Transcript Slide 1

Novel Uses for
Antithrombotics
Jim Holliman, M.D., F.A.C.E.P.
Program Manager
Afghanistan Health Care Sector Reconstruction Project
Center for Disaster & Humanitarian Assistance Medicine
Uniformed Services University of the Health Sciences
Bethesda, Maryland, U.S.A.
Novel Uses of Antithrombotics :
Lecture Outline and Goals
List
of standard approved uses for
antithrombotics (thrombolytics)
Present “new” and unusual clinical uses for
antithrombotic agents
Indications
Agent names and dosages
Complications
Review of antithrombotics use in cardiac
arrest
Current Standard Approved Clinical
Indications for Antithrombotics
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Acute myocardial infarction
Acute ischemic stroke
Acute peripheral arterial thrombosis
Pulmonary embolus with hemodynamic
compromise
“Cathflo Activase” by
Genentech
• Recombinant human tissue plasminogen
activator (t-PA) (alteplase)
• Action of alteplase is as an enzyme
(serine protease) which binds to fibrin in
a thrombus, converts entrapped
plasminogen to plasmin, thereby
initiating local fibrinolysis
• Each vial contains 2.2 mg of sterile,
lyophilized alteplase powder
Clinical Indications for Cathflo
Activase
• Restore patency to central venous access
devices which are malfunctioning
– This malfunction defined as inability to withdraw
at least 3 cc. of blood from the device
– Restoration of patency defined as successful
withdrawl of 3 cc. of blood and instillation of at
least 5 cc. of saline in the device
Types of Central Venous Access
Devices for Which Cathflo
Activase Can Be Used
• PICC (“peripheral intravenous central
catheter”) lines
• Hickman catheters
• Broviac catheters
• Implanted subcutaneous ports
• Swan-Ganz catheters
• Standard central venous catheters
• Central venous insertion sheaths
Other Causes of Central Venous
Catheter Malfunction to Consider
Besides Thrombosis
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Catheter malposition or kinking
Mechanical failure
Constriction by a suture
Lipid deposits or medication precipitates
in the catheter lumen
Contraindications to Use of
Cathflo Activase
• Non-thrombotic cause for the
malfunction
• Allergy to Activase
• High risk for bleeding or embolization
• Most studies have also excluded
hemodialysis catheters and patients less
than 2 years of age or 10 kg weight
Administration of Cathflo
Activase
• Vial reconstituted with 2.2 ml of sterile
water
• First dose of 2 ml gently injected into the
device
• May repeat 2 mg dose if not patent after
30 to 120 minutes
• Using more than two doses has not yet
been studied
Success Rates for Cathflo
Activase
• Several studies compiled :
– 50 to 70 % after first dose
– 80 to 85 % after second dose
– Similar success rates across all types of
catheters and all age groups
Complications of Cathflo
Activase
• Note that the incidence of all these has
been low in studies so far (only a few
cases each in > 1000 patients) :
– Sepsis
– Gastrointestinal bleeding
– No allergic reactions
– No intracranial hemorrhage
Use of Antithrombotics to Treat
Intraventricular (Intracranial)
Hemorrhage
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First studied in 1986
Followup series reports in 2004 and 2005
Both t-PA and urokinase studied
Intraventricular injection of the
thrombolytic
– Speeds intraventricular clot resolution
– Allows better CSF drainage thereby
preventing hydrocephalus
Use of Fibrinolytic Therapy for
Pleural Infection (Empyema)
• Pathophysiology behind this :
– Fibrin strands bridge pleural membranes &
transform free-flowing pleural fluid in the early
“exudative” stage of empyema into loculations &
fibrous peels in the late “organized” stage
– Patients who progress thru the intermediate
fibrinopurulent stage commonly do not benefit
from chest tube drainage & require surgical
intervention (thoracotomy and decortication)
Use of Fibrinolytic Therapy for
Pleural Infection (cont.)
• So the rationale behind this is that
intrapleural fibrinolytic agents are
thought to disrupt the fibrin loculations,
thereby enhance chest tube drainage,
and obviate the need for surgical
drainage
Studies on Intrapleural
Fibrinolytics
• First controlled clinical studies reported
in 1997
• Some studies used urokinase (no longer
readily available in the U.S.)
• Several other studies used streptokinase
• Recent studies have used alteplase
(doses of 2 to 50 mg in different studies)
Problems in Comparing the
Different Empyema Fibrinolytic
Treatment Studies
• Different agents, doses, dosing intervals,
agent dwell times, antibiotic regimens,
chest tube sizes, & verification means for
chest tube position
• Some enrolled patients at all stages (rather
than just early stages)
• Different proportions of elder patients and
those with poor baseline health status
Metaanalysis Conclusions About
Empyema Fibrinolytic Studies
• “Clinical evidence of benefit remains marginal”
• Most studies have not shown improved mortality or
decreased need for surgical drainage
• American College of Chest Physicians Empyema
Panel : “fibrinolytic therapy & surgical drainage
techniques represent competing options, but that
appropriate patient selection & the relative timing of
the procedures remain uncertain”
Recent Advocacy for Use of
Intrapleural Alteplase
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Two case series reports in 2007
2 mg dose (Cathflo Activase) used
Dwell time 2 hours
Dose interval 4 to 8 hours
Up to 9 doses used
No cases have needed surgical
intervention
General Conclusions About
Empyema Fibrinolytic Studies
• Features needed in future studies :
– Utilize modern minimally invasive surgical techniques,
such as video-assisted thoracoscopy & muscle-sparing
thoracotomy
– Enroll patients with potential to benefit from fibrinolysis
– Adjust outcomes to the severity of infection
– Use computed tomography to determine the stage of
empyema prior to treatment
• Current data favor early use of video-assisted thoracoscopy
for cases of fibrinopurulent empyemas that cannot be
managed by chest tube drainage, with fibrinolytic therapy
reserved for patients who are poor surgical candidates
Intrapericardial Use of
Thrombolytics
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First reported in 1997 (streptokinase)
Found useful in management of purulent pericarditis
No controlled studies due to rarity of cases
Feb. 2007 report of use of tenecteplase (TNKase) 3
doses over 3 days to facilitate pericardial catheter
drainage of a malignant pericardial effusion
• Does not appear to have any systemic anticoagulant
effect
Direct Intraclot Injection of
Alteplase for Leg DVT
• Reported in Feb. 2008 in Radiology
• National Institutes of Health in Bethesda,
Maryland conducted the study
• Goal was to avoid post-phebitic syndrome and
lessen the potential bleeding complications
related to systemic use of Alteplase
• Concurrent systemic anticoagulation used
Features of the Direct Injection
Alteplase DVT Study
• 20 patients, first onset acute DVT
• 50 mg of alteplase per leg was injected
directly intraclot
• Maximum of 4 treatments per leg
• Full systemic anticoagulation
• Mean followup period was 3.4 years
Conclusions of the Direct
Injection Alteplase DVT Study
• Antegrade blood flow restored in the deep venous system in
80 % during thrombolysis
• Recovery of plasminogen activator inhibitor within 2 hours
after termination of dosing
• Ventilation / perfusion scans showed 40 % incidence of
pulmonary embolus prior to treatment and 15 % during
treatment, but no cases were clinically important during
treatment
• No patient developed postthrombotic syndrome or recurrent
thromboembolism
Use of Thrombolytic Agents in
Cardiac Arrest
• Cochrane Library review published in 2006
• Rationale is that 50 to 70 % of cardiac arrest cases
are caused by massive pulmonary embolism or
acute myocardial infarction, & thrombolytics are
effective for these
• First case reported in 1974
• 33 single case reports and 10 case series found
(total of 87 patients reported)
• 63 survivors (72.4 %) ; 6 cases after > 90 minutes of
CPR (? selective reporting bias ?)
Cochrane Review of the Six
Prospective Studies Done on
Cardiac Arrest
• One using 50 mg of alteplase in 40 patients
found increased survival (15 vs. 6 %)
• One showed no effect (but treatment was 36
minutes after arrest)
• 3 studies had major design flaws
• Only one survivor (in control group) in a 35
patient randomised controlled trial using 50
mg of tenecteplase
The Thrombolysis in Cardiac
Arrest Trial
• Aim of this study is to correct the flaws in
randomization and blinding in prior studies
• Goal is to recruit 1000 patients across 60 study
centers
• Now underway in 5 European countries
• Includes all presenting cardiac rhythms
• Intervention is early (right after first cycle of
advanced life support)
• Study endpoints include 30 day survival and
neurologic status
Novel Uses of Antithrombotics
Lecture Summary
• 2 mg doses of alteplase are available and
useful for resolving central venous
catheter thrombosis
• More study is needed to clarify use of
thrombolytics for treatment of empyema,
pericardial effusions, and in cardiac
arrest
QUESTIONS ?
Thanks for Your Attention