Deep Vein Thrombosis: Diagnosis & Treatment Reginald E. Smith ...

Deep Vein Thrombosis:
Diagnosis & Treatment
Reginald E. Smith, Pharm.D.
Cardiac Services & Thrombosis Clinic
Royal Jubilee Hospital & Victoria Heart Institute
Victoria, B.C. Canada

Outline
VTE: Diagnosis & Treatment
VTE Pathophysiology & Background
Diagnosis of DVT (D-Dimer/Ultrasound)
Diagnosis of Pulmonary Embolism
Post Thrombotic Syndrome
Pharmacological Treatment of DVT/PE
Cancer & VTE
New Antithrombotics
13:30 hrs
2

Fail or Win
3

Child Safety Fail
4

Virchow’s Triad and Thrombus Formation
Described by Rudolf Virchow 150
years ago
Vascular Injury, Hypercoaguability,
Venous Stasis
One or more of these components
is present in the majority of
patients with thrombosis
Virchow’s
Triad
Venous Stasis
Adapted from Joist JH. Semin Thromb Hemost. 1990;16:151-157.
6
6

Associated Conditions
Surgery – Particulary Orthopedic of
Lower Limbs, Abdomen, Pelvis
Cancer – Known Cancer, Or Can Be
The First Sign Of Occult Cancer
Hereditary Or Acquired Thrombophilia
Travel (Air or Long Distance Auto)
Pregnancy, Estrogens
Adapted from Joist JH. Semin Thromb Hemost. 1990;16:151-157.
7
7

Pathophysiology of DVT
Most Often In Deep Veins Of
Leg or Calf
Embolus
Thrombus
Venous
valve
Also Occurs In Arms, Thorax
(Subclavian), Hepatic Portal,
Messenteric, and Pelvic Veins
Pressure Increases In Veins
Below Thrombus
DVT=deep vein thrombosis
1. Hirsh J, Hoak J. Circulation. 1996;93:2212-2245.
2. Figure from Tapson VF. N Engl J Med. 2008;358:1037-1052. Copyright ©2008 Massachusetts Medical Society. All rights reserved.
8
8

Patients are at Risk for DVT Across
a Broad Range of Hospital Settings
DVT=deep vein thrombosis
Geerts WH et al. Chest. 2004;126(3 Suppl):338S-400S.
9
9

Late Presentation Is Common
The Risk Continues Post- Discharge
TKR
1 month
THR
3 months
White R.H., et al. Arch Intern Ned 1998; 158:1525-1531.
N=43,645
11

Symptoms of DVT
• Leg pain (90%)
• Tenderness (85%)
• Ankle edema (76%)
• Calf swelling (42%)
• Dilated veins (33%)
• Dusky discoloration (30%)
• Warmth
50% NO SYMPTOMS
Symptomatic DVT
“DVT cannot be reliably diagnosed on the basis of
history and physical exam, even in high-risk patients”

WELLS Scale For Pretest Probability
Score
-2 to 0 Low Pretest Probability
1 or 2 Moderate Pretest Probability
> 2 High Pretest Probability

Diagnostic algorithm using D-dimer testing and
ultrasound imaging in patients with suspected DVT
Scarvelis & Wells, 2006
14 1
4
14

Sensitivity & Specificity Of D-Dimer
Test For Deep Vein Thrombosis
Subgroup Sensitivity Specificity Negative
Predictive Value
Low or
Moderate
Pretest
Probability
High Pretest
Probability
Patients With
Cancer
97.1% 62.7% 99.6%
100% 40% 100%
100% 45.5% 100%
D-Dimer False Positive With Surgery, Injury, Infection, Cancer, Pregnancy
Bates, S. M. et. al. Ann Intern Med 2003;138:787-794

Compression Ultrasound Lower Extremity:
Deep Veins

Compression Ultrasound
Lower Extremity: Deep Veins
No DVT
Superficial Femoral Vein
Normal Compression – No DVT
Superficial Femoral Vein
Vein Does Not Compress - DVT

Venous Anatomy Of The Leg
Proximal
DVT
Thrombosis in
Trifurcation
or Higher

Deep Vein Clots Are Big
Measured In Centimeters
Measured In Millimeters
VS
DVT Clots Can Be As Round As Your
Finger And As Long As Your Leg
Coronary Clots Very Small

Washing Instructions -- FAIL
20

Pulmonary Embolism
21

Pulmonary Embolism
Shortness of breath
Pleuretic Chest + Rib Pain
(worsens with breathing)
Bloody sputum
Dyspena, Fatigue
LA=left atrium; LV=left ventricle; PE=pulmonary embolism; RA=right atrium; RV=right ventricle
Figure from Tapson VF. N Engl J Med. 2008;358:1037-1052.
Copyright ©2008 Massachusetts Medical Society. All rights reserved.
22
22

Pulmonary Embolism:
A Life-threatening Disease
Cumulative mortality following acute PE
Mortality rate (%; excluding PE
first recognised at necropsy)
16
14
12
10
8
6
4
2
0
15.3% Mortality
At 3 months
International Cooperative Pulmonary
Embolism Registry
N=2454
0 10 20 30 40 50 60 70 80 90
Time from diagnosis (days)
PE=pulmonary embolism
Goldhaber SZ et al; for ICOPER. Lancet. 1999;353:1386–1389.
23 2
3
23

Wells Scoring System for Diagnosing
Pulmonary Embolism
High Probability 7 or Higher
Intermediate 2 to 6 PE Is Likely If Score > 4
Low Probability Less Than 2
DVT=deep vein thrombosis; PE=pulmonary embolism
Lee CH et al. Med J Aust. 2005;182:569-574.
24 2
4
24

Diagnostic Testing for PE
CT Angiography
Coronal Axis
Saggital Axis

Heart Sounds
S1 = Tricuspid + Mitral
S2 = Pulmonic + Aortic
Massive Pulmonary Embolism Can Produce A Split S2

Acute Pulmonary Embolism
R Axis Deviation
T Wave Inversion
Q Wave in III
S1 Q3 T3 – Pattern
ST Depression In Anterior Leads Also Possible

Post Thrombotic Syndrome
Develops in
Half of
Patients
at two
years 1

Grade IA
Symptomatic Proximal DVT
Gradient 30-40 mmHg Minimum 2 Years, Longer if PTS
(40-50% Reduction in PTS)
Elastic Bandages Can Be Applied
Initially
GCS Fitting Once Acute Swelling
Has Subsided

Treatment of Deep
Vein Thrombosis &
Pulmonary Embolism
31

Therapy: Do We Need To Anticoagulate
Patients With Acute VTE ?
19 Patients With PE Randomized To No Therapy
16 Patients Wit PE Randomized toHeparin 10,000 U SQ
Q6H x 6 Doses Then Oral Anticoagulation x 2 Weeks
Group
Mortality
No Therapy 26.3%
Heparin/ 0%
Oral Anticoag
ARR= 26.3% NNT 3.8
Barrett and Jordan, Lancet 1960:1:1309
32

Do You Need A Fast Acting
Anticoagulant Up Front ?
patients with objectively proven acute lower-limb DVT
randomized trial of IV standard heparin + oral
anticoagulants or oral anticoagulants alone
Symptomatic
Recurrences
Asymptomatic
Recurrences
All
Recurrences
OAC alone
Heparin + OAC
12 / 60 39.6 %
4 / 60 8.2 %
58.3 %
13 %
ARR = 45% NNT = 2.2
Brandjes et al. NEJM 1992:327;1485
33

Overlapping Heparins, LMWH or
Fondaparinux With Warfarin
II
Longest
T1/2
VII
Shortest
T1/2
Factor II Depleted
By Day 5
Heparin/LMWH or Fondaparinux Minimum 5 Days
Continue Until At Least 2 Sequential INRs In Range (2-3)
LMWH Anti-Inflammatory: May Continue > 10 Days For Extensive DVT
34

Heparin Induced Skin Necrosis
Patient May Be Developing Heparin Induced Thrombocytopenia & Thrombosis
Stop Heparins Immediately – Check For HIT Antibodies
Start Argatroban Infusion
35

Does SYMPTOMATIC Calf DVT Require Treatment ?
Calf DVT, treated initially with intravenous UFH
then long term therapy OAC vs no treatment
Recurrence during
first 3 months
Recurrence during
first year
OAC
No Rx
0 / 23 (0%) 1 / 23
8 / 28 (28.5%) 9 / 28
Recurrence 3 Months: Treatment vs No Treatment ARR=28.5% NNT= 3.5
Lagerstedt Lancet 1985:2;515
36

Treatment of DVT/PE
Recommendations from 8th ACCP Guidelines
First-episode secondary to transient risk factor
Warfarin for 3 months
First-episode idiopathic
Warfarin for at least 3 months;
Long-term therapy based upon risk-benefit ratio
Antiphospholipid antibodies or ≥2 thrombophilic
conditions
Treat for 12 months; consider indefinite
anticoagulant therapy
First episode with deficiency of antithrombin III,
protein C or S, factor V Leiden or prothrombin
20210 gene mutation, hyperhomocysteinemia, or
high factor VIII levels
Treat for 6 to 12 months; indefinite therapy for
patients with idiopathic thrombosis
≥2 episodes
Indefinite treatment
Kearon C, et al. Chest 2008;133;454S-545S
37

Cancer Associated Thrombosis
38

Cancer & VTE
39

Treatment Of Cancer Associated
Thrombosis
Chest Guidelines 2008: LMWH First 3-6 Months Then LMWH or Warfarin Until Cancer In Remission
40

Slogan -- FAIL
41

Novel Anticoagulants:
The Future of Warfarin
Reginald E. Smith, Pharm.D.
Cardiac Services & Thrombosis Clinic
Royal Jubilee Hospital & Victoria Heart Institute
Victoria, B.C. Canada
42

Current Limitations of Existing Drugs
UFH
LMWH
VKAs
Limitations
► Parenteral
► Unpredictable due to
unspecific binding
► Risk of HIT
► Parenteral
► Risk of HIT
► Unpredictable
► Slow onset of action
► Narrow therapeutic window
► Food and drug interactions
Consequences
► Inconvenient for
long term use
► Monitoring of
aPTT required
► Inconvenient and
expensive for long term
use
► Monitoring of platelets
► Regular monitoring and
dose adjustments
► Risk of adverse events
(bleeding)
Fondaparinux
► Parenteral ► Inconvenient and
expensive for long term
use
Lassen MR. Vasc Health Risk Manag. 2008;4(6):1373-86.

New Oral Anticoagulant Agents In
Development
Heparin
LMWH
Fondaparinux
Idraparinux
Semuloparin
Antithrombin III
X
TF/VIIa
VIIIa
Xa
II
Va
IXa
IX
TTP889
Rivaroxaban
Apixaban
LY517717
YM150
DU-176b
Betrixaban
Dabigatran
IIa
Fibrinogen
Fibrin
Adapted from Turpie Eur Heart J 2008

Dabigatran

Dabigatran etexilate:
a novel direct thrombin inhibitor
N
N
CH 3
N
N
NH
H 3
C
O
O
O
O
N H 2
N
O CH 3
Half life of 12-17 h
~ 80% renally excreted & 6.5% bioavailability
Predictable and consistent anticoagulant effects
Low potential for drug-drug interactions (Verapamil Increases Effect),
no drug-food interactions
No requirement for routine coagulation monitoring
Rapid onset of action (1-4 hrs)

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

RE-LY ® – study design
Atrial fibrillation with ≥ 1 risk factor
Absence of contraindications
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
Dabigatran etexilate
110 mg bid
N=6000
Dabigatran etexilate
150 mg bid
N=6000
Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin
Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up
Ezekowitz MD, et al. Am Heart J 2009;157:805-10.
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

Time to first stroke / SSE
Cumulative hazard rates
0.05
0.04
0.03
0.02
0.01
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
RR 0.91
(95% CI: 0.74–1.11)
p

Major bleeding rates
3.50
3.00
2.50
RR 0.80 (95% CI: 0.69–0.93)
2.71
p=0.003 (sup)
RRR
20%
RR 0.93 (95% CI: 0.81–1.07)
3.11
p=0.31 (sup)
3.36
% per year
2.00
1.50
1.00
0.50
0.00
D110 mg BID D150 mg BID Warfarin
Connolly SJ., et al. NEJM published online on Aug 30th 2009.
DOI 10.1056/NEJMoa0905561
322 / 6,015 375 / 6,076 397 / 6,022
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation

Intra-cranial bleeding rates
90
80
70
RR 0.31 (95% CI: 0.20–0.47)
p

Most common adverse events
Dabigatran
110 mg
%
Dabigatran
150 mg
%
Warfarin
%
Dyspepsia* 11.8 11.3 5.8
Dyspnea 9.3 9.5 9.7
Dizziness 8.1 8.3 9.4
Peripheral edema 7.9 7.9 7.8
Fatigue 6.6 6.6 6.2
Cough 5.7 5.7 6.0
Chest pain 5.2 6.2 5.9
Arthralgia 4.5 5.5 5.7
Back pain 5.3 5.2 5.6
Nasopharyngitis 5.6 5.4 5.6
Diarrhea 6.3 6.5 5.7
Urinary tract infection 4.5 4.8 5.6
Upper respiratory tract infection 4.8 4.7 5.2
*Occurred more commonly on dabigatran p

A phase III, randomised, double blind, parallel-group
study of the efficacy and safety of oral dabigatran
etexilate (150 mg bid) compared to warfarin (INR 2.0–
3.0) for 6 month treatment of acute symptomatic venous
thromboembolism, following initial treatment (5–10
days) with a parenteral anticoagulant approved for this
indication.
Dabigatran etexilate is in clinical development and
not licensed for clinical use for acute treatment of VTE

RE-COVER TM Trial Design
Singledummy
period
Double-dummy period
Warfarin
placebo
Dabigatran etexilate 150 mg bid
Objective
confirmation
of VTE
72 h
Warfarin
Initial parenteral
therapy
Warfarin placebo
Dabigatran etexilate placebo bid
Warfarin
(INR 2.0–3.0)
30 days
follow up
E R
E= enrolment
R= randomization
Until INR ≥2.0 at
two consecutive
measurements
(8-11 days)
6 months
End of treatment
54

Cumulative risk of recurrent VTE
and related death
Dabigatran
Warfarin
No. at risk
Months Since Randomization
Dabigatran was non-inferior to warfarin for prevention of recurrent or fatal VTE
(P

Cumulative risk of first event of
major bleeding and of any bleeding
Warfarin, any bleeding
Dabigatran, any bleeding
Warfarin, MBE
Dabigatran, MBE
Warfarin and any bleeding
29% RRR
Dabigatran and
any bleeding
Dabigatran and
major bleeding
Warfarin and
major bleeding
Months since First Intake of Study Drug
The hazard ratio for any bleeding at 6 months is 0.71 (95% CI, 0.59–0.85) in
favor of dabigatran (P=0.0002).
56

Most common Adverse Events
Treatment period Only oral treatment Parenteral / oral treatment
Dabigatran
n = 1226
Warfarin
n = 1214
Dabigatran
n = 1273
Warfarin
n = 1266
Headache (%) 60 (4.9) 64 (5.3) 79 (6.2) 88 (7.0)
Pain in extremity (%) 59 (4.8) 69 (5.7) 64 (5.0) 71 (5.6)
Nausea (%) 43 (3.5) 43 (3.5) 49 (3.8) 58 (4.6)
Diarrhea (%) 46 (3.8) 34 (2.8) 57 (4.5) 38 (3.0)
Nasopharyngitis (%) 47 (3.8) 53 (4.4) 50 (3.9) 54 (4.3)
Dyspnea (%) 33 (2.7) 47 (3.9) 41 (3.2) 53 (4.2)
Back pain (%) 42 (3.4) 44 (3.6) 46 (3.6) 50 (3.9)
Arthralgia (%) 45 (3.7) 30 (2.5) 48 (3.8) 33 (2.6)
Peripheral edema (%) 41 (3.3) 45 (3.7) 43 (3.4) 48 (3.8)
Dyspepsia (%) 36 (2.9) 7 (0.6) 39 (3.1) 9 (0.7)*
*p

Dabigatran: How To Measure Effect?

Thrombin Time Ratio Best
Approximates Dabigatran Plasma Levels
INR Poor Indicator of Dabigatran Effect

Bleeding Management
Withhold Dabigatran/Rivaroxaban
5 Half Lives
2.5-3.5 days for Dabigatran,
1.8 – 2.5 Days Rivaroxaban)
Blood Transfusion
Medical/Surgical Measures

Rivaroxaban

Rivaroxaban
Brand name Xarelto ® , Bayer
High oral bioavailability
(>80%)
Onset of action 2-4 hours
Half-life 9-12 hours
Prophylactic Dose 10 mg qd
Treatment Dose 20 mg daily
Primarily renal elimination
(66%), remainder feces p
glycoprotein
No laboratory monitoring
required
No dosage adjustment for
gender, age, extreme
body weight

Rivaroxaban Is Structurally Similar To Linezolid
Linelzolid
(Antibiotic)
Rivaroxaban
(Antibiotic)
No Antimicrobial Activity, No Observed Mitochondrial Toxicity

Effect of Rivaroxaban On Coagulation
Parameters: PT Ratio

Effect of Rivaroxaban On Coagulation
Parameters: apTT Ratio