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.