Transcript The DVT & PE Treatment Revolution

Prevention, Diagnosis and
Treatment of DVT & PE
Arthur P. Wheeler, M.D.
Associate Professor of Medicine
Director MICU, Co-chair P&T
Division of Allergy, Pulmonary and Critical Care
Medicine
Vanderbilt Medical Center
Copyright A.P. Wheeler 2009
Thromboembolism epidemiology
5 million DVT’s
900,000
PE’s
290,000 fatalities
Heit J. Blood. 2005;106:910.
Thromboembolism is a disease
of hospitalized patients
1000
71% received no prophylaxis
in prior 30 days
100
50% in nursing homes or
<90 days post-discharge
Cases / 10,000
person years
10
1
Hospitalized
Heit Mayo Clin Proc 2001; 76:1102
Goldhaber Am J Cardiol 2004; 93:259
Community
Outpatient and Inpatient VTE Are
Linked
An observational study of 1897 patients with
confirmed VTE
• 74% of patients developed VTE as outpatients
• 60% were hospitalized in the past 3 months
• 67% diagnosed within 1 month of hospital discharge
• Only 43% had received anticoagulant prophylaxis
during their hospital stay
Spencer FA, et al. Arch Intern Med. 2007;167(14):1471-1475.
Virchow’s triad
Advancing age
Immobilization
Stroke - cord injury
Anesthesia
Heart or lung failure
Hyperviscosity
Surgery
Prior DVT
Venous access
Trauma
Sepsis
Vasculitis
Hypercoagulable State
Cancer
Estrogen
Family history
Sepsis
HIT
Protein C, S or AT III deficiency
Activated protein C resistance
(Leiden)
Hyperhomocystenemia
Antiphospholipid antibody
Prothrombin 20210 mutation
DVT Incidence absent prophylaxis
Cord Injury
Nicolaides 1997
Stroke
Nicolaides 1997
MICU
Hirsch 1995
General Surgery
Gallus 1994
Acute MI
Handley 1972
General Medical
Mismetti 2000
0
Geerts Chest 2004; 38S
20
40
60
80
100
Risk stratification in surgery
Calf DVT
%
Proximal
DVT %
Clinical
PE %
Fatal PE
%
<2
0.4
0.2
.002
Moderate
10-20
2-4
1-2
.1-.4
High
20-40
4-8
2-4
04-1
Very High
40-80
10-20
4-10
0.2-5
Low
Geerts Chest 2004; 38S
Medical prophylaxis: placebo
controlled trials
Nadroparin
3800-5700
U QD
p=0.05
30
25
20
Percent
15
VTE
placebo
heparin
5000 UFH
BID
p=NS
Enoxaparin
40 mg qd
p<0.001
5000 UFH
BID
p=NS
Enoxaparin
60 mg qd
p=0.04
Nadroparin
7500 U QD
p=NS
10
5
0
Halkin 1982 Gardlund
1996
n=1358
n=11,693
Dahan
1986
n=270
Samama
1999
Caulin
1989
n=1102
n=2474
Fraisse
2000
n=223
DVT prophylaxis:
Important, not perfect
LMWH / FPX
$ 16
Use in cancer, CHF or respiratory failure or
reduced mobility & 1 other risk factor: 1A
$ 2-13
UFH tid
ICD
$ 150
Use in high bleeding risk 1C or
as adjunct to anticoagulants 2A
$ 100
Stockings
$1
ASA
0
“Should not be used”: 1A
10
20
30
40
50
60
DVT Relative Risk Reduction
Geerts WH. Chest. 2008;133:381S-453S.
70
80
Physician response to prompts
& overall prophylaxis rate
50%
40%
*
Total Prophylaxis Rate
30%
20%
10%
0%
Control
Neutral
Conner Chest 118: 162S, 2000
Educational
Risk
Prophylaxis following consistent
reminders
Computerized prophylaxis prompts
35
Control
Prompted
30
25
Percent
20
15
Δ 41 %
10
5
0
Prophylaxis rates
Kucher N NEJM 2005; 352:969
VTE indicence
63% had risk score >4
Venous thromboembolism
5-30%?
90%
~50%
~50%
~10%
63-70% of fatal PE’s
unsuspected during life
Stein Chest 1995; 110:978
Sandler J R Soc Med 1989; 82:203
Clinical prediction rules
Factor
points
• Signs and symptoms of DVT
3
• Alternate diagnosis less likely
3
• Pulse >100
1.5
• Immobilization / surgery w/i 4 wk
1.5
• Previous DVT/PE
1.5
• Hemoptysis
1
• Malignancy
1
High > 6 (50%), Moderate 2-6 (19%), Low <2 (2%)
Wells Ann Intern Med 1998; 129, 997
DVT Diagnostic Methods
• Contrast venogram
• 75% positive in proven PE
• Venous ultrasound with Doppler flow
• 50-70% positive in proven PE
• 30% if chest studies not-high probability
• 5-10% positive in practice if lung scan nondiagnostic
• Impedance plethysmography
• MRI or CT
Chest radiographs in PE
Oligemia
Vascular congestion
Infiltrate
n=2322
Atlectasis
PA enlargement
Elevated diaphragm
Pleural effusion
Normal
Cardiac enlargement
0
Elliott Chest 2000; 118:33
5
10
15
Percent
20
25
30
ABG’s in PE
• No combination of PaO2, PCO2 or A-aDO2
excludes a pulmonary embolism.
• Normal A-a DO2 in up to 20% of proven PE.
−
−
−
−
−
−
Ely Am J Med 1997; 103:541
Stein Chest 1996; 109:78
Rodgers AJRCCM 2000; 162;2105
McFarlane Am J Med 1994; 96:57
Stein Chest 1995; 107:139
Cvitanic Chest 1989; 95:48
ECG’s in PE
• Transient non-specific abnormalities in 85%
• Most common: precoidal T wave inversions
• Less common:
− Atrial & ventricular arrhythmias
− Right axis deviation and RBBB
• S1Q3T3 in < 10%
Stein Chest 1991; 100:598
Stein Prog Cardiovasc Dis 1975; 17:247
d-dimer assays
• Results depend on method:
−
−
−
ELISA (sensitive, time consuming, expensive)
Latex agglutination (less sensitive, fast, cheap)
Whole blood agglutination
• Sensitivity 73-100%
• Specificity 30-70%
• Negative predictive value 99.5%
Quinn AJRCCM 1999; 159:1445
d-dimer assay positive in
•
•
•
•
•
•
•
•
•
Pneumonia
Sepsis
Myocardial infarction
Cancer
Pregnancy
Post-operative
Multiple trauma
Renal failure
Thromboembolic disease
d-dimer in low risk outpatients
• A negative sensitive test effectively
excludes clot (2/2040).
– Wells NEJM 2003; 349:1227
– Perrier Lancet 1999; 353, 190
– Kruip Arch Intern Med 2002;162, 1631
• Assays with moderate sensitivities (>85%)
rule out DVT with low Wells score.
– Wells Ann Intern Med 2001; 135, 98
VQ scan results
Finding
Freq
Normal or
14 %
near normal
Indeterminate
73 %
High
13 %
VQ only VQ + Clinical Prob.
(% angio +) (% angio +)
4%
Low
2
Intermediate 6
High
0
23 %
Low
10
Intermediate 22
High
59
87 %
Low
56
Intermediate 88
High
96
PIOPED I JAMA 1990; 263: 2753
VQ scan – CTA results
VQ/CTA only VQ + Clin. prob.
Finding
Freq (% angio +) (% angio +)
Normal or
14 %
4%
Low
2
near normal
Intermediate 6
16-22%
High
0
Indeterminate 73 %
23 %
Low
10
Intermediate 22
22%
High
59
High
13 %
87 %
Low
56 58
Intermediate 88 93
78-84%
High
96 96
PIOPED I JAMA 1990; 263: 2753
PIOPED II NEJM 2006;354: 2317
14% of CTs could not be interpreted
Factors affecting outcome of
contrast enhanced CT’s
• Detector array
– 1 to 16 rows
• Acquistion speed
– 10-24 seconds
• Contrast protocol
– Volume
– Flow rate
– Timing / gating
• Collimation
– 1-5 mm
• Reconstruction interval
– 2 mm
• Patient weight
• Breath-hold ability
• Low flow states or
asymmetric PVR
• Radiologist skill
Contrast CT vs VQ
CT
VQ
• Main PA or lobar clot = High probability
• Segmental or
= Indeterminate
subsegmental defect
• Normal CT
= Low probability
5% of patients with non-diagnostic VQ + negative US, +
normal CT have clot found at PA ‘gram or during 3 month
clinical follow-up.
Perrier Ann Intern Med 2001; 135:88
Ferretti Radiology 1997; 205:453
Ost Am J Med 2001; 110:16
Lorut AJRCCM 2000; 162:1413
PIOPED III
•
•
•
•
371 adults with suspected PE
MRA +/-MRV for diagnosis
25% of MRA studies “technically inadequate”
Technically adequate MRA
– 78% sensitivity
– 99% specificity
• 48% of MRA+MRV studies technically adequate
– 92% sensitivity
– 96% specificity
Stein PD Ann Intern Med 2010; 152:434
Pulmonary angiography
• Rarely used. (<10 % indeterminate V/Q’s).
− Sostman AJR 1995; 194:313
− Henschke Chest 1995; 107:940
• 4% non-diagnostic
• Sensitivity and specificity unknown
Angiography complications
Study
N
Deaths
Major
Minor
complications complications
1.9%
2.4%
Mills 1980
1350
0.2%
Stein 1992
1111
0.5%
0.8%
5.4%
Zuckerman
1996
Hudson
1996
Totals
547
0
0.9%
4.8%
1434
0
0.3%
4.8%
4442
0.2%
1.0%
2.9%
Outcome after negative angiogram
PE Incidence
Follow-up
6/380 (1.6%)
6/144 (2.7 %)
1/44 (4.2%)
3/167 (1.8%)
12 months
13 months
variable
6 months
Study
Henry, Chest 1995
Cheely, AJM 1981
Hull, Ann Int Med 1983
Novelline, Radiol 1978
NB: 10-20% with negative arteriograms have DVT.
Hull, Arch Intern Med 1994
U.S. Treatment of VTE patients
Retrospective review of 1173 patients 2001-2003
IV UFH
LMWH
DVT
n=590
43%
48%
PE
n=357
52%
41%
DVT+ PE
n=226
54%
42%
SQ UFH
7.6%
6.4%
4.4%
Thrombin Inhibitor
0.5%
0.6%
0.4%
Treatment
* 30-40% discharged without 2 PT’s in range
Tapson V. NABOR study, ACCP 2003
UFH recommendations
•
•
•
•
•
•
•
Begin empiric therapy
Bolus 80-100 U/kg
Infusion > 18 U/kg/hr
PTT 6 hr post-bolus
Achieve PTT ratio > 1.5 within 24 hours
Start warfarin early
Use a protocol
Effectiveness of non-protocolized
unfractionated heparin
100
80
Percent
60
PTT's > 1.5 x
40
control
20
0
1
2
3
4
5
6
7
8
Days after Starting Heparin
Wheeler Arch Int Med 1988; 148:1321
9
10
Challenges to effective UFH use
• 311 patients with thrombosis at MGH
• Average: bolus 70 U/kg, infusion 15 U/kg/hr
• Therapeutic success:
– 58% on first PTT.
– 71% in first day
– 7% for 4 consecutive days.
• > ½ the patients had 5 or more PTT’s per day
Hylek EM, Arch Int Med 2003; 163:621
PTT for Patients Receiving IV Heparin
aPTT for Patients Receiving IV Heparin
Cleveland Clinic Foundation Inpatients, October-December 2004*
75
50
Frequency
400
300
200
100
0
20
40
60
80
100
120
140
160
aPTT
*Includes all values from 24 hours after drip was ordered until drip was discontinued; 48% within therapeutic
ranges; manual chart review for validation has not yet occurred.
Snow V, Ann Intern Med. 2007;146:204.
Outpatient LMWH for DVT
Levine
10
198
(Exoxaparin BID)
8
Percent or
days
LMWH
UFH
6
Koopman
(Nadroparin BID)
202
253
247
4
2
Levine NEJM 1996; 334:667
Koopman NEJM 1996; 334:682
LO
S*
h
ea
t
D
B
le
ed
R
ec
ur
re
nc
e
LO
S*
h
ea
t
D
B
le
ed
R
ec
ur
re
nc
e
0
Dolovich Arch Intern Med 2000
on
bu
s
so
n
an
ro
19
99
19
97
19
97
20
00
20
00
19
96
19
96
8
Sp
i
ne
au
um
ol
Si
m
C
Vi
n
llm
an
e
Percent
10
Ti
oo
pm
K
Le
vi
n
l1
99
2
ul
H
Incidence of recurrent of VTE
Outpatient option
UFH
LMWH
6
4
2
0
Incidence of major bleeding
6
UFH
LMWH
4
Outpatient option
3
2
1
Dolovich Arch Intern Med 2000
97
19
on
ne
au
19
97
Si
m
C
ol
um
bu
s
20
Vi
ns
on
20
an
Ti
llm
00
00
6
K
oo
pm
an
19
9
96
19
in
e
Le
v
ul
l1
99
2
0
H
Percent
5
Inpatient LMWH for DVT and PE
900 hospitalized
patients with DVT +/PE randomized to:
– UFH n=290
– 1.5 mg/kg enoxaparin qd
n=298
– 1 mg/kg enoxaparin BID
n=312
5
Percent of Patients

UFH
QD LMWH
BID LMWH
4
3
2
1
0
Recurrence
Merli G. Ann Intern Med 2001; 134:192
Major bleed
Death
Thrombolytic therapy for DVT
35
30
TPA
Heparin
Percent
25
20
N=363
15
10
5
0
>50% Clot lysis
All
Major Bleeding
Complications
Forster Chest 2001; 119:572
Review of 5 randomized studies
Intracranial
Bleeding
Thrombolytic therapy for PE
• Resolves angiographic and V/Q defects faster
than heparin.
• Reduces PVR by greater degree at 24 hours.
• Typically produces only partial resolution of clot.
• No study demonstrates reduced mortality.
• 6-14% chance of major hemorrhage
• 1-2% risk of intracranial bleed.
Hyers Chest 2001; 119:176S
Hamel Chest 2001; 120:120
IVC Filter
Venacaval filters
• 568 published references through 9/02
– 13% animal or in vitro
– 7% reviews
– 8% miscellaneous
– 65% retrospective case reports & series
– 7% prospective studies
» 16 studies with >100 subjects
» 1 randomized trial
Girard Chest 2002 122; 963
Venacaval filters
• 400 patients with
proximal DVT +/- PE
• Anticoagulated > 3
months (50% at 8 yr)
• Randomized: +/- filter
• Non-blinded
• 8 year follow up
Decousus NEJM 1998; 338:409
PREPIC study group Circ 2005 112;. 416
*
*
Venacaval filters
70% had PTS
*
Decousus NEJM 1998; 338:409
PREPIC study group Circ 2005 112;. 416
ACCP warfarin Recommendations
•
•
•
3 – 6 months
– First event with reversible or time limited risk
factor
> 6 months
– Idiopathic VTE, first event
12 months to lifetime
– First event with:
» Cancer
» Anticardiolipin antibody
» AT III deficiency
– Recurrent event, idiopathic or with thrombophilia
Hyers. Chest. 2001;119:176S
Outcomes after first DVT
DVT
355 Pts LMWH or UFH
+ Warfarin
35
30
25
Percent 20
recurrence 15
3 months
Warfarin
8 years
78 Recurrences
45% ipsilateral
36% contralateral
19% PE (9 fatal)
10
5
0
3
6
24
60
Prandoni P Ann Intern Med.1996;125:1 Months after diagnosis
96
Coagulation Activity and Dosing
Coagulation Factor Activity (%)
Loading, then Maintenance Dose
100
80
60
II
IX
40
X
VII
20
0
0
1
2
3
4
5
6
Observation Time (days)
Snow V, Ann Intern Med. 2007;146:204.
7
8
Initial Management of DVT
• Short-term treatment with SC LMWH, IV UFH, monitored
SC UFH, fixed dose-SC UFH, or SC fondaparinux (1A)
– LMWH SC q12 or 24 over UFH as an outpatient if possible (1C)
and inpatient if necessary (1A), unless renal failure (2C)
– IV UFH infusion with aPTT monitoring (1C)
– SC UFH: initial dose 17,500 U or weight-adjusted dose of 250
U/kg bid, with subsequent dosing to maintain aPTT (1C)
• Initiate treatment while awaiting diagnostic tests (1C)
• Treat for > 5d with an anti-thrombin until INR ≥2.0 for 24
h (1C)
• Start warfarin on first day of anti- thrombin treatment
(1A)
Kearon C. Chest. 2008;133:454S-545S.
Initial Management of PE
• For acute nonmassive PE, LMWH recommended over IV
UFH (Grade 1A)
Kearon C. Chest. 2008;133:454S-545S.
Quality of Life after VTE
• Post-thrombotic syndrome
develops in 25-40% of
DVTs.
• DVT recurs in ~30% after
anticoagulation stopped
• Permanent disability for 15
million Americans
National initiatives
• Surgeon general: “Call to action” 2008
• ACCP: Every hospital should develop a prevention
program. Grade 1A evidence for pharmacological DVT
prophylaxis in patients with VTE risk factors.
• SCIP: Prophylaxis using ACCP recommended methods
ordered on admission, given +/-24 hr from surgery.
• AHRQ: 1 of 8 “major patient safety concerns “ “Appropriate
VTE prophylaxis in patients at risk.”
• NQF: Safety goal 3E. “Evaluate each patient upon
admission, and regularly thereafter, for the risk of
developing DVT/VTE and given appropriate prophylaxis.”
National initiatives
• The Joint Commission
• 6 VTE measures were endorsed by the NQF in 2008
»
»
»
»
»
VTE prophylaxis
Anticoagulation overlap therapy
UFH dosages/platelet count monitoring by protocol / nomogram
VTE discharge instructions
Incidence of potentially preventable VTE
• Data collection and reporting begin autumn 2009. Complete
measures available spring 2010
• CMS: 2009 Hospital acquired conditions. Proposal that VTE
within 30 days non-reimbursed
Conclusions
• Give prophylaxis to adults at risk
• No routine inpatient lab excludes VTE.
• In a “low” clinical probability outpatient, a
negative d-dimer excludes VTE.
• US finds essentially all proximal leg clots
but misses some calf clots.
• A normal Q scan excludes a PE diagnosis.
Conclusions
• A negative CT ≈ a low probability VQ.
• With “high clinical probability” a positive US,
a high probability VQ, or a CT showing main
PA or lobar clot establishes VTE and should
be treated.
• Angiography is safe
• UFH or LMWH heparin can be used to treat
DVT or PE.
• Outpatient therapy is safe, effective and cost
effective.