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Article Reviewed:

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Low-dose tissue plasminogen activator thrombolysis in children.

Wang M, Hays T, Balasa V, et al.

J Pediatr Hematol Oncol. 2003 May;25(5):379-86. [abstract]

Reviewed by Mubeen Rafay MD, The Hospital for Sick Children, Toronto, Ontario, Canada.

Review posted October 31, 2005

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I. What is being studied?:

The study objective:

1. Describe the comparative efficacy of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing (1, 2).
2. Identify a minimally effective dose of TPA in children.
3. Describe complications/toxicity associated with TPA administration in children.

The study design:

This is a retrospective, descriptive case series. Study subjects were children seen at six medical centers by a pediatric hematologist and were enrolled retrospectively from the individual hematologist's own clinical database. The small number of patients in the study was intended as purely descriptive study, in anticipation of a future controlled trial.

The patients included:

Children, birth to 18 years of age, with objectively confirmed evidence of either venous or arterial thrombi treated with either systemic or local thrombolysis were included. Only children with adequately available information were included. Thirty five children were studied, 29 with acute thrombi and 6 with chronic thrombi. Of the 29 with acute thrombi, 12 received standard dose TPA (0.1-0.5 mg/kg per hour) and 17 received low dose TPA (0.01-0.06 mg/kg per hour) regimen. Of the 6 with chronic thrombi, all received standard dose TPA except one.

The patients excluded:

Children with active bleeding, major surgery or central nervous system bleeding within 10 days, a major asphyxial event within 7 days such as birth asphyxia, an invasive procedure within 72 hours, seizures within 48 hours, or the inability to maintain a platelet count of at least 50,000/mcL or fibrinogen at least 100 mg/dL were excluded for TPA thrombolysis. However, numbers of patients excluded are not mentioned.

The interventions compared:

The two doses that were used included published standard (adult) dose (0.1-0.5 mg/kg per hour) and a low-dose regimen (0.01-0.06 mg/kg per hour), which has never been described in children. During TPA infusion, 42% of patients received concomitant prophylactic unfractionated or low-molecular-weight heparin infusion, at the attending physician's discretion, based on recently published reports of safety (3).

The outcomes evaluated:

1. Effectiveness of low dose TPA based on clot resolution
2. Safety of low dose TPA based on evaluation of complications including bleeding and postthrombotic syndrome.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

No. The study data was collected retrospectively.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Unclear. The investigators used their clinical databases to identify patients but do not mention if they were certain they captured all patients receiving TPA. They did not use a standard method of identifying patients such as use of appropriate medical record coding system. Therefore, the possibility of the selection bias is highly likely. The pooling of data from multiple centers may have been helpful in reducing this; however this might have resulted in heterogeneous data collection.

Was followup complete?

Yes. Clinical information was available for all subjects until the primary study outcome was achieved (clot resolution or no resolution). The authors provide limited information about the type and results of the diagnostic imaging studies.

Were patients analyzed in the groups to which they were randomized?

No. Patients were not randomized in this retrospective case series, nor were they were assigned appropriately for analysis. A significant proportion of patients with acute thrombi treated with low dose TPA (5/29 patients) required dose escalation because of lack of response. In these patients, the total escalated dose was equal to standard dose TPA regimen (e.g., patient 26, 27, 28 and 29 received 0.1 mg/kg/hr and 0.2 mg/kg/hr respectively). One patient (patient 25), reported to be treated with low dose, actually received standard dose TPA (0.3 mg/kg/hr) at the beginning of infusion.

In addition, patients were treated for significantly longer duration then recommended standard dose guidelines for TPA infusion which is 0.1 to 0.6 mg/kg/hr for 6 hours 1. A majority of children received TPA for more than 6 hours. Patients in the low dose TPA regimen were treated for longer duration compared to standard dose TPA regimen (mean 12.7 hours in standard dose TPA regimen versus 40 hours in low dose TPA regimen). Authors also commented that 5 of the low dose courses required extended infusions beyond 48 hours. The total calculated dose of TPA in these patients was equivalent to standard dose regimen. These patients should have been analyzed with the patients who received the standard dose TPA regimen.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

No.

4. Were the groups similar at the start of the trial?

No, there was marked heterogeneity between and within the studied groups. The study groups differed with respect to age (both neonates and older children and term and preterm neonates were included), age of the thrombus (acute versus chronic), type of thrombus (arterial versus venous), etiology and risk factors for thrombosis (catheter related versus existence of prothrombotic disorders), associated co-morbid medical conditions, location of thrombus and diagnostic imaging methods for determining the presence of thrombus.

5. Aside from the experimental intervention, were the groups treated equally?

No. Several treatment differences existed between as well as within the studied groups:

1. The method of treatment varied greatly between the individual subjects. Patients either received local or systemic therapy. In addition, some patients also received bolus doses prior to initiation of infusions.
2. During administration of TPA infusion, 42% of patients received concomitant prophylactic unfractionated or low-molecular-weight heparin infusion. The duration of heparin treatment has not been described in the study. In addition, it is unclear whether heparin therapy preceded thromblytic therapy.
3. A significant proportion (83%) of children had multiple co-morbid conditions, and likely received widely varying supportive therapies apart from the TPA regimen, the details of which have not been described in the study. Of note is the fact that the role of anticoagulants and thrombolyis in some of these conditions is still controversial such as infectious causes and tumor extension in arteries and veins.

III. What were the results?

1. How large was the treatment effect?

The usual measures of treatment effect could not be calculated because of the lack of efficacy data and control group in this study. Summary of the findings is presented below:

Effectiveness:

In this study, either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. Five courses of low-dose therapy for acute thrombi and one course of high-dose therapy for a chronic thrombus were dose-escalated for lack of clot lysis. All five escalated low-dose therapies resulted in complete clot lysis. Five courses of low-dose therapy for very extensive thrombi (three for acute thrombi, two for chronic thrombi) were extended beyond 48 hours, with excellent results in all.

The data shown in the tables is misleading. If one carefully examines the data, of the 12 patients with acute thrombi and treated with standard dose, all had complete lysis except one, in whom the infusion was discontinued prematurely because of recent surgery (absolute contraindication for the treatment). So basically the resolution rate in this group is actually 100%.

Of the 17 patients with acute thrombi treated with low dose regimen, there were total of 8 patients who failed treatment since 5 courses of low dose regimen required dose escalation to standard doses (as well as longer treatment duration) and 2 additional patients required treatment beyond 48 hours (mentioned in results). So the failure rate for the low dose regimen in this study was 47% (8 out of 17). However, the authors did not count these patients as failures.

The authors also reported that route of administration (local or systemic) did not affect efficacy. However, because of heterogeneity of patients and small sample size, this can not be determined from their study. It is important to note that present study provides no information about the relative timing of clot lysis after initiation of TPA therapy in each group. Although complete resolution of clot is one of the study outcomes, rapidity or delay in clot lysis and its relationship to development of complications such as embolic stroke, pulmonary embolism and post thrombotic syndrome would have been useful in evaluating the efficacy and safety of different dosing regimen.

In addition, all children with acute thrombi and who were treated with concomitant heparin therapy had complete resolution of clot except one, leading one to speculate the significant contribution of heparin therapy in clot lysis.

Safety:

In the present study, bleeding was observed in 9 of 35 (26%) patients; seven complications consisted of minor oozing at venipuncture sites and one child with minor hematuria and hematoma. One preterm neonate (patient 29) had life threatening hemorrhage consisting of subdural hemorrhage requiring subdural drain. This neonate required progressive dose escalation (from 0.03 to 0.24 mg/kg per hour) based on progressive clot enlargement. Although according to authors, bleeding complications showed no apparent relationship to TPA total dose, TPA concentration, or duration of infusion. Careful examination of the data revealed that 5 children with low dose regimen compared to 3 children with high dose regimen had bleeding complications, excluding the patient who required dose escalation. In addition, all children with bleeding received longer (more than 12 hours) duration of infusion, which is twice the published recommended duration of 6 hours1.

The authors also reported that concomitant prophylactic unfractionated or low-molecular-weight heparin infusion did not increase the risk of bleeding. Again it is difficult to determine this with the already mentioned limitations of the current study.

One patient (Patient 14) with huge left atrial thrombus secondary to very poor cardiac function (ejection fraction decreased from 15% to 9%), developed a major complication consisting of an embolic stroke following 6 hours of low dose TPA (0.03 mg/kg per hour), although the intra-cardiac clot did completely resolve by the end of infusion. One possible explanation might be delay in clot lysis with low dose TPA compared to standard dose TPA.

Postthrombotic syndrome associated with dilated collaterals with or with out pain and swelling following aerobic exercise developed in two children. Both patients were treated with short-duration, standard-dose TPA. The authors correctly pointed out that it is impossible to determine the relationship of TPA and development of post thrombotic syndrome with the current study limitations.

2. How precise was the estimate of the treatment effect?

Either low dose or standard dose TPA infusions resulted in complete lysis of clot in 28 of 29 patients (97%) with acute thrombi, with a calculable 95% confidence interval of 0.81 to > 0.99. However, other estimates of treatment effect could not be calculated because of the lack of a control group and lack of efficacy data in children.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Lack of controlled studies and the morbidity and mortality associated with intravascular thrombosis in children make this a relevant issue for study. The effectiveness and safety of thrombolysis with TPA compared to anticoagulation with heparin in arterial versus venous thrombi still needs to be determined in children. Several published case reports and case series of pediatric patients have shown that TPA has lysed thrombi in critically ill infants and children. In one retrospective study without controls, about 65% of clots had complete resolution, particularly in the post-cardiac catheterization groups (p=0.006) (4) and according to a recent literature review, bleeding complications requiring packed red cell transfusions occur in 20% of children receiving TPA thrombolysis (5).

The present study by Wang and colleagues is aimed at evaluating the minimal effective and safe dose of TPA for thrombolysis in children. Overall, the limitations in study design (retrospective case series, diagnostic imaging methods with varying sensitivity/specificity profiles, concomitant treatment with heparin therapy etc) and suboptimal reporting of results do not allow the reader to draw particularly strong inferences from the data. This study did demonstrate that TPA was consistently effective in lysis of acute thrombi similar to previous reports. However, the complication rate was higher then reported in literature (26%) (5). The rate of major complications might be justifiable if the patient were at significant risk for life-threatening embolism (pulmonary and cerebrovascular) or perhaps loss of a limb. The rate may not be acceptable if the risk were only for loss of the vein and subsequent recanalization of collaterals. In addition, the study does not attempt to address any benefit that might result from resolving the thrombus (clot) and also the complications that might result from delayed clot resolution. These questions will remain problematic and unanswered until a prospective randomized clinical trial is conducted to verify the efficacy as well as the short term and long term safety of TPA (with varying dosing and duration of therapy) in children.

2. Were all clinically important outcomes considered?

Yes. The study included a description of major clinical events including clot lysis, death, bleeding and postthrombotic syndrome.

3. Are the likely treatment benefits worth the potential harms and costs?

The " efficacy" and "safety" of this intervention (numbers needed to treat, absolute risk of complications, number needed to harm) cannot be ascertained by the way the study as designed. Only observed apparent successes and complications can be reported.

References:

1. Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 2001; 119 (1 Suppl):344S - 370S. [abstract]
2. Valji K. Evolving strategies for thrombolytic therapy of peripheral vascular occlusion. J Vasc Interv Radiol 2000; 11: 411- 420. [abstract]
3. Giugliano RP, McCabe CH, Antman EM, et al. Lower-dose heparin with fibrinolysis is associated with lower rates of intracranial hemorrhage. Am Heart J 2001; 141:742- 750. [abstract]
4. Gupta AA, Leaker M, Andrew M, et al. Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children. J Pediatr. 2001 Nov; 139(5):682- 688. [abstract]
5. Leaker M, Massicotte MP, Brooker L, et al. Thrombolytic therapy in pediatric patients: a comprehensive review of the literature. Thromb Haemost 1996; 76: 132 - 134. [abstract]

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