Transcript Document

New Developments in
Venous Thromboembolic
Disease
Karen Hauer, MD
University of California,
San Francisco
Outline
• Diagnosis
– VQ, Ultrasound, Helical CT, D-dimer
• Risk factors
• Treatment
– Heparins
– Warfarin: duration of treatment
– New agents
• Prophylaxis
• IVC filters
48 year old woman presents with 2 weeks right
LE pain, 2 days “trouble catching my breath.”
PMH: dysfunctional uterine bleeding due to
fibroids, recently treated with OCPs.
PE: afebrile. BP 120/70, HR 110, RR 20,
O2 95% RA. Normal chest & CV exam, CXR.
What is your clinical suspicion of PE?
What is your next diagnostic step?
Clinical probability of PE
Wells, Ann Intern Med 2001
Leg swelling, tenderness
Pulse > 100
Immobilization, surgery
Prior DVT/PE
Hemoptysis
Cancer
No other more likely Dx
< 2 = Low probability
2-6 = Moderate
> 6 = High
3
1.5
1.5
1.5
1
1
3
VQ scan for PE
PIOPED, 1990
Clinical Suspicion
High
VQ
Intermed
Low
High
96%
88%
56%
Intermed
66%
28%
16%
Low
40%
16%
4%
0
6%
2%
Normal
Non-diagnostic in 640/887 (72%) patients
Lower Extremity Veins
Iliac
Internal
Saphenous
(Superficial)
Femoral
Deep
(Common)
Femoral
Popliteal
External Saphenous
Lower Extremity Ultrasound for PE
• 90% PE’s originate in lower extremity DVT
• 1st symptomatic DVT
– Sensitivity 95%, specificity 96%
– Increased sensitivity:
• serial US at 5-7 days
• combining with clinical suspicion
Ultrasound after Non-diagnostic VQ
• After non-diagnostic lung scan, serial US has NPV
of 99.5% (Wells, Ann Intern Med, 1998)
– Avoids angiogram
• 71% vs. 29% require angio (Stein, Arch Intern Med, 1995)
• Caution:
–
–
–
–
Recurrent DVT: 50% US still abnormal at 1 year
Asymptomatic DVT: lower sensitivity
Isolated calf DVT: lower sensitivity
Serial US not for high cardiopulmonary risk
D-dimers: what is the role?
• D-dimer: degradation product of cross-linked fibrin
• The appeal: a simple blood test
• High sensitivity, low specificity
• Quantitative D-dimer < 500 ng/ml makes PE less likely
• Elevated d-dimer common w/o clot - especially
• Cancer
• Post-op
• Pregnancy
• Inpatients
• Prior DVT
D-dimers: use selectively
• Multiple assays
• Can’t generalize from one to another
• Goal: high negative predictive value
• To rule out clot
• Use D-dimers with clinical suspicion or
other testing
– In outpatients, ED
D-dimers
Pretest probability (930 ED patients)
Low: n=527 (57%)
D-dimer
(-)
N=437 (47%)
No PE
Not low: n=403 (43%)
D-dimer +VQ
(+)
VQ
Wells, Ann Intern Med, 2001
The Role of Helical CT in
Diagnosing PE
Where does Helical CT fit into the algorithm?
Suspected PE
V/Q scan
60-70% nondiagnostic
Serial US
unsafe if unstable patient
Angiography
invasive
D-dimer
negative may rule out PE
Helical CT: Reviewing the Evidence
Rathbun, Ann Intern Med 2000
Mullins, Arch Intern Med 2000
Rathbun
Sensitivity 53% - 100%
Specificity 81% - 100%
• Limitations
Mullins
64% - 93%
89% - 100%
– Include subsegmental PE?
• Sensitivity for central PE = 83% - 100%, PPV = 95%
• Sensitivity for subsegmental PE = 29%
– Variations in quality of technology, reader
CT: the Primary Diagnostic Test?
van Strijen, Ann Intern Med 2003
510 patients with suspected PE
Helical CT
PE
124 (24%)
alternate Dx
130 (26%)
normal
248 (49%)
2 DVT on US
Helical CT: Evidence-based Practice
• Does a normal helical CT rule out PE?
– Enough to withhold anticoagulation? Stop workup?
– Yes.
• Does a positive helical CT rule in PE?
– Yes, no need for further testing.
– At centers with CT experience - radiology, scanner
The Role of Helical CT in
Diagnosing PE
Stable patient
Equivocal V/Q <-Helical CT
Suspected PE
-->Unstable
patient: Helical CT
V/Q scan
Serial US
Angiography
D-dimer
A 48 year old Caucasian woman recently started on
OCPs presents with symptoms of acute DVT and PE.
V/Q scan is high probability for PE, LE ultrasound is
diagnostic of DVT, and helical CT shows a saddle
PE. You initiate anticoagulation, stop the OCP’s, and
consider whether she has a hypercoagulable state. Do
you. . .
A. Send protein C, protein S, antithrombin III levels
B. “Pan scan” for malignancy
C. Test for Factor V Leiden, prothrombin mutation
D. All of the above
E. None of the above
Clues to Inherited Hypercoagulability
• Age < 50
• Unusual location or severity
• “Idiopathic” thrombosis
– BUT, inherited disorders augment other
risks - i.e. surgery, pregnancy
• Recurrent thrombosis
• Family history
Inherited Hypercoagulability
Factor V Leiden
Prothrombin
mutation
Homocysteinemia
Prevalence Prevalence Diagnosis
with VTE w/o VTE
12-21%
6%
PCR
6-8%
Protein C, S
2-4%
deficiency
Antithrombin III 1-2%
deficiency
Any thrombophilia 24-37%
2%
PCR
Homocysteine
level
< 1%
<1%
Pro C, S
levels
ATIII level
10%
Antiphospholipid antibody: ACLA, PTT or other
twice over 6 weeks
Acquired risk factors:
oral contraceptives
35
30
25
Relative
risk
20
15
10
5
0
1st/2nd gen
prog
3rd gen
FV Leiden
OCP + FV
Leiden
Screening for hypercoagulability
before oral contraceptives
Pro
Con
• Thrombophilia
common
• PE: high morbidity,
mortality
• Cost
• Risk of clot low
• Difficulty predicting
who will clot
• H/o DVT/PE: already
a contraindication
• May still miss
thrombophilia
Acquired risk factors - cancer
Risk of cancer
after PE/DVT
3
2
Relative
risk
1
0
<6
>6
months after PE/DVT
• Cancer in patients with
DVT/PE:
– Higher risk of
metastases, worse
prognosis
– Recommendation:
careful H & P, routine
cancer screening
Sorensen, NEJM 2000
A healthy 48 year old with acute DVT and PE
is treated with warfarin and heparin. Potential
benefits of LMWH for this patient include all
of the following except:
A.
B.
C.
D.
Fewer lab tests
Potential for home therapy
Reduced mortality risk
Easier reversal of anticoagulation in case of
bleeding
E. Lower risk of heparin induced-thrombocytopenia
LMWH
Advantages
• Longer half life
• No need to monitor PTT
• Better bioavailability after
SQ injection
• Less heparin-induced
thrombocytopenia
• Less osteoporosis
• Better outcomes with
cancer
Disadvantages
• Incompletely reversed by
protamine
• Unpredictable response
with renal failure, obesity
LMWH vs. UFH: 13 Studies
Dolovich, Arch Int Med 2000
DVT/PE
PE
Major bleeding
Minor
bleeding
Total mortality
Thrombocytopenia
1.00
Pooled Relative Risk
LMWH better 0.50
1.50
UFH better
Treating to prevent
Post thrombotic syndrome
• Venous insufficiency after DVT
• Risk factors
– Elderly
– Recurrent DVT
– Obesity
– Proximal thrombosis
• Chronic pain, edema, ulcers, skin discoloration
Compression hose prevent
post thrombotic syndrome
• 1st proximal DVT, anticoagulated >= 3 months
• Intervention
– Below-knee elastic stocking on affected leg for 2
years, started 5-10 days after DVT diagnosis
• Stockings reduced post thrombotic syndrome:
– 49% vs. 26% (NNT = 4 to prevent 1 case)
– Compression hose well tolerated
– No difference in rate of recurrent DVT
Prandoni, Ann Intern Med 2004
Duration of Treatment:
VTE as a Chronic Disease
Recurrence rate
45
40
35
30
25
20
15
10
5
0
1st VTE
Warfarin 3 mo
Warfarinextended
Recurrent VTE
6
12
18
months
24
Warfarin 6 mo
Warfarinextended
Kearon, NEJM, 1999
Schulman, NEJM 1997
Warfarin for Secondary Prevention after
Idiopathic DVT/PE
• Placebo
Recurrence/year
7%
Bleeding/year
• INR 1.5-2
2-2.6%
1%
• INR 2-3
0.6%
1%
PREVENT, NEJM 2003
ELATE, Blood 2003
Duration of Treatment Guidelines
1st event, reversible risk factor
3-6 months
1st event, spontaneous
>= 6 months
2nd event
>=12 months or
lifelong
Lifelong
2nd spontaneous event, or 1st
spontaneous and life threatening
3rd event or
Ongoing risk factors
Lifelong
The Decision to Stop Warfarin:
•
Risk factors for clot recurrence
1. Initial clot burden
2. Modifiable vs. persistent, major vs. minor
3. Thrombophilia
•
Indicators of increased risk
– Elevated d-dimers 1 mo after stopping anticoag
– Residual thrombosis on ultrasound after anticoag
– Other markers of coagulation activity
ACCP 2004
Hron, JAMA 2006
Young, J Thromb Haemost 2006
Inherited risk factors and
recurrent venous thromboembolism
Meta-analysis of 10 studies evaluating risk of
recurrent clot in 3000 patients after anticoagulation
stopped - with or without genetic mutation
Factor V Leiden
21% of patients
Odds of recurrence: 1.4
Prothrombin G20212A
10% of patients
Odds of recurrence: 1.7
Elevated risk, but not enough to warrant lifelong
anticoagulation
Ho, Arch Intern Med, 2006
recurrent clot (%)
Treatment of Thromboembolism with
Cancer: LMWH Superior
20
18
16
14
12
10
8
6
4
2
0
Dalteparin
Warfarin
1
2
3
4
months
5
6
7
Lee. NEJM 2003
Thrombosis in Pregnancy
A 34 year old woman G1 who is 35 weeks pregnant
presents with left leg swelling, dyspnea, and right sided
pleuritic chest pain.
How do you proceed?
A. Reassure her - these are common symptoms in
pregnancy
B. MRI of the lower extremities
C. D-dimer
D. V/Q scan
E. IV Heparin
Thrombosis in Pregnancy
• Challenges in diagnosis
– Edema, tachypnea, dyspnea common
– D-dimer levels rise during pregnancy
• Test as you would for non-pregnant patient
– Ultrasound for DVT, PE
• Consider MRI
– V/Q or CT for PE
• Treat with LMWH, heparin, fondaparinux
On the horizon. . . New therapies
• Fondaparinux
– Synthetic Factor Xa inhibitor
– FDA approved for prophylaxis, treatment
• Prophylaxis: 2.5/d SQ
• Treatment: weight based 5, 7.5 or 10/d SQ
– Start warfarin simultaneously, continue 5-7 days as with
heparin
• Avoid with GFR < 30
Off the horizon 2006. . . Ximelagatran
• Direct thrombin inhibitors
• Alternative to warfarin
– Oral - fixed dose
• Acute clot or orthopedic prophylaxis: 36 mg bid
• Secondary prevention: 24 mg bid
– No monitoring, no initial heparin
• Safety questions
– No antidote
– Can elevate LFTs
Preparing for surgery
Deemed no longer a candidate for estrogens, the patient
is scheduled for hysterectomy due to menorrhagia
worsened on anticoagulation. What DVT prophylaxis
do you recommend?
A.
B.
C.
D.
Ted hose, early ambulation
IV heparin
UFH 5000 u SQ bid
Enoxaparin 30 mg SQ bid + ted hose,
early ambulation
DVT prophylaxis: Surgery
• Low risk
– Age < 40 AND surgery <30 min
• Moderate risk
– Non major surgery or age 40-60 or other risks*
• High risk
– Age >60, LE ortho or cancer surgery, other risks*
*e.g. thrombophilia, CHF, malignancy
DVT prophylaxis: Surgery
• Low risk
– Early ambulation
• Moderate risk
– UFH 5000 u SQ bid or LMWH, IPC, ted hose
• High risk
– LMWH - may combine with IPC, ted hose
LMWH in Medical Patients at
Moderate Risk for DVT
Samama, NEJM. 1999
• 866 patients: respiratory failure, infection,
CHF, treated 6-14 days
– DVT at day 14:
• enoxaparin 40 mg/dy: 5.5%
• enoxaparin 20 mg/dy, placebo: 15%(p = 0.001)
– Similar mortality, side effects
BUT. . . mostly asymptomatic, distal DVT
no UFH comparison group
Preventing DVT in Medical Patients
• UFH or LMWH effective
– 60% risk reduction in DVT, PE
– Borderline decrease in hemorrhage with LMWH
• Target high risk patients
– CHF
– Severe respiratory disease
– Bedridden plus additional risk factor
• Consider compression hose for low risk patients
Case
A 30 year old woman with ulcerative colitis is
admitted with bloody diarrhea. On day 3 she
develops dyspnea and hypoxia. Helical CT
reveals PE. What is the best management
strategy:
A.
B.
C.
D.
Unfractionated heparin, goal aPTT 50-60, followed by LMWH
IVC filter, avoid anticoagulation
IVC filter, initiate anticoagulation when bleeding controlled
Unfractionated heparin, warfarin with goal INR 1.5-2
Indications for IVC filter
• Clot with active bleeding
• Clot despite anticoagulation
• Massive PE with chronically compromised
pulmonary vasculature?
• Prevention?
IVC filters: benefits and risks
Decousus, NEJM 1998
400 patients with proximal DVT, 50% with PE
PE at day 12
PE at 2 years
DVT at 2 years
Death
Major bleed
Filter
No filter
1%
3%
21%
22%
9%
5%
6%
12%
21%
12%
p
0.03
NS
0.02
NS
NS
Retrievable IVC filters
• FDA approved
• Ideal for young patients with reversible
PE risk factors
• Left in, they become permanent
– Current duration < 2 weeks
Summary
• Diagnosis
– Combine clinical suspicion, test results
• Risk factors
– Higher yield for inherited thrombophilia
• Treatment
– LMWH as good, possibly superior to UFH
– Warfarin: Longer treatment course
• Prophylaxis
– Risk stratify