Fibrinolytic

Therapy for Venous Thrombosis Charles W. Francis and Victor J. Marder

T

HE HIGH INCIDENCE and serious consequences of deep vein thrombosis (DVT) make it a major health problem in the United States. It contributes significantly to the morbidity of the chronically ill or bedridden, but also affects otherwise healthy individuals, particularly at times of increased risk such as during pregnancy or following surgery or trauma. DVT is also the precursor of pulmonary thromboembolism that results in 50,000 to 100,000 deaths per year and is a contributing cause of death of chronically ill and debilitated patients.‘,2 Treatment of DVT often requires several months of oral anticoagulation, which in turn requires frequent laboratory monitoring and results in bleeding complications in 5% to 10% of patients.3 DVT also may result in permanent vein damage and venous insufficiency manifested as chronic leg swelling, pain, and ulcerations that affect up to 500,000 individuals.‘,’ Treatment goals and strategies must be evaluated by their ability to successfully modify the short- and long-term consequences of DVT. Initially, relief of symptoms and prevention of pulmonary embolism are needed, whereas longterm goals include prevention of recurrent DVT and development of the postphlebitic syndrome. These goals should be accomplished with a minimum of treatment-related complications. Currently, acute DVT frequently is managed with bed rest, leg elevation, and intravenous (IV) heparin anticoagulation followed by a longer period of several months of out-patient oral anticoagulation. This strategy meets several of the treatment goals including initial relief of symptoms and prevention of pulmonary embolism and recurrent DVT. Unfortunately, anticoagulation does not accelerate the slow pace of clot dissolution and permanent valve damage, vein scarring, and development of collaterals that often lead to manifestations of the postphlebitic syndrome. In this setting, fibrinolytic therapy is an attractive alternative, offering the potential for rapid clot dissolution needed to preserve normal vein function and avoid long-term venous insufficiency. Rapid advances in fibrinolytic therapy including elucidation of fundamental biochemical Progressin

Cardiovascular

Diseases,

Vol XXXIV,

No 3 (November/December),

mechanisms, development of new agents, and much wider application for arterial thrombosis, particularly in the setting of acute myocardial infarction have been seen in recent years. However, despite these advances, the impact on treatment of DVT has been limited. The foundations for adoption of fibrinolytic therapy for myocardial infarction include the ability to rapidly lyse thrombus, induce coronary artery reperfusion, relieve ischemia, improve ventricular function, and reduce mortality. These considerations do not apply to DVT in which ischemic necrosis is not a significant issue, a much larger thrombus must be dissolved, and an important goal is to prevent symptoms that may develop years later. Thus, despite increasing familiarity with fibrinolytic therapy and recommendations from a National Institute of Health (NIH) consensus development conference,4 fibrinolytic therapy has not been widely adopted for treatment of DVT. The reasons most frequently cited include potential bleeding risks and lack of convincing evidence that acute symptomatology, pulmonary embolism, or chronic venous insufficiency can be prevented. The purpose of this review will be to evaluate the current status of fibrinolytic therapy for DVT of the leg and arm, primarily evaluating early radiographic and late functional outcomes and bleeding complications. DRUGS AND TREATMENT

REGIMENS

In the overall treatment plan for DVT, fibrinolytic agents are appropriate only in the initial phase of therapy, administered to rapidly dissolve the maximum amount of thrombus and to restore vascular patency and function. FollowFrom the Hematology Unit, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY Supported in part by Grant No. HL-30616fiom the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to Charles W. Francis, MD, Hematology Unit, PO Box 610, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642. Copyright 0 1991 by W.B. Saunders Company 0033.0620/91/3403-0003$5.0010

1991:

pp 193-204

193

FRANCIS

194

ing fibrinolytic therapy, heparin anticoagulation is administered to prevent immediate rethrombosis, and subsequent oral anticoagulation provides long-term protection against recurrence. Most experience has been with streptokinase (SK), the dosages of which have been evaluated to maximize benefit. As a result of prior streptococcal infections, most adults have antistreptococcal antibodies capable of neutralizing therapeutically administered SK. To overcome this effect, a loading dose of 250,000 U is infused that exceeds the blood neutralizing capacity of 95% of the population.’ A maintenance dose of 100,000 U/hr is commonly administered as a constant infusion, although intermittent infusions of up to 1.5 x lo6 U/h for 6 hours have also been employed.6 Streptokinase results in a marked plasma “lytic state” with systemic plasminemia, depletion of plasminogen, and degradation of circulating fibrinogen. Kakkar et a17.8have postulated that plasminogen depletion during fibrinolytic therapy may inhibit thrombolysis and have administered plasminogen intermittently as an adjunct to therapy. Favorable results were reported, but the limited trials did not establish a benefit over SK alone. Most trials have administered SK intravenously by peripheral vein to achieve a systemic effect. A study by Schulman and Lockner’ has shown no apparent benefit with regional administration in leg DVT. There have been fewer studies of urokinase (UK), which has been used generally at the dose applied in treating pulmonary embolism, namely, a systemic loading dose of 2,000 U/lb followed by a maintenance infusion of 2,000 U/lb/h. D’Angelo and Mannucci” found similar results comparing four different UK regimens varying from 1,500 U/kg to 4,000 U/kg given over a period of 2 to 7 days. The optimal duration of fibrinolytic therapy for DVT has not yet been established. Most studies have used regimens of 3 or more days, but examples of complete lysis of extensive DVT have been observed after treatment intervals of only 12 hours.” Because the amount of thrombus dissolved decreases daily during therapy,‘* presumably because recent, fresh thrombus is most susceptible to treatment, and because the risk of bleeding or other side effects continues throughout therapy, short courses of

AND

MARDER

therapy may provide the optimal benefit-to-risk ratio. However, in cases where there is extensive clotting, successful treatment often requires several days of therapy; in Europe, a 4 to 6 day course of SK is not unusual. UK has been given for even longer periods.13 Small trials of recombinant tissue plasminogen activator (rt-PA) have used varying regimens, but no clinical trials are available evaluating single-chain UK plasminogen activator or acylated plasminogenSK activator complex (APSAC) in DVT. CLINICAL

STUDIES

Controlled trials evaluating fibrinolytic agents usually compare results with anticoagulation alone to fibrinolytic therapy followed by anticoagulation. Therefore, fibrinolytic treatment supplements rather than replaces anticoagulation, but the agents are usually administered sequentially rather than simultaneously. Prevention of pulmonary embolism is an important goal of treatment that is apparently achieved with fibrinolytic therapy, although controlled trials using lung scans for objective diagnosis are not available. The isoIated reports of serious puImonary embolization during fibrinolytic therapy could well be coincidental, and symptomatic emboli appear not to be a clinical problem. Evaluation of the short-term effectiveness of thrombolytic therapy in DVT has been determined by comparison of pretreatment and posttreatment venograms. Table 1 summarizes the results in 11 prospective studies comparing venographic results with anticoagulation alone compared with SK therapy plus anticoagulation. 12~14-23 The results are difficult to evaluate for several reasons. First, there is no single study large enough to yield a statistically convincing result of the comparison. Second, the adequacy of randomization and blinding in interpretation of results is variable. Third, venographic interpretation of lysis is often qualitative and subjective, and responses can only be grouped into categories such as complete or substantial lysis, partial lysis, no change, or worsening of thrombosis, or expressed as overall percent reduction in thrombus size. Further, treatment regimens and timing of posttreatment venography differ among studies. Despite the shortcomings, the combined data from these 11 studies strongly

FIBRINOLYTIC

THERAPY

FOR VENOUS

Table

1. Short-term

Browse

Venographic

et aI”

Robertson

et alI6

Results

Substantial

Treatment

Study

195

THROMBOSIS

et al”

Lysis

Partial

Therapy

NO Change

Lysis

0

1

5

5 4 6

0

5 9 7

6 2

4

1

3

Rasch Marder

et aIla

SK’

et alI9

Ancrod SK Heparin

et alI4

Amesen Elliot

NOTE.

and

Some

15 22 26 12 12 16

2 4 17 0

0 are noted

between

the substantial

14 26 24

9 22

8 1 39

SK Heparin changes

3

IO

5 6

SK Heparin

venographic

19 15 17

12 19

Heparin SK Heparin

Watz and Savidgez2 Duckert et al”

between reported

15 2

Heparin SK

et al”

9 10

14 1

SK

et a120

9

6 9

IO

SK

0 1

2 3

1

1

Tibutt

for DVT

Heparin SK

Heparin Ancrod Tsapogas

v Anticoagulant

SK

Heparin SK

Kakkar’*

of Fibrinolytic

and

4 5

11

23 4

30 37

partial

6

lysis

columns,

18 17 1

93 42

1

because

no distinction

was

made

the results in 6 of the 12 studies. Studies by Browse et alz3 and Duckert et alI5 were not randomized. Kakkar et al was previously for only the SK patientsz5 or without qualitative distinctions of response26. The report by RGsch et al was published separately,”

earlier

reports

by Robertson

et al used

less well-defined

criteria

suggest that more clot lysis occurred in groups that received SK. Studies with UK indicate roughly equivalent results.10~24 Only nine studies were randomized and used adequate pretreatment and posttreatment venography as criteria for efficacy.12,‘4.‘6-22 Table 2 summarizes these short-term evaluations of success. A total of 297 patients are equally divided into those who received SK plus anticoagulation and those who received anticoagulation alone. Substantial improvement was found in 45% of SK-treated patients on the posttreatment venogram, and 61% showed either substanTable

2. Early

Venographic

Results

of Streptokinase

for lysis.28‘29

tial or partial improvement. In contrast, only 5% of patients treated with anticoagulants alone showed substantial improvement and 25% substantial or partial improvement. The posttreatment venogram showed no change or progression in 75% of patients treated solely with anticoagulants. Similar conclusions were reached by Goldhaber et al” who pooled results from six randomized studies in which phlebography was used to confirm the diagnosis of DVT and to evaluate therapeutic efficacy. They found that the risk ratio for achieving thrombolysis was more than Y Anticoagulant

Therapy Venographic

Therapy

Patients

148

Streptokinase Anticoagulantt *Venograms

Substantial lnlprovement

45 5

149 performed

t124 patients received Data from references

5 days

after

therapy.

heparin and 25 patients 12, 14-22.

ancrod.

(%I

Partial Improvement

16 20

(%I

of DVT in Nine

Controlled

Studies

Result’ NO Change 1%)

37 69

Progression

2 6

(%I

196

FRANCIS

1.0 for patients receiving SK compared with patients receiving heparin in each of the six trials evaluated. Using pooled data, thrombolysis was achieved 3.7 times more often among patients treated with SK than patients treated with heparin, with 95% confidence limits of 2.5 to 5.7 (P < .OOOl). FACTORS

INFLUENCING

RESPONSE

To optimize the benefit-to-risk ratio of fibrinolytic therapy, it is best to choose patients most likely to respond and to avoid treating patients with resistant thrombi. The duration of symptoms before onset of therapy is the clearest predictor of outcome, with the best success with early treatment of newly formed thrombi. The declining responsiveness of longer duration is most likely related to changes in the composition of thrombi that render them resistant to fibrinolysis, such as cellular infiltration and especially factor XIII-mediated crosslinking of the fibrin?“32 This increased resistance with delay after symptoms has been established in several clinical trials including that by Marder et all4 who found a poor response in patients with symptoms for more than 7 days, by Seaman et a127and Astedt et a133for symptoms for more than 5 days, and by Theiss et a134for symptoms for more than 3 days. Typical findings are those of Hess35 who found a progressive decrease in clot resolution determined by posttreatment venograms as the duration of symptoms before treatment increased (Table 3). Although symptom duration is a good overall predictor, there are exceptions, and some patients with longstanding symptoms have responded favorably to fibrinolytic treatment.” The study by Bonnet et a136used SK or UK to treat 40 cases of proximal chronic DVT, all more than 7 days’ duration, Table

3. Results

of Treatment Duration

Duration of Symptoms (Days) 0=2 2=5 6=9 10 = 21 Overall Data from

Hess.”

of DVT with of Symptoms

SK Related

to the

Venogram Success 70 65 33 0 60

(%)

Failure 30 35 67 100 40

(%)

AND

MARDER

and found venographic improvement in 24 patients (6 total lysis and 18 partial lysis). Because it can be difficult to accurately determine the duration of symptoms and thrombus extension proximally, some patients with chronic complaints, but with a recent exacerbation, may warrant a therapeutic attempt. Other characteristics are less important determinants of therapeutic success. Thrombus location is not a strong predictor of response, although some reports suggest that proxima1 thrombi may be more likely to dissolve than those in the calf.15’37The overall response may be somewhat better with nonocclusive thrombi,39 but completely occlusive thrombi also respond well to fibrinolytic therapy. Although pelvic or abdominal carcinoma that obstructs venous return from the legs would be expected to limit the degree of thrombolysis, such patients have responded to therapy as well as patients without obstructive neoplasm.‘4 VENOUS THROMBOLYSIS WITH TISSUE PLASMINOGEN ACTIVATOR

Several studies have evaluated rt-PA in patients with DVT, including four prospective trials with pretherapy and posttherapy venographic assessment,39-42(Table 4). An optimal dosage regimen has not been established, with reports of treatment varying between 35 mg over 4 hours to as much as 185 mg over 35 hours. Two studies had patients treated with less than 60 mg of rt-PA for less than 6 hours.41,42The results of the two studies are at variance, with the group reported by Turpie et a141showing a more than 50% decrease in clot size in 58% of patients, while none of the seven patients treated by Marder et a142showed a response of more than 40%. In the trial reported by Turpie et a141 infusion of the same rt-PA dose (35 mg) given over 8 hours and repeated 24 hours later resulted in only a 21% response. Two groups of patients were treated by constant infusion for a period of 24 hours with either 100 mg” or 135 mg.42 These studies showed comparable results, with complete or partial lysis reported in 30% of 53 patients in the trial reported by Goldhaber et a1,40and a more than 40% decrease in thrombus size in 25% of patients reported by Marder et

FIBRINOLYTIC

THERAPY

FOR VENOUS

197

THROMBOSIS

Table

4. Results

of Studies

Using

t-t-PA for DVT Bleeding

No. of Study

Verhaege et alag

Goldhaber et a14’ Turpie et a14’

Marder

Treatment

0 4 8 I I I mg -L--_------_-----

Heparin n-PA*

15o~~&--------~?A

rt-PA

lOO~Z--------pmfl

Heparin n-PA

100~

12 I

(hrs)

I

Patients

24 I

I

28 II

32

_____

Decrease

in 3%

-

-

5

Decrease Decrease

in 12% in 35%

33% 40%

72% 60%

-1oo~T?z7m

12 53

Complete Complete

0%, Partial 6%, Partial

--_-------

42

> 50%

decrease

12

&PA

7opm---------pm

28

> 50% > 50%

decrease decrease

541w?j 135 136~ 99 -4 189~~99WC5,+%%?J~

*Includes

the pilot

tlncludes

both

&PA study

heparin

using control

the same groups,

Total

7

n-PA

rt-PA n-PA

Major

18

35&g

et a14’

Response

36 40 1 I

_---_--_---

Heparint

Venographic

treatment ie, those

5% 58% 21%

0% 25%

0% 2%

0% 26%

5% 33% 3%

7

> 40%

decrease

0%

14%

71%

4

> 40% > 40%

decrease decrease

25% 57%

50% 14%

75% 71%

7 regimen.

receiving

one

a1.42A small group of patients treated by Verhaege et a139 using two 50 mg infusions on successive days showed a 35% response, curiously more than the 12% response noted with 100 mg plus 50 mg over the same period. The best response was observed in the group receiving 185 mg over 35 hours with a more than 40% decrease in thrombus size, and overall response of 4 of 7 (57%) patients. Certainly, the results show greater lysis in patients receiving rt-PA than in patients receiving heparin; they also suggest that a higher dose and longer duration of treatment results in greater thrombolysis. Additional studies are needed to define the optimum rt-PA regimen. Bleeding is more frequent with rt-PA than with heparin regimens (Table 4). A low incidence of bleeding was reported by Goldhaber et a1,4obut the overall complication rate appears to be similar to that reported with SK, approximately 15%. Treatment with rt-PA induces predictable decreases in plasma fibrinogen concentrations of 40% to 60%, although a minimal decrease of only 11% was found in patients receiving interrupted treatment with 70 mg.41 The study reported by Marder et a142showed a decrease to approximately 50% with treatment for 6, 24, or 35 hours, sustained throughout the rt-PA infusion, and taking some 36 to 48 hours for recovery to pretreatment levels.

or two 8 hour

heparin

LONG-TERM

infusions.

FOLLOW-UP OF FIBRINOLYTIC THERAPY

A primary goal of fibrinolytic therapy for DVT is rapid clot dissolution, which would preserve venous valve function and prevent chronic venous insufficiency. There is substantial evidence that an acute episode of symptomatic DVT can result in both venous functional abnormalities and the postphlebitic syndrome. Strandness et al” found that 67% of patients had symptoms of venous insufficiency 39 months after an episode of acute DVT, and Bauer44 found such symptoms in 91% of patients 10 years after an acute DVT episode. Approximately one half of the patients with chronic venous insufficiency give a history of prior DVT,45.46 while the remainder are unexplained or attributed to episodes of subclinical thrombosis. DVT especially involving proximal leg veins, also leads to objective evidence of valve dysfunction. For example, Ginsberg et a147found venous valvular incompetence ih 29 of 33 (88%) patients with proximal DVT using Doppler ultrasonography or photoplethysmography 2 to 8 years after the episode; Strandness et al”’ and Killewich et a14* showed a close association of symptoms of chronic venous insufficiency with valve damage and incompetence in distal leg veins.

198

FRANCIS

It is difficult to establish benefit of fibrinolytic therapy in reducing the subsequent development of chronic venous insufficiency, because follow-up up to 10 years is difficult to achieve, and additional episodes of DVT can occur during the follow-up period. Furthermore, patients without prior DVT may have venous insufficiency. For example, Lindhagen et al49 studied 154 patients subject to venography because of symptoms suggestive of DVT. After a follow-up period of 5 to 8 years, they found symptoms of venous insufficiency equally common in patients with (44%) and without (51%) venographically proven thrombi. Similarly, Browse et al”’ found symptomatic deep venous insufficiency in 32% of patients 5 to 10 years after a negative venogram, a significant but lower incidence than in patients with mild (55%), moderate (79%), or severe (67%) DVT. Long-term follow-up evaluation of patients who received either fibrinolytic or anticoagulant therapy for DVT is available in several small studies (Table 5).19,2’,22,2-1~5’~53 Follow-up evaluation includes venography, venous functional studies, and clinical evaluation, but the follow-up periods are generally too short to have allowed full development of the syndrome of chronic venous insufficiency in all susceptible patients. Of 148 patients, normal venograms were found in 57% treated with SK compared with only 7% of those treated with anticoagulants alone. Almost all patients (89%) treated Table

5. Long-term

Evaluation

of Fibrinolytic

Treatment

Study

Kakkar

Bieger Riisch

et al”

SK Heparin

et aP et aP

12

Watz Amesen Total

Evaluation

Clinical Follow-up Interval

Normal

Postthrombotic

4 1

3 7

7 8

0 2 1

7 3 (calf) 4 (femoral)

7 5 5

Total

SK

7

7

8

15

3

2 12

10 9

12 21

?

Most

21

11 1 7 0 43 (57%)

1 7 9 18 33 (43%)

12 8 18 18 76

5 (7%)

67 (93%)

72

SK

et all*

Heparin SK Hoisoth”

of DVT in Six Randomized

4

et aP

and

Therapy

Ancrod SK Heparin Heparin

Elliot

Heparin SK Heparin SK Heparin

2 76

MARDER

with anticoagulants alone had chronic postthrombotic changes including residual fibrosis, collateral flow, or incompetent venous valves between 2 and 76 months after initial therapy. An uncontrolled study of SK treatments4 has demonstrated that patients with normal venograms are often asymptomatic with normal venous outflow and valve function, while patients with thrombotic remnants usually have symptoms of the postphlebitic syndrome. The clinical evaluation of patients summarized in Table 5 supports these observations, in that the percentage of asymptomatic patients is similar to the percentage with normal venograms. In disagreement with this evaluation is the report by Kakkar and Lawrence5’ of 153 patients treated with either SK or heparin who were followed-up prospectively for 2 years for evaluation of clinical and hemodynamic features (foot volumetry) of the postphlebitic syndrome. Severe hemodynamic impairment was seen in approximately 20% of limbs with calf DVT and 50% of those with proximal thrombi. Thrombolytic therapy apparently did not influence the outcome, the proportion of affected patients being the same as patients treated with heparin. Also at variance with the results summarized in Table 5 was their finding that complete clot dissolution during therapy did not prevent subsequent hemodynamic deterioration. A preliminary report of long-term follow-up of a randomized trial comparing two dosing

v Anticoagulant

Venographic Follow-up Interval (mol

AND

(mo)

Asymptomatic

4

3 5

19

76

Studies Evaluation Symptomatic

Total

2 0

5

12

8

2

19

20 21

13 6 30 (71%)

4 12 12 (19%)

11 (25%)

33 (75%)

5

17 18 42 44

FIBRINOLYTIC

THERAPY

FOR VENOUS

199

THROMBOSIS

regimens of rt-PA plus heparin versus heparin alone” showed a lower incidence, 3 of 12 (25%), of the postphlebitic syndrome in patients in whom more than 50% lysis was achieved than in patients in whom lysis was less than 50% (19/34, 56%). These preliminary results showed a trend favoring fibrinolytic therapy, although the data were not statistically significant (P = .07). SAFETY

OF FIBRINOLYTIC

THERAPY

The potential benefits of rapid clot dissolution and prevention of postphlebitic symptoms must be balanced against the risks of adverse reactions, principally bleeding, in choosing fibrinolytic therapy for DVT. Most episodes of bleeding during fibrinolytic therapy are minor and related to prior invasive procedures, often performed during diagnostic procedures or in treating the thromboembolic complication. The UK pulmonary embolism trial (UPET)” in which patients received either heparin or a 12-hour course of UK provided detailed information on bleeding sites. The overall incidence of hemorrhagic complications was 45% in patients treated with thrombolytic therapy compared with 27% in the heparin group (Table 6). However, most episodes of bleeding were secondary to superficial traumatic injury, such as venous cutdowns for catheterization and venous puncture and arterial puncture for cardiac catheterization and blood gas determination. Only 9% of the patients experienced bleeding that required blood replacement or cessation of treatment. Table

6. Bleeding Therapy

Associated

with

Cutdown Gastrointestinal Retroperitoneal Intramuscular Other

6

4 6

5 3 3 1 0

Total incidence Meaningful incidence

Adapted

from

discontinuation in hematocrit Marder

UK (82) Severe

and

Moderate

14

15

8

0

3 3 2

8

13 0

0 2

1 3

8 6

0 0 0 45%

27% 4%

NOTE. “Meaningful” bleeding during the initial 12 or 24 hour to cause or a drop

(78) Moderate

6

Early overt bleeding Late overt bleeding Location

or Heparin

Embolism

Heparin Severe

enough fusion,

Fibrinolytic

of Pulmonary

9%

is defined as that occurring infusion of drug and serious of therapy, of more than

Bell”;

data

from

replacement 5%. reference

trans57.

The control heparin-treated group also had an excess incidence of bleeding (25% of treated patients). Bleeding after heparin therapy was considerably less frequent under ordinary clinical circumstances than was observed in such studies that required invasive procedures. Serious bleeding occurred in the heparin-treated group less often than with UK, 4% versus 9%, respectively.” Similar results have been found in other studies. Goldhaber et a13’ reviewed bleeding complications in prospective randomized studies of thrombolytic therapy for DVT. In the three studies1”.2’.58 suitable for an analysis of pooled data, the incidence of major bleeding complications in SK-treated patients was between 8% and 38%, while it was 0% to 12% in the heparin-treated patients. The incidence of bleeding was not statistically significant in any of the three studies alone, but a pooled analysis of data indicated a relative risk of major bleeding of 2.9 times with SK compared with heparin, with 95% confidence intervals of l.l-fold to &l-fold (P < .04). The frequency of fatal hemorrhage or intracranial hemorrhage is very low, and the available data from clinical trials of DVT are insufficient to make a reliable estimate of the comparative incidence with fibrinolytic or anticoagulant therapy. However, extrapolating from the large experience with acute myocardial infarction, an incidence of (0.2% to 0.5%) associated with SK treatment is reasonable.59 Considering that fibrinolytic therapy for acute myocardial infarction is of shorter duration, this incidence may be higher for longer treatment intervals of several days, as used for DVT. The clear relation between performance of invasive procedures and the occurrences of bleeding complications strongly suggests that most bleeding complications of thrombolytic therapy are the result of hemostatic plug dissolution. This is an expected outcome of thrombolytic therapy, because fibrinolytic agents cannot distinguish between fibrin in pathological thrombi and in hemostatic plugs. Most evidence indicates that the lytic state does not induce bleeding because the degree of abnormality in individual laboratory tests either does not correlate or correlates poorly with the risk of bleeding. Thus the UPET studys7 and the study by

200

Marder et all4 showed no correlation between laboratory derangements of clotting tests and bleeding manifestations. For example, the range and mean values of fibrinogen were the same in patients with or without bleeding complications. Analysis of data from studies of thrombolytic therapy for acute myocardial infarction reinforce this interpretation. Overall, the data indicate that the risk of bleeding complications during fibrinolytic therapy for acute myocardial infarction is the same with SK as with rt-PA, although the latter induces a less intense lytic state. In the thrombolysis in myocardial infarction-phase I trial, a weak correlation was found among rt-PA-treated patients between the occurrence of hemorrhagic complications and the drop in plasma fibrinogen.@’ Among patients receiving SK in this trial, there was no clear relation between the drop in fibrinogen and bleeding complications, although some correlation was found with the elevation in fibrinogen degradation products. In the study by Califf et a161 in which patients with acute myocardial infarction received 150 mg of rt-PA, the risk of bleeding was highly correlated with performance of invasive procedures, but the relation between drop in plasma fibrinogen was significant although not as strong. Because the risk of serious bleeding is most clearly related to preexisting lesions and the performance of invasive vascular procedures, patients can be selected and managed to minimize serious bleeding complications. The absolute contraindications to fibrinolytic therapy are those that may result in intracranial hemorrhage or massive, life-threatening bleeding. The possibility of treating patients with thrombotic stroke is under current study,62 but until results and guidelines are established, the possibility of inducing bleeding in such patients makes treatment unacceptably hazardous. Similarly, patients with recent head trauma or an intracranial neoplasm should be excluded. The risk of major bleeding following recent major surgery should be avoided as is the risk with current active major bleeding sites such as those in the gastrointestinal tract. Some minor bleeding may be unavoidable, but most can be prevented by careful selection and avoiding trauma once thrombolytic therapy is considered. Invasive procedures such as veni-

FRANCIS

AND

MARDER

puncture or arteriotomy for blood gas measurements should be minimized or avoided whenever possible. Some bleeding from superficial wounds or biopsy sites may be acceptable, and treatment of patients with a remote history of gastrointestinal or genitourinary bleeding is reasonable. Most instances of bleeding in these situations are neither life-threatening nor difficult to control, and bleeding may result equally from heparin or thrombolytic therapy. Therefore, these conditions do not represent absolute contraindications, but require careful clinical judgement with the expected benefit weighed against the severity of possible complications. UPPER EXTREMITY

THROMBOSIS

Primary axillary/subclavian DVT occurs in otherwise healthy individuals following strenuous arm exercise or trauma, sometimes in association with extrinsic rib compression and thoracic-outlet obstruction. Thrombosis occurs more frequently in patients with chronic central venous catheters that are used increasingly for parenteral nutrition or in patients with permanent transvenous cardiac pacemakers. The clinical presentation of acute axillary/subclavian DVT is comparable to that of leg DVT with variable pain, swelling, and venous engorgement of the arm and shoulder, symptoms that may also involve the neck, head, and occasionally breasts, if there is proximal extension of thrombus. Patients treated with rest, arm elevation, and anticoagulation may suffer troublesome chronic symptoms of arm pain, swelling, and weakness, but the frequency of development of chronic disability varies among reports. For example, Ameli et aP3 found only 5 of 20 patients with residual swelling and 2 of 20 with minor discomfort 42 months following conservative management. In contrast, Swinton et al@ found 21 of 23 patients with major (9) or minor (12) chronic symptoms after a mean follow-up of 8 years. Chronic arm symptoms in 68% of 23 patients were reported by Adams et a1,65and more than 50% of the patients reported by Campbell et aY6 had pain, swelling, and venous distention after an average of 4 years. Systemic fibrinolytic therapy using SK administered by peripheral vein for periods of 48 to 72 hours is successful in most cases as judged by venographic response (Table 7)67-79and the

FIBRINOLYTIC

THERAPY

FOR VENOUS

Table

Study

7. Venographic

Primary

Rubenstein” Bradof et al6’ Becker

at ale9

Appleby Collier Painter

and Heller” et al” and Karpf72

201

THROMBOSIS

CatheterRelated

Results

of Fibrinolytic

Therapy

Treatment Regimen

Agent

for Upper

Extremity

DVT

Venographic

Duration lhrs)

0

1

SK

Systemic

0 4

1 0

SK SK UK

Systemic Local 5,OOOihr Local 20,00O/hr

1 2

0 1

SK SK

Local Local

2

1

SK

Systemic

1 5

0 4

SK SK

Systemic Local 5,000

72 72 20-38 24-65 72 48

5,00O/hr 10,OOOihr

up to 96

ReSpOllSe

Complete

resolution

Complete No change Patency

resolution

Marked resolution Complete resolution 2 complete resolutions 1 no improvement

Wilson Drury

et al73 et al’?

or UK Smith

et al’5

Taylor et al” Fraschini et al”* Landercasper O’Leary

et al” et al’9

*Dose

-

1 0

SK SK

Systemic Systemic

0

35

UK

Local 500 2,000 U/kg/hr

3 1 1

0 0

SK UK SK

Systemic Systemic Local 10,000

UK

Local

0 0

6-36

Almost complete resolution Improvement or resolution

10,000 U/hr 1,000 U/kg/hr

0 2

1 *UK tUK

72

50,000

48

Patency

48-72

Patency

up to 216

Good

U/hr

48-72 144 12-18

Doppler Doppler Patency

U/hr

12

Patency

response

in 26/35

or venographic or venographic

patency patency

therapy followed failure of SK. used only if SK had been used previously. was escalated

if there

was no response

on serial

venograms.

absence of chronic symptoms. Successful therapy is possible as well using local infusion of fibrinolytic agent immediately distal or into the thrombus, using SK in doses of 5,000 to 10,000 U/hr or UK at several doses. With either systemic or local therapy, successful thrombolysis was induced in patients with primary DVT and duration of symptoms of up to 7 weeks@‘; and most patients were asymptomatic after follow-up periods from a few months to 4 years. Additional treatment including angioplasty for stenotic lesions or rib ressection was required in SOme caSeS~WW>W9 Patients with catheter-related thrombosis differ from those with primary thrombosis as they often have chronic illnesses including malignancies and may be receiving long-term chemotherapy. Systemic or local fibrinolytic treatment of venous occlusion complicating indwelling catheters is often, but not uniformly, successful. In the largest reported study, Frashini et a177administered UK locally in escalating doses of 500 to 2,000 U/kg/h, and achieved complete lysis of 25 of 30 thrombi in which the catheter could be positioned for direct infusion into the thrombus; success was achieved only

after a median duration of 4 days with therapy extending up to 9 days in some cases. Therapy was less successful if the catheter could not be placed directly into the thrombus or if there was active vein inflammation, but a response could be attained even with symptom duration of up to 30 days. No further thrombosis occurred in 10 of 16 cases, even though the catheter was not removed, while 6 suffered rethrombosis after initial treatment. Only minor bleeding complications occurred in 14 of 36 patients. In patients with chronic venous catheters, thrombotic catheter occlusion is less serious but a more frequent problem than DVT. It is particularly troublesome, because it may preclude use of the catheter for IV infusion or for blood drawing. In this setting, fibrinolytic agents are almost uniformly successful in restoring catheter patency using direct instillation of 5,000 to 20,000 U of SK or UK.80-8* SUMMARY

In the treatment of DVT fibrinolytic therapy offers the possibility of rapid clot dissolution resulting in symptomatic relief of the acute episode as well as preservation of venous valve

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function and prevention of long-term disability from chronic venous insufficiency. A review of published studies comparing fibrinolytic therapy with SK to anticoagulation alone indicates that substantial venographic improvement occurs in 45% of SK treated patients compared with only 5% receiving only anticoagulation. Substantial data indicate a high incidence of venous valvular dysfunction and eventual development of chronic venous insufficiency in patients with extensive leg DVT treated with anticoagulants alone. The available data on the long-term benefits of thrombolytic therapy in preventing chronic venous insufficiency suggest that fibrinolytic therapy reduces long-term morbidity. Because best results are obtained by treatment soon after the onset of symptoms, it follows that the postphlebitic syndrome can be

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best avoided by prompt thrombolytic therapy of patients with acute DVT. Bleeding complications are more frequent after thrombolytic therapy than anticoagulant therapy, but most are related to invasive vascular procedures and can be minimized by proper patient selection and management. Available studies of rt-PA in treatment of DVT indicate that infusion durations of 24 hours or more may be required; further studies will be needed to evaluate the response to rt-PA compared with those of SK or UK. Thrombosis of the axillarylsubclavian veins of the upper extremity, occurring spontaneously or in association with indwelling venous catheters, also respond well to regional or systemic fibrinolytic therapy, which may reduce the likelihood of developing chronic arm symptoms related to venous insufficiency.

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