Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children.

Gupta AA, Leaker M, Andrew M, et al.

J Pediatr. 2001;139(5):682-8. [abstract]

Reviewed by John Berger MD, Children's National Medical Center, Washington, DC

Review posted December 6, 2004

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I. What is being studied?:

The study objective:

• Determine effectiveness of tPA (Alteplase) in treatment of intravascular blood clots as measured by return of palpable pulses or objective imaging (angiography, ultrasound or radionuclide scan) in children.
• Determine complications of tPA administration in children.
• Determine factors associated with thrombus resolution or complications.

The study design:

Retrospective case series of 80 consecutive episodes of arterial or venous thrombosis in children that were treated with systemic or local tPA (Alteplase) therapy (79 patients) at a single institution.

The patients included:

All children identified by a pharmacy database as receiving tPA between 1985 and 1999. Only children with intravascular blood clots were included although the authors do not include specific data regarding the clinical interventions employed to find these cases. Patients were divided into 3 groups (See table). Median age at time of treatment was 6 months (range 2 days to 17.8 years).

Sub-Group	Inclusion criteria (i.e. documentation of clot)	n	Notes
Arterial thrombus after cardiac catheterization	Clinical (pulse loss, cool or mottled extremity and decreased capillary refill)	56	Pulse assessment by Doppler was performed in 33 patients
Arterial thrombus independent of cardiac catheterization	Angiography, renal scan, ultrasonography, or echocardiogram	9
Venous Thrombus	Venography, ultrasonography, lung V/Q scan	15	6 patients with PE 9 with venous thrombus

The patients excluded:

Patients who had received tPA for central venous line occlusions or ophthalmologic procedures.

The interventions compared:

Patients received intravenous infusion of tPA at 0.5 mg/kg/hour for either: a) 6 hours by protocol, b) patient had signs of clot resolution or c) uncontrolled bleeding. During tPA infusion, patients received concomitant heparin infusion. Patients had been treated with heparin for a variable time prior to tPA infusion without showing resolution of thrombus.

The outcomes evaluated:

Effectiveness of Alteplase: Complete clot resolution (return of peripheral pulse by palpation or thrombus not detected by diagnostic imaging), partial clot resolution (intermittent presence of pulse or reduction in clot size by diagnostic imaging), or no resolution

Complications

• Major- Hemorrhage requiring blood product transfusion, CNS hemorrhage, or CNS ischemia secondary to profound blood loss
• Minor- Hemorrhage not requiring blood product transfusion

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

No. This is a retrospective case series.

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

Was followup complete?

Yes. Clinical information was available for all subjects until hospital discharge. No information was provided for patients who were identified by the database but for whom clinical records were unavailable. The authors provide limited information about the diagnostic imaging studies used as well as the results of these studies.

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

Patients were not randomized in this retrospective case series.

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, the study groups differed with respect to etiology of the thrombus, and diagnostic methods for determining the presence of thrombus.

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

No. This heterogeneous group of patients likely received widely varying supportive therapies apart from the tPA/heparin regime.

III. What were the results?

1. How large was the treatment effect?

This is a retrospective case series without a control group; therefore it is not possible to calculate usual measures of treatment effect. Summary of findings is presented below:

Effectiveness:

Group (n)	Complete Resolution	Partial Resolution	No Response
Overall (80)	65%	20%	15%
Cardiac Catheterization Arterial (56)	73%	20%	7%
Arterial Thrombus (9)	56%	0%	44%
Venous Thrombus (15)	40%	33%	27%

The authors report increased effectiveness in the post-cardiac catheterization groups (p = 0.006) however, the study groups are not comparable for reasons listed above.

Safety:

32 patients (40%) had "major complications" (defined as bleeding requiring transfusion, CNS hemorrhage, or CNS ischemia attributable to profound blood loss), and 24 patients (30%) had "minor complications" (defined as bleeding not requiring transfusion). 24 patients (30%) had no observable complications. The major complications included 31 patients who required blood transfusions, 3 patients with CNS bleed and 2 patients with CNS ischemia associated with profound blood loss. There were two deaths in this series of patients treated with tPA. However, the deaths were not thought to be attributable to the tPA infusion. The prevalence of complications was not significantly different among patient groups (P = 0.73).

Major complications were associated with significantly longer duration of tPA infusion (median 8.5 hours vs. 4.3 hours for patients with minor or no complications; P < 0.006), lower patient weight (p = 0.06) and greater decline in fibrinogen level (p = 0.07) although the last two associations did not reach statistical significance. Significantly fewer major complications occurred in patients who had greater clot resolution (major complications occurred in 32% of those with complete resolution, 50% of those with partial resolution, and 61% of those with no change; P = 0.046).

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

Not calculable due to the lack of a control group.

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

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

It is hard to know whether or not the group of patients included in this study is representative of most PICU patients, because the authors provide so few details on their clinical status and comorbidities. Nonetheless, the morbidity and mortality associated with intravascular thrombosis in children make this a relevant issue for study.

This study demonstrates that tPA can resolve intravascular thrombi in children, particularly those which occur following cardiac catheterization, but its administration may be associated with clinically significant complications including CNS hemorrhage. Administering tPA locally rather than systemically may not substantially affect the complication rate. Effectiveness of tPA compared to other agents or continued heparin infusion is not assessed in this study. Overall, the limitations in study design (retrospective single-center case series, diagnostic imaging methods with varying sensitivity/specificity profiles, etc) do not allow the reader to draw particularly strong inferences from the data.

The study does not allow a clinician to calculate the relative risks and benefits for using tPA versus other therapies.

The study does not attempt to address any benefit that might accrue from resolving the thrombosis. The rate of major complications might be justifiable if the patient were at significant risk for life-threatening pulmonary embolism or perhaps loss of a limb. The rate would surely not be acceptable if the risk were only for loss of the vein and subsequent recanalization of collaterals.

2. Were all clinically important outcomes considered?

Yes. The study included a description of major clinical events including death, bleeding and CNS injury.

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

The major strength of this report is the description of adverse events in patients treated with tPA. Since the there is no control group, the clinician will need to balance of the risks of bleeding versus the risk of the thrombus based on clinical judgment. It should be noted that the "safety" of this intervention (absolute risk increase of complications, number needed to harm) cannot be ascertained by the way the study is designed. Only observed complications can be reported.

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