7 Thrombolytic therapy for venous thrombosis and pulmonary embolism

7 Thrombolytic therapy for venous thrombosis and pulmonary embolism A . S. G A L L U S

MB BS, FRACP, FRCPA, FRCP(C)

Haematologist and Director SouthPath SA, Flinders Medical Centre and Repatriation General Hospital, Adelaide, South Australia, Australia

Streptokinase, urokinase, tissue plasminogen activator and similar drugs can all cause lysis of venous thrombi and pulmonary emboli, but there is small evidence that accelerated lysis achieves a significantly better clinical outcome, on average, in the shorter or longer term, than heparin alone. Thrombolytic therapy for deep leg vein throfnbosis aims to restore flow and to preserve venous valves, and so to prevent chronic post-phlebitic disability, but no trial has convincingly demonstrated that the last can be achieved in more than a few patients. Only a small minority of people with extensive proximal thrombosis develop disabling post-phlebitic venous insufficiency, and there are no good clinical predictors of this outcome. As a result, any widespread use of thrombolytics would bring an immediate risk of major bleeding to many people who will never be destined to develop a clinically important problem. Thrombolytic therapy after venous thrombosis should be avoided except, perhaps, in a few carefully selected patients with severe obstruction. The case for using thrombolytics after recent pulmonary embolism is strongest in the limited number of patients with ongoing hypoxia, respiratory distress, pulmonary hypertension and right heart failure, because thrombolytic thei~py often achieves an impressive and almost immediate clinical benefit in this clinical setting. Whether early relief from pulmonary artery obstruction translates into longer-term advantage over heparin remains uncertain, however, because no comparative trial has ever shown these drugs to reduce mortality after pulmonary embolism. In all cases, both the physician and the patient must balance the certainty of an immediate bleeding risk against the uncertainty of a better than marginal real benefit. Key words: thrombolysis; venous thrombosis; pulmonary embolism; bleeding risk; efficacy; surrogate endpoint; streptokinase; urokinase; tissue plasminogen activator. T h r o m b o l y t i c treatment for venous t h r o m b o e m b o l i s m ( V T E ) has two main aims: to prevent disabling late post-phlebitic disability after venous thrombosis (VT), and to reduce early morbidity or mortality after p u l m o n a r y e m b o l i s m (PE) t h r o u g h rapid relief f r o m p u l m o n a r y artery obstruction. A g a i n s t these potential benefits, physicians and their patients m u s t w e i g h the high risk o f p r o v o k i n g m a j o r bleeding. Baiili~re k Clinical Haematology-Vol. l 1, No. 3, September I998 ISBN 0-7020-2461-9 0950-3536/98/030663 + 11 $12.00/00

663 Copyright © 1998, by Bailli6re Tindall All fights of reproduction in any form reserved

664

A.S. GALLUS

When examining the evidence for effectiveness of thrombolytic drugs in VTE, it is important to discriminate between clinically important outcomes such as disability or death and surrogates such as the extent of residual thrombosis measured by venography. No benefit can be expected if thrombus remains, but partly or wholly removing a thrombus is no guarantee of clinical benefit. For instance, deep vein thrombi may not be dissol.ved soon enough to prevent the valve damage largely responsible for venous insufficiency, while pulmonary artery occlusion resolves over time with anticoagulant therapy alone. In addition, it is possible that reporting bias may have coloured the results of many early venogram endpoint evaluations of thrombolytic drugs in deep vein thrombosis (DVT), overestimating the treatment benefit, because venography is subject to significant interobserver variation (Bounameux et al, 1992b).

THROMBOLYTIC DRUG REGIMENS Although many approaches have been used, including various combinations of thrombolytic drugs with plasminogen, plasmin and each other, there is most experience with streptokinase (SK), urokinase (UK) and tissue plasminogen activator (rt-PA). To dissolve deep vein thrombi, thrombolytic drugs have generally been given for 3-5 days, usually by continuous intravenous infusion, and starting within 3-5 days of onset, although repeated intravenous bolus injections have also been explored. For PE, the drugs are given as a shorterterm intravenous infusion or by intermittent bolus injection (Table 1). Local administration, through a cannula placed close to or within the thrombus or embolism, has also been evaluated. Table 1. Generally accepted thrombolytic treatment regimens for deep vein thrombosis or pulmonary embolism,

Drug

Regimen

Duration

SK UK rt-PA

250 000 i.v., then 100 000 U/hour 4400 IU/kg Lv., then 4400 IUlkg per hour 100 mg

3-5 days (DVT) or 24 hours (PE) 1-2 days (DVT) or t2 hours (PE) 2 hour infusion for PE

Adapted from Hyers et al (1995, Chest 108: 335S-351S).

THROMBOLYTIC THERAPY FOR DEEP LEG VEIN THROMBOSIS Evidence for thrombolytic efficacy All thrombolytic drugs tested to date are capable of inducing some degree of lysis in recent DVT. The evidence is most extensive for SK, UK and rt-PA and comes mainly from trials that used venography to measure the extent of thrombosis resolution. The few small randomized comparisons

THROMBOLYTIC THERAPY

665

with heparin consistently demonstrate more lysis after thrombolytic therapy (Table 2). Because most patients treated with thrombolytic therapy are left with some residual DVT, and as no trial shows a clear superiority of one thrombolytic drug over others, there have been many attempts to improve efficacy by adjusting the treatment regimen. Ultrahigh-dose SK may increase the extent of lysis and the proportion of completely cleared venous segments (Heinrich and Heinrich, 1996), but local infusion of rt-PA or ultrahigh-dose SK into a foot vein is no more effective than systemic administration (Schwieder et al, 1995; Martin et al, 1996). Repeated bolus doses of UK are no more effective than heparin (Goldhaber et al, 1996). Attention has focused lately on interventional radiology: catheterdirected infusion of thrombolytic drugs into the venous thrombus, combined in some cases with thrombectomy or stenting (Comerota et al, 1994; Semba and Dake, 1994; Bjarnason et al, 1997; Verhaeghe et al, 1997). These recent approaches still lack information about long-term follow-up or functional outcomes. Despite good evidence of partial or complete thrombolysis in a fair proportion of treated patients, it remains difficult to attribute a level of clinical significance to these observations, partly because the results of treatment are often expressed as a percentage overall reduction in thrombus burden without a detailed analysis of anatomical site or extent, but largely because of questions these studies were not designed to answer. In order to prevent post-phlebitic disability, how much lysis is enough? Must lysis be complete or is partial thrombolysis better than none? Are some parts of the venous tree more critical than others? How soon after the onset of DVT must lysis happen if critically placed venous valves are to retain their function? Attempts to correlate venographic or ultrasound results with the presence and severity of post-phlebitic syndrome have given conflicting signals. In some reports, the best predictor is the initial extent of DVT: the greater this is, the higher the likelihood of late discomfort (55% 13 years after calf, popliteal, femoral and iliac VT, compared with 4% after isolated calf VT) (Eichlisberger et al 1994a). Others find that the site of thrombosis is more important than its extent, with popliteal and tibial vein involvement the most critical element (Monreal et al, 1993; Johnson et al, 1996). Yet others emphasize the importance of reflux, or of reflux plus obstruction, regardless of site or extent (Milne et al, 1994; Franzeck et al, 1997). Several retrospective case series have sought to identify clinical predictors of treatment success or failure as judged by venography. An early report of 145 treated cases found SK to be more effective in proximal than distal VT and for non-occlusive thrombi and that thrombi were readily lysed until 15 or more days after presentation although the best results were obtained in patients treated within 24 hours (Duckert et al, 1975). In a more recent survey of 174 patients treated for proximal DVT where SK was used together with a temporary caval filter, results were best with partially occluding proximal venous thrombi (60% complete lysis), while few wholly occluding thrombi were totally removed (14%) and popliteal

Gormsen and Laursen (1967); Browse et al (1968); Kakkar et al (1969); Porter et al (1975); ROsch et al (1976); Elliot et al (1979) Duckert et al (1975)*

van de Loo et al (1983)t

Bounameaux et al (1992a)~

SK

UK

rt-PA

1 0

1 0 0 2 1 0

10 high UK 10SK 14 low rt-PA 15 higher rt-PA 36 rt-PA 17 rt-PA + heparin 12 heparin

42% 0%

93 SK 42 heparin 11 low UK

30% 5%

Complete thrombolysis

93 SK 101 heparin

Patients

6 8 8 4 0

5

7

4

25% 10%

33% 17%

Partial thrombotysis

8 7 26 12 12

4

4

5

32% 88%

37% 78%

Minimal or no thrombolysis

* Non-randomized comparison. Heparin-treated patients were concurrent with SK-treated patients but were judged unsuitable for SK. t UK 4400 U/kg, then 2200 U/kg per hour for 12 hours (high) or 1100 U/kg per hour for 12 hours (low), each alternating for 72 hours with 12 hours of heparin. ?- Low rt-PA, 5 mg, then 0 2 5 mg/kg in 24 hours + hepatin; higher rt-PA, 5 mg, then 0.50 mg/kg in 24 hours + heparin.

Goldhaber et al (1990)

Reference

Drug

Table 2. The extent of lysis demonstrated by vertography repeated after 3 - 5 days of treatment for extensive recent DVT in randomized and other comparisons of thrombolytic drugs with heparin where results were repol~ed as partial, complete or no thrombolysis.

r--

G-,

TH R O M B O L Y T I C T H E R A P Y

667

thrombi were more resistant to lysis than proximal clots (Th6ry et al, 1992). Meyerovitz et al (1992) made similar observations with rt-PA. If popliteal VT is critical to the genesis of post-phlebific disability (Monreal et al, 1993; Johnson et al, 1996), then its relative resistance to thrombolytic therapy is a cause for concern.

Results of venography done late after thrombolytic therapy for deep vein thrombosis In general, venography done some months to years after presentation finds that SK increases the likelihood that veins are patent and valves are preserved (R6sch et al, 1976; Watz and Savidge, 1979; Arnesen et al, 1982).

Evidence for clinical efficacy A complete clinical evaluation of thrombolytic therapy requires a long follow-up because it takes some years for post-phlebitic venous insufficiency to become fully expressed. None of the clinical endpoint comparisons of thrombolytic treatment with heparin is of a sufficient size to allow firm judgement, so that most of the relevant information comes fi'om cohort studies that record post-phlebitic symptoms among patients with or without acute clearance of DVT by initial treatment. Some follow-up studies suggest that patients treated with SK after extensive proximal DVT are more likely to be left with clinically normal legs than those given heparin (Arnesen et al, 1982) and that patients with fully patent veins after SK do best (Th6ry et al, 1992). Others find that few SK-treated patients have normal venography after 2-3 years and that most have some leg symptoms at that time (Albrechtsson et al, 1981). As a result, it is not yet possible to draw clear-cut conclusions about the extent of long-term clinical benefit attributable to thrombolytic therapy for DVT, although it remains likely that at least the minority of patients with early and complete clearance of DVT (Table 2) gains real benefit. There is no evidence to suggest that thrombolysis reduces the likelihood of recurrent VTE during or after subsequent anticoagulant treatment.

THROMBOLYTIC THERAPY FOR PULMONARY EMBOLISM Evidence for thrombolytic efficacy All thrombolytic drugs dramatically accelerate the natural rate of lysis following PE. This has been documented with pulmonary angiography and/or lung scanning in many trials for SK (Miller et al, 1971; Tibbutt et al, 1974; Ly et al, 1978), UK in standard dose (Urokinase Pulmonary Embolism Trial Study Group, 1970) or reduced dosage (Molina et al, 1992; Gonzalez-Juanatey et al, 1992), short infusions of rt-PA (Dalla-Volta et al, 1992; Goldhaber et al, 1993), bolus injections of rt-PA (Levine et al, 1990) and other agents.

668

A.s. GALLUS

Despite this early and often dramatic improvement in lung perfusion, lung scanning done 7-30 days after presentation finds that perfusion is now similar regardless of whether patients were initially treated with SK, UK, rt-PA or heparin alone (Urokinase Pulmonary Embolism Trial Study Group, 1970; Levine et al, 1990; Dalla-Volta et al, 1992). Comparisons of thrombolytic drugs with each other show substantially similar results. The extent of clot resolution achieved with UK is slightly greater after 24 hours than after 12 hours of treatment, while 24 hours of UK may be marginally superior to 24 hours of SK (Bell et al, 1974). Bolus rt-Pa may achieve more rapid lysis of pulmonary emboli than UK infusion, as measured by a faster reduction in mean pulmonary artery pressure, although lung scan results are identical after 24 hours (Goldhaber et al, 1988; Meyer et al, 1992). Results with bolus rt-PA and bolus UK are similar (Goldhaber et al, 1992), as are the results of rt-PA given systemically or into the pulmonary artery (Verstraete et al, 1988). A novel approach in massive PE combines thrombolytic therapy with mechanical clot fragmentation using an angiographic catheter (Essop et al, 1992). Evidence for clinical efficacy The indirect evidence for clinical benefit is that early reperfusion diminishes pulmonary resistance and improves fight ventricle function (Bell et al, 1974; Dalla-Volta et al, 1992; Meyer et al, 1992; Goldhaber et al, 1993) and is followed by improved long-term lung capillary perfusion and diffusion (Sharma et al, 1980). Others report no long-term benefit as measured by right heart catheter data or ventilatory function (Lund et al, 1987). More direct evidence is lacking. Most patients with PE who survive long enough to be recruited for treatment trials do well with heparin therapy alone, because treatment for submassive PE with standard heparin or lowmolecular-weight heparin is followed by death, recurrence or major bleeding in no more than 3% of patients (Columbus investigators, 1997; Simonneau et al, 1997). It is then hardly surprising that randomized comparison with heparin alone can find no further decrease in mortality after SK, UK or rt-PA. It remains probable that thrombolytic therapy does bring immediate clinical benefit to some people with massive PE and especially those with ongoing cardiorespiratory failure where a short course of treatment can bring dramatic haemodynamic improvement and symptom relief. BLEEDING AND OTHER RISKS The bleeding risk from thrombolytic therapy is high, three-fold greater with SK than with heparin alone (Goldhaber et al, 1984), and major bleeding has been reported in up to 30% of patients treated with SK, UK or rt-PA for DVT or PE (Levine et al, 1995).

THROM BOLYTIC THERAPY

669

In DVT, this is probably due to the need for a prolonged (3-5 days) infusion, tn PE, where reperfusion is more rapid, bleeding mostly complicates vascular access sites and can be minimized by avoiding pulmonary angiography. There is, however, an unavoidable risk of intracranial bleeding (Meissner et al, 1987; Levine et al, 1995) and no strong evidence that any drug is safer than another (Levine et al, t995). Because of the bleeding risk, it is vital that candidates for thrombolytic treatment are carefully screened. Only a small percentage (7-22%) of patients with extensive DVT have no contraindications (Brown and Goldhaber, 1989; Markel et al, 1992), although patients with PE are more likely to be acceptable (Terrin et al, 1989). Bleeding during anticoagulant therapy is most strongly associated with recent trauma or surgery, performance status, body surface area, comorbidity, older age and malignancy (Nieuwenhuis et al, 1991; Landefeld and Beyth, 1993; Wester et al, 1996). There are anecdotal reports of massive embolism coincident with thrombolytic therapy for DVT (e.g. Hill, 1991) but the incidence of 'breakaway' emboli is no more frequent after SK than heparin (Rogers and Lutcher, 1991). BENEFIT VERSUS RISK

Few patients, when asked to balance a major early bleeding risk that may reach 30% against an uncertain benefit, either immediate or long term, will choose thrombolytic therapy over heparin or a low-molecular-weight heparin, and this strong clinical impression is backed by formal decision analysis (O'Meara et al, 1994). Justifying thrombolytic treatment to individuals with DVT is especially difficult, because the onset and ultimate severity of post-phlebitic disability are hard to predict at the time of presentation, and much of the damage can be minimized by conservative management with compression stockings, which decrease the likelihood of severe symptomatology after 5 years from 23% to 11% (Brandies et al, 1997). In recent studies, the proportion of heparin-treated patients with disabling disability late after DVT has been as low as 2 - 4 % and few have leg ulcers (Eichlisberger et al, 1994b; Beyth et al, 1995; Janssen et al, 1997). It is therefore most important, except perhaps when thromboembolism is massive and life threatening, that patients fully participate in the decisionmaking process. CONCLUSION The temptation to use thrombolytic therapy for extensive recent proximal DVT or major PE should usually be resisted. The bleeding risk is high and there is, on average, no clear-cut reduction in post-phlebitic venous insufficiency or important long-term gain of lung or cardiac function. There

670

A . S . GALLUS

is, however, a strong clinical impression of benefit in massive acute embolism with ongoing hypoxia, pulmonary hypertension and right heart failure. A weaker although still reasonable case can also be made for attempting thrombolysis in some people with seriously symptomatic recent extensive proximal DVT, provided that the bleeding risk is low and the patient agrees to treatment after a frank discussion of the evidence concerning risks and benefits. While no drug or drug regimen is clearly more effective or safer than others, bolus rt-PA for major PE has the advantage of simplicity.

REFERENCES Albrechtsson U, Anderson J, Einarsson E et al (1981) Streptokinase treatment of deep venous thrombosis and the postthrombotic syndrome. Follow-up evaluation of venous function. Archives (~'Surgery 116: 33-37. Arnesen H, Hoiseth A & Ly B (1982) Streptokinase or heparin in the treatment of deep vein thrombosis. Follow-up results of a prospective study. Acta Medica Scandinavica 211: 65-68. *Bell WR, Simon TL, Stengle JM & Sherry S (1974) The urokinase-streptokinase pulmonary embolism trials (phase II) results. Circulation 50" I070-107I. *Beyth R J, Cohen AM & Landefeld CS (1995) Long-term outcomes of deep-vein thrombosis. Archives of Internal Medicine 155: 1031-1037. Bjarnason H, Kruse JR, Asinger DA et ol (1997) lliofemoral deep venous thrombosis: safety and efficay outcome during 5 years of catheter-directed thrombolytic therapy. Journal of Vascular and Interventional Radiology 8:405-418. Bounameux H, Banga JD, Bluhmki E et al (1992a) Double-blind, randomized comparison of systemic continuous infusion of 0.25 versus 0.50 mg/kg/h of alteplase over 3 to 7 days for treatment of deep venous thrombosis in heparinized patients: results of the European Thrombolysis with rt-PA in Venous Thrombosis (ETTT) Trial. Thrombosis and Haemostasis 67: 306-309. Bounameux H, Prins TR, Schmitt H-E et al (1992b) Venography of the lower limbs. Pitfalls of the diagnostic standard. Investigative Radiology 27:1009-1011. *Brandjes DPM, Btiller HR, Heijboer H e t al (1997) Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 349: 759-762. Brown WD & Goldhaber SZ (1989) How to select patients with deep vein thrombosis for tPA therapy. Chest 95: 276S-278S. Browse NL, Lea Thomas M & Pim HP (1968) Streptokinase and deep vein thrombosis. British Medical Journal 3: 717-720. Columbus investigators (1997) Low-molecular weight heparin in the treatment of patients with venous thromboembolism. New England Journal of Medicine 337: 657-662. Comerota AJ, Aldridge SC, Cohen G et al (1994) A strategy of aggressive regional therapy tbr acute ilofemoral venous thrombosis with contemporary venous thrombectomy or catheter-directed thrombolysis. Journal of Vascular Surgery 20: 244-254. Dalla-'vblta S, Palla A, Santolicandro R et al (1992) PIMS 2: 01teplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen Activator Italian Multicenter Study 2. Journal of the American College of Cardiolagy 20: 520-526. Duckert F, Mtiller G, Nyman D et al (1975) treatment of deep vein thrombosis with streptokinase. British Medical Journal 1:479-48 I. Eichlisberger R, Frauchiger B, Widmer LK et al (1994a) Late sequelae of deep venous thrombosis: a 13 year follow-up of 223 patients. Vasa 23: 234-243. Eichlisberger R, Widmer MT, Frauchiger B et al (1994b) The incidence of post-thrombotic syndrome. Wiener Medizinische Wochenschrifl 144:192-195. Elliot MS, Immelman EJ, Feffery P et al (1979) A comparative randomised trial of heparin versus streptokinase in the treatment of acute proximal venous thrombosis: an interim report of a prospective trial. British Journal of Surgery 66: 838-843.

THROMBOLYTIC THERAPY

671

Essop MR, Middlemost S, Skoularigis J & Sareli P (1992) Simultaneous mechanical clot fragmentation and pharmacologic thrombolysis in acute massive pulmonary embolism. American Journal of Cardiology 69: 427-430. Franzeck UK, Schalch I & Bollinger A (1997) On the relationship between changes in the deep veins evaluated by duplex sonography and the postthrombotic syndrome 12 years after deep vein thrombosis, Thrombosis and Haemostasis 77:1109-I 112. *Goldhaber SZ, Bufing JE, Lipnick RJ & Hennekens CH (J 984) Pooled analysis of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis. American Journal of Medicine 76- 393-397. Goldhaber SZ, Kessler CM, Heit J et al (1988) Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 2: 293-298. Goldhaber SZ, Meyerovitz MF, Green D et al (1990) Randomized controlled trial of tissue plasminogen activator in proximal deep venous thrombosis. American Journal of Medicine 88: 235-240. Goldhaber SZ, Kessler CM, Heir JA et al (1992) Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial. Jourmd of the American College of Cardiology 20: 24-30. Goldhaber SZ, Haire WD, Feldstein ML et al (1993) Alteplase versus heparin in acute massive pulmonary embolism: a randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 341:507-511. Goldhaber SZ, Hirsch DR, MacDougall RC et al (1996) Bolus recombinant urokinase versus heparin in deep venous thrombosis: a randomized controlled trial. American Heart Journal 132: 314-318. Gonzalez-Juanatey JR, Valdes L, Amaro A et al (1992) Treatment of massive pulmonary thromboembolism with low intrapulmonary doses of urokinase, Short-term angiographic and haemodynamic evolution. Chest 102:341-346. Gormsen J & Laursen B (1967) Treatment of acute phlebothrombosis with streptase. Aeta Medica Scandinavica 181: 373-383. Heinrich F & Heinrich U (1996) Results of the North Baden Venous Lysis--NBVL--Study. Prospective phlebographically controlled randomized multicenter evaluation of ultra high versus conventional dose streptokinase in acute thrombosis of the leg and pelvis veins. Medizinische Klinik 91: 1-13. Hill LN (1991) Streptokinase therapy and breakaway pulmonary emboli. American Journal of Medicine 90:411-412. *Hyers TM, Hull RD & Weg JG (1995) Antithrombotic therapy for venous thromboembolic disease. Chest 108:335S-351S. Janssen MC, Haenen JH, van Asten WN et al (1997) Clinical and haemodynamic sequelae of deep venous thrombosis: retrospective evaluation after 7-13 years. Clinical Science 93: 7-12. Johnson BF, Manzo RA, Bergelin RO & Strandness DE Jr (1996) The site of residual abnormalities in the leg veins in long-term follow-up after deep vein thrombosis and their relationship to the development of the post-thrombotic syndrome. International Angiology 15: 14-19. Kakkar VV, Flanc C, Howe CT et al (1969) Treatment of deep vein thrombosis. A trial of heparin, streptokinase and arvin. British Medical Journal 1: 806-810. *Landefeld CS & Beyth RJ (1993) Anticoagulant-related bleeding: clinical epidemiotogy, prediction, and prevention. American Journal of Medicine 95: 315-328. Levine M, Hirsh J, Weitz J e t al (1990) A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest 98: 1473 - 1479. *Levine MN, Goldhaber SZ, Gore JM et al (1995) Hemorrhagic complications of thrombolytic therapy in the treatment of myocardial infarction and venous thromboembolism. Chest 108:291 S-301S. van de Loo JCV~; Kriessman A, Trubestein G e t al (t983) Controlled multicenter pilot study of urokinase-heparin and streptokin~se in deep vein thrombosis, Thtwmbosis and Haemostasis 50: 660-663. Ltmd O, Niel~n TT, Ronne K & Schifter S (t987) Pulmonary embolism: Iong-lerm follow-up after treatment with full-dose heparin, streptokinase or embolectomy. Acta Medica Seandinavica 221: 61-71. Ly 13, Arnesen H, Eie H & Hol R (1978) A controlled clinical trial of streptokinase and heparin in the treatment of major puhnonary embolism. Acre Medica Scandinavica 203: 465-470.

672

A . S . GALLUS

Markel A, Manzo RA & Strandness DE (1992) The potential role of thrombolytic therapy in venous thrombosis. Archives of Internal Medicine 152: 1265-1267. Martin M, Heimig T, Fiebach BJ & Riedel C (1996) Fibrinolytic treatment with ultra-high streptokinase infusion via the dorsalis pedis vein offers no advanlage over systemic infusion via the brachial vein in patients with deep vein thrombosis of the leg. Vasa 25: 275-278. Meissner AJ, Misiak A, Ziemski JM et al (1987) Hazards of thrombolytic therapy in deep vein thrombosis. British Journal of Surgery 74:991-993. Meyer G, Sors H, Charbonnier Bet al (1992) Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. Journal of the American College of Cardiology 19: 239-245. Meyerovitz M, Polak JF & Goldhaber SZ (1992) Short-term response to thrombolytic therapy in deep venous thrombosis: predictive value of venographic appearance. Radiology 184: 345-348. Miller GAH, Sutton GC, Kerr IH et al (1971) Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. British Medical Journal 2:681-684. Mitne AA, Stonebridge PA, Bradbnry AW & Ruckley CV (1994) Venous /'unction and clinical outcome following deep vein thrombosis. British Journal of Surge~y 81: 847-849. Molina E, Hunter W, Yedlicka JW & Cerra FB (1992) Thrombolytic therapy for postoperative pulmonary embolism. American Journal of Surgery 163: 375-380. Monreal M, Martorell A, Callejas JM et al (1993) Venographic assessment of deep vein thrombosis and risk of developing post-thrombotic syndrome: a prospective study. Journal of Internal Medicine 233: 233-238. Nieuwenhuis IlK, Albada J, Banga JD & Sixma JJ (1991) Identification of risk factors for bleeding during treatment of acute venous thromboembolism with heparin or low molecular weight heparin. Blood 78: 2337-2343. *O'Meara JJ, McNutt RA, Evans AT et al (1994) A decision analysis of streptokinase plus heparin as compared with heparin alone for deep-vein thrombosis. New England Journal of Medicine 330: 1864-1869. Porter JM, Seaman AJ, Common HH et al (1975) Comparison of heparin and streptokinase in the treatment of venous thrombosis. American Surgeon 41:511-519. Rogers LQ & Lutcher GL (1994) Streptokinase therapy and breakaway pulmonary emboli. American Journal of Medicine 90: 412-413. R6sch J, Dotter CT, Seaman AJ et al (1976) Healing of deep venous thrombosis: venographic findings in a randomized study comparing streptokinase and heparin. American Journal of Roentgenology 127: 553-558. Schwieder G, Grimm W, Siemens HJ et al (1995) Intermittent regional therapy with rt-PA is not superior to systemic thrombolysis in deep vein thrombosis (DVT)--a German nmlticentre trial. Thrombosis and Haemostasis 74: 1240-1243. Semba CP & Dake MD (1994) lliofemoral deep venous thrombosis: aggressive therapy with catheterdirected thrombolysis. Radiology 191: 487-494. Sharma GVRK, Burleson VA & Sasahara AA (1980) Effect of thrombolytic therapy on pulmonarycapillary blood volume in patients with pulmonary embolism. New England Journal of Medicine 303: 842-845. Simonneau G, Sors H, Charbonnier B et al (1997) A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. New England Journal of Medicine 337: 663-669. Terrin M, Goldhaber SZ, Thomson B & the TIPE investigators (1989) Selection of patients with acute pulmonary embolism for thrombolytic therapy. Chest 95: 279S-281S. *Thtry C, Bauchart J J, Lesenne M e t al (1992) Predictive factors of efectiveness of streptokinase in deep venous thrombosis. American Journal of Cardiology 69:117-122. *Tibbutt DA, Davies JA, Anderson JA et al (1974) Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. British Medical Joarnal 1: 343-347. Urokinase Pulmonary Embolism Trial Study Group (1970) Urokinase pulmonary embolism trial. Phase 1 results. Journal of the American Medical Association 214:2163-2172. Verhaeghe R, Stockx L, Lacroix H et al (1997) Catheter-directed lysis of iliofemoral vein thrombosis with use of rt-PA. European Radiology 7: 996-1001. Verstraete M, Miller GAH, Bounameux H et al (1988) Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of massive pulmonary embolism. Circulation 77: 353-360.

TH ROM BOLYTIC THERAPY

673

Watz R & Savidge GF (1979) Rapid thrombolysis and preservation of valvular venous function in high deep vein thrombosis. Acta Medica Scandinavica 205: 293-298, Wester J J, de Valk HW, Nieuwenhuis HK et al (1996) Risk factors for bleeding during treatment of acute venous thromboembolism. Thrombosis and Haemostasis 76: 682-688.