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Prevention, Diagnosis and Prevention, Diagnosis and Treatment of DVT & PETreatment 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
MedicineVanderbilt Medical Center
Copyright A.P. Wheeler 2009
Thromboembolism epidemiologyThromboembolism epidemiology
5 million DVT’s
900,000 PE’s
290,000 fatalities
Heit J. Blood. 2005;106:910.
Thromboembolism is a disease Thromboembolism is a disease of hospitalized patientsof hospitalized patients
1
10
100
1000
Hospitalized Community
Cases / 10,000 person years
Heit Mayo Clin Proc 2001; 76:1102Goldhaber Am J Cardiol 2004; 93:259
50% in nursing homes or50% in nursing homes or<90 days post-discharge<90 days post-discharge
71% received no prophylaxis71% received no prophylaxis in prior 30 daysin prior 30 days
Outpatient and Inpatient VTE Are Outpatient and Inpatient VTE Are LinkedLinked
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 triadVirchow’s triad
Veno
us S
tasis
Veno
us S
tasis
Hypercoagulable StateHypercoagulable StateEndothelial Injury
Endothelial Injury
Advancing ageImmobilizationStroke - cord injuryAnesthesiaHeart or lung failureHyperviscosity
SurgeryPrior DVTVenous accessTraumaSepsisVasculitis
CancerEstrogenFamily historySepsisHIT
Protein C, S or AT III deficiency Activated protein C resistance (Leiden)HyperhomocystenemiaAntiphospholipid antibodyProthrombin 20210 mutation
DVT Incidence absent prophylaxisDVT Incidence absent prophylaxis
0 20 40 60 80 100
General Medical
Acute MI
General Surgery
MICU
Stroke
Cord Injury
Geerts Chest 2004; 38S
Mismetti 2000
Nicolaides 1997
Nicolaides 1997
Gallus 1994
Handley 1972
Hirsch 1995
Risk stratification in surgeryRisk stratification in surgery
Geerts Chest 2004; 38S
Calf DVT
%
Proximal DVT %
Clinical PE %
Fatal PE%
Low < 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
Medical prophylaxis: placebo Medical prophylaxis: placebo controlled trialscontrolled trials
0
5
10
15
20
25
30
Percent VTE
Halkin 1982 Gardlund1996
Dahan1986
Samama1999
Caulin1989
Fraisse2000
placebo
heparin
n=1358 n=2474n=270n=11,693 n=1102 n=223
5000 UFHBID
p=NS
Nadroparin 7500 U QD
p=NS
Enoxaparin40 mg qdp<0.001
Enoxaparin60 mg qdp=0.04
5000 UFHBID
p=NS
Nadroparin 3800-5700
U QD p=0.05
DVT prophylaxis: DVT prophylaxis: Important, not perfectImportant, not perfect
0 10 20 30 40 50 60 70 80
ASA
Stockings
ICD
UFH tid
LMWH / FPX
DVT Relative Risk Reduction
Geerts WH. Chest. 2008;133:381S-453S.
$ 1
$ 100
$ 150
$ 2-13
$ 16
“Should not be used”: 1A
Use in high bleeding risk 1C oras adjunct to anticoagulants 2A
Use in cancer, CHF or respiratory failure orreduced mobility & 1 other risk factor: 1A
Physician response to prompts Physician response to prompts & overall prophylaxis rate& overall prophylaxis rate
0%
10%
20%
30%
40%
50%
Control Neutral Educational Risk
Total Prophylaxis Rate
*
Conner Chest 118: 162S, 2000
Prophylaxis following consistent Prophylaxis following consistent remindersreminders
Computerized prophylaxis promptsComputerized prophylaxis prompts
0
5
10
15
20
25
30
35
Prophylaxis rates VTE indicence
Percent
ControlPrompted
Kucher N NEJM 2005; 352:969
Δ 41 %
63% had risk score >4
Venous thromboembolismVenous thromboembolism
~50%~50%
~50%~50%
~10%~10%
90%90%5-30%?5-30%?
63-70% of fatal PE’s63-70% of fatal PE’s unsuspected during lifeunsuspected during life
Stein Chest 1995; 110:978Sandler J R Soc Med 1989; 82:203
Clinical prediction rulesClinical prediction rules
FactorFactor pointspoints• 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 1High > 6 (50%), Moderate 2-6 (19%), Low <2 (2%)
Wells Ann Intern Med 1998; 129, 997
DVT Diagnostic MethodsDVT 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 non-
diagnostic• Impedance plethysmography• MRI or CT
Chest radiographs in PEChest radiographs in PE
0 5 10 15 20 25 30
Cardiac enlargement
Normal
Pleural effusion
Elevated diaphragm
PA enlargement
Atlectasis
Infiltrate
Vascular congestion
Oligemia
Percent
Elliott Chest 2000; 118:33
n=2322
ABG’s in PEABG’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 PEECG’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; 100:598Stein Prog Cardiovasc Dis 1975; 17:247
d-dimer assaysd-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 ind-dimer assay positive in• Pneumonia• Sepsis• Myocardial infarction• Cancer• Pregnancy• Post-operative• Multiple trauma• Renal failure• Thromboembolic disease
d-dimer in d-dimer in low risk outpatientslow 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 resultsVQ scan resultsVQVQ onlyonly VQ + Clinical Prob.VQ + Clinical Prob.
FindingFinding FreqFreq (% angio +)(% angio +) (% angio +)(% angio +)
Normal or 14 % 4 % Low 2
near normal Intermediate 6
High 0
Indeterminate 73 % 23 % Low10 Intermediate 22
High 59
High 13 % 87 % Low56
Intermediate 88
High 96PIOPED I JAMA 1990; 263: 2753
VQ scan – VQ scan – CTACTA results resultsVQ/VQ/CTACTA onlyonly VQ + Clin. prob.VQ + Clin. prob.
FindingFinding FreqFreq (% angio +)(% angio +) (% angio +)(% angio +)
Normal or 14 % 4 % Low 2
near normal Intermediate 6
High 0
Indeterminate 73 % 23 % Low10 Intermediate 22
High 59
High 13 % 87 % Low56
Intermediate 88
High 96PIOPED I JAMA 1990; 263: 2753
PIOPED II NEJM 2006;354: 2317
589396
16-22%
22%
78-84%
14% of CTs could not be interpreted
Factors affecting outcome of Factors affecting outcome of contrast enhanced CT’scontrast 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 VQContrast CT vs VQ
CT• Main PA or lobar clot• Segmental or
subsegmental defect• Normal CT
VQHigh probability
Indeterminate
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; 135:88Ferretti Radiology 1997; 205:453Ost Am J Med 2001; 110:16Lorut AJRCCM 2000; 162:1413
PIOPED IIIPIOPED 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 angiographyPulmonary 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 complicationsAngiography complications
Study N Deaths Major complications
Minor complications
Mills 1980 1350 0.2% 1.9% 2.4%
Stein 1992 1111 0.5% 0.8% 5.4%
Zuckerman 1996
547 0 0.9% 4.8%
Hudson 1996
1434 0 0.3% 4.8%
Totals 4442 0.2% 1.0% 2.9%
Outcome after negative angiogramOutcome after negative angiogram
PE Incidence PE Incidence Follow-up Follow-up StudyStudy6/380 (1.6%) 12 months Henry, Chest 1995
6/144 (2.7 %) 13 months Cheely, AJM 1981
1/44 (4.2%) variable Hull, Ann Int Med 1983
3/167 (1.8%) 6 months Novelline, Radiol 1978
NB: 10-20% with negative arteriograms have DVT.
Hull, Arch Intern Med 1994
U.S. Treatment of VTE patientsU.S. Treatment of VTE patients
Treatment DVT
n=590
PE
n=357
DVT+ PE
n=226
IV UFH 43% 52% 54%
LMWH 48% 41% 42%
SQ UFH 7.6% 6.4% 4.4%
Thrombin Inhibitor 0.5% 0.6% 0.4%
* 30-40% discharged without 2 PT’s in range
Retrospective review of 1173 patients 2001-2003
Tapson V. NABOR study, ACCP 2003
UFH recommendationsUFH 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 Effectiveness of non-protocolized unfractionated heparinunfractionated heparin
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10
Days after Starting Heparin
Percent PTT's > 1.5 x
control
Wheeler Arch Int Med 1988; 148:1321
Challenges to effective UFH useChallenges 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 HeparinPTT for Patients Receiving IV Heparin
*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.
aPTT for Patients Receiving IV HeparinCleveland Clinic Foundation Inpatients, October-December 2004*
Fre
que
ncy
aPTT20 40 60 80 100 120 140 160
400
300
200
100
0
50 75
Outpatient LMWH for DVTOutpatient LMWH for DVT
0
2
4
6
8
10
Recurre
nce
Bleed
Death
LOS*
Recurre
nce
Bleed
Death
LOS*
Percent or days
LMWHUFH
LevineLevine(Exoxaparin BID)(Exoxaparin BID)
KoopmanKoopman(Nadroparin BID)(Nadroparin BID)
247
202253
198
Levine NEJM 1996; 334:667Koopman NEJM 1996; 334:682
Incidence of recurrent of VTE Incidence of recurrent of VTE
0
2
4
6
8
10
Hull 19
92
Levin
e 19
96
Koopm
an 1
996
Tillm
an 2
000
Vinso
n 200
0
Colum
bus 19
97
Simonne
au 1
997
Spiro 1
999
Per
cen
t
UFHLMWH
Dolovich Arch Intern Med 2000
Outpatient option
Incidence of major bleedingIncidence of major bleeding
0
1
2
3
4
5
6
Hull 19
92
Levin
e 19
96
Koopman
199
6
Tillm
an 2
000
Vinso
n 200
0
Colum
bus 19
97
Simonnea
u 199
7
Per
cen
t
UFHLMWH
Dolovich Arch Intern Med 2000
Outpatient option
Inpatient LMWH for DVT and PEInpatient LMWH for DVT and PE
0
1
2
3
4
5
Recurrence Major bleed Death
Per
cen
t o
f P
atie
nts
UFH
QD LMWH
BID LMWH
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
Merli G. Ann Intern Med 2001; 134:192
Thrombolytic therapy for DVTThrombolytic therapy for DVT
0
5
10
15
20
25
30
35
>50% Clot lysis AllComplications
Major Bleeding IntracranialBleeding
Per
cen
t
TPAHeparin
Forster Chest 2001; 119:572Review of 5 randomized studies
N=363
Thrombolytic therapy for PEThrombolytic 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; 119:176SHamel Chest 2001; 120:120
IVC FilterIVC Filter
Venacaval filtersVenacaval 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 filtersVenacaval 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; 338:409PREPIC study group Circ 2005 112;. 416
*
*
Venacaval filtersVenacaval filters
Decousus NEJM 1998; 338:409PREPIC study group Circ 2005 112;. 416
*70% had PTS
ACCP warfarin RecommendationsACCP 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
0
5
10
15
20
25
30
35
3 6 24 60 96Months after diagnosis
Percent recurrence
78 Recurrences78 Recurrences45% ipsilateral 45% ipsilateral 36% contralateral36% contralateral19% PE (9 fatal)19% PE (9 fatal)
3 monthsWarfarin
8 years
DVT355 Pts LMWH or UFH
+ Warfarin
Prandoni P Ann Intern Med.1996;125:1
Outcomes after first DVTOutcomes after first DVT
Coagulation Activity and DosingCoagulation Activity and Dosing
Snow V, Ann Intern Med. 2007;146:204.
Observation Time (days)0 1 2 3 4 5 6 7 8
100
80
60
40
20
0Co
agu
latio
n F
acto
r A
ctiv
ity (
%)
VII
IXX
II
Loading, then Maintenance Dose
Initial Management of DVT 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 PEInitial 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 VTEQuality 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 initiativesNational 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 initiativesNational 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
ConclusionsConclusions
• 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.
ConclusionsConclusions• 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.