Acta Med Scand 21 1: 65-68. 1982

Streptokinase or Heparin in the Treatment of Deep Vein Thrombosis

F o l l o ~ w p Resirlts qf” Prospec t ive Stirdy

Harald Arnesen, Arne Heriseth and Bernt Ly

From Medical Depurtment 8 und the Department of Rudioloxy, UIIevdl Hohpitul, University Clinic, Oslo, Norway

ABSTRACT. In a previous study on 42 patients with acute deep vein thrombosis, randomly allocated to treatment with streptokinase or heparin, we found that 71.4 % of the streptokinase-treated patients achieved phlebographically significant thrombolysis as compared to 23.8% in the heparin group. These patients have been reevaluated after a mean observa- tion period of 64 years. Seven patients had died and there were no other drop-outs. Thus, 35 patients were subjected to the follow-up study consisting of phlebography and clinical examination. The evalua- tions were performed without knowledge of the initial therapy. Seven patients had phlebographically nor- mal veins, and all belonged to the streptokinase group. This difference between the treatment groups is statistically highly significant (p cO.01). At clinical examination, 13 of the 17 patients in the strepto- kinase group had normal legs and 4 exhibited mod- erate postthrombotic changes. In contrast, 3 of the heparin-treated patients showed serious postthrom- botic changes with open leg ulcers, and only 6 of 18 patients in this group had normal legs. The present results strongly support the assumption that strepto- kinase therapy is the best treatment at present in patients with acute deep vein thrombosis. This has been shown for the initial thrombolysis, and now also for the avoidance of late postthrombotic changes.

Key words: thrombolysis, streptokinase, heparin, deep vein thrombosis, postthrombotic changes, late results in DVT. Acta Med Scand 21 1: 65-68, 1982.

Received June 24, 1981.

In 1978 we published initial results of a prospective trial on medical patients with acute deep vein thrombosis randomly allocated to treatment with streptokinase or heparin (1). We found that 71.4% of 21 patients treated with streptokinase and 23.8% of 21 heparin-treated patients showed phlebo-

5-822981

graphically significant thrombolysis during the acute phase.

The exact potential advantage of fibrinolytic therapy with streptokinase in patients with acute deep vein thrombosis cannot be established without knowledge of the ultimate fate of the thrombosed veins, that is, the frequency of late postthrombotic changes. Only few controlled studies are available on the late results of streptokinase or heparin thera- py in deep vein thrombosis (3, 5) .

The patients in our above mentioned prospective trial have been reinvestigated after a mean observa- tion time of about 6$ years.

PATIENTS AND METHODS Table I shows the clinical material as it appeared in the

One patient in the heparin group had died because of pulmonary embolism after 2 weeks, and one in the strepto- kinase group because of seminoma of the testis after 6 months. The other 5 deaths, mostly several years later, were probably unrelated to the thrombotic event. No regular drop-outs occurred. The mean observation time in the two treatment groups was 76 and 77 months, respec- tively.

Seven patients, 4 in the streptokinase group and 3 in the heparin group, had had clinical evidence of repeated deep vein thrombosis in the same leg. These patients are commented on specifically in Results (Tables I 1 and 111).

The duration of anticoagulant therapy after the initial thrombotic event was usually 3-6 months, and only 1 pa- tient in each treatment group was kept on permanent anticoagulation (Table 111).

All originally treated thromboses were extensive (Table 11). Thus, 14 patients had thromboses extending from the calf veins to the iliac vein, 9 from the calf veins to the femoral vein, 8 from the calf veins to the popliteal vein (one patient in the streptokinase group was not subjected

follow-up study.

Correspondence to: H. Arnesen, M.D., Int. Dept. 8. Ullev%l Hospital, Oslo 1, Norway.

Acrcc Mrd Siimd 211

66 H . Arnrsrn r t id

Table 1. Clinicul mciteriul Table 11. Phlehogrciphic evciluation

Strepto- kinase Heparin group group

Initial no. of pats. 21 21 Died before follow-up 4 3 Available for follow-up 17 18

Females 7 8 Males 10 10

Age at follow-up (mean and range) Females 47 50

Males 58 58 (30-70) (2678)

(21-77) (3479) Observation time (mo., mean and range) 76 77

(42-102) (4 1-106)

to phlebography because of pregnancy), and 4 patients had thromboses isolated to the femoral and iliac veins.

Phlebographic examination. A standard method of ascending phlebography was used, including a rubber tourniquet around the ankle and the patient in a semi- upright position. To avoid complications due to the con- trast medium, the non-ionic contrast medium metriza- mide was used (Amipaque, supplied by Nyegaard, Oslo, Norway).

The phlebograms were evaluated by a radiologist (A. H . ) without knowledge of the original therapy. The resblts were classified as “normal veins”, “slight postthrombotic changes”, including recanalization with pathological vein wall contours and lack of normal valves, and “major postthrombotic changes” with persistent occlusion of main stems.

Clinical examination was performed without knowledge of the original therapy. Special attention was paid to new episodes of thromboembolic disease in the follow-up peri- od, particularly in the actual leg, as well as to medication, especially anticoagulation.

On the basis of subjective complaints and clinical signs, the postthrombotic changes were classified as “no signs”, that is normal leg, “moderate signs” including oedema and/or varicose veins and/or pathological pigmentation, and “serious signs” with open leg ulcers in addition.

RESULTS

Phlehogrmphic ewlirution. The results of the phle- bographic evaluation are shown in Table 11. Al- together 7 patients had normal phlebograms, and all of them belonged to the streptokinase group.

Among the 7 patients who had experienced re- peated thrombosis in the actual leg, 3 of 4 in the streptokinase group and 2 of 3 in the heparin group showed “major postthrombotic changes” on phle-

Ai 111 M d Sr iiiiil 21 I

~ ~~ ~

Strepto- kinase Heparin group group

n % n % -~

lnitiul thrombiis extension fi’om culf vein5 to Iliac vein

Total no. 8 Normal veins 3 Slight postthrombotic changes 0

Major postthrombotic changes 5“

Femoral vein Total no. 5 Normal veins 2 Slight postthrombotic changes 1

Major postthrombotic changes 2

Total no. 1 Normal veins 1 Slight postthrombotic changes 0

Major postthrombotic changes 0

Popliteal vein

6 0

1

5 0

4 0

0

4*

6 0

46

2

Initial thromboses isolated in jkmoral and iliac veins Total no. 2 2 Normal veins 1* 0 Slight postthrombotic changes 1 1 Major postthrombotic changes 0 1

Entire series Total no. 16 18 Normal veins 7 4 4 0 Slight postthrombotic

Major postthrombotic changes 2 12 6 33

changes 7“ 44 12‘ 67

Repeated DVT in the same leg during observation time, “ n =3, bn = I , = 2 .

bography. The other two showed “normal veins” and “slight postthrombotic changes”, respectively.

Stutisticul trnri1ysi.r of the phlebographic results showed that the difference in the number of “normal veins” between the two treatment groups was highly significant. Using the Fisher-Irwin test, the p-value was 0.0043, even when calculated for the original number of 21 patients in each group.

In subgroups of patients defined according to the extension of the original thromboses, the results of streptokinase treatment were equally good (Table 11). Thus, 3 of 8 patients with extensive

Late results o f S K atid hepwin in DVT 67

Table 111. Clinicrrl ewluLition oj' postthrotnhotic syndrom (7

Strepto- kinase Heparin group group

n % n %

Total no. 17 18 No signs (normal leg) 13 76.5 6 33.3 Moderate signs (oedema, and/or varicose veins, and/or Pigmentation) 4 23.5 9 50

Serious signs (leg ulcer in addition) 0 3 16.7

Repeated DVT in the same leg during observation time 4" 36

On permanent anticoagulation 1 I

". * Moderate signs of postthrombotic syndrome. I' I I = 1, bn=2 .

thromboses from the calf veins into the iliac vein showed normal veins at the follow-up examination. In contrast, the best phlebographic results in the heparin group were seen in patients with more limited thromboses extending proximally into the popliteal vein only. N o complications were seen after the phlebographic examinations.

Clinical evulurrtion. The results of the clinical evaluation are shown in Table 111. Clinically normal legs were found in 19 patients, 13 in the strepto- kinase group and 6 in the heparin group, whereas 3 patients, all in the heparin group, showed serious postthrombotic changes including open leg ulcers.

Four patients in the streptokinase group and 3 in the heparin group had experienced repeated venous thrombosis in the actual leg during the follow-up period. One of the former and 2 of the latter showed signs of moderate but none of serious postthrom- botic changes.

All patients with normal veins at phlebography were without clinical signs, and all 3 patients with serious postthrombotic syndromes had major phle- bographic changes.

DISCUSSION

The present study comprises 42 patients with acute deep vein thrombosis, originally allocated at ran- dom to treatment with streptokinase or heparin. All thrombi were extended proximally into the pop- liteal, femoral or iliac veins. In about 72% of the streptokinase-treated patients, phlebographical thrombolysis was achieved in the acute phase, com-

pared to about 24 % of the heparin-treated patients ( 1 ) .

After a mean observation time of about 64 years, 35 patients were still alive. N o regular drop-outs occurred, although 1 patient was pregnant and thus not subjected t o phlebography.

The duration of anticoagulant therapy after the initial thrombotic event was usually 3-6 months, and only 1 patient in each treatment group was kept on permanent anticoagulation. Repeated thrombo- sis in the actual leg might be suggested to interfere with the evaluation of the late results of the original therapeutic regimen. Altogether 7 patients had ex- perienced repeated thrombosis in the same leg, 4 in the streptokinase group and 3 in the heparin group. Three of these patients in the streptokinase group showed major postthrombotic changes at phlebography, the fourth had normal veins. Two of these patients in the heparin group had major post- thrombotic changes at phlebography, the third had slight changes. As regards the clinical evaluation, none of the patients with repeated thrombosis had serious postthrombotic changes with leg ulcers. Thus, repeated thrombosis in the observation pe- riod does not seem to have influenced to any im- portant degree the ultimate results of the present study.

As could be expected, all 7 patients with phlebo- graphically normal veins at the follow-up examina- tion had achieved initial thrombolysis during strep- tokinase therapy.

Whereas no correlation was found between the primary extension of the thrombus and the late results in the streptokinase group, the best results in the heparin group were found among patients with an initial proximal extension of the thrombus into the popliteal vein only. This fact justifies fur- ther the assumption that minor thromboses can be treated with heparin alone.

It is well known that the clinical condition of the leg does not exactly reveal the anatomical status of the veins after a thrombotic event. Correspond- ingly, the clinical evaluation gave much better results than the phlebography. This fact is of main importance to the patient. Nevertheless, a marked difference in clinical condition between the two treatment groups was noted. Thus, altogether 13 of the 17 patients in the streptokinase group had no clinical signs of their previous thrombosis. Four patients had moderate signs such as oedema, varicose veins and/or pathological pigmentation,

68 H . Arnesen et (11.

but none had serious signs with open leg ulcers. In contrast, 3 of the 18 patients in the heparin group had open leg ulcers, 9 showed moderate postthrom- botic changes, and only 6 were without clinical signs.

Previous studies on the late results of strepto- kinase or heparin therapy in deep vein thrombosis are few, although optimistic results have been re- ported (2, 4, 6). To our knowledge, only 2 reports on originally randomized trials have so far been published. Common et al. (3) found that 6 of 15 streptokinase-treated patients had normal veins after a mean period of 7 months compared to only 1 of 12 patients on initial heparin therapy. These results correspond well with ours. Johansson e t al. ( 5 ) reinvestigated 19 patients 8-14 years after treat- ment with streptokinase or heparin. The data were considered too small for statistical analysis, but the authors concluded that severe postthrombotic changes were seen less often after initial therapy with streptokinase.

The present follow-up study strongly supports the assumption that streptokinase therapy is the best therapy at present in patients with acute deep vein thrombosis. The treatment should be con-

ducted according to a standardized scheme a s de- scribed previously ( I ) , with a loading dose of 250000 IU and a maintenance dose of 100000 lU/ hour for 3-6 days.

REFERENCES 1. Arnesen, H., Heilo, A., Jakobsen, E., Ly, B. & Skaga,

E.: A prospective study of streptokinase and heparin in the treatment of deep vein thrombosis. Acta Med Scand 203: 451, 1978.

2. Bieger, R.. Boekhout-Mussert, R. J., Hohmann, F. & Loeliger, E. A.: Is streptokinase useful in the treatment of deep vein thrombosis? Acta Med Scand 199:81, 1976.

3. Common, H. H., Seaman, A. J., Rssch, J., Porter, J . M. & Dotter, C.: Deep vein thrombosis treated with streptokinase or heparin. Follow-up of a randomized study. Angiology 27: 645, 1976.

4. Johansson, E., Ericson, K. & Zetterquist, S.: Strepto- kinase treatment of deep vein thrombosis of the lower extremity. Acta Med Scand 199: 89, 1976.

5. Johansson, L., Nylander, G., Hedner, U. & Nilsson, I. M.: Comparison of streptokinase with heparin: Late results in the treatment of deep vein thrombosis. Acta Med Scand 206: 93, 1979.

6. Kakkar, V. V . , Howe, C. T., Laws, J. W. & Flane, C.: Late results of treatment of deep vein thrombosis. Br Med J 1: 810, 1969.