Jim Holliman, M.D., F.A.C.E.P.

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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.
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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

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Current Standard Approved Clinical Indications
for Antithrombotics

• Acute myocardial infarction
• Acute ischemic stroke
• Acute peripheral arterial thrombosis
• Pulmonary embolus with hemodynamic compromise

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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

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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

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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

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Other Causes of Central Venous Catheter
Malfunction to Consider Besides Thrombosis

• Catheter malposition or kinking
• Mechanical failure
• Constriction by a suture
• Lipid deposits or medication precipitates in the
  catheter lumen

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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

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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

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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

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Complications of Cathflo Activase

• Note that the incidence of all these has been low
  in studies so far (only a few cases each in gt
  1000 patients)
• Sepsis
• Gastrointestinal bleeding
• No allergic reactions
• No intracranial hemorrhage

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Use of Antithrombotics to Treat Intraventricular
(Intracranial) Hemorrhage

• 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

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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)

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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

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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)

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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

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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

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Recent Advocacy for Use of Intrapleural Alteplase

• 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

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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

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Intrapericardial Use of Thrombolytics

• 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

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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

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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

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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

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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 gt 90
  minutes of CPR (? selective reporting bias ?)

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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

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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

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Novel Uses of AntithromboticsLecture 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

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QUESTIONS ?
Thanks for Your Attention