1. Judicious Use of Anticoagulation: A Case-Based Approach
Michael B. Streiff, MD, FACP
Associate Professor of Medicine and Pathology
Division of Hematology
Medical Director, Johns Hopkins Anticoagulation Management Service and Outpatient Clinics

2. Disclosures Research Funding Consulting Speaking Honoraria
Bristol-Myers Squibb
NIH/NHLBI
Consulting
Sanofi-aventis
Eisai, Inc.
Daiichi-Sankyo
Janssen Healthcare
BiO2
Speaking Honoraria
Sanofi-aventis
Ortho-McNeil
Educational Grants
Sanofi-Aventis
Covidien

3. Anticoagulation for pregnancy loss
32 year old woman with 2 previous first trimester pregnancy losses asks about LMWH to prevent miscarriages. You advise her to
Start therapeutic dose LMWH
Start prophylactic dose LMWH
Start prophylactic dose LMWH + Aspirin 100 mg
Start no antenatal prophylaxis

4. LMWH does not improve pregnancy outcomes: The ALIFE Study
Placebo
(N=121)
Completed
Study (N=103)
364 women
with at least 2
pregnancy
losses
Aspirin 80 mg
(N=120)
Completed
Study (N=97)
Aspirin 80 mg +
Nadroparin 2850 IU
(N=123)
Completed
Study (N=99)
Kaandorp S et al. NEJM 2010

5. Baseline characteristics
Aspirin + LMWH (N=123)
Aspirin
(N=120)
Placebo
(N=121)
Age (yrs.)
34±5
33±5
Previous miscarriages
3 (2-15)
3 (2-9)
3 (2-12)
≥ 3 miscarriages
73 (59%)
71 (59%)
74 (61%)
≥ 1 late losses
40 (33%)
38 (32%)
35 (29%)
Previous live birth
53 (43%)
45 (38%)
46 (38%)
Thrombophilia
13 (12%)
17 (17%)
Kaandorp S et al. NEJM 2010

6. LMWH did not increase the live birth rate
Kaandorp S et al. NEJM 2010

7. Thrombophilia did not affect live birth rate
Kaandorp SP et al. NEJM 2010

8. Anticoagulation does not prevent early pregnancy loss
Open-label RCT of enox 40 mg/d + ASA 75 mg vs. surveillance alone
PMHx ≥ 2 losses 24 weeks or less
Begin 7 weeks gestation or less
Conclusion- Prophylactic AC does not improve pregnancy outcomes
N=294
Clark P et al. Blood 2010

9. Heparin + Aspirin reduces pregnancy loss in Antiphospholipid Syndrome
Metanalysis of 5 RCTs of UFH/LMWH + aspirin versus aspirin
Regimens- UFH units + aspirin mg and LMWH aspirin mg
Conclusion- UFH/LMWH + ASA improves live birth rates
RR 1.3
Mak A et al. Rheumatol 2010

10. Anticoagulation- Less or More?
A 65 year old man with a St Jude aortic valve is scheduled to undergo a prostatectomy for cancer. When should he resume full-dose anticoagulation?
12 hours post-op
24 hours post-op
36 hours post-op
72 hours post-op

11. Perioperative AC- Is less more?
Metanalysis of 34 studies of 12,278 patients
Outcomes- Thromboembolism and Bleeding
Limitation- Lack of RCT
Conclusion- Value of perioperative bridging unclear
Siegal D et al. Circulation 2012

12. Less is more for perioperative AC
Prospective Cohort of 1262 patients
Low risk- AVR w/o Afib-prophylactic LMWH
High risk- MVR, AVR w/Afib or stroke- Enox 0.7 mg/kg q12h
Post-op- resume AC day 1-3 based upon hemostasis
Pengo V et al. Circulation 2009

13. Thromboembolism Risk Stratification
Thromboembolic Risk
Atrial Fibrillation
Mechanical Valve
Venous Thromboembolism
High
CHADS2 score 5 or 6
Any Mitral valve
Older valve (Caged-ball, Tilting disk)
Recent stroke/TIA
Recent (within 3 mos.) VTE
Severe thrombophilia
Intermediate
CHADS2 score 3 or 4
Bileaflet Aortic valve + TE risk factors
VTE within 3-12 mos.
Recurrent VTE, Active Cancer
Non-severe thrombophilia
Low
CHADS2 score 0-2
Bileaflet Aortic valve w/o TE risk factors
VTE > 12 mos.
TE risk factors= A fib, Cardiac failure, HTN, DM, Age > 75, Stroke/TIA
Douketis JD Blood 2011

14. Bleeding Risk Assessment
Low Bleeding Risk Procedures
High Bleeding Risk Procedures
Cholecystectomy
Abdominal hysterectomy
GI Endoscopy ± biopsy or stent
Pacemaker insertion, EP testing
Dental extractions
Carpal tunnel repair
Dilatation/currettage
Skin Cancer excision
Abdominal hernia
Hydrocele repair
Cataract surgery
Bronchoscopy ± biopsy
Central Venous Catheter removal
Skin, Thyroid, Breast, Lymph node biopsy
Cardiac surgery
Abdominal aneurysm repair
Neurosurgery
Urologic surgery
Head and Neck surgery
Hip/knee replacement
Back surgery
Kidney biopsy
Polypectomy/sphincterotomy
Transurethral prostate resection
General surgery
Vascular surgery
Any major surgery (> 45 minutes)
Spyropoulos AC and Douketis JD Blood 2012

15. AC Management Surgical Bleeding risk Pre-operation Post-operation Low
Last dose LMWH 24 hours before
Resume LMWH 24 hours post-op if hemostasis adequate
Start warfarin with LMWH
High
Resume LMWH hours post-op if hemostasis adequate or start prophylactic dose 24 hours post-op or avoid LMWH

16. Anticoagulation for VTE
65 year old man develops a right femoral-popliteal vein DVT 1 week after right knee replacement. A thrombophilia evaluation reveals he is heterozygous for the factor V Leiden mutation. How long should he be treated?
6 weeks
3 months
12 months
Indefinite

17. Anticoagulation for VTE
48 year old man presents with progressive dyspnea over 1 week and left leg discomfort. CT angiogram identifies bilateral PE. Duplex study finds a left leg DVT. No VTE risk factors are identified. How long should he be treated?
3 months
6 months
12 months
Indefinite

18. Do the Results of Thrombophilia Tests Help to Determine Duration of Therapy?
( )
HR 1.8
(1-3.1)
HR 1.4
( )
Recurrent VTE (%)
HR 1.5
( )
(N= 570)
24 mos.
(N=474)
84 mos.
(N=267)
46 mos.
(N=1626)
50 mos.

19. Thrombophilia-Assessing the risk
High risk thrombophilia
Antithrombin deficiency % per year (95% CI %)
Protein C deficiency % per year ( %)
Protein S deficiency - 1.9% per year ( %)
Moderate risk thrombophilia
Factor V Leiden - 0.5% per year ( %)
Prothrombin gene mutation - 0.3% per year ( %)
Factor VIII - 0.5% per year ( %)
Low risk thrombophilia
Factor IX - 0.1% per year ( %)
Factor XI - 0.2% per year ( %)
Hyperhomocysteinemia – 0.1% per year ( %)
Lijfering WM et al. Blood 2009

20. Antiphospholipid syndrome is associated with recurrent thromboembolism
Recurrent VTE (%)
Months
Schulman S , et al. Am J Med 1998; 104:

21. VTE recurrence rate varies depending upon initial trigger for the event
Cumulative recurrent VTE (%)
Time after cessation of therapy (months)
Baglin T et al., Lancet 2003

22. VTE Setting influences recurrence risk
Systematic review of prospective cohort studies and RCTs
15 Studies
5159 Subjects
Follow up months
Conclusion- Setting of thrombosis strongly influences recurrence rate
Iorio A et al. Arch Intern Med 2010

23. D dimer and recurrent VTE
D dimer- an indirect marker of activated coagulation
PROLONG study (Palareti G et al. NEJM 2006)
F/U 1.4 years
Systematic Review (Verhovsek M et al. Ann Intern Med 2008)
7 studies, 1888 patients
Recurrent VTE- Abnl vs. nl DD (8.9% vs. 3.5% per year)
N=608

24. How do we identify the low risk patient with idiopathic VTE?
Prospective cohort study of 665 patients with idiopathic VTE
Enrolled at 12 centers, 4 countries prior to DC of warfarin after 5-7 months of therapy
Information of 76 laboratory and clinical variables associated with VTE were collected
Multivariate analysis used to develop clinical prediction rule for recurrent VTE
Results
F/U population 600/665 (90%)
Mean F/U -18 months (1-47 mos.)
Annual risk of recurrent VTE 9.3% per year (7.7%-11.3%)
Men 13.7% (10.8%-17%)
Women 5.5% (3.7%-7.8%)
Rodger MA, et al. CMAJ 2008;179(5):417-26

25. Clinical prediction rule for recurrent VTE in women
Rodger MA, et al. CMAJ 2008;179(5):417-26

26. Risk stratification for idiopathic VTE: The Vienna Risk Model
Eichinger S et al. Circulation 2010

27. Indefinite Anticoagulation: Weighing the risks
Thrombosis
Bleeding

28. Assessing Bleeding Risk: The HAS-BLED Score
Hypertension (uncontrolled SBP>160) = 1 point
Abnormal renal/liver function = 1 or 2 points
Stroke = 1 point
Bleeding (or anemia) = 1 point
Labile INRs (TTR<60%)= 1 point
Elderly (Age > 65 years)= 1 point
Drugs or alcohol= 1 or 2 points
Pisters R et al. Chest 2010; Olesen JB, et al. JTH 2011

29. Central Venous Catheter Prophylaxis
67 year old man has just had a right subclavian Hickman CVC placed for chemotherapy for recently diagnosed NHL. What should be used for CVC thrombosis prophylaxis?
Warfarin 1 mg daily
Enoxaparin 40 mg daily
Dalteparin 5000 units daily
No prophylaxis necessary

30. CVC Prophylaxis Open RCT of low dose warfarin 1 mg vs. no warfarin
Start 3 days before CVC insertion
Outcome-Venogram with symptoms or at 90 days
Conclusion- Low dose warfarin prevents CVC thrombosis
P<0.001
Bern MM et al. Ann Intern Med 1990

31. Catheter Prophylaxis Study Regimen Outcome assessment DVT (%) P Value
Bern et al. 1990
Warfarin 1 mg
No treatment
Venogram
9.5
37.5
<0.001
Monreal et al. 1996
Dalteparin 2500 6 62
0.002
Reichardt et al. 2002
Dalteparin 5000
Clinical
3.7
3.4
0.9
Couban et al. 2003
Placebo
4.6 4
0.81
Verso et al. 2004
Enoxaparin 40 mg
14.1 18
0.35

32. Adjusted dose warfarin prevents CVC thrombosis: WARP study
A multicenter (N=68) open label study of warfarin CVC prophylaxis (N=1590)
Study Arms-
No warfarin (404) vs. warfarin 1 mg (408)
Warfarin 1 mg (471) vs. warfarin (INR ) ( 473)
Conclusion- Dose-adjusted warfarin is required to prevent CVC DVT
P=0.002
Young AM, et al. Lancet 2009

33. Elevated INR- Less vitamin K is more
70 year old man taking warfarin for atrial fibrillation has an INR of 7. He does not have any signs of bleeding. What should you do?
Hold warfarin and administer vitamin K 2.5 mg po
Hold warfarin and administer vitamin K 2.5 mg IV
Hold warfarin and recheck INR in 1-2 days
Hold warfarin and administer Vitamin K 2.5 mg and 3 units of FFP

34. Less vitamin K is more safe
RCT of vitamin K 1.25 mg or placebo for pts. with INR
Setting- 14 AC clinics in US, Canada, Italy
Outcomes- Symptomatic bleeding or thromboembolism within 90 days
Conclusion- Oral Vit K does not improve outcomes with INR
Crowther MA et al. Ann Intern Med 2009

35. Is less is more?
72 year old man with atrial fibrillation who has been on warfarin 5 mg daily for 3 months. Today his INR is 1.8. No reason identified. What should you do with his warfarin dose?
Increase his dose to 7.5 mg MWF, 5 mg ROW (21% dose increase), recheck 1 week
Increase his dose to 7.5 mg daily (50% dose increase), recheck 1 week
Increase his dose to 7.5 mg W, 5 mg ROW (7% dose increase, recheck 1 week
Continue same dose, recheck 1 week

36. Less dose adjustment=more time in range
Observational study of warfarin management
Setting- 94 AC clinics, 3961 patients
Outcome- Time in therapeutic range
Conclusion- Excessive warfarin dose changes lead to poorer INR control
Rose AJ et al. J Thromb Haemost 2009

37. Is less LMWH more?
A 65 year old man with an atrial fibrillation (CHADS2 score 3) who has been on warfarin for 4 months has an INR of 1.5. Your nurse asks you for advice. You suggest…
LMWH + warfarin dose increase
Warfarin dose increase only

38. Less LMWH is safe
Retrospective study of patients in Kaiser CO AC clinics
Low INR and therapeutic INR groups
Only 13 patients received LMWH
Outcomes- Bleeding and TE at 90 days
Conclusion- LMWH not necessary for most patients with low INR
Clark NP et al. Pharmacother 2008

39. Conclusions
Anticoagulation is not indicated for recurrent early pregnancy loss except perhaps APS
Therapeutic AC should be used sparingly in the post-operative period
Setting rather than presence of thrombophilia dictates duration of therapy
Risk stratification models can help determine the risk of recurrent VTE and bleeding in patients with idiopathic VTE
Central venous catheter prophylaxis remains of unproven benefit
Studies continue to optimize warfarin management

40. Questions ?