic-resistant thrombi Thrombolytics used concurrently with antiplatelet agents, i.e., Prostaglandin E~, monoclonal antibodies directed against platelet membrane glycoproteins IIb/IIIa, disintegrin viper venoms

urokinase administration. All 22 rt-PA patients received their total intended dose of medication with no major complications. Minor bleeding, particularly at venipuncture or catheterization sites, occurred in both groups with 11 urokinase patients manifesting hematocrit decrements of greater than 10% versus 4 rt-PA subjects. The average fibrinogen concentrations decreased 45% from baseline 2 after 2 h of rt-PA versus 39% in the urokinase group (p = 0.26). The mean fibrinogens determined 24 h after the initiation of therapy remained equally depressed at levels comparable to the 2 h values. Therefore, despite the fact that there was no difference in efficacy between these two regimens, rt-PA appeared to have a greater safety margin. Our current trial randomizes patients with angiographically documented pulmonary emboli to receive either the same rt-PA regimen as above or a high dose urokinase regimen administered peripherally over a short period (.1 million units IV over 10 min followed by 2 million units over the next 110 min). Because our previous study indicated that the vast majority of bleeding complications occurred fairly late into therapy, this new dosing schedule may increase the safety margin for urokinase, as it has in European coronary reperfusion studies [25]. Statistical analysis of the 2 h pulmonary angiographic endpoints for the first 28 patients has not yet revealed any statistical difference between the treatment arms. Safety and efficacy data continue to accrue with ongoing patient recruitment; however, the preliminary results of other high dose, rapidly administered thrombolytic treatment regimens for pulmonary emboli show definite promise in improving safety and efficacy [26, 27] and provide the impetus to continue to explore innovative strategies to achieve the safest, most efficacious thrombolytic treatment regimens (Table 2). Simultaneously, efforts must be made to assess the tangible benefits of thrombolytic therapy for pulmonary emboli, i.e., prevention of pulmonary hypertension, elimination of recurrent thromboembolism, improved pulmonary function and exercise tolerance, and reduced mortality, as well as the intangible advantages, i.e., improved "quality of life." Large epidemiologic studies will be required to answer some of these questions, but they may remain unanswered until and unless extremely safe and efficacious treatment regimens

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are available and physician confidence levels are elevated sufficiently to employ them in clinical situations.

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20. Timmis AD, Griffin B, Crick JCP, Sowton E (1987) Anisoylated plasminogen streptokinase activator complex in acute myocardial infarction: a placebo-controlled arteriographic coronary recanalization study. J Am Coil Cardiol 10:205-210 21. Kessler CM, 1989, unpublished data 22. Goldhaber SZ, Vaughan DE, Markis JE, Selwyn AP, Myerovitz MF, Loscalzo J, Kessler CM, et al (1986) Acute pulmonary embolism treated with tissue plasminogen activator. Lancet ii:886-889 23. Come PC, Kim D, Parker JA, Goldhaber SZ, Braunwald E, Markis JE (1987) Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with intravenous plasminogen activator. J Am Coil Cardiol 10:971-978 24. Goldhaber SZ, Kessler CM, Heit J, Markis J, et al (1988) Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet ii:293-298 25. Neuhaus KL, Tebbe U, Gottwik M, Weber MAJ, Feuerer W, Niederer W, et al (1988) Intravenous recombinant tissue plasminogen activator and urokinase in acute myocardial infarction: results of the German Activator Urokinase Study. J Am CoU Cardiol 12:581-587 26. Shiffman F, Ducas J, Hollett P, Israels E, Greenberg D, Cooke R, et al (1988) Treatment of canine embolic pulmonary hypertension with recombinant tissue ptasminogen activator: efficacy of dosing regimes. Circulation 78:214-220 27. Levine MN, Weitz J, Turpie AGG, Andrew M, Cruickshank M, Hirsh J (1989) A new dosage regimen of recombinant tissue plasminogen activator in patients with thromboembolic disease. In: Goldhaber SZ, ed. Tissue plasminogen activator in acute pulmonary embolism. Chest 95(Suppl.):282S-289S