11
Thrombolytic therapy for venous thromboembolism SAMUEL Z. G O L D H A B E R
The use of thrombolytic agents to treat pulmonary embolism (PE) and deep venous thrombosis (DVT) continues to generate controversy. Although this treatment strategy was sanctioned by the US Food and Drug Administration more than a decade ago, thrombolytic agents are utilized prior to heparin anticoagulation only in about 1-5% of patients with venous thromboembolism. Traditionally, 5-10 days of heparin therapy, without thrombolysis, followed by 3-12 months of oral anticoagulation with Coumadin (warfarin), constitutes the standard therapeutic approach to PE and DVT. Heparin prevents additional thrombus from forming and permits endogenous fibrinolytic mechanisms to dissolve slowly the thrombus that already exists. Although heparin can cause haemorrhage and thrombocytopenia, it is safer than the available thrombolytic agents and can be cautiously administered to some patients in whom thrombolysis carries a prohibitively high haemorrhagic risk. Therefore, the burden of proof for utilization of thrombolysis rests squarely on those who advocate more widespread use of these potent drugs. When new therapeutic regimens fail to gain popularity, there are often reasons that warrant careful examination. In the case of thrombolysis for venous thromboembolism, the disadvantages are immediately apparent, whereas most of the potential advantages are theoretical rather than proven (Table 1). Available evidence suggests that, for venous thromboembolism, standard heparin treatment is not entirely satisfactory. The majority of PE patients have evidence of persistent pulmonary arterial thrombus if they have a repeat angiogram several weeks after initial heparin treatment (Dalen et al, 1969). This indicates that endogenous fibrinolytic mechanisms are not completely effective in lysing previously formed clot. Furthermore, when perfusion lung scanning is repeated 4 months after initial heparin therapy, one-third of patients do not demonstrate improvement in pulmonary perfusion (Tow and Wagner, 1967). This suggests that without thrombolysis, some patients may suffer permanent impairment with standard anticoagulant treatment. In addition, it is possible that undissolved thrombus in the pulmonary arteries may serve as a nidus for the development of a dreaded disabling long-term complication of PE: chronic pulmonary hypertension. Baitli~re's Clinical Haematotogy--
Vol. 3, No. 3, July 1990 ISBN0-7020-1474-5
693 Copyright© 1990,byBailli~reTindall All rights of reproduction in any formreserved
694
s . z . GOLDHABER
Table 1. Potential advantages and disadvantages of thrombolysis in the trealment of venous thromboembolism. Advantages
Disadvantages
Pulmonary embolism Reduce mortality rate Accelerate reversal of heart failure Reduce rate of recurrent pulmonary embolism Reduce risk of chronic pulmonary hypertension Accelerate pulmonary tissue reperfusion Improve pulmonary capillary blood volume
Pulmonary embolism~Deep vein thrombosis Increase bleeding risk Increase cost Increase time spent with nursing, pharmacy and laboratory staff
Deep vein thrombosis' Prevent pulmonary embolus by lysing deep vein thrombosis in situ Prevent chronic venous insufficiency of legs by minimizing damage to valves in pelvic and deep leg veins
Deep vein thrombosis Cause pulmonary embolism by lysing deep vein thrombosis partially with subsequent embolization to the lungs
More widespread use of prophylaxis against venous thromboembolism has resulted in a decline in the frequency of PE (Gillum, 1987). However, between 1979 and 1985, there has been no decline in the death rate from PE (Figure 1) (Goldhaber, 1988). These problems with standard heparin treatment suggest that the role of thrombolytic therapy in the management of venous thromboembolism should be augmented. The three thrombolytic agents that have been used to treat PE and DVT are streptokinase (SK), urokinase (UK), and recombinant human tissuetype plasminogen activator (rt-PA). These agents work by directly or indirectly activating plasminogen to the active enzyme plasmin, which digests fibrin clot in addition to fibrinogen, factor V and factor VIII. When plasminogen is activated to plasmin endogenously, low physiological concentrations of plasmin are more likely to lyse fibrin within a thrombus than to digest circulating clotting factors because the concentration of plasmin's inhibitor, antiplasmin, is low at the site of the thrombus. However, in the systemic circulation, a relative excess of antiplasmin rapidly neutralizes endogenously released plasmin. Only when thrombolytic agents are administered exogenously, in pharmacological concentrations, does the circulating antiplasmin become rapidly depleted, leading to an imbalance that favours unopposed thrombolysis, development of a systemic lytic state, and enhancement of haemorrhagic complications (particularly at sites of prior venepuncture or arterial puncture). SK, a foreign protein produced commercially from ultrafiltrates of Lancefield group C cultures of Streptococcus haernolyticus, forms an activator complex by combining with plasminogen in an equimolar (1 : 1) ratio. This activator complex converts other plasminogen molecules to plasmin. The SK-plasminogen complex is gradually converted to an SK-plasmin complex, which also activates and converts plasminogen to plasmin. There is more clinical experience worldwide with SK than with all other thrombolytics combined. It is about one-tenth the price of UK or rt-PA. Its dis-
695
T H R O M B O L Y T I C S FOR V E N O U S T H R O M B O E M B O L I S M A
30,
8 x
.-
20
E ~
2
J I l I f I
I
I o ..r
0
979
198:
1985
Figure 1. Data from the US National Hospital Discharge Survey provide the ratio of all deaths with any mention of PE on the death certificate to the number of discharge forms with PE coded as a primary or secondary diagnosis. These ratios approximate a case fatality ratio but are probably overestimates, because the numerator may not be completely included in the denominator. The death rates are: 1979-23.6%: 1983-24.0%; 1985-24.7%. Modified from Goldhaber (1988).
advantage compared with other drugs in its class is an association with allergic reactions (e.g. fever, chills, hypotension, bradycardia) in about 10-15% of patients. Furthermore, patients who receive SK form high antibody titres and generally cannot receive an effective second treatment course within 6-12 months of prior administration. UK, a direct plasminogen activator, is produced by human fetal kidney cell cultures. UK converts plasminogen to plasmin through cleavage of a single peptide bond. For treatment of PE, there is more published experience with UK than with SK, and UK has secured a niche as the standard thrombolytic agent for PE against which novel clot-dissolving agents must be compared. rt-PA, produced by recombinant DNA technology, is a relatively fibrin specific serine protease that has a high ratio of activity for fibrin bound plasminogen compared with plasma plasminogen, rt-PA is composed of 527 amino acids with a molecular weight of 59 000 (unglycosylated). The aminoterminal end has a high degree of sequence homology with the kringle regions of plasminogen. The carboxy-terminal end contains a domain responsible for the protease activity. In animal models of venous thromboembolism, rt-PA appeared more potent than SK or UK and possibly safer. Unlike SK, rt-PA has not been reported to be antigenic, nor has rt-PA been linked causally to allergic reactions. The central issue surrounding thrombolysis is whether this strategy should only be used in rare circumstances, such as haemodynamically unstable, life-threatening PE, or whether its application to PE and DVT should be broadened. If thrombolysis is utilized more often, then one must decide which agent (SK, UK or rt-PA) should be chosen and what dosing regimen should be employed. To compare differing treatment strategies, the randomized clinical trial is a powerful tool that minimizes bias, chance or
696
s . z . GOLDHABER
Table 2. Randomized controlled trials of thrombolysisversus heparin in pulmonaryembolism. Reference Phase I of Urokinase Pulmonary Embolism Trial (1973)
n
Thrombolytic agent
160
Urokinase
Tibbutt et al (1974)
30
Streptokinase
Ly et al (1978)
20
Streptokinase
Findings in thrombolyticgroup Accelerated clot lysis, pulmonary tissue reperfusion, and normalization of pulmonary arterial pressure at 24 h, but increased bleeding. By 7 days, no difference in lung scans Accelerated clot lysis and normalization of pulmonary arterial pressure Accelerated clot lysis but increased bleeding
confounding. With respect to PE, three randomized controlled trials have compared thrombolysis to heparin (Urokinase Pulmonary Embolism Trial, 1973; Tibbutt et al, 1974; Ly et al, 1978) and have demonstrated accelerated clot lysis, pulmonary tissue reperfusion and reduced pulmonary artery pressures, compared with heparin alone (Table 2). A subset of patients from one of these trials was investigated 2 weeks and 1 year after treatment, and improved pulmonary capillary blood volume was observed in the group that received thrombolysis (Sharma et al, 1980). None of these trials demonstrated a reduction in mortality or an improvement in quality of life among patients randomly assigned to thrombolytic therapy. As expected, patients randomized to thrombolysis experienced more bleeding complications than heparin treated patients. Furthermore, in phase I of the Urokinase Pulmonary Embolism Trial ( U P E T ) , there was no difference in lung scans between the two groups when compared 1 week after initiation of therapy ( U P E T , 1973). Thus, the allure of thrombolysis for PE treatment resides more in its potential rather than proven benefit. For example, in the U P E T there was a strong hint that thrombolytic therapy might reduce both mortality and recurrent P E compared with heparin treatment. However, the differences between these two treatment modalities did not attain statistical significance, possibly due to a relatively small sample size. In the U P E T , of the 78 patients who received heparin, 7 (9%) died, 18 (23%) had recurrent PE, and 24 (31%) died or had recurrent PE within the first 2 weeks of treatment. By comparison, among the 82 U K treated patients, 6 (7%) died and 14 (17%) had recurrent PE, and 19 (23%) died or had recurrent PE within 2 weeks. Thus, the rate of death or recurrent PE was 25% lower among the U K treated patients (31% for heparin versus 23% for UK), but this difference was not statistically significant. Nevertheless, the trend supports the hypothesis that thrombolytic therapy can save lives and reduce morbidity from recurrent PE. Given the U P E T sample size and event rate in the heparin group, reductions in event rates would have had to have been about 60% to be detected with 80% power. In the treatment of DVT, thrombolytic therapy may lyse thrombus in situ
4
4
5
14
8
Kakkar et al (1969)
Robertson et al (1970)
Tsapogas et al (1973)
Porter et al (1975)
Elliot et al (1979)
600
250
500§
Twice the titrated dose't
500
Twice the titrated doset
100/h
100/h
100/h
100/h
900/6 h
100/h
35
35
2-35
3
-> 5
1:~
10
0,15/kg
7
7.5
10
7.5
Heparin loading dose (units x l0 s)
5-6
10
A continuous infusion was adjusted to maintain partial thromboplastin time at x 2-2.5 the control value, for 10 days 10/6 h via constant infusion pump (but adjusted to maintain partial thromboplastin time at x 2.5-3 the control value) for 7 days
2-3
6-8
Approximately every 2 days
5-6
Phlebographic follow-up period (days)
1.5/h (but adjusted to maintain partial thromboplastin time at x 2-2.5 the control value) for 9 to 10 days
17.5/10.5 h; 25/12 h for 2.5 days
10-15/6 h for 5 or more days via continuous infusion (adjusted to maintain thrombin clotting time in 16-120 s range)
42.5/22 h via continuous infusion; 25/12h s,c, for 2 days; 12.5/12h s.c. for 3 days; 12.5 s,c, daily for 1 to 2 days
Sequence and route* of heparin administration after loading dose (units x 103)
* Administered intravenously unless otherwise specified. "t Method of Nilsson and Olow (1962). $ Patients were then switched to heparin regimen. § The investigators gave a 500 000 unit dose unless the titrated dose, using the method of Fletcher et al (1959), was less than 300 000 units; such patients were given the titrated dose plus 100000 units. From Goldhaber et al (t984) with permission.
4
Robertson et al (1968)
Reference
Maximum duration of symptoms Streptokinase Streptokinase Streptokinase (days prior to loading dose infusion dose infusion treatment) (units x 103) (units x 103) period (days)
Table 3. Randomized controlled trials of streptokinase versus heparin in deep vein thrombosis.
o
o
o
o
Thrombolytic therapy for venous thromboembolism SAMUEL Z. G O L D H A B E R
The use of thrombolytic agents to treat pulmonary embolism (PE) and deep venous thrombosis (DVT) continues to generate controversy. Although this treatment strategy was sanctioned by the US Food and Drug Administration more than a decade ago, thrombolytic agents are utilized prior to heparin anticoagulation only in about 1-5% of patients with venous thromboembolism. Traditionally, 5-10 days of heparin therapy, without thrombolysis, followed by 3-12 months of oral anticoagulation with Coumadin (warfarin), constitutes the standard therapeutic approach to PE and DVT. Heparin prevents additional thrombus from forming and permits endogenous fibrinolytic mechanisms to dissolve slowly the thrombus that already exists. Although heparin can cause haemorrhage and thrombocytopenia, it is safer than the available thrombolytic agents and can be cautiously administered to some patients in whom thrombolysis carries a prohibitively high haemorrhagic risk. Therefore, the burden of proof for utilization of thrombolysis rests squarely on those who advocate more widespread use of these potent drugs. When new therapeutic regimens fail to gain popularity, there are often reasons that warrant careful examination. In the case of thrombolysis for venous thromboembolism, the disadvantages are immediately apparent, whereas most of the potential advantages are theoretical rather than proven (Table 1). Available evidence suggests that, for venous thromboembolism, standard heparin treatment is not entirely satisfactory. The majority of PE patients have evidence of persistent pulmonary arterial thrombus if they have a repeat angiogram several weeks after initial heparin treatment (Dalen et al, 1969). This indicates that endogenous fibrinolytic mechanisms are not completely effective in lysing previously formed clot. Furthermore, when perfusion lung scanning is repeated 4 months after initial heparin therapy, one-third of patients do not demonstrate improvement in pulmonary perfusion (Tow and Wagner, 1967). This suggests that without thrombolysis, some patients may suffer permanent impairment with standard anticoagulant treatment. In addition, it is possible that undissolved thrombus in the pulmonary arteries may serve as a nidus for the development of a dreaded disabling long-term complication of PE: chronic pulmonary hypertension. Baitli~re's Clinical Haematotogy--
Vol. 3, No. 3, July 1990 ISBN0-7020-1474-5
693 Copyright© 1990,byBailli~reTindall All rights of reproduction in any formreserved
694
s . z . GOLDHABER
Table 1. Potential advantages and disadvantages of thrombolysis in the trealment of venous thromboembolism. Advantages
Disadvantages
Pulmonary embolism Reduce mortality rate Accelerate reversal of heart failure Reduce rate of recurrent pulmonary embolism Reduce risk of chronic pulmonary hypertension Accelerate pulmonary tissue reperfusion Improve pulmonary capillary blood volume
Pulmonary embolism~Deep vein thrombosis Increase bleeding risk Increase cost Increase time spent with nursing, pharmacy and laboratory staff
Deep vein thrombosis' Prevent pulmonary embolus by lysing deep vein thrombosis in situ Prevent chronic venous insufficiency of legs by minimizing damage to valves in pelvic and deep leg veins
Deep vein thrombosis Cause pulmonary embolism by lysing deep vein thrombosis partially with subsequent embolization to the lungs
More widespread use of prophylaxis against venous thromboembolism has resulted in a decline in the frequency of PE (Gillum, 1987). However, between 1979 and 1985, there has been no decline in the death rate from PE (Figure 1) (Goldhaber, 1988). These problems with standard heparin treatment suggest that the role of thrombolytic therapy in the management of venous thromboembolism should be augmented. The three thrombolytic agents that have been used to treat PE and DVT are streptokinase (SK), urokinase (UK), and recombinant human tissuetype plasminogen activator (rt-PA). These agents work by directly or indirectly activating plasminogen to the active enzyme plasmin, which digests fibrin clot in addition to fibrinogen, factor V and factor VIII. When plasminogen is activated to plasmin endogenously, low physiological concentrations of plasmin are more likely to lyse fibrin within a thrombus than to digest circulating clotting factors because the concentration of plasmin's inhibitor, antiplasmin, is low at the site of the thrombus. However, in the systemic circulation, a relative excess of antiplasmin rapidly neutralizes endogenously released plasmin. Only when thrombolytic agents are administered exogenously, in pharmacological concentrations, does the circulating antiplasmin become rapidly depleted, leading to an imbalance that favours unopposed thrombolysis, development of a systemic lytic state, and enhancement of haemorrhagic complications (particularly at sites of prior venepuncture or arterial puncture). SK, a foreign protein produced commercially from ultrafiltrates of Lancefield group C cultures of Streptococcus haernolyticus, forms an activator complex by combining with plasminogen in an equimolar (1 : 1) ratio. This activator complex converts other plasminogen molecules to plasmin. The SK-plasminogen complex is gradually converted to an SK-plasmin complex, which also activates and converts plasminogen to plasmin. There is more clinical experience worldwide with SK than with all other thrombolytics combined. It is about one-tenth the price of UK or rt-PA. Its dis-
695
T H R O M B O L Y T I C S FOR V E N O U S T H R O M B O E M B O L I S M A
30,
8 x
.-
20
E ~
2
J I l I f I
I
I o ..r
0
979
198:
1985
Figure 1. Data from the US National Hospital Discharge Survey provide the ratio of all deaths with any mention of PE on the death certificate to the number of discharge forms with PE coded as a primary or secondary diagnosis. These ratios approximate a case fatality ratio but are probably overestimates, because the numerator may not be completely included in the denominator. The death rates are: 1979-23.6%: 1983-24.0%; 1985-24.7%. Modified from Goldhaber (1988).
advantage compared with other drugs in its class is an association with allergic reactions (e.g. fever, chills, hypotension, bradycardia) in about 10-15% of patients. Furthermore, patients who receive SK form high antibody titres and generally cannot receive an effective second treatment course within 6-12 months of prior administration. UK, a direct plasminogen activator, is produced by human fetal kidney cell cultures. UK converts plasminogen to plasmin through cleavage of a single peptide bond. For treatment of PE, there is more published experience with UK than with SK, and UK has secured a niche as the standard thrombolytic agent for PE against which novel clot-dissolving agents must be compared. rt-PA, produced by recombinant DNA technology, is a relatively fibrin specific serine protease that has a high ratio of activity for fibrin bound plasminogen compared with plasma plasminogen, rt-PA is composed of 527 amino acids with a molecular weight of 59 000 (unglycosylated). The aminoterminal end has a high degree of sequence homology with the kringle regions of plasminogen. The carboxy-terminal end contains a domain responsible for the protease activity. In animal models of venous thromboembolism, rt-PA appeared more potent than SK or UK and possibly safer. Unlike SK, rt-PA has not been reported to be antigenic, nor has rt-PA been linked causally to allergic reactions. The central issue surrounding thrombolysis is whether this strategy should only be used in rare circumstances, such as haemodynamically unstable, life-threatening PE, or whether its application to PE and DVT should be broadened. If thrombolysis is utilized more often, then one must decide which agent (SK, UK or rt-PA) should be chosen and what dosing regimen should be employed. To compare differing treatment strategies, the randomized clinical trial is a powerful tool that minimizes bias, chance or
696
s . z . GOLDHABER
Table 2. Randomized controlled trials of thrombolysisversus heparin in pulmonaryembolism. Reference Phase I of Urokinase Pulmonary Embolism Trial (1973)
n
Thrombolytic agent
160
Urokinase
Tibbutt et al (1974)
30
Streptokinase
Ly et al (1978)
20
Streptokinase
Findings in thrombolyticgroup Accelerated clot lysis, pulmonary tissue reperfusion, and normalization of pulmonary arterial pressure at 24 h, but increased bleeding. By 7 days, no difference in lung scans Accelerated clot lysis and normalization of pulmonary arterial pressure Accelerated clot lysis but increased bleeding
confounding. With respect to PE, three randomized controlled trials have compared thrombolysis to heparin (Urokinase Pulmonary Embolism Trial, 1973; Tibbutt et al, 1974; Ly et al, 1978) and have demonstrated accelerated clot lysis, pulmonary tissue reperfusion and reduced pulmonary artery pressures, compared with heparin alone (Table 2). A subset of patients from one of these trials was investigated 2 weeks and 1 year after treatment, and improved pulmonary capillary blood volume was observed in the group that received thrombolysis (Sharma et al, 1980). None of these trials demonstrated a reduction in mortality or an improvement in quality of life among patients randomly assigned to thrombolytic therapy. As expected, patients randomized to thrombolysis experienced more bleeding complications than heparin treated patients. Furthermore, in phase I of the Urokinase Pulmonary Embolism Trial ( U P E T ) , there was no difference in lung scans between the two groups when compared 1 week after initiation of therapy ( U P E T , 1973). Thus, the allure of thrombolysis for PE treatment resides more in its potential rather than proven benefit. For example, in the U P E T there was a strong hint that thrombolytic therapy might reduce both mortality and recurrent P E compared with heparin treatment. However, the differences between these two treatment modalities did not attain statistical significance, possibly due to a relatively small sample size. In the U P E T , of the 78 patients who received heparin, 7 (9%) died, 18 (23%) had recurrent PE, and 24 (31%) died or had recurrent PE within the first 2 weeks of treatment. By comparison, among the 82 U K treated patients, 6 (7%) died and 14 (17%) had recurrent PE, and 19 (23%) died or had recurrent PE within 2 weeks. Thus, the rate of death or recurrent PE was 25% lower among the U K treated patients (31% for heparin versus 23% for UK), but this difference was not statistically significant. Nevertheless, the trend supports the hypothesis that thrombolytic therapy can save lives and reduce morbidity from recurrent PE. Given the U P E T sample size and event rate in the heparin group, reductions in event rates would have had to have been about 60% to be detected with 80% power. In the treatment of DVT, thrombolytic therapy may lyse thrombus in situ
4
4
5
14
8
Kakkar et al (1969)
Robertson et al (1970)
Tsapogas et al (1973)
Porter et al (1975)
Elliot et al (1979)
600
250
500§
Twice the titrated dose't
500
Twice the titrated doset
100/h
100/h
100/h
100/h
900/6 h
100/h
35
35
2-35
3
-> 5
1:~
10
0,15/kg
7
7.5
10
7.5
Heparin loading dose (units x l0 s)
5-6
10
A continuous infusion was adjusted to maintain partial thromboplastin time at x 2-2.5 the control value, for 10 days 10/6 h via constant infusion pump (but adjusted to maintain partial thromboplastin time at x 2.5-3 the control value) for 7 days
2-3
6-8
Approximately every 2 days
5-6
Phlebographic follow-up period (days)
1.5/h (but adjusted to maintain partial thromboplastin time at x 2-2.5 the control value) for 9 to 10 days
17.5/10.5 h; 25/12 h for 2.5 days
10-15/6 h for 5 or more days via continuous infusion (adjusted to maintain thrombin clotting time in 16-120 s range)
42.5/22 h via continuous infusion; 25/12h s,c, for 2 days; 12.5/12h s.c. for 3 days; 12.5 s,c, daily for 1 to 2 days
Sequence and route* of heparin administration after loading dose (units x 103)
* Administered intravenously unless otherwise specified. "t Method of Nilsson and Olow (1962). $ Patients were then switched to heparin regimen. § The investigators gave a 500 000 unit dose unless the titrated dose, using the method of Fletcher et al (1959), was less than 300 000 units; such patients were given the titrated dose plus 100000 units. From Goldhaber et al (t984) with permission.
4
Robertson et al (1968)
Reference
Maximum duration of symptoms Streptokinase Streptokinase Streptokinase (days prior to loading dose infusion dose infusion treatment) (units x 103) (units x 103) period (days)
Table 3. Randomized controlled trials of streptokinase versus heparin in deep vein thrombosis.
o
o
o
o
