VTE: It’s still a killer in
Canada
Sam Schulman, MD, PhD
Dept. of Medicine
McMaster University
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
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.
Mitigating Potential Bias
• All treatment alternatives are discussed
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
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.
• SaO2 94-98% all the time
• Surgery Day 4 in late afternoon. Suspected MI in
recovery  arrest. CPR unsuccessful – large PE
PE - mortality
• 10% succumb within 1 h
– Usually before arrival at the hospital
• PE – 3rd leading cause of cardiovascular
death
Risk factors for VTE
•
•
•
•
•
•
•
•
•
•
• 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
Surgery
Trauma
Immobility, paresis
Malignancy
Cancer therapy
Previous VTE
Increasing age
Pregnancy / postpartum
Estrogens
Selective estrogen
receptor modulators
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
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: 227-77
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 1966-1990, 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
1.
2.
3.
4.
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
Survival after VTE
After
7-day
30-day
1-year
DVT
96.2%
94.5%
85.4%
PE
±DVT
VTE
59.1%
55.6%
47.7%
74.8%
72.0%
63.6%
• Olmsted County inception cohort
• Followed 1966-1990, n=2218
Risk factors for death
PE
Age
BMI
Patient location @ onset
Malignancy
CHF
Heit JA et al. Arch Intern Med 1999;159:445-53
More risk factors
Neurologic disease
Chronic lung disease
Recent Sx
Hormone Rx
Smoking tobacco
Chron renal disease
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
Effect of age
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
Adults 18 years and older with VTE in USA (millions)
Prevalence of VTE is predicted to double by 2050
2
1.5
1
0.5
0
2002 2003 2004 2005 2006 2008 2010 2015 2020 2025 2030 2035 2040 2045 2050
Year
VTE cases per 100 000:
20
02
20
03
20
04
20
05
20
06
20
08
20
10
20
15
20
20
20
25
20
30
20
35
20
40
20
45
20
50
31 34 37 40 42 42 43 45 47 50
7
1
1
1
2
6
2
3
8
5
VTE = venous thromboembolism
Deitelzweig SB et al. Am J Haematol 2011;86:217–20
52
7
54
4
55
6
56
3
56
7
15
Patients at highest risk
•
•
•
•
Recent VTE
Malignancy
Spinal cord injury
Heparin-induced thrombocytopenia
Increased prophylactic dose
• Spinal cord injury
• Burn injury
• Bariatric surgery
Bariatric surgery
Consecutive patients 1979-2000
Early ambulation
& mechanical
• >100,000
procedures
in the USproph.
• Incidence
of reported30VTE
0.1%
- 1%, fatal
Group 1: enoxaparin
mg bid
(n=92)
PE 0.2%
DVT 5.4%
• Mainly after discharge
Group 2: enoxaparin 40 mg bid (n=389)
• 95% ofDVT
US surgeons
give prophylaxis
0.6%
• LMWH, UFH tid or fondaparinux: May add
Scholten DJ et al. Obes Surg 2002;12:19-24
mechanical.
• Higher doses than standard
Extended postop prophylaxis,
i.e. up to 1 month instead of 1 week
1. High risk of VTE + pelvic/abdominal Sx
for cancer (Grade 1B)
a) Results in 13 fewer non-fatal events per 1000
without significant increase in bleeding
2. Major orthopedic surgery (THR, TKR,
HFS) – minimum 10-14 d (Grade 1B) and
suggest up to 35 d (Grade 2B)
a) Results in 9 fewer non-fatal events per 1000
without significant increase in bleeding
ACCP Guidelines. CHEST 2012; 141 Suppl
Spinal cord injury
•
•
•
•
In case of paraplegia:
Very high risk at least first month
Continued increased risk 3 months
Then normalization
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
The Primary Outcomes – Ortho Sx
D
a
b
i
R
i
v
a
A
p
i
x
a
•
•
•
•
•
•
•
•
•
•
•
RE-MODEL
RE-MOBILIZE
RE-NOVATE
RE-NOVATE II
RECORD 1
RECORD 2
RECORD 3
RECORD 4
ADVANCE 1
ADVANCE 2
ADVANCE 3
TKR
TKR
THR
THR
THR
THR
TKR
TKR
TKR
TKR
THR
Non-inferior
Inferior
Non-inferior
Non-inferior
Superior
Superior
Superior
Superior
Non-inferiority not met
Superior
Superior
Suspected DVT / PE
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
Reduction of imaging diagnostics
•
•
Active cancer
1
Use Wells’ score and
D-dimer
Paralysis,
recent–immob
1
Recently
bedridden
d
1 in
– Only if low score + neg
D-dimer
will>2result
Localized tenderness
1
No imaging
Calf swelling >3 cm
1
D-dimer: Not useful Unilat pitting edema
1
Collateral superf. veins
1
– In generally ill patients
Previous documented DVT 1
– Shortly after surgeryAlt. Dx at least as likely
-2
– Differential vs cellulitis
<2 p – unlikely
– Very elderly (>80) >2 p - likely
– Long duration of symptoms
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
Do we have to treat distal DVT?
 Analysis
of 5 studies of sympt calf DVT
without treatment (Rhigini et al 2006):
 Progression
 RCT
(N=196):
VKA
alone
Progression
0-8 w
proximally in 25 of 353 (7%)
11%
UFH
5,000 x2
11%
UFH
Placebo
12,000 x1
7%
78%
2.3%
2.3%
0%
9-24 w
(ultrasound)
Belcaro G et al. Minerva Med 1997;88:507-14
25%
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
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
Suspected PE
Wells’ clinical prediction score for PE
Previous PE or DVT
Heart rate > 100/min
Recent surgery or immobilization
Clinical signs of DVT
Alternative diagnosis less likely than PE
Hemoptysis
Cancer
Dichotomized rule
Unlikely
Likely
+1.5
+1.5
+1.5
+3
+3
+1
+1
<4
>4
Wells PS et al. Thromb Haemost. 2000;83:416-20
Clinical probability assessment
Low or intermediate
High
D-dimer
Below cut-off
Above cut-off
CUS 1 or MDCTA
Negative 3
No anticoagulant therapy
2
Positive
Anticoagulant therapy
Can my PE-patient in ER go home?
• Pulmonary Embolism Severity Index (PESI)
–
–
–
–
–
–
Age
Male sex
Cancer
CHF
Chron lung dis.
 mental status
1 p / yr
10 p
30 p
10 p
10 p
60 p
SBP <100
Pulse >110
RR>30
Temp <36
SaO2 <90%
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;261:597-604
30 p
20 p
20 p
20 p
20 p
Simplified PESI
• Retrospective analysis of RIETE registry
–
–
–
–
–
–
–
Age >80
History of Cancer
Chron cardiopulmonary dis.
Pulse >110
CHF
SBP <100
SaO2 <90%
1p
1p
1p
1p
1p
1p
1p
• 0 = low risk, 1 or more = high risk
Jiménez D et al. Arch Intern Med. 2010;170:1383-9
Simplified PESI result
Jiménez D et al. Arch Intern Med. 2010;170:1383-9
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 0.3-0.7 IU/mL – at 6 h for s.c.
1B
FIDO-Study
UFH 250 U/kg bid vs
LMWH 100 IU/kg bid
Clinical Outcomes During the Study Period
Event
UFH
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;296:935-942.
Copyright restrictions may apply.
LMWH
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 protocol @ Hamilton for CrCl <30
– 1st dose 250 IU per kg
– Then 200 IU per kg q 12 h.
Oral Factor Xa inhibitor, rivaroxaban:
EINSTEIN-DVT/PE
EINSTEIN-DVT
Objectively
confirmed DVT
without
symptomatic PE
Randomisation
Eligible patients
N~2900
Predefined treatment period of
3, 6, 12 months
Rivaroxaban
15 mg twice daily
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
DVT=deep vein thrombosis; INR=international normalised ratio; LMWH=low molecular weight heparin
PE=pulmonary embolism; VKA=vitamin K antagonist
Day 30
after last dose
Rivaroxaban – a new option
Einstein DVT
Major or clinically relevant bleeding in 8.1% per group
Bauersachs R et al.NEJM 2010; 363: 2499-510
Rivaroxaban – a new option
Einstein PE
Major or clinically relevant bleeding in 10.3% (riva) vs.
11.4% (standard Rx)
Büller HR et al. NEJM 2012
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
Standard duration of
anticoagulation is now 3 m.
6 months?
27 months?
Schulman S et al. N Engl J Med 1995; 332: 1661-5
Kearon C et al. N Engl J Med 1999; 340: 901-6
1A
WODIT
0.30
3 months
1 year
Cumulative Hazard
0.25
0.20
0.15
0.10
0.05
0.00
0
3
6
9
12
15
18
21
24
27
30
33
36
Months
Agnelli et al. NEJM 2001
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)
PE as a risk factor
A meta-analysis on individual data
N=2474
HAZARD OF VTE (OFF TREATMENT)
60
PE at baseline
No
Yes
50
40
30
20
10
0
0
10
20
30
40
50
Time since qualifying VTE (months)
Pinede et al. ASH 2003
Decision on long-term at 3 m
• Long-term treatment for
– Unprovoked VTE
– Second episode
– Cancer
• Unless bleeding risk or adequate monitoring
unavailable
1B
Suggestions for duration of VKA
• Proximal DVT and permanent risk or PE
Bleeding,
Old age
Poor
Needs ASA
compliance Female?
3m
6m
Mild
thrombophilic
defect /
Second VTE
Third VTE or more,
Severe thrombophilia,
Severe venous insuff.,
Pulmonary hypertension
12 m
Patient preferences
24 m
Indefinitely
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
Probability of
recurrence (%)
Elevated D-dimer
40
30
20
10
0
0
1
2
3
Years of follow-up
4
EichingerH
EichingerN
Palareti(idiop)H
Palareti(idiop)N
Palareti(thr-philia)H
Palareti(thr-philia)N
CosmiH
CosmiN
Management strategy –
unprovoked VTE
D-dimer
Dx
0
3-6 m
Pos
+1 m
Neg
Pos 8.9%/yr
Neg
Neg 3.5%/yr
Verhovsek M. Ann Intern Med. 2008;149:481-90
D-dimer in males
• Several studies indicate that males have
despite normalization of D-dimer a higher
risk of recurrence.
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