1. VTE: It’s still a killer in Canada
Sam Schulman, MD, PhD
Dept. of Medicine
McMaster University

2. Faculty/Presenter Disclosure
Faculty: Dr. Sam Schulman
Program: 51st Annual Scientific Assembly
Relationships with commercial interests:
Grants/Research Support: N/A
Speakers Bureau/Honoraria: Boehringer Ingelheim and Bayer Healthcare for work in study-related committees
Consulting Fees: N/A
Other: N/A

3. Disclosure of Commercial Support
This program has received financial support from Boehringer Ingelheim and Bayer Healthcare in the form of Honorarium.
This program has received in-kind support from N/A
Potential for conflict(s) of interest:
Dr. Sam Schulman has received Honorarium from Bayer Healthcare and Boehringer Ingelheim whose products are being discussed in this program.
Bayer Healthcare and Boehringer Ingelheim sell products that will be discussed in this program: rivaroxaban and dabigatran.

4. Mitigating Potential Bias
All treatment alternatives are discussed

5. Contents Case discussion Epidemiological data
Who is at the highest risk
Extended prophylaxis – when?
Diagnosis – missing and overinterpreting
Treatment – a lot easier now
How long after VTE – a dilemma

6. Unfortunate case 65 y.o. male, fell from ladder.
X-rays normal except for L4 burst # on CT
No bleeding, Hgb stable
Sharp back pain, remains bedridden in hospital. On day 3 urinary problems and weakness in one leg  scheduled for decompression laminectomy next day.
SaO % all the time
Surgery Day 4 in late afternoon. Suspected MI in recovery  arrest. CPR unsuccessful – large PE

7. PE - mortality 10% succumb within 1 h
Usually before arrival at the hospital
PE – 3rd leading cause of cardiovascular death

8. Risk factors for VTE Surgery Trauma Immobility, paresis Malignancy
Cancer therapy
Previous VTE
Increasing age
Pregnancy / postpartum
Estrogens
Selective estrogen receptor modulators
Acute medical illness
Heart or respiratory failure
Inflam. bowel disease
Nephrotic syndrome
Myeloprolif disorders
PNH
Obesity
Smoking
Varicose veins
Central venous catheter
Thrombophilic defect
ACCP Guidelines on Antithrombotic and Thrombolytic Therapy

9. Cancellation of Sx day after day – not an uncommon phenomenon
Waiting time for hip# Sx often 3 days
Typical order: ”NPO for surgery in a.m.”, ”Hold heparin”
Heparin or LMWH evening before does not increase bleeding.
These patients have to receive LMWH qHS
Even neuraxial anesthesia next morning is OK (10-12 h after last dose)
American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines, 3rd ed., 2010

10. Postop VTE prophylaxis
Necessary if patient not mobilizing within 24 h
Bleeding risk – use mechanical devices
Otherwise ”chemoprophylaxis” – usually until discharge. Consider extension if patient not mobilizing at that time point
Use a risk assessment score, e.g. Caprini
Gould MK et al. ACCP Guidelines. CHEST 2012; 141 Suppl:

11. Data on incidence of VTE
Worcester, MA – all medical records 1999 with VTE diagnosis: 104 per 100,0001
Olmsted County, MN – medical records of all residents with VTE , incl PE on autopsy: 117 per 100,0002
Sweden – Men born 1913, followed from age 50: 387 per 100,0003
Bretagne, France – Diagnosis data: 184/100,0004
Spencer FA. J Gen Intern Med 2006
Silverstein MD. Arch Intern Med 1998
Hansson PO. Arch Intern Med 1997
Oger E and EPI-GETBO. Thromb Haemost 2000

12. Survival after VTE Olmsted County inception cohort
7-day
30-day
1-year
DVT
96.2%
94.5%
85.4%
PE ±DVT
59.1%
55.6%
47.7%
VTE
74.8%
72.0%
63.6%
Olmsted County inception cohort
Followed , n=2218
Risk factors for death PE
Age
BMI
Patient onset
Malignancy
CHF
More risk factors
Neurologic disease
Chronic lung disease
Recent Sx
Hormone Rx
Smoking tobacco
Chron renal disease
Heit JA et al. Arch Intern Med 1999;159:445-53

13. Survival after VTE
>1/3 of deaths were on day of onset/unrecognized VTE
Heit JA et al. Arch Intern Med 1999;159:445-53

14. Effect of age White, R. H. Circulation 2003;107:I-4-I-8
Annual incidence of VTE among residents of Worcester MA 1986, by age and sex
White, R. H. Circulation 2003;107:I-4-I-8
Copyright ©2003 American Heart Association 14 14

15. Prevalence of VTE is predicted to double by 2050
Adults 18 years and older with VTE in USA (millions)
0.5 1
1.5 2
2002
2003
2004
2005
2006
2008
2010
2015
2020
2025
2030
2035
2040
2045
2050
VTE cases per :
Year
2002
2003
2004
2005
2006
2008
2010
2015
2020
2025
2030
2035
2040
2045
2050
317
341
371
401
422
426
432
453
478
505
527
544
556
563
567
VTE = venous thromboembolism
Deitelzweig SB et al. Am J Haematol 2011;86:217–20 15

16. Patients at highest risk
Recent VTE
Malignancy
Spinal cord injury
Heparin-induced thrombocytopenia

17. Increased prophylactic dose
Spinal cord injury
Burn injury
Bariatric surgery

18. Bariatric surgery >100,000 procedures in the US
Consecutive patients
Early ambulation & mechanical proph.
Group 1: enoxaparin 30 mg bid (n=92)
DVT 5.4%
Group 2: enoxaparin 40 mg bid (n=389)
DVT 0.6%
Scholten DJ et al. Obes Surg 2002;12:19-24
>100,000 procedures in the US
Incidence of reported VTE 0.1% - 1%, fatal PE 0.2%
Mainly after discharge
95% of US surgeons give prophylaxis
LMWH, UFH tid or fondaparinux: May add mechanical.
Higher doses than standard

19. Extended postop prophylaxis, i.e. up to 1 month instead of 1 week
High risk of VTE + pelvic/abdominal Sx for cancer (Grade 1B)
Results in 13 fewer non-fatal events per 1000 without significant increase in bleeding
Major orthopedic surgery (THR, TKR, HFS) – minimum d (Grade 1B) and suggest up to 35 d (Grade 2B)
Results in 9 fewer non-fatal events per 1000 without significant increase in bleeding
ACCP Guidelines. CHEST 2012; 141 Suppl

20. Spinal cord injury In case of paraplegia:
Very high risk at least first month
Continued increased risk 3 months
Then normalization

21. Logistics not an excuse now
LMWH/fondaparinux are parenteral.
Rivaroxaban 10 mg or dabigatran 150/220 mg once daily or apixaban 2.5 mg twice daily are available and approved for THR and TKR
Effective and safe, cost-effective vs LMWH

22. The Primary Outcomes – Ortho Sx
D a b i
R i v a
A p i x a
RE-MODEL TKR Non-inferior
RE-MOBILIZE TKR Inferior
RE-NOVATE THR Non-inferior
RE-NOVATE II THR Non-inferior
RECORD 1 THR Superior
RECORD 2 THR Superior
RECORD 3 TKR Superior
RECORD 4 TKR Superior
ADVANCE 1 TKR Non-inferiority not met
ADVANCE 2 TKR Superior
ADVANCE 3 THR Superior

23. Suspected DVT / PE

24. Typical case 36 y.o. lady with pain in the R calf x 3d
Previously healthy
Went for a long walk last weekend
Was on COC for 10 years, stopped at age 28, restarted 3 months ago.
Physical: Tender calf, no edema or SOB

26. Reduction of imaging diagnostics
Active cancer
Paralysis, recent immob 1
Recently bedridden >2 d 1
Localized tenderness 1
Calf swelling >3 cm 1
Unilat pitting edema 1
Collateral superf. veins 1
Previous documented DVT 1
Alt. Dx at least as likely -2
<2 p – unlikely
>2 p - likely
Use Wells’ score and D-dimer –
Only if low score + neg D-dimer will result in No imaging
D-dimer: Not useful
In generally ill patients
Shortly after surgery
Differential vs cellulitis
Very elderly (>80)
Long duration of symptoms

27. Ultrasound pitfalls
Very difficult to tell new from old if no comparison
If proximal swelling – ask for iliac and inferior v cava veins
Should do both legs even if unilat spt

28. Do we have to treat distal DVT?
Analysis of 5 studies of sympt calf DVT without treatment (Rhigini et al 2006):
Progression proximally in 25 of 353 (7%)
RCT (N=196):
VKA alone
UFH 5,000 x2
UFH 12,000 x1
Placebo
11% 7%
78%
2.3% 0%
25%
Rhigini: progression in 7% on venography or US.
Progression
0-8 w
9-24 w
(ultrasound)
Belcaro G et al. Minerva Med 1997;88:507-14

29. Calf DVT: Risk factors for progression
Positive D-dimer
Extensive calf DVT or close to proximal
Unprovoked or persistent risk factor
Active cancer
History of VTE
Hospitalized patient
Kearon C et al. ACCP Guidelines. CHEST 2012; 141 Suppl

30. Practical approach
Treat if very symptomatic or risk factors for extension (Grade 2C)
With increasing risk of bleeding – consider not treating – but do serial ultrasound. (Grade 2C) Progression is most common first 2 w.
Kearon C et al. ACCP Guidelines. CHEST 2012; 141 Suppl

32. Suspected PE Wells’ clinical prediction score for PE
Previous PE or DVT +1.5
Heart rate > 100/min +1.5
Recent surgery or immobilization +1.5
Clinical signs of DVT +3
Alternative diagnosis less likely than PE +3
Hemoptysis +1
Cancer +1
Dichotomized rule
Unlikely < 4
Likely > 4
Wells PS et al. Thromb Haemost. 2000;83:416-20

34. Can my PE-patient in ER go home?
Pulmonary Embolism Severity Index (PESI)
Age 1 p / yr SBP < p
Male sex 10 p Pulse > p
Cancer 30 p RR>30 20 p
CHF 10 p Temp <36 20 p
Chron lung dis. 10 p SaO2 <90% 20 p
 mental status 60 p
85 p or less = low risk of fatal PE – NPV = 99%
Aujesky D et al. Am J Resp Crit Care Med 2005;172:1041–6 External validation in: J Intern Med 2007;261:

35. Simplified PESI Retrospective analysis of RIETE registry
Age >80 1 p
History of Cancer 1 p
Chron cardiopulmonary dis. 1 p
Pulse > p
CHF 1 p
SBP < p
SaO2 <90% 1 p
0 = low risk, 1 or more = high risk
Jiménez D et al. Arch Intern Med. 2010;170:1383-9

36. Simplified PESI result
Jiménez D et al. Arch Intern Med. 2010;170:1383-9

37. Initial standard anticoagulation
Generally same treatment for DVT and PE (=VTE):
UFH iv – weight adjusted (bolus 80 U/kg, infusion at 18 U/kg/h)*
UFH s.c. 250 U/kg bid *
UFH s.c. 17,500 U bid *
UFH s.c. 333 U/kg 1st dose, then 250 U/kg bid without monitoring
LMWH s.c. without monitoring
Fondaparinux s.c. 7.5 ±2.5 mg daily
Rivaroxaban 15 mg p.o. BID x 3 w, then 20 mg q.d. – LU-code 444
* Monitored to keep anti-Xa at IU/mL – at 6 h for s.c. 1B

38. Clinical Outcomes During the Study Period
UFH 250 U/kg bid vs LMWH 100 IU/kg bid
FIDO-Study
Clinical Outcomes During the Study Period
Event UFH LMWH
Recurrence 3.8% 3.4%
Maj Bleed 1.7% 3.4%
Any Bleed 8.3% 8.5%
Death 5.2% 6.3%
Kearon, C. et al. JAMA 2006;296:
Copyright restrictions may apply.

39. UFH sc in renal failure
Increased risk of bleeding with any anticoagulant – NOACS, warfarin, LMWH, heparin
Lack of good studies but reduce dose for
NOACS, LMWH and UFH
UFH sc Hamilton for CrCl <30
1st dose 250 IU per kg
Then 200 IU per kg q 12 h.

40. Oral Factor Xa inhibitor, rivaroxaban: EINSTEIN-DVT/PE
Objectively confirmed DVT without symptomatic PE
Randomisation
Predefined treatment period of 3, 6, 12 months
Eligible patients
Rivaroxaban
15 mg twice daily
N~2900
Rivaroxaban
20mg once daily R
EINSTEIN-PE
Objectively confirmed PE with or without symptomatic DVT
N~3300
Enoxaparin twice daily for at least
5 days, plus VKA target INR 2.5
(INR range 2–3)
Day 1
Day 21
Day 30
after last dose
DVT=deep vein thrombosis; INR=international normalised ratio; LMWH=low molecular weight heparin
PE=pulmonary embolism; VKA=vitamin K antagonist 40

41. Rivaroxaban – a new option Einstein DVT
Major or clinically relevant bleeding in 8.1% per group
Bauersachs R et al.NEJM 2010; 363:

42. Rivaroxaban – a new option Einstein PE
Major or clinically relevant bleeding in 10.3% (riva) vs % (standard Rx)
Büller HR et al. NEJM 2012

43. Caveats for rivaroxaban
Not for severe renal dysfunction (calc CrCl <30 mL/min)
Few of the study patients hade extensive DVT or large PE. These patients might benefit from intial parenteral Rx.
Dose change at 3 weeks (15 mg BID  20 mg q.d.)
Dose with food – more reliable absorption

44. Standard duration of anticoagulation is now 3 m.
6 months?
27 months?
Schulman S et al. N Engl J Med 1995; 332:
Kearon C et al. N Engl J Med 1999; 340: 901-6 1A

45. WODIT
Agnelli et al. NEJM 2001

46. Recurrent DVT after stopping
Patients with unprovoked DVT
3 months Rx – 10% first year after (WODIT)
6 months Rx – 10% first year after (DURAC)
12 months Rx – 10% first year after (WODIT)
24 months Rx – 10% first year after (LAFIT)
No difference 3 vs 6 months in patients with proximal DVT or PE in DOTAVK
Pinede et al: Circulation; May 27, 2001 (DOTAVK)

47. A meta-analysis on individual data N=2474
PE as a risk factor
A meta-analysis on individual data N=2474
Pinede et al. ASH 2003

48. Decision on long-term at 3 m
Long-term treatment for
Unprovoked VTE
Second episode
Cancer
Unless bleeding risk or adequate monitoring unavailable 1B

49. Suggestions for duration of VKA
Proximal DVT and permanent risk or PE
Bleeding, Poor compliance
Old age
Needs ASA Female?
Mild thrombophilic defect /
Second VTE
Third VTE or more, Severe thrombophilia, Severe venous insuff., Pulmonary hypertension
3 m m m m Indefinitely
Patient preferences

50. Or … Provoked and small DVT or small PE: 3 m Unprovoked small DVT: 3 m
Unprovoked extensive DVT: 6 m
Unprovoked extensive PE: 1 y

51. Elevated D-dimer

52. Management strategy – unprovoked VTE
D-dimer Dx
m m
Pos
Neg Pos 8.9%/yr
Neg Neg 3.5%/yr
Verhovsek M. Ann Intern Med. 2008;149:481-90

53. D-dimer in males
Several studies indicate that males have despite normalization of D-dimer a higher risk of recurrence.

54. Conclusions
Several risk scores and risk stratification tools are available and should be used
Diagnostic algorithm for DVT/PE is helpful
Many options for treatment of VTE exist
Decide at 3-6 months regarding stopping or indefinite anticoagulation
Extended postoperative prophylaxis after THR, TKR, HFS and abdominal/pelvic Sx for cancer