1. 2013 Update on Venous Thromboembolism University of North Carolina4 5
2013 Update on Venous Thromboembolism
Stephan Moll, MD
University of North Carolina
Chapel Hill, NC
Advocate Lutheran General Hospital; Park Ride, IL,
March 2nd, 2013

2. Disclosures Consultant: Janssen, Boehringer-Ingelheim, Daiichi
Speaker bureau: none

3. The 3 Major Developments in 2012
Publication of ACCP Guidelines 2012 I
Approval of Rivaroxaban for VTE II
Approval of Apixaban for atrial fibrillation
III

4. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?

5. Case - PE HPI 63 year old man, quite healthy
4 days h/o moderate CP + SOB; now SOB with 1 flight of stairs.
No leg symptoms
No preceding trauma, immobility, surgery, long-distance travel
Arthroscopic knee surg 2 yrs ago
HTN; Obesity (BMI 32.3)
No h/o cancer; no h/o bleeding
PMH
Negative for VTE FH

6. Case Physical Exam BP 135/87; P 92 / min
RR at rest 16 min, not SOB when talking; O2 on RA 93 %
BMI 32.3; lungs clear; legs R=L
CTA chest
RUL segmental PE, L UL and LL subsegmental PE

7. Question – Outpatient vs. Inpatient?
Diagnosis
Unprovoked PE. VTE risk factors: (a) obesity.
How to manage this patient?
Outpatient?
Admit?

8. ACCP 2012
Recommend home treatment for DVT (1B) and early d/c for low-risk PE. (2B).
Acute Treatment
[Kearon C et al. Chest 2012;141(2)(Suppl):e419S-e494S]

9. Outpatient vs. Inpatient – HESTIA Criteria
1. Hemodynamically unstable?
2. Thrombolysis or embolectomy needed?
3. Active bleeding or high risk of bleeding?
4. Oxygen needed to keep O2 saturation > 90 % for > 24 hrs?
5. PE dx’d during anticoagulant therapy?
6. iv pain meds for > 24 hrs?
7. Medical or social reason for admission?
8. GFR < 30 ml/min?
9. Severe liver impairment?
10. Pregnant?
11. Documented h/o HIT?
Hestia (Greek) = home and hearth. She is the goddess of the hearth, architecture, and the right ordering of domesticity, the family and the state.
[Zondag W et al. J Thromb Haemost 2011;9:1500-7]
[Zondag W et al. J Thromb Haemost 2013(Jan 6th )ePub]

10. PESI = Pulmonary Embolism Severity Index
[Aujesky D et al. Am J Respir Crit Care Med 2005;15;172(8):1041-6]

11. Outpatient vs. Inpatient – HESTIA Score
Teaching point #1
Outpatient PE management
Suitable for, may be, 50 % of PE patients;
HESTIA criteria can be useful for decision making.

12. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q2:
Thrombolytics?

13. Thrombolytics?
For PE, with hypotension or high risk for hypotension: suggest thrombolytics, systemically. 2C
For DVT, suggest anticoagulant therapy alone over thrombolysis (catheter-directed or systemic). 2C
[Kearon C et al. Chest 2012;141(2)(Suppl):e419S-e494S]

14. PE: Indicators of Poor Outcome
ESC criteria (based on consensus; lack of validation)
Criteria
mortality
High risk
Cardiovascular shock or persistent hypotension
> 30 %
Intermediate risk
Lab (troponin, BNP)  or RV dysfunction
1-30 %
Low risk
nl labs (troponin, BNP); nl RV function
< 1 %
[Torbicki A et al. Eur Heart J 2008; ]

15. Thrombolytics?
PEITHO trial: 1,006 patients with RV stain PLUS pos. troponin: thrombolytics versus placebo; results spring 2013.
ATTRACT trial 392/692 patients enrolled as of Jan 8th, 2013. [ [

16. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q2:
Thrombolytics?
Q3:
LMWH/warfarin or rivaroxaban?

17. Question –Anticoagulant Choice
Outpatient management is chosen. CBC, PT, aPTT normal; Creatinine 0.95; liver enzymes normal. How would you treat?
LMWH or fondaparinux / warfarin
Rivaroxaban (Xarelto)
Dabigatran (Pradaxa)
Apixaban (Eliquis)

18. New Oral Anticoagulants
Dabigatran
Rivaroxaban
Apixaban
tmax
hrs
2 - 4 hrs
1 - 3 hrs
Half life
hrs
hrs
8 - 15hrs
Renal excretion
80%
66 %
ca. 25 %
FDA approval
A. fib
VTE prevention
VTE treatment
[Garcia D et al. Blood Jan 7;115(1): Review]
In clinical development: Edoxaban, Betrixaban (not FDA approved)

19. Rivaroxaban in Acute DVT and PE
A. DVT study
B. PE study
[Bueller H et al. NEJM 2010;363: ]
[Bueller H et al. NEJM 2012;366: ] 19

20. Rivaroxaban
BLEEDING
Clinically relevant bleeding (composite of major and clinically relevant non-major bleeding): Same.
Major bleeding: Same (DVT study) or less (PE study).
[Bueller H et al. NEJM 2010;363: ]
[Bueller H et al. NEJM 2012;366: ]
Nov 2012 20

21. Rivaroxaban In which patient do I consider rivaroxaban?
Acute DVT or PE
All patients treated as outpatients
Mild to moderate DVT; HESTIA criteria for PE
On long-term warfarin
I discuss it with all patients
Fluctuating INRs, high “warfarin hate factor” 21

22. Rivaroxaban In which patient would I NOT use rivaroxaban?
Renal impairment: GFR < 30 ml/min (or 40; “buffer zone”) by Cockroft-Gault
Liver disease
Increased bleeding risk; particularly GI bleeding
Acute cerebral vein thrombosis
BMI > 40 or “low” body weight
Cancer
Patient who doesn’t like idea of “no known reversal agent/strategy”.
(140-age) x kg / serum creatinine x 0.85 for women 22

23. Rivaroxaban Things to consider when starting rivaroxaban
LABS: CBC, creatinine, AST, ALT, t. bili
GFR > 30 ml/min
Check with insurance carrier ($ 335 / month)
15 mg bid for 3 weeks, then 20 mg qd
Take with food (AM or PM)
Drug interactions: HIV meds, antifungal, sz drugs, St. John’s wort
F/u with you in 3 weeks and in 3 months, then yearly. 23

24. Rivaroxaban Teaching point #2
Acute or previous VTE: Rivaroxaban is a possible treatment option.
Teaching point #2 24

25. Other Drug Approvals in 201225

26. Apixaban in Atrial Fibrillation
[Granger CB et al. N Engl J Med 2011;365:981-92] 26

27. Apixaban in Atrial Fibrillation
is MORE effective than warfarin
leads to LESS major bleeding.
Dec 2012 27

28. Hospital Guide for New Oral Anticoagulants
Dabigatran:
Rivaroxaban:
Apixaban:
Comprehensive management documents: : UNC and rivaroxaban
Teaching Point #3 28

29. New Oral Anticoagulants: Cost
Per day: $ 9.20 to $ (ca. $ /day)
Per month: $ to (ca. $ /mo)
Qty
AWP *
CVS
Walgreens
Walmart
Apixaban 5 mg bid 60
$300.44
$335.99
$308.99
$276.16
Rivaroxaban 20 mg qd 30
$300.42
$324.99
$281.46
Dabigatran 150 mg bid
$330.99
$303.99
$286.32
[personal communciations: evaluation of Average Wholesale Price (AWP) and inquiry from 3 national pharmacy chains; Jan 28, 2013] 29

30. VTE Brochure [

31. VTE Brochure
Teaching point #4

32. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q4:
Compression stockings?
Q2:
Thrombolytics?
Q3:
LMWH/warfarin or rivaroxaban?

33. Compression Stockings?
SOX trial
[Kahn SR;ASH 2012;abstract 393]
Compression stockings probably/possibly do not prevent PTS.
Teaching point #5

34. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q4:
Compression stockings?
Q5:
D/c anticoag or long-term?
Q2:
Thrombolytics?
Q3:
LMWH/warfarin or rivaroxaban?

35. How Long To Treat With Anticoagulation?
VTE due to transient risk factor
3 months
Woman with DVT or PE, hormones
Woman with DVT, not hormones
Strong Thrombophilia
- D-dimer +
Woman with PE
Man with DVT
Long-term
Man with PE
Other risk factors for recurrence: Obesity?; age?
Other considerations: Bleeding, fluctuating INRs, lifestyle impact, pt preference

36. How Long to Treat with Anticoagulation?
[Palareti G et al. NEJM 2006;355:1780-9]
[Verhovsek M et al. Systematic review on D-dimer to predict recurrent VTE. Ann Int Med 2008;149(7):481‐490] 36

37. VTE Recurrence – Risk Assessment Scores
HERDOO-2 score
[Rodger M et al; CMAJ 2008;179: ]
DASH score
[Tosetto A et al. J Thromb Haemost 2012 Jun;10(6): ]

38. How Long to Treat With Warfarin? - HERDOO-2
Women
Conclusion:
Women ≤ 1 d/c anticoagulation.
Men, no matter what the score, need to continue anticoagulation.
HERDOO-2 rule
HER =
Hyperpigmentation or
Edema or
Redness
D = D-dimer positivity (on warfarin)
O= obesity, BMI ≥ 30
O = Older age, ≥ 65 yrs
2 = score of ≥ 2: continue warfarin
[Rodger M et al; CMAJ 2008;179: ]

39. How Long to Treat With Warfarin? - DASH
DASH score
D = D-dimer pos (off warfarin) + 2
A = age < 50 years
S = sex (male)
H = hormone use
Conclusion:
Score ≤ 1: d/c anticoagulation
Summary: The DASH score (details described below) can separate patients with unprovoked VTE into those with a low risk of recurrence in whom anticoagulation can be discontinued after few months of treatment, and those who should be on long-term anticoagulation because of a high risk of recurrence (abstract #544). However, at this point I would not use the DASH score for clinical decision-making.
Details: The authors performed a meta-analysis of 7 prospective studies of patients with unprovoked DVT who had been treated for at least 3 months with vitamin K antagonists, and determined what characteristics were indicators of a high risk of recurrent VTE. Main predictors of recurrence were abnormal D-dimer after stopping anticoagulation, age < 50 years, male gender, and VTE not associated with hormonal therapy. A predictive recurrence score was then created – “DASH score” (D-dimer, Age, Sex, Hormones) -, with the following points: (a) +2 for abnormal post-anticoagulation D-dimer, (b) +1 for age < 50 years, (c) +1 for male gender, (d) -2 for hormone use. The annual recurrence rate was: 3.1 % for DASH score ≤1; 6.4 % for DASH score of 2; 12.3 % for score of ≥ 3. As the risk of recurrence is low with a DASH score of ≤1, these are patients with unprovoked VTE in whom long-term anticoagulation is not needed. These are about 50 % of patients with unprovoked VTE. The DASH score needs to be validated. In addition, a discrepancy with another existing scoring system - the HERDOO-2 score (also not validated) - needs to be resolved. The discrepancy is that in the DASH score a younger age (< 50 years) is a predictor of recurrence, whereas in the HERDOO-2 score age > 70 years predicts a higher risk of recurrence. So, it is not clear at this point whether it is worse to be young or old when it comes to VTE recurrence risk.
Annual VTE recurrence rate:
≤ 1: %
2: %
≥ 3: %
[Tosetto A et al. J Thromb Haemost 2012 Jun;10(6): ]

40. Patient‘s Preference
“Coumadin hate factor” 10 40

41. VTE: Length of Anticoagulation
Conglomerate decision of:
Risk of recurrent VTE (a)…., (b)…., (c) …..
Risk of Bleeding (a)…., (b)…., (c) …..
Patient preference “Coumadin hate factor” 41

42. ACCP 2012 Guidelines: Highlights
Treatment beyond Acute Period
Surgery-associated DVT/PE: recommend 3 months. (1B)
Non-surgical transient risk factor: recommend 3 months over 6 or more months. (1B)
Unprovoked DVT/PE and low/intermediate risk for bleeding: suggest extended anticoagulation (2B). High bleeding risk: 3 months (1B).
Cancer patient with DVT/PE: recommend/suggest extended therapy. LMWH rather than VKA (2C).
[Kearon C et al. Chest 2012;141(2)(Suppl):e419S-e494S]

43. VTE: Length of Anticoagulation
Teaching point #6
How long to treat with anticoagulation?
Risk factors for VTE: (a)…., (b)….., (c)……
Risk factors for bleeding: (a)…., (b)….., (c)……
Patient preference 43

44. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q4:
Compression stockings?
Q5:
D/c anticoag or long-term?
Q2:
Thrombolytics?
Q6:
Warfarin or rivaroxaban?
Q3:
LMWH/warfarin or rivaroxaban?

45. Rivaroxaban in VTE, Secondary Prophylaxis
VTE extension study
[Bueller H et al. NEJM 2010;363: ] 45

46. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q4:
Compression stockings?
Q5:
D/c anticoag or long-term?
Q2:
Thrombolytics?
Q6:
Warfarin or rivaroxaban?
Q3:
LMWH/warfarin or rivaroxaban?
Q7:
Aspirin vs anticoagulant?

47. Aspirin and VTE Prevention
A. WARFASA study
placebo
aspirin
HR 0.58
95% CI 0.36 to 0.93
p= 0.02
[Becattini C et al; NEJM 2012; 366: ]

48. Aspirin and VTE Prevention
B. ASPIRE study
[Brighton TA, et al. N Engl J Med Nov 22;367(21): ]

49. Aspirin and VTE Prevention – Meta-Analysis
C. Meta-analysis
[Brighton TA, et al. N Engl J Med Nov 22;367(21): ]

50. ASA and VTE Teaching point #7
Not clear whether Aspirin prevents recurrent VTE.
But it does lead to a net “vascular benefit” (arterial and venous together).
Teaching point #7

51. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q4:
Compression stockings?
Q5:
D/c anticoag or long-term?
Q8:
Surgery
Q2:
Thrombolytics?
Q6:
Warfarin or rivaroxaban?
Q3:
LMWH/warfarin or rivaroxaban?
Q7:
Aspirin vs anticoagulant?

52. When to d/c at Times of Surgery
Renal function
[CrCl, mL/min]
Half-life
[hours]
When to stop drug before surgery (after last drug dose)
Standard bleeding risk
High bleeding
risk
Dabigatran
> 80
13 (11-22)
24 hrs
2-4 d
> 50 to ≤ 80
15 (12-34)
> 30 to ≤ 50
18 (13-23)
≥ 2 d
4 d
≤ 30
27 (22-35)
2-5 d
> 5 d
Rivaroxaban
>30
12 (11-13)
2 d
< 30 mL/min
Unknown
Modified after [van Ryn J et al. Thromb Haemost 2010;103: ]
[UNC treatment guidelines] 52

53. When to d/c at Times of Surgery
Apixaban
No published data exist on optimal perioperative management
d/c ≥ 24 h or ≥48 h prior standard / high risk procedures
For all new oral anticoagulants: D/c before surgery: 24 hrs for standard risk surgery; 2-4 d for high risk. Consider renal fx.
Teaching point #8 53

54. Patient Diagnosis few days later 3 mo any time Q1: Outpatient
or inpatient?
Q4:
Compression stockings?
Q5:
D/c anticoag or long-term?
Q8:
Surgery
Q9:
Major bleed
Q2:
Thrombolytics?
Q6:
Warfarin or rivaroxaban?
Q3:
LMWH/warfarin or rivaroxaban?
Q7:
Aspirin vs anticoagulant?

55. Major Bleeding – Reversal, Management?
Best strategy not known
Problem with existing data:
NO meaningful patient data published
Animals: Mice and rat tails
Human volunteers: reversal of coagulation tests
Ex vivo plasma spiking tests: reversal of coagulation tests
Mice intracranial bleeding model
Zhou 2013 article: rivaroxaban and collagen-induced mice brain injury: FFP, PCC, rVIIa were beneficial.
[Zhou W et al. Stroke 2013:44:ePub]

56. Major Bleeding Treatment Options Supportive care! Activated charcoal
Hemodialysis for Dabigatran, not for Rivaroxaban or Apixaban
No clotting factor therapy

57. Major Bleeding Treatment Options
Non-activated PCC (prothrombin complex concentrate)
Activated PCC
Recombinant factor VIIa
FFP
Anti-fibrinolytic drugs (aminocaproic acid, tranexamic acid)

58. Summary Outpatient VTE management
Suitable for, may be, 50 % of PE patients;
HESTIA criteria for PE risk can be useful for decision making.
Rivaroxaban for VTE (acute; previous): possible treatment option.
New oral anticoagulants
Starting the drugs;
D/c before surgery (24 h for standard risk; 2-4 d for high risk;
Major bleeding management.

59. Summary VTE Patient brochure available
Compression stockings probably/possibly do not prevent PTS.
How long to treat with anticoagulation?
Risk factors for VTE: (a)…., (b)….., (c)……
Risk factors for bleeding: (a)…., (b)….., (c)……
7. Aspirin: Not clear whether it prevents recurrent VTE. I do encourage the use.