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

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.

2. 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

3. Current Standard Approved Clinical Indications for Antithrombotics • Acute myocardial infarction • Acute ischemic stroke • Acute peripheral arterial thrombosis • Pulmonary embolus with hemodynamic compromise

4. “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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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)

14. 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

15. 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)

16. 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

17. 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”

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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 ?)

25. 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

26. 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

27. 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

28. QUESTIONS ? Thanks for Your Attention