DVT-PE

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DVT-PE

• Nitin Bhatt MD
• Director, ICU
• VAMC, Reno

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Q3, A 45-year-old woman is evaluated in the
emergency department because of the sudden onset
of shortness of breath and chest tightness
earlier this afternoon. She has been in excellent
health and returned 2 days ago from a trip to
Japan. On physical examination, her pulse rate is
116/min and respiration rate is 36/min.
Cardiopulmonary examination is otherwise
unremarkable, and a chest radiograph shows no
infiltrates. Measurement of arterial blood gases
on room air shows the following pH 7.48, Paco2
24 mm Hg, and Pao2 78 mm Hg oxygen saturation is
96.

• What is the most appropriate immediate next
  step in this patients management?
• ( A ) Pulmonary angiogram( B ) Compression
  ultrasonography of the lower extremities( C )
  Therapy with diazepam( D ) Intravenous heparin(
  E ) Ventilation-perfusion lung scan

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DVT-PE

• Different stages of same disease
• 90-95 of PE originate from clots in lower
  extremities
• 600,000 per year remain undiagnosed in USA as
  signs and symptoms are nonspecific

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Asymptomatic PE in DVT pts

• About 40 of patients with venogram proven DVT
  had asymptomatic PEs when investigated by
  pulmonary angiogram.
• Ken Moser et al

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Of an estimated 200,000 deaths per year in the
United States, only 13,000 (6) occur in patients
who have received treatment. The vast majority of
patients (94) who die of pulmonary embolism do
not receive treatment because the diagnosis is
not made
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PE

• Difficulty of Diagnosis
• Multiple clinical presentations
• Nonspecific signs and symptoms
• Mortality Rates
• With treatment 5 to 8 (more recent data
  suggests 2-3)
• Without treatment 25 to 30

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Q3, A 45-year-old woman is evaluated in the
emergency department because of the sudden onset
of shortness of breath and chest tightness
earlier this afternoon. She has been in excellent
health and returned 2 days ago from a trip to
Japan. On physical examination, her pulse rate is
116/min and respiration rate is 36/min.
Cardiopulmonary examination is otherwise
unremarkable, and a chest radiograph shows no
infiltrates. Measurement of arterial blood gases
on room air shows the following pH 7.48, Paco2
24 mm Hg, and Pao2 78 mm Hg oxygen saturation is
96. What is the most appropriate immediate
next step in this patients
management? ( A ) Pulmonary angiogram( B )
Compression ultrasonography of the lower
extremities( C ) Therapy with diazepam( D )
Intravenous heparin( E ) Ventilation-perfusion
lung scan
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Q3, AnsD, When venous thromboembolism is
strongly suspected, the first action taken should
be to administer heparin in a therapeutic dose
(in the absence of contraindications to
anticoagulation) to prevent new clot formation,
allow unopposed fibrinolytic activity to
facilitate thrombus resolution, and avoid
progression into the pulmonary circulation.
Therapy should be started before performing
confirmatory diagnostic tests such as a
ventilation-perfusion scan, pulmonary angiogram
or compression ultrasonography of the lower
extremities. Subtherapeutic or delayed
anticoagulation is associated with unacceptable
recurrence rates of venous thromboembolism, and
is a common error in the initial phases of
treatment. Although relatively less heparin is
required to prevent the coagulation cascade from
being initiated, more is required after the
cascade is under way. Therefore, early
administration of an adequate dose is required.
For continuous infusions, the activated partial
thromboplastin time should be monitored regularly
to ensure that the dose is therapeutic.
Inadequate initial heparin therapy also has been
associated with late recurrences of
thromboembolism. Anxiolytic therapy would not be
an appropriate as the initial step in this
patients manageme
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Virchows Triad

• Venous stasis
• Injury to the intima
• Change in the coagulability of blood

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Acquired Risk Factors for VTE

• Surgery and Trauma
• Prolonged Immobilization
• Age greater than 40
• Obesity, Inflammatory Bowel Disease, CHF
• Cancer, PNH, Nephrotic syndrome
• Myeloproliferative Disorder
• Previous DVT or PE, Air-travel
• Pregnancy and puerperium
• Contraceptives or Hormone Replacement Therapy
• Resistance to Activated Protein-c (not F-5
  Leiden)
• Lupus Anticoagulant/ Antiphospholipid antibody
• Mild-moderate Hyperhomocystinemia

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Factor V Leiden and VTE

• 9253 randomly selected Danish people,
  heterozygous and homozygous F V Leiden was
  associated with hazard ratio for VTE of 3 and 18
  respectively, compared to non-carrier population.
• Simultaneous presence of smoking, obesity and old
  age increased 10 year absolute risk of VTE to 10
  and 51 in Heterozygous and homozygous, resp.
• 
  Juul et al, AIM 2004 140330-337

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Natural history

• DVT originates as a platelet nidus near venous
  valves of lower exremities and grows by accretion
  of platelets and fibrin
• Newly formed clot more likely to get detached to
  cause embolism to the FILTER organ, lung, or may
  be lysed by endogenous lytics
• Organization of venous clots cause damage to
  venous valves and lead to post-phlebitic syndrome

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P.E.Physiology

• Hypoxemia in majority, leading to respiratory
  alkalosis
• V/Q mismatch is predominant cause of hypoxemia,
  some R?L shunting occurs
• Serotonin from platelets ?? PVR
• Bronchoconstriction due to mediators from
  thrombii

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P.E. physiology

• If no pre-existing cardio-pulmo disease,
  obstruction of 25-30 of pulmo vascular bed leads
  to PHTN, gt75 obstruction will lead to acute RV
  failure as normal RV can not generate pressure
  gt50 mm Hg
• Lack of increase in CVP with large P.E. may
  suggest severe RV failure

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PHTN after first episode of PE

• Excluding patients with persistent risk factors
  for VTE, in a prospective study of idiopathic or
  transient risk factor associated PE, about1 risk
  of chronic thromboembolic pulmonary hypertension
  was noted, confirmed by pulmonary angiography, 14
  to 22 months after acute PE- Becattini et al,
  Chest 2006130 172-5

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Q-952 yr woman, 1 yr h/o dyspnea. Heavy smoker
in past, h/o HTN.O/E loud P2, elevated JVP,mild
bilat ankle edema. CBC, Chem-panel, HIV, ANA ,
Rh. Titer negative. CXR prominent Pulm.
Arteries, echo normal EF, RVE, PA-syst pressure
60, PFTs normal volumes, DLCO 40 pred, V/Q
mild heterogeneity of perfusion, Swan Ganz RAP
10, RVP 50/10, PAP 50/20, PAOP 26, CI 2. ?DX

• 1, LV diastolic dysfunction
• 2, Chronic Pulmonary embolism
• 3, Primary pulmonary HTN
• 4, Pulmonary veno-occlusive disease
• 5, Constrictive pericarditis

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A-9A
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DVT Clinical diagnosis ?

• Clinical suspicion based on symptoms e.g. leg
  edema, calf pain, etc., only 30 of clinically
  suspected to have DVT, ultimately have diagnosis
  proven.
• Homans sign is not specific or sensitive for DVT
• Myositis, cellulitis, hematoma and edmatous state
  are commonly included in differential diagnosis
  of DVT

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Fedullo and Tapson,NEJM,9-25-03
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Fedullo Tapson,NEJM9-25-03Low10,
Inter30 and Highgt70
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From JAMA1/11/06
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Prediction of PE in ED.byGal et
al,AIM7 Feb 2006
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DVT

• Contrast venography
• Compression ultrasound
• Impedence plethysmography

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VenogramPopliteal Vein Thrombosis
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Compression ultrasound (Goldhaber)Artery
compressed, but vein did not DVT
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CUS in suspected PE?

• Retrospective analysis of data from prospective
  study, showed that in patients proven to have PE,
  gt60 had positive CUS. Age gt70 and signs and
  symptoms of DVT were independent predictors of
  positive CUS
• Girard et al, Chest 2005, P 1593-00

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MRI in Dx Of DVT

• 101 Pts who underwent venogram for diagnosis of
  dvt were included.All pts with positive venogram
  and ¼ of those with negative venogram included
• Magnetic Resonance Direct Thrombus Imaging
  (MRDTI) was used in all patients within 48 hrs of
  venography and interpreted by 2 reviewers
• Sensitivities and specificities were gt90 . Even
  isolated calf thrombii had 82-92 sensitivities.
  Fraser et al, Ann Int Med 1-15-02

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Pelvic DVT diagnosis by MRA

• 24 patients with proven PE and negative CUS, were
  studied.
• 29 had pelvic DVT
• Common iliac vein involved in 5 patients.
• 
  Stern et al, Chest 2002122 115-21

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Pulmonary Embolism, NEJM 7-9-98
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Goldhaber,NEJM7-9-98
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SYMPTOMS AND SIGNS IN 117 PATIENTS WITH ACUTE
PULMONARY EMBOLISM WITHOUT PRE-EXISTING CARDIAC
OR PULMONARY DISEASE (Stein, Chest 1991)
SYMPTOMS OF PATIENTS SIGNS OF PATIENTS
DYSPNEA 73 TACHYPNEA gt20/min 70
PLEURITIC PAIN 66 RALES (CRACKLES) 51
COUGH 37 TACHYCARDIAgt100 30
LEG SWELLING 28 FOURTH H.S. 24
HEMOPTYSIS 13 LOUD P2 23
PALPITATIONS 10 DVT 11
WHEEZING 9 DIAPHORESIS 11
ANGINA 4 TEMP. gt38.5C 7
WHEEZES 5
HOMANS SIGN 4
Significantly More RIGHT VENR. LIFT 4
Common in PE PLEURAL RUB 3
THIRD H.S. 3
CYANOSIS 1
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During fibrinolysis of fibrin, plasmin cleaves
factor XIIIacross-linked fibrin into an array of
intermediate forms. The D-dimer and E fragments
are the result of terminal fibrin degradation.,
P.Bockenstedt,NEJM 9-25-03
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Plasma D-Dimer

• Sensitive but not a specific test for PE,
  therefore use for excluding PE, not useful to
  make the diagnosis.
• Not recommended as stand alone test, use with
  either clinical criteria or V/Q scan or
  Ultrasound, several diagnostic algorhythms now
  reported using D-dimer

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D-Dimer in diagnosis of VTEAJRCCM, Feb 2002
345-8

• Strong correlation noted between location of P.E.
  and D-Dimer concentration, plt0.001
• Sensitivity of D-Dimer was 93 for excluding
  segmental or larger P.E. but only 50 for
  subsegmental P.E.

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D-Dimer and Ultrasound in DVTWells et al,NEJM
9-25-03

• Suspected PE cases were excluded
• All patients had clinical stratification as high
  or low likelihood for DVT
• Low clinical suspicion and negative D-Dimer rules
  out DVT
• High clinical suspicion but negative D-Dimer and
  negative US of legs rules out DVT
• 39 in D-Dimer group did not need ultrasound, but
  overall prevalence of DVT-PE was only 15.7

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D Dimer and DVT

• Low clinical probability and negative D Dimer
  value rules out DVT effectively.
• High or intermediate clinical probability makes D
  dimer value unhelpful
• Moderate clinical probability and negative D
  dimer by HIGH sensitivity assey can have DVT
  ruled out. (Meta-analysis by Wells et al JAMA Jan
  11 2006 p 199-207)

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D dimer in evaluation of PE

• Low clinical probability combined with negative D
  dimer (SimpliRED whole blood agglutination test)
  had negative predictive value of 99.5 for
  excluding PE in a prospective cohort study of ER
  patients.
• Wells et al AIM 200113598-107
• In a prospective randomized trial ( Kearon et al,
  AIM 2006 p 812-21) low clinical probability and
  negative d-dimer was associated with lt.5
  incidence of VTE on follow up. 50 of out-pt and
  20 of inpatient fell into this category.

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D dimer and PE

• Negative simplify D-dimer test and a low clinical
  probability of PE, resulted in 0.7 incidence of
  VTE on 90 day follow up of ER patients. Kline et
  al Chest June 2006, 1417-23

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EKG in a pt with Pulm Embolism, NEJM 7-9-98
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PE

• CXR
• In majority of cases of PE, cxr is abnormal but
  nondiagnostic e.g. Atelectasis, Small pleural
  effusion
• Enlarged right descending PA, Decreased pulmonary
  vascularity (Westermark sign)
• Wedge-shaped peripheral infiltrate (Hamptons
  hump)
• Normal

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Chest radiograph showing pulmonary infarct in the
right lower lobe. This patient had low-grade
fever, hemoptysis, and pleuritic chest pain. The
ventilation-perfusion scan was read as high
probability for pulmonary embolism. A
pleural-based density in the lower lobe with the
convexity directed toward the hilum signifies
pulmonary infarction. This sign is also known as
Hamptons hump.From Bones Atlas
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67 yr man with 5 days of cough and dyspnea and 1
day of pleuritic pain cxr shows left pleural
based infarction at left base. (Hamptons
hump).And avascularity (Westermarks sign) in
RUL. Perfusion scan shows significant
corrensponding defects. NEJM 11-1-01
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Pulmonary infiltrate and small pl.eff. RLL area
from PE, These clear on cxr 2 weeks later (Murray
and Nadel)
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Normal perfusion scan, excludes PE (Murray
Nadel)
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PE by high probability perfusion scan( Murray and
Nadel)
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PIOPED
Scan category Sensitivity Specificity
High Probability 41 97
High or Intermediate 82 52
High or Intermediate or low 98 10
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PIOPED value of clinical assessmentLikelihood
of P.E...Scan. Clinical suspicion..
V/Q Scan Category 80-100 high 20-79 intermediate 0-19 low
High 96 88 56
Intermediate 66 28 16
Low 40 16 4
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V/Q Scan and PE

• Majority of patients undergoing V/Q scans have
  NON-DIAGNOSTIC V/Q scans, i.e. do not have normal
  or high probability V/Q scan
• Majority of patients who have PE do not have high
  probability V/Q scans
• Majority of patients who are suspected to have PE
  but later rule out for PE, have abnormal V/Q scans

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(Q-8) A 59 yr female is evaluated for dyspnea of
acute onset. She was diagnosed to have
non-metastatic ca-breast 2 mo ago and c/o fatigue
and insomnia since then. T 100, P1105,RR 22, BP
158/88, PSaO2 95 on RA. No JVP, Lung clear,
Heart normal, No edema, Abdomen Neg. CXR neg.
EKG S.tach. V/Q 2 segmental perfusion defects,
minimum ventilation defect. Next ?

• 1, Spiral CT with IV contrast
• 2, Thrombolytic RX
• 3, IV heparin
• 4, Doppler US of lower extremities

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Ans8 3

• High probability scan and high clinical
  suspicion95 PPV for P.E.
• No hemodynamic compromise, no need for
  thrombolytic therapy

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Pleural Effusions in PE

• 60 patients reviewed, 100 exudate
• 67 had RBCs gt10,000/cc
• 60 had predominenet PMNs in differential WBC
  counts
• 18 had pleural fluid eosinophilia gt10
• Retrospective study
• Candeira, Chest
  2002121465-69

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Spiral CT in PE

• Spiral cat scan allows for rapid imaging during a
  single breath hold
• Contrast may be administered peripherally
• Sensitivity is now felt be in 70-80 range while
  specificity remains gt90

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Spiral cat scan in a patient with massive saddle
Pulm. Embolism, before and after thrombolytic
Rxwith TPA. NEJM, 10-10-02
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Three advantages of helical CT deserve
mention. 1, The value of CT's ability to identify
an alternative diagnosis in up to a third of
patients with suspected PE 2, As with lung
scanning, when the combination of pretest
probability and helical CT results yield
sufficiently high or low post-test probabilities,
the test obviates the need for conventional
angiography and its associated higher morbidity.
3, In practice settings in which clinicians can
obtain a CT scan more quickly than a lung scan or
an angiogram, the use of CT may prevent delays in
therapy Matthew B. Stanbrook, MD Brigham and
Women's Hospital, Harvard Medical School
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CT scan in P.E.
Isolated thromboembolism of the subsegmental
pulmonary arteries is not unusual, occurring in 6
to 30 percent of patients with embolism in
different series. Filling defects involving the
main or lobar pulmonary arteries can be
considered diagnostic of embolism, whereas a
normal CT scan may indicate a substantially
reduced likelihood of embolism but cannot be used
to rule out the possibility of embolism with the
same degree of certainty that a negative
ventilationperfusion scan provides. Outcome
studies have demonstrated that withholding
anticoagulant therapy in patients with a negative
CT scan coupled with a negative ultrasonographic
study of the legs is a safe strategy, except in
those patients who present with a high clinical
probability of embolism Fedullo and Tapson,
NEJM 9-25-03
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Role of D-dimer, Clinical Prediction and Spiral
CAT scan Christopher study, JAMA 1/11/2006

• True management study. 20 incidence of PE.
• Low clinical suspicion plus negative D-dimer,
  associated with 0.5 incidence of VTE in 3 months
• If Spiral CT (10 single and 90
  multidetector-row) negative, 3 month incidence of
  VTE was 1.3 and fatal PE in 0.5 (in other
  studies, negative Pulmonary angio was associated
  with 1.7 VTE and 0.3 fatal PE)
• Work up completed in about 98 and management
  decision made in 98 with this strategy
• Await further confirmation, some patients had US
  or v/q scans done before CAT scans.

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CT chest and PE

• Meta-analysis in JAMA (4/27/2005 P 2012-17)
  included 15 studies and 3500 patients. Risk of
  recurrent event, in patient with suspected PE but
  negative spiral CT (single slice or multidetector
  row scanners used) was similar to that of
  negative angiography. NPV of negative CT was
  99.1
• An editorial by Hull in JAMA after reviewing
  Christopher study showing safety of withholding
  anticoagulation in negative multi-slice CT
  patients, still recommended caution with this
  strategy alone until more data seen. Using D
  dimer and clinical probability with CT data was
  recommended.

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Should CAT scan of chest be accompanied by US of
legs to rule out VTE?

• 2004 data suggested this. More recent data seem
  to show much better NPV with negative CAT scans.
  At 3 mo follow up, 1.4 VTE and .51 fatal PE
  (letters to editor, AIM, Moore et al,
  Meta-analysis AIM 2004141866-74). If DVT is
  also a consideration, combined CT-angio, CT
  venography may become available in many
  hospitals soon.

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How long does it take to resolve PEs?

• of patients with residual pulmonary embolii is
  87 at 8 days, 68 after 6 weeks, 65 after 3
  months, 57 after 6 months and 52 after 11
  months. The follow up studies were angiograms, CT
  or V/Q scans. Retrospective review.
• 
  Nijkeuter et al, Chest 2006129192-7

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Left pulmonary artery filling defect in PE.
(Murray and Nadel)
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Pulmonary AngiographyPIOPED data

• Includes 1111 pts who underwent angiography in
  PIOPED study
• 0.5 mortality and 1 major and 5 minor
  complications noted, major complications were
  noted mostly in ICU patients
• PA pressure, volume of contrast and presence of
  PE did not affect complication rate
• Surveillance showed 0.6 of negative angiogram
  pts have PE on followup. 96 of angiograms were
  diagnostic, 3 nondiagnostic 1 incomplete

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Indications for Pulmonary Angiogram

• After reasonable workup substantial suspicion for
  alternate diagnosis (other than PE) exists
• High clinical suspicion for PE, but low
  probability V/Q scan and nondiagnostic results of
  CT and (-) US
• Intermediate clinical probability, (-) CT, high,
  low or intermediate probability V/Q scan, (-)
  U.S.
• Low clinical probability, high probability V/Q
  scan and (-) U.S.

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Echocardiogram in pulmonary embolism Goldhaber,
NEJM 7-9-98
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Echocardiogram in PE

• Right ventricular dilatation
• Right ventricular hypokinesis
• Tricuspid regurgitation
• Bulging of inter ventricular septum into left
  ventricle
• Reduced LV size with D shaped LV

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Fedullo and Tapman,NEJM9-25-03
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Fedullo Tapman,NEJM9-25-03
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Fedullo and TapmanNEJM9-25-03Note low
clinical prob low prob V/Q may stop workup
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Fedullo and TapmanNEJM9-25-03
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Q-10 A 52 yr man c/o mild dyspnea and chest pain
after carrying light luggage from car following a
9 hr drive. Has h/o COPD, PUD and Hodgkins
Lymphoma in remission x 4 yr after radioRX.
Auto-Accident 1 yr ago, had R leg DVT, Rx Heparin
x 5 D, then coumadin x 3 mo., P/E, EKG, CXR
unremarkable, V/Q low probability. ? Next in DX
test

• 1, Restart Heparin
• 2, ABG
• 3, D-Dimer, if high then restart IV Heparin
• 4, D-Dimer, if high then US of lower extr.

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A-104

• Pre-test probability of PE is intermediate to
  high, therefore low probability V/Q scan does not
  rule out P.E. and 15 likelihood of P.E. remains.
• If D-dimer is negative, may choose repeat US at
  day 2 and 7 and if negative, do not treat or test
  further. If D-Dimer AND US are positive, treat
  for DVT (and P.E.)

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Treatment for PE

• Virchow offered no insights on the treatment or
  prevention of PE. The first therapy for PE,
  pulmonary embolectomy, was proposed by
  Trendelenburg in 1908
• Dalen,
  Chest, Nov 2002

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Bed rest in DVT and PE patients

• No difference in recurrent PE incidence in PE
  patients or new PE in DVT patients with or
  without bedrest
• Trujillo-Santos et al, Chest 2005 p 1631-36

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Heparin and PE

• 35 patients with suspected PE randomized to
  treatment with heparin vs. no heparin
• Untreated group had 5 deaths from PE vs. none in
  heparin treated group
• Barritt Lancet 1309,
  1960

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Cumulative Probability of Recurrent Venous
Thromboembolism in Patients with a Second
Episode, According to the Duration of Assigned
Anticoagulant Therapy. Schulman et al, NEJM
2-6-1997
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Duration of Anticoagulation
During therapy with vitamin K antagonists, the
risk of recurrence is very effectively reduced
by approximately 90 percent, to 0.7 episode per
100 person-years. In the 6 to 12 months
immediately after the discontinuation of therapy,
a catch-up phenomenon occurs, resulting in an
absolute incidence of recurrence of venous
thromboembolism of 5 to 10 percent. This
phenomenon has been observed after 3, 6, and 12
months of vitamin Kantagonist therapy and
therefore suggests that prolonging this therapy
simply delays recurrence until the therapy is
stopped, rather than reducing the risk of
recurrence. During the subsequent years, the
risk of recurrence stabilizes, and the annual
incidence of recurrence is 1 to 2 percent.
Buller and Prins, NEJM 8-14-03
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Bates and Ginsberg, NEJM 7-15-04
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What Intensity of Anticoagulation ?
low-intensity anticoagulant therapy (INR 1.5 to
1.9) reduces the risk of recurrent thrombosis by
about 75 percent, whereas conventional-intensity
therapy (INR 2 to 3) reduces this risk by over 90
percent, and no increase in major bleeding (
kearon et al NEJM 8-14-03)
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Q2 A 76-year-old woman with metastatic breast
cancer is evaluated because of a 3-day history of
swelling of her right leg and pleuritic chest
pain. Ultrasonography shows an occlusive thrombus
in the femoral vein. Results of a
ventilation-perfusion scan are normal, and
therapy with continuous intravenous heparin is
begun. On the fourth day of heparin therapy and
after oral warfarin has been started, the
activated partial thromboplastin time is
therapeutically prolonged, but the prothrombin
time has not yet reached the therapeutic range
at this time, the patient develops dyspnea. On
physical examination, her blood pressure is
140/90 mm Hg she is tachypneic and tachycardic,
but the remainder of her cardiopulmonary
examination is normal. Chest radiograph shows no
abnormalities. Measurement of arterial blood
gases reveals new hypoxemia on room air.
Ventilation-perfusion scan shows perfusion
defects in the entire right lower lobe and the
inferior subsegment of the lingula.
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Q2 continued

• Which one of the following should be part of this
  patients management at this time?
• ( A ) Continued observation until warfarin dosing
  is therapeutic
• (B) Placement of IVC filter
• ( C ) Readminister heparin bolus and increase
  the rate of the continuous infusion
• ( D ) Administer an increased dose of warfarin

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Q2 Answer is B

• This patient had a pulmonary embolism while in
  the early stages of therapy for recognized venous
  thrombosis. Heparin therapy is at a dosage in the
  therapeutic range, and warfarin is not yet
  therapeutic. The appropriate management strategy
  would be placement of an IVC-filter, which should
  prevent recurrent pulmonary embolization.
  IVC-filters are placed fairly easily
  transcutaneously and have a low incidence of
  adverse reactions (5) and very low associated
  mortality ( 0.1). Potential complications
  include malpositioning, infection, air
  embolization during placement, local wound
  problems (for example, hematoma formation),
  perforation of the vena caval wall, migration
  from the site of placement, and rarely induction
  of venous thrombosis at the site of insertion.
  Indications for filter placement include
  contraindication to anticoagulation,
  anticoagulation failure or complication (such as
  in this patient), and pulmonary embolism
  prophylaxis. It has been reported that the risk
  of venous thrombosis is increased in the 2 years
  after an IVC-filter is placed. The risk of
  recurrent venous thrombosis dictates a full
  course of therapy with anticoagulation unless
  specifically contraindicated by hemorrhagic
  diatheses.
• Because she is adequately anticoagulated with
  heparin, there is no need to adjust her heparin
  dosage. Increasing the dose of warfarin is
  unlikely to have an immediate effect due to the
  relatively long time required for warfarin to
  inhibit its target coagulation factors, and it
  may lead to supratherapeutic effect with an
  increased risk of bleeding. Because the patient
  has a large clot persisting in her leg, simple
  observation does not further reduce her risk of
  repeat pulmonary embolism.

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Venacaval Interruption

• 1 Recurrent PE after 24 hours of adequate
  anticoagulation
• 2 Anticoagulation is contraindicated
• 3 Concurrent with pulmonary embolectomy or
  cardiotomy for PE
• 4 In an unstable patient who is unlikely to
  tolerate recurrence of PE

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Urokinase Pulmonary Embolism Trial(UPET)

• Urokinase resulted in improved resolution of
  embolii by angiography, lung scan and right sided
  hemodynamics compared to heparin
• No difference in recurrent PE or 2 week
  mortality.
• Higher incidence of bleeding with Urokinase

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Thrombolytic in PE

• Indications
• A Hypotension due to PE
• B Refractory hypoxemia
• C Severe DVT in a young patient
• D ? RV hypokinesis with PE
  
  
  

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FDA approved thrombolytic regimens for PE

• Sreptokinase 250,000 U bolus over 30 min, then
  100,000 U/hr for 24 hours
• Urokinase 4400 U/kg over 10 min, then 4400
  U/kg/hr for 12-24 hours
• TPA 100 mg over 2 hours

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Thrombolytic Rx in Pulm.EmbolismNEJM, 10-8-02
Methods We conducted a study of patients with
acute pulmonary embolism and pulmonary
hypertension or right ventricular dysfunction but
without arterial hypotension or shock. The
patients were randomly assigned in double-blind
fashion to receive heparin plus 100 mg of
alteplase or heparin plus placebo over a period
of two hours. The primary end point was
in-hospital death or clinical deterioration
requiring an escalation of treatment, which was
defined as catecholamine infusion, secondary
thrombolysis, endotracheal intubation,
cardiopulmonary resuscitation, or emergency
surgical embolectomy or thrombus fragmentation by
catheter
98
Thrombolytics in submassive P.E.

• Treatment with heparin plus placebo was
  associated with almost three times the risk of
  death or treatment escalation compared to the
  risk associated with heparin plus alteplase
  (P0.006). No fatal bleeding or cerebral bleeding
  occurred in patients receiving heparin plus
  alteplase.
• 
  (NEJM 10-08-02)

99
(No Transcript)
100
Chart review by Anderson, of hospitalized
patients who received DVT prophylaxis

• Previous PE 68
• Old age 34
• Cancer 29
• Trauma 39
• Stroke 30
• AMI 40
• Ortopedic surg 39

• Previous DVT 36
• Prolonged Immobilization 39
• Obesity 37
• LE fracture 34
• Surgery 34
• CHF 41

101
Q-11 32 yr BM, 4 mo h/o progressive dyspnea on
exertion. P/E High JVP, Large V waves in neck,
Holosystolic M at L lower parasternal area. Mild
ascitis and bilateral mild ankle edema. High
resolution CT shows mosaic perfusion. FVC83,
FEV1/FVC75, TLC76,RV73, DLCO22 . ? DX

• 1, IPF
• 2, Emphysema
• 3, Chronic thrombo-embolic disease
• 4, CHF
• 5, Cirrhosis of Liver

102
A-113
103
Q1 A 63-year-old woman is scheduled to undergo
a total knee replacement and needs prophylaxis
for deep venous thrombosis. She has no previous
history of increased bleeding or of a
hypercoagulable state. She takes aspirin, 325
mg/d, for primary prevention of cardiovascular
disease and wants to continue taking it she does
not want subcutaneous injections

• Which one of the following would you recommend
  for prophylaxis?
• ( A ) Aspirin( B ) Full-dose intravenous
  heparin( C ) Intermittent pneumatic
  compression( D ) Warfarin( E ) Elastic
  stockings

104
Q 1, AnsD Warfarin is recommended for
prophylaxis for deep venous thrombosis in
patients undergoing total knee replacement. There
are several regimens for starting prophylaxis in
the perioperative period, including one tablet on
the night before surgery, or starting with the
first dose on the first day after surgery. The
target INR is between 2 to 3. Although
subcutaneous low-molecular-weight heparin in
prophylactic doses is a reasonable alternative to
warfarin in this setting, full-dose intravenous
unfractionated heparin is not recommended. Total
knee replacement surgery carries a risk of calf
deep venous thrombosis of 40 to 80, a risk for
proximal deep venous thrombosis of 10 to 20, a
risk for clinical pulmonary embolism of 5 to
10, and a risk for fatal pulmonary embolism of
1 to 5. Aspirin is not effective for
prophylaxis of deep venous thrombosis. The
patient should stop taking aspirin 7 days before
this procedure to reduce the risk of bleeding
complications. Elastic stockings and pneumatic
compression are additive for prophylaxis, but are
not sufficient for effective prophylaxis in
themselves.
105
Q4, A 75-year-old man comes to the emergency
department because of a 2-day history of a
swollen and tender left calf following a 10-hour
automobile trip. Ultrasonography confirms the
presence of a deep venous thrombosis of the left
calf extending to the popliteal region. The
patient has an extensive smoking history, but his
medical history is otherwise unremarkable.
Physical examination is normal, and a stool
specimen is negative for occult blood. The
complete blood count, prothrombin time, activated
partial thromboplastin time, and routine serum
chemistry studies are normal.

• In addition to a thorough physical examination,
  which one of the following should be included in
  the evaluation of this patient?
• (A) CXR
• (B) Abdominal CAT scan
• (C) PSA and Cystoscopy
• (D) Serum CEA level

106
Q4,AnsA. Deep venous thrombosis, particularly
in an elderly patient, always raises concern
about an underlying neoplasm. Although such
patients may have an increased incidence of
occult malignancy, several studies have
demonstrated that an extensive search for a
neoplasm rarely yields positive results. A
neoplasm amenable to curative therapy is found
even more rarely. Therefore, a nondirected and
extensive evaluation of this patient for occult
malignancy is very unlikely to identify a
treatable neoplasm and is not cost effective.
However, any clues obtained from the H P
(including a digital rectal examination)
suggestive of a neoplasm should be pursued. In
this patient, the extensive smoking history
justifies a screening CXR despite the lack of
symptoms. Since the patient has no other
complaints or findings suggestive of an
underlying neoplasm (weight loss, stools positive
for occult blood, abdominal pain). Therefore, a
more extensive evaluation is not indicated.
Measurement of the serum carcinoembryonic antigen
level may be useful in following the progression
of colon cancer once a diagnosis and baseline CEA
levels are established but is not sensitive or
specific when used as a screening assay.
107
Q5, A 38-year-old man is receiving warfarin
therapy for treatment of a deep venous thrombosis
of the left leg that he developed 3 weeks ago. He
comes for his scheduled prothrombin time INR
determination. He denies gingival bleeding,
hematuria, nosebleeds, or gastrointestinal
disorders but reports a sore throat and fever
that started about 1 week ago. He has not been
able to swallow and has consequently been on a
mostly clear liquid diet for the last week. On
physical examination, his temperature is 38.0 C
(100.4 F). His posterior pharynx is erythematous
but without exudate. There are several scattered
ecchymoses on the forearms and legs. The
remainder of the examination is normal. The
laboratory evaluation reveals a hematocrit of
41 activated partial thromboplastin time of 37
s and a prothrombin time INR of 6.0.
108
Q 5 continued

• Which of the following is most appropriate for
  initial management of this patients elevated
  INR?
• ( A ) Transfuse two to four units of fresh frozen
  plasma( B ) Stop warfarin give vitamin K,
  orally( C ) Stop warfarin give vitamin K,
  intravenously( D ) Stop warfarin give vitamin
  K, intramuscularly( E ) Stop warfarin

109
Q5, AB, This patient has a supratherapeutic
INR. The ecchymoses are a minor bleeding
complication, but he has a normal hemoglobin
level and no evidence of more serious bleeding.
The deep venous thrombosis of the left leg is
relatively new, and he is at risk of further
propagation of the clot if anticoagulation is not
maintained. This patient therefore needs to have
the warfarin effect lowered without fully
reversing the anticoagulation. Vitamin K therapy
will correct the INR without the risk associated
with transfusing a blood product. Additional
vitamin K overrides the warfarin blockade of the
?-carboxylation pathway and results in production
of functional clotting factors within hours. The
dose of vitamin K determines how much of the
warfarin effect will be reversed. A dose of 5 mg
of vitamin K will significantly reverse the
anticoagulant effect of warfarin within 12 to 24
hours if the patient has good liver function. A
10-mg dose will usually block the warfarin effect
completely and interfere with attempts to resume
anticoagulation with warfarin. The risk of
clotting versus the risk of bleeding determines
how much vitamin K to give and how long to
withhold the warfarin dose.
110
Q5 AB, continued For patients such as the one
described, the dose of vitamin K should be low
enough to allow resumption of anticoagulation
with warfarin as soon as the INR has dropped into
the therapeutic range. Studies have shown that
vitamin K, 1 to 2 mg subcutaneously or 2.5 mg
orally, will bring the INR into the therapeutic
range without causing overcorrection. Low-dose
vitamin K should decrease this patients INR
without placing him at risk for another
thrombosis. Fresh frozen plasma is the most
rapid way to replace vitamin K clotting factors
and reverse the anticoagulation. However, because
of the infectious and allergic risks associated
with blood products, fresh frozen plasma is only
used to reverse warfarin if a patient has a
serious bleeding complication or excessive risk
of bleeding. Therefore, giving this patient fresh
frozen plasma places him at greater long-term
risk than the immediate risk imposed by the
excessive anticoagulation. Intramuscular
medications should not be given to patients with
a coagulopathy because these patients have a high
risk of developing an intramuscular hematoma.
Furthermore, bleeding into the muscle will hamper
attempts to resume anticoagulation for the
underlying thrombosis. This patient's poor oral
intake over the last several days will result in
low vitamin K stores. Stopping the warfarin with
no other therapy (that is, without replacing
vitamin K) will result in a slow reversal of the
anticoagulant effect and prolong the risk of
bleeding.
111
Q6, A 23-year-old otherwise healthy woman has a
pulmonary embolism while hospitalized after a
motor vehicle accident. She is 8 weeks pregnant.
She has completed 1 day of therapy with
unfractionated heparin.

• In addition to completing 5 to 7 days of
  intravenous administration of unfractionated
  heparin, which of the following is the next
  management option for this patient?
• ( A ) Unfractionated heparin( B )
  Low-molecular-weight heparin( C ) Warfarin( D )
  Inferior vena cava filter( E ) Compression
  stockings

112
Q6, AnsB

• Therapy with low-molecular-weight heparin is
  expensive but is appropriate in the management of
  deep venous thrombosis (DVT) and pulmonary
  embolism (PE) when other forms of therapy are
  ineffective or contraindicated.
  Low-molecular-weight heparin also has been used
  for outpatient management of uncomplicated DVT
  and PE. Intermittent administration of
  unfractionated heparin has been used for
  management of PE but has been rejected in recent
  years because of higher rates of bleeding and
  recurrent PE compared with continuous
  administration of heparin. Warfarin therapy is
  contraindicated during pregnancy because of its
  teratogenic and fetopathic properties. Insertion
  of an intravenous filter is not indicated without
  great risk of reoccurrence of the PE and the
  inability to use antithrombotic preventive
  measures. Compression stockings are not practical
  for patients with lower extremity fractures.

113
Q7, A 24-year-old man is evaluated because of a
swollen right calf. The calf has been swollen for
1 day. He had a deep venous thrombosis of the
opposite leg when he was 17 years old, for which
he took warfarin for 3 months. He has never
smoked cigarettes. His father also had a deep
venous thrombosis, but he is currently in good
health. Physical examination shows a tender,
swollen, right calf. Doppler studies confirm a
deep venous thrombosis.

• Which of the following is the most likely risk
  factor for hypercoagulability in this patient?
• ( A ) Antiphospholipid antibodies( B ) Occult
  malignancy( C ) Paroxysmal nocturnal
  hemoglobinuria( D ) Factor V Leiden mutation( E
  ) Homocysteinemia

114
Q7,AnswerD

• This patient requires an evaluation for
  hypercoagulability state because he has a
  recurrent thrombosis and because of his young
  age. The patient's history suggests a genetic
  cause of hypercoagulability. The most common
  inherited cause of hypercoagulability in white
  patients is factor V Leiden mutation, which leads
  to resistance to activated protein C.
  Approximately 5 of white patients have this
  mutation. There are many other inherited causes
  of hypercoagulability, including genetic
  deficiencies of protein C, protein S, and
  antithrombin III. This patient could have had an
  acquired cause of hypercoagulability, the most
  common of which is the antiphospholipid antibody
  syndrome, but this is rarely familial.

115
Hemorrhage occurs in up to 7 percent of patients
during initial treatment the risk is affected by
the heparin dose, the patient's age, and
concomitant use or nonuse of thrombolytic and
antiplatelet agents. Long-term use of heparin
(i.e., longer than one month) can cause
osteoporosis.26,27,28 Heparin-induced
thrombocytopenia is immune-mediated and in 30 to
50 percent of cases is associated with venous or
arterial thrombosis.26 Patients with previous
heparin-induced thrombocytopenia should receive
alternative anticoagulant agents, such as
danaparoid, lepirudin, or argatroban.26 NEJM
7-15-04
116
Dalen, Chest, Nov 2002
Mortality of Untreated PE (Clinical Diagnosis)

Source Year Mortality,

Barritt and Jordan2 1960 38
Coon et al3 1969 1825
Zilliacus4 1946 32
Hermann et al5 1961 35
Morrell et al6 1963 30
Composite 3035

117
Dalen, Chest Nov 2002
When to Treat for VTE

Positive pulmonary angiogram, positive chest CT, or high probability    V / Q      scan.
Echocardiographic diagnosis of intracardiac thrombus.
Echocardiographic diagnosis of clot in main pulmonary artery, right pulmonary artery, or left pulmonary artery, and right ventricular dilatation.
Diagnosis of DVT by venogram, compression ultrasound, or impedance plethysmography.

118
Dalen, Chest Nov 2002
When to Withhold Therapy for Suspected PE

Normal pulmonary angiogram or normal perfusion scan findings
Low clinical probability of PE plus
 Normal d-dimer, or
 Normal compression ultrasound legs, or
 Indeterminate V/Q   scan, or
 Normal chest CT finding

119
Treatment of VTE

Treatments First Clinical Report First Randomized Controlled Trial

Surgical embolectomy Trendelenburg,7 1908 None
Femoral vein ligation Homans,8 1934 None
Unfractionated heparin Murray and Best,9 1938 Barritt and Jordan,2 1960
Oral anticoagulants Allen et al,72 1947 Duration of anticoagulant
Trial Study Group,74 1995
IVC ligation Collins et al,12 1943 None
Thrombolytic agents
 Urokinase Hansen et al,13 1961 UPET,14 1973
 Streptokinase Browse and James,15 1964 UPET, phase 2,22 1974
 rt-PA Bounameaux et al,16 1985 rt-PA trials,23 24 199098
IVC filter by catheter Mobin-Uddin et al,17 1969 Decousos et al,18 1998
Embolectomy, catheter Greenfield et al,19 1971 None
Low-molecular-weight heparin, subcutaneous
 For DVT Holm et al,20 1986 Hull et al,21 1992 Prandoni et al,26 1992
 For PE Thery et al,25 1992 Columbus Investigators,28 1997 Simonneau et al,27 1997

120
Dalen, Chest, Nov 2002
Incidence of Shock in Patients With PE Documented
by Pulmonary Angiography
Source Patients, No. With Shock,

UPET,22 1974 167 7
Alpert et al,40 1976 144 13
Greenfield and Langham,42 1984 313 10
UKEP,43 1987 129 6
Totals 753 9.3

121
Mortality of Angiographically Documented PE With
Shock
Source no Treatment Mortality,

UPET,14 1973, UPET,22 11 Heparin, with or without urokinase 18
Alpert et al,40 1976 19 Anticoagulation and/or IVC interruption 32
Meyer et al,36 1991 78 Embolectomy 42
Diehl et al,44 1992 15 rt-PA 20
Greenfield et al,39 1993 46 Catheter embolectomy 30
Gulba et al,45 1994 24 rt-PA 33
Totals 193 35
122
Ximelagatran in VTEJAMA 2005 293681-89

• Oral, Direct thrombin inhibitor, works rapidly
  therefore no need for IV therapy. No need to
  monitor INR
• Compared to LMH coumadin, it was safe and
  effective in preventing recurrent VTE over 6
  months of therapy after VTE
• 10/1240 ACS vs 1/1249
• Elevated liver enzymes in 9.6 with Ximelagatran
  therapy