Addressing thrombembolic treatment and prophylaxis and introducing new drug Pradax.

1. Thromboprophylaxis and DVT in General
Surgery
J.van Leeuwen , surgeon
Klinische Conferentie
3/11/10

2. We should be aware that . . .
• 70% of all VTE is hospital-acquired
• VTE is the commonest preventable
cause of hospital death
• Thromboprophylaxis the number 1
ranked patient safety strategy in
hospitalized patients

3. As general surgeons or
clinicians . . .
• What can you do to reduce the burden
of VTE?
• Be knowledgeable about VTE
• Assess your patients for VTE risk and
use thromboprophylaxis routinely
• Support hospital-wide
thromboprophylaxis

4. DVT Blood Clots: A Potentially Fatal Health
Problem
• Up to 2 million people in the United States suffer
from
DVT blood clots every year
• Approximately 600,000 experience pulmonary
embolism (PE)
• In the US, complications from DVT blood clots kill
almost 300,000 people a year — more than AIDS
and breast cancer combined

5. DVT
•Common, potentially life – threatening
• medical problem
•Is better prevented but once happened should
• by aggressively treated
•Risk factors (Virchow’s Triad)
•50% of DVT are “silent”

6. DVT
 Swelling of the leg
 Pain or tenderness in the leg; the pain is
usually in 1 leg and may only be present
when standing or walking
 Leg feels warm to the touch
 Red or discolored skin

7. PE
 Unexplained shortness of breath
 Chest pain or palpitations
 Anxiety and/or sweating
 Coughing up blood
 Fatigue and/or fainting

8. Some of the risk factors that may
increase risk of DVT
• Age 40 years or older
• Being overweight
• A personal or family history of blood clots
• Birth control pills
• Hormone replacement therapy (HRT)
• Cancer

9. • Certain heart problems
• Respiratory failure
• Varicose veins
• Pregnancy
• Surgery, especially hip, knee,
or abdominal surgery
• Currently have restricted mobility due to a
long illness
or surgery

12. DVT Prophylaxis
Early ambulation
Stockings with or without
pneumatic compression
Antiplatelets
Anticoagulant (low dose heparin)

13. Indications For Antithrombotic Therapy
• Venous thromboembolic disease
• Deep venous thrombosis (DVT)
• Pulmonary embolism (PE)
• Arterial thromboembolic disease
• Prosthetic heart valves
• Mitral valve disease
• Congestive cardiomyopathies
• Atrial fibrillation
• Mural cardiac thrombi
• Transient ischemic attacks
• Stroke in evolution
Disseminated intravascular coagulation
• Maintenance of patency of vascular grafts, shunts, bypasses

15. Practical measures
Elevate the affected leg whenever possible
• Apply heat to relieve pain and reduce
swelling
• Wear compression bandages or
support hose
• Avoid long periods of immobility

16. Treating DVT
• Treatment of DVT can help reduce
complications
such as PE
• The main goals in treating DVT are to:
• Stop the clot from getting larger
• Reduce the chance of developing
another clot
• Reduce the risk of the clot breaking off
in your vein
and moving to your lungs

17. Complications of DVT
 PE
Secondary varicose veins
Postphlebitic limb:
 Varicose veins, ulcer, pain,
change of colour, lipodermatosclerosis

18. Treatment of DVT
Legs elevation
 iv. heparin infusion and monitoring by
PTT
acenocoumarol and monitoring by INR
LMWH, fibrinolytic Rx
I.V.C. filter
Surgical thrombectomy

19. Anti Platelet Drugs
Drug Mechanism Uses
Aspirin Permanently
inhibits COX-1
and COX-2
CAD
Stroke-TIAs
NSAIDs Reversibly
inhibits COX-1
Limited
Dipyridamole Inhibits PDE;
increases cAMP
TIAs
Ticlopidine
Clopidrgrel
Inhibits ADP
PlatAg;active
metabolite
TIAs;Stroke
CAD;PVD

20. Platelet Receptor Mediated
Pathways: Drugs
Arachidonic Acid ASA
NSAIDs
ADP Ticlopidine
Clopidogrel
Thrombin
-Final Common Pathway
-Promotes Platelet
Adhesion (Fibrinogen,
vWF)
GP IIB/IIIA Inhibitors
Abciximab (ReoPro)
Eptifibatide (Integrilin)
Tirofiban

21. Contraindications to
Antithrombotic Therapy
-Recent thoracic, abdominal, or
central nervous system surgery
-Recent cerebrovascular
accident, trauma, or neoplasm
-Bleeding ulcer
-Hypertension
-Anticipated invasive procedures
(arterial punctures, biopsies, central
lines)
-Concurrent hemostatic
dysfunction

22. Contraindications to
Antithrombotic Therapy
• Specific to acenocoumarol (ambulatory
patients)
-Early and late pregnancy
-Poor patient cooperation,
understanding, reliability
-Unsatisfactory laboratory or patient
follow-up
-Occupational risk to trauma

23. Contraindications to Antithrombotic
Therapy
• General risk factors
-Pre-existing coagulation or platelet defect,
thrombocytopenia, or other bleeding abnormality
-Inaccessible ulcerative lesion (e.g., gastrointestinal tract
lesion)
-Central nervous system lesion (e.g., caused by stroke,
surgery, trauma)
-Spinal anesthesia or lumbar puncture
-Malignant hypertension
-Bacterial endocarditis
-Advanced retinopathy
-Old age (relative)
-Aspirin or other antiplatelet drugs
-Neoplastic disease

28. www.freelivedoctor.com

30. Low Dose Unfractionated
Heparin
• Surgical Prophylaxis
• 5,000 Units SQ 2 hr preop
• 5,000 Units SQ every 12 hours
• Medical Prophylaxis
• 5,000 Units SQ every 12 hours
• No monitoring required

31. Monitoring of
Anticoagulant Therapy
Heparin
s.q. – no monitoring required
i.v. - partial thromboplastin time (P.T.T.)
mechanism – measures intrinsic pathway
therapeutic goal – 2-2.5 times normal
control value (-30 sec)

32. Unfractionated Heparin
• High Dose
• Treatment of venous/arterial thrombi
• Requires monitoring
• IV- 5,000 Units bolus, then 30,000-
35,000 units/24 hrs
• 80 Units/kg bolus, then 18 Units/kg/hr
to maintain aPTT in therapeutic range

33. Dabigatran etexilate is a novel medicine, small
molecule, reversible, direct thrombin inhibitor
For oral administration the prodrug dabigatran
etexilate was developed in 75 and 110 mg
NH2
N
NH
N
N
CH3
N
OO
O
N
O
O CH3
CH3
Dabigatran etexilate
What is Pradaxa?

34. • Oral prodrug, converted to dabigatran, a potent
reversible direct thrombin inhibitor (DTI)
• Half life of 12-17 h,
• ~ 80% renally excreted
• 6.5% bioavailability
• Rapid onset of action
• Predictable and consistent anticoagulant effects
• Low potential for drug-drug interactions,
no drug-food interactions
• No requirement for routine coagulation monitoring
• Potent antithrombotic effects are achieved with direct thrombin inhibitors
by specifically blocking the activity of thrombin (both free and clot-
bound), the central enzyme in the process responsible for clot
(thrombus) formation
Dabigatran etexilate:

35. What is Pradaxa used for?
• Pradaxa is used to prevent the formation
of blood clots in the veins in adults who
have had an operation to replace a hip or
knee , or any operation with risk of forming
clots.

36. How is Pradaxa used?
• Start with one 110 mg capsule taken one
to four hours after the end of the operation.
Treatment then continues with two 110 mg
capsules (220 mg) once a day for 28 to 35
days after hip replacement and for 10 days
after knee replacement.
• A lower dose (150 mg once a day) is used
in patients with mild or moderate kidney
problems

37. How does Pradaxa work?
• The active substance in Pradaxa,
dabigatran etexilate, is a ‘prodrug’ of
dabigatran. This means that it is converted
into dabigatran in the body. Dabigatran is
an anticoagulant, meaning that it prevents
the blood from coagulating (clotting). It
blocks thrombin, which is central to the
process of blood clotting, reducing the risk
of blood clots forming in the vein

38. How has Pradaxa been
studied?
• The effectiveness of Pradaxa was studied
in three main studies, both of which
compared Pradaxa with enoxaparin
(another anticoagulant).
• Orthopedic surgery study and Re-LY study
in the efficacy of this drug for AF

39. The RE-LY Study:
Randomized Evaluation of
Long-term anticoagulant therapY
Dabigatran Compared to Warfarin in 18,113 Patients with
Atrial Fibrillation at Risk of Stroke
Connolly SJ., et al. NEJM published online on Aug 30th 2009.
DOI 10.1056/NEJMoa0905561
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation

40. RE-LY® – summary results
versus warfarin
• Statistically significant reduction in stroke/systemic embolism
• Statistically significant reduction in hemorrhagic stroke
• Statistically significant reduction in vascular mortality
• Comparable rates of major bleeding rates
• Significant reduction in total bleeds, life threatening bleeds and
intracranial bleeds
Connolly SJ., et al. NEJM published online on Aug 30th 2009.
DOI 10.1056/NEJMoa0905561

41. • The other studies involved a total of 2,101
patients who had had a knee replacement
operation, and
• The second involved a total of 3,494
patients who had had a hip replacement.

42. • In these studies, the main measure of
effectiveness was the number of patients
who formed blood clots in the veins or who
died of any cause during the treatment
period. In most cases, blood clot formation
was detected using scans of the veins or
by looking for signs of blood clots in the
lungs.

43. What benefit has Pradaxa
shown during the studies?
• In both studies, Pradaxa was as effective
as enoxaparin in preventing the formation
of blood clots or death.
• In the study of patients undergoing knee
replacement, blood clots were detected in
182 (36%) of the 503 patients taking
Pradaxa, compared with 192 (38%) of the
512 receiving enoxaparin.

44. • There was only one death in each group
(less than 1%). After hip replacement,
blood clots were detected in 50 (6%) of the
880 patients taking Pradaxa, compared
with 60 (7%) of the 897 receiving
enoxaparin.
• Three patients in the Pradaxa group died
(less than 1%), but two of these deaths
were unrelated to blood clots.

45. • After hip replacement, blood clots were
detected in 50 (6%) of the 880 patients
taking Pradaxa, compared with 60 (7%) of
the 897 receiving enoxaparin.
• Three patients in the Pradaxa group died
(less than 1%), but two of these deaths
were unrelated to blood clots.

46. What is the risk associated with
Pradaxa?
• The most common side effect with
Pradaxa (seen in more than 1 patient in
10) is bleeding.
• Pradaxa should not be used in people who
may be hypersensitive (allergic) to
dabigatran etexilate or any of the other
ingredients.
• Not use in patients who have severe
problems with kidneys, active significant
bleeding, tissue damage that could lead to
bleeding, problems with the blood clotting
process .