VENOTHROMBOEMBOLISM MADE EASY

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VENOTHROMBOEMBOLISM MADE EASY

• DR. A. KAROVITCH
• UNIVERSITY OF OTTAWA
• 2008

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Objectives

• Understand the importance of VTE prophylaxis
• Understand the options for VTE prophylaxis
• Be aware of the different modalities available to
  diagnose/rule-out VTE
• Be able to apply these principles to typical
  long-term care patients

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Conflicts

• I have no personal conflicts with the
  pharmaceutical industry
• Our Thrombosis Unit receives free samples of
  tinzaparin (Innohep) in order to teach patients
  how to self inject

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Case No. 1 Diagnosis

• 39 yo man. Well, no sign PMHx.
• FHx one sister had IUFD, one had STP
• presents with sudden right C/P, pleuritic, SOB.
  No leg Sx, no hemoptysis.
• On exam dyspneic, HR 116, lungs clear, CVS
  normal, legs normal
• CXR, EKG, tnt all normal
• DOES HE HAVE A PE???

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What tests do you want to start with?
V/Q scan Spiral CT of chest Pulmonary
angiogram Leg dopplers D-dimer Clinical
assessment (prediction model)
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V/Q SCAN

• Still a good first test (most data, best clinical
  experience)
• However ..usefulness depends on clinical picture
• 50-70 of pts will have non-diagnostic scan
• NPV and PPV depend on clinical pretest prob
• if PTP mod/high and V/Q high then 98 PPV
• if PTP low and V/Q high then 60-80 PPV
• if PTP low and V/Q low then 96 NPV
• if PTP high and V/Q low then 60-70 NPV

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Pulmonary Angiography

• Invasive, not widely available
• higher complication rates
• gold standard
• NPV of 98-99
• 1-2 of pts with negative angio present in the
  next 3 mos with VTE or complications of VTE

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Leg Dopplers

• If proximal vein clots then dx is made
• of those pts with PE who have non-diagnostic lung
  scans, only 10 have positive initial dopplers
  (with no leg symptoms)

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D-Dimer

• Degradation product of cross-linked fibrin clot
• test non-specific and not helpful
• - test useful in terms of thinking of NPV
• NPV depends on clinical PTP of PE
• low PTP, then - d-dimer has 99 NPV
• high PTP, then - d-dimer has 64 NPV
• overall the NPV of a negative d-dimer is 90

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What to do?

• You obviously need to know what your clinical PTP
  is
• this is what we do
• Wells et al.
• validated on gt 900 outpatients
• if this algorithm is applied, the overall rate of
  pts representing with VTE/complications is 1.4
  (same as normal V/Q or normal angio)

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What about spiral chest CT?

• Attractive, use increasing, the new CXR
• direct visualization of main, lobar, segmental
  and ?subsegmental pulm arteries
• may be useful in dx alternate causes of Sx
• technology improving quickly (not so for V/Q)
• specificity is high (95)

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Spiral CT

• However.
• User/reader dependent (we have been burned)
• Over interpretation (one subsegmental) is an
  issue
• dye/radiation (breast exposure)
• cooperation (hold breath for segmental a.)
• broad sensitivity (50-100) depending on the study

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Spiral CT

• Is a normal CT alone good enough
• study of 510 pts suggested that a normal CT was
  good (only 1.6 of pts were subsequently dx with
  VTE on doppler or on representation) Arch Int
  Med Feb 18, 2003
• meta-analysis Annals Int Med Dec 7, 2004 suggests
  it is safe to withhold AC in pts with negative
  CT. Rate of recurrence was 1.4. Most studies
  did not use CT alone however. Patients with a
  high pre-test probability for PE were generally
  excluded.

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Spiral CT

• Christopher study JAMA Jan 2006
• 3306 pts with query PE (82 outpts)
• CT only
• At 3 mos f/u in those with negative CT, 1.3
  represented with VTE
• The incidence of fatal PE was 0.5
• Included pts with high PTP /- d-dimer

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PEDS

• Anderson et al. JAMA Dec 2007
• Algorithm with V/Q or CT for 1400 out-patients
• Normal CT was considered non-diagnostic
• Outcomes similar but CT picked up more events and
  therefore more treatment (19 vs. 14)
• No diff in bleeding but not powered to do so
• Little value in doing leg dopplers if no symptoms
  or in doing serial dopplers
• Since outcomes the same maybe CT is picking up
  clinically insignificant clots.

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Spiral CT

• What do we do?
• Dont forget that pts with abn CXR can still have
  diagnostic V/Q scans
• if CT is ordered we are leery of over
  interpretation of results
• If negative some of us do leg CUS or even serial
  leg CUS depending on d-dimer, pre-test
  probability and leg symptoms

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DVT diagnosis

• Remember CUS is not perfect
• misses below knee clots (we dont even scan)
• misses pelvic clots (pregnancy etc.)
• as with PE the combination of PTP, d-dimer and
  CUS should be used

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DVT Prevention and some other stuff too!
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Epidemiology

• Consequences of DVT
• Pain, swelling
• Post phlebitic syndrome (severe in 3-10)
• Pulmonary embolism
• Occurs in 50 of DVT, symptomatic in 20
• If DVT/PE untreated death in 5-10, if treated
  death from PE decreases to 1

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Burden of Disease

• Lifetime incidence of venous thromboembolic
  disease is 1.5 to 3 but
• 6/100,000 age 20-30, 25/100,000 age 30-39,
  300/100,000 age 50- 69 and 620/100,000 age gt70
• In Ottawa 700 cases per year DVTPE 31

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Risk Factors for DVT/PE

• Surgery (60-70 post orthopedic)
• cancer
• immobilization (cast, paralysis, illness)
• prior DVT/PE
• trauma
• transfusion OR 1.74
• surgery OR 2.3
• of femur/tibia OR 4.8
• spinal cord injury OR8.6

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Low Molecular Weight Heparin

• Derived from UFH by chemical or enzymatic
  techniques
• Sugar chains, average 5,000 Daltons
• Binds to / works via antithrombin III
• potentiates ATIIIs anti-IIa, anti-Xa activities

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LMWH- products and treatment doses

• Tinzaparin (Innohep)- 175 U/kg SC daily
• Enoxaparin (Lovenox)- 1.5 mg/kg SC daily
• Dalteparin (Fragmin)- 200U/kg SC daily
• May use q12h for certain situation
• Bleeding risk
• Weight
• Renal
• pregnancy

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LMWH- Products and Doses Prophylaxis

• Dalteparin (Fragmin)- 5000 U SC daily
• Tinzaparin (Innohep)- 3500 -4500 U SC daily
• Enoxaparin (Lovenox)- 30 mg BID 40 mg daily SC

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Fondaparinux- Arixtra

• Effective DVT prophylaxis post ortho Sx
• Renal
• No HIT (too small)
• 2.5 mg SC daily
• Treatment doses for VTE are 5.0 10.0 mg SC
  daily depending on patient weight

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DVT Rates With Best Prophylaxis

• After THA 14 proximal and 27 total DVT
• After TKA 7 proximal and 30 total DVT
• After arthroscopy 2-3 proximal and 5 to 13
  total DVT

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DVT Prevention

• 79 yo woman admitted to CTU with CHF
• 28 yo man admitted for acute spinal cord injury
• 56 yo woman post THR
• 62 yo man post hemicolectomy for colon cancer
• 82 yo woman admitted to neurology for dense right
  CVA

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Case No. 1

• 79 yo woman hx of CHF, CRF, DM2, OA
• exacerbation of CHF and admitted to hosp
• no MI
• meds ACE-I, metoprolol, glyburide, Advil
• ?risk of DVT
• ?risk of bleeding ( a lot of your pts have ?risk)
• what to do?

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DVT prevention in medical patients

• Pts with CHF, COPD, pneum, other infectns
• DVT rate is 16
• autopsy proven fatal PE around 2.5
• UFH (5000 q8-q12h) lowers absolute rates by 18
• LMWH (enox 40mg) lowers rates by 10
• largely under-utilized

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Meta-analysis of RCTs in medical patients

• July 2007 Arch Int Med
• UFH 5000 q8h was more effective in preventing VTE
  than UFH 5000 q12h when compared with the control
  (RR 0.27 vs. 0.52)
• Neither UFH or LMWH changed mortality
• UFH vs. LMWH compared directly no difference in
  bleeding but LMWH had a lower risk of VTE (RR
  0.47 95 CI, 0.36-0.62)

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DVT prevention in medical patients

• Two large trials have compared LMWH to UFH
• no difference in VTE/mortality
• bleeding 0.4-1.5 for LMWH and 1.5-3.6 for UFH
• Bottom line
• use something (probably for 7-10 days)
• vs. convenience
• in this case UFH may be best if CRF significant
• When I use UFH, I use q8h dosing

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Case No. 2

• 28 yo man. MVA. Acute spinal cord injury and
  multiple trauma victim.
• Risk of DVT
• what to do?

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ASCI and Trauma

• Major trauma DVT rate is gt50 (10-20 proximal)
• 67-100 if acute SCI involved
• fatal PE up to 2
• 3rd leading cause of death if pt survives the
  first 24 hours

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ASCI and Trauma

• RCT (trauma)
• UFH
• total DVT 44, prox DVT 15
• LMWH (enox 30 bid)
• total DVT 31, prox DVT 6
• RCT (ASCI subgroup)
• UFH
• total DVT 67, prox DVT 13
• LMWH (enox 30 bid)
• total DVT 50, prox DVT 0

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ASCI and Trauma

• How long to Rx?
• The trauma studies used 14 days of Rx
• ASCI is different
• Chen et al. 1649 pts at 18 Rehab Units. 10
  developed DVT and 3 developed PE at Rehab
• Yelnik et al. 14 developed new DVT on venogram
  within one month of starting rehab

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ASCI and Trauma

• Bottom line
• for trauma use LMWH
• studies used enoxaparin 30 bid for 14 days
• for ASCI use LMWH (enox 30 bid again)
• total Rx should be for at least 3 mos even if
  they are at rehab etc. Could consider changing
  over to OAC at some time.

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Case No. 3

• 56 yo woman OA, HTN. Elective THR. Meds Vioxx,
  HCTZ, HRT. Father had a PE post chole.
• What to do?
• For how long?

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Prophylaxis THA

• Low molecular weight heparin very effective
• compared to placebo OR 0.36
• compared to UFH OR0.72 (also less bleeding)
• compared to warfarin (non-significant difference)
• Fondaparinux also good
• however, these ORs determined by venography

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Prophylaxis TKA

• LMWH very effective
• compared to placebo OR 0.17
• compared to UFH OR0.68 (0.28 for proximal DVT
  and also less bleeding)
• compared to warfarin (0.62 but more bleeding with
  LMWH OR 2.0)
• Fondaparinux better but more bleeding
• however, these Odds Ratios determined by
  venography

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Clinically Relevant DVT

• DVT detected by venography in asymptomatic
  patients may not always be clinically relevant
• many post-op DVT are small, non-occlusive,
  limited to calf veins
• it is hard to know the long term significance of
  these DVT (PPS)

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THR DVT Prevention

• How long is enough?
• Most studies used 9-10 days of RX
• this should be the minimum
• in reality this is often cut to 4-5 days since
  pts recover quickly and are often discharged
  early
• How about extended out of hospital Rx?

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THR Extended Prophylaxis

• Many studies have looked at continuing LMWH for
  about 1 month post D/C
• most are venographically driven
• most end points are asymptomatic DVT (some of
  which are above knee and may result in more PPS,
  PE etc)

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THR Extended Prophylaxis

• Asymptomatic DVT at day 30
• total drops from 27 to 12
• proximal drops from 12 to 4
• Symptomatic VTE
• total drops from 3.3 to 1.3

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THR Extended Prophylaxis

• If universally applied cost would be staggering
• If cost is 10/day then 280 000 per life saved
• Not just trying to save lives though
• could it be cost effective?
• Maybe (no real study has looked at this)
• fewer visits and investigations
• less PPS and long term management issues

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When Is Extended Prophylaxis Reasonable?

• Very high risk patients
• Previous DVT
• Not very mobile or not likely to be very mobile
  in a reasonable time frame
• Cancer
• Diagnosed asymptomatic DVT
• Significant cardiopulmonary disease
• ?family hx ?thrombophilia

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Back to the case

• 56 yo woman, THR, fam hx of PE
• what to do?
• Stop HRT (RR 2 and mostly in high risk settings)
• OAC or LMWH min of 9-10 days
• longer??

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Hip Fracture Surgery (HFS)

• VTE common
• PE 4th leading cause of death in these pts
• PE accounts for 14 of all deaths
• DVT in 50 of pts with no prophylaxis
• Increased risk with
• Age (almost all pts)
• Delay of surgery (almost all pts)

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HFS

• Cochrane review of 31 trials (3000 pts)
• Both heparin and LMWH good
• A smaller study compared dalteparin 5000 vs.
  heparin 5000 TID
• VTE 20 UFH vs. 44 dalteparin
• Another study looked at fondaparinux 2.5mg vs.
  enoxaparin 40mg
• VTE 8.3 vs. 19
• PE 0.9 vs. 4.3
• No bleeding difference

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HFS

• Do something
• Fondaparinux 2.5mg
• LMWH (dalteparin 5000 U, enoxaparin 40mg)
• UFH 5000 U TID
• If delayed surgery, treat while waiting (good
  luck)
• Length of prophylaxis unknown
• Until mobile? Until discharge? A few weeks if
  still at risk?

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Case No. 4

• 62 yo man, post hemicolectomy for colon CA.
  Previously well. No meds. No fam hx.
• What to do?

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General Surgery Prophylaxis

• Pooled data for significant general surgery
  suggests VTE rate is 19-25
• 29 if pt has cancer
• most asympt below knee clots
• prox DVT 7
• PE 1.6
• fatal PE 0.9

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General Surgery Prophylaxis

• With UFH total DVT drops to 8
• one meta-analysis suggests 5000 q8h better than
  q12h
• little data compares UFH to LMWH
• likely equally effective
• maybe less bleeding with LMWH

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General Surgery Prophylaxis

• What about extended Rx?
• NEJM March 28, 2002
• LMWH continued for 21 days after general cancer
  surgery (compared to placebo at home)
• all VTE 12 to 4.8
• prox DVT 1.8 to 0.6
• almost no symptomatic events occurred in either
  group

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Back to the case

• Basically for general surgery use LMWH or UFH
  while immobile and while in hospital
• Use q8h preferably
• if cancer related then consider extending out Rx
  especially if very high risk and ongoing
  immobility

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Case No. 5

• 82 yo woman dense right CVA/hemiparesis
• started on ASA by neurology
• CT shows large area of edema and hypodensity
• what to do?

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Ischemic CVA

• Untreated DVT in the paretic limb as high as 55
• 5 of early deaths post CVA are from PE
• In Rehab centres, up to 20 of CVA pts on
  admission/during stay are found to have proximal
  DVT on dopplers
• Pambianco et al. Arch Phys Med Rehab 1995

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Ischemic CVA

• UFH, LMWH, danaparoid all lower incidence of VTE
• for example UFH 71 RR reduction
• venographically driven studies show that LMWH
  better than UFH at reducing asymptomatic VTE
• doesnt mean it is actually preferable agent

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Ischemic CVA

• Meta-analysis of RCTs LMWH vs. UFH
• Chest October 2007
• Some trials used UFH q12h, some q8h (so beware)
• No difference in bleeds, mortality
• LMWH has fewer total VTE (OR 0.54), proximal DVT
  (OR 0.53), PE (OR 0.26).

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Ischemic CVA

• What to do?
• Treat min. 10-14 days (LMWH or UFH q8h)
• longer if significant paresis, bed rest, afib etc
• can change to OAC if needed
• no extended trials exist
• no trials looking at hemorrhagic CVA exist
• do it as soon as safe
• consider mechanical devices

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CONCLUSIONS

• Use combo of clinical models, d-dimer, and
  imaging to dx VTE
• be aggressive with DVT prophylaxis
• it is generally under-utilized