journal club

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journal club

• Ryan Sanford
• 01/09/08

2
a dilemma

• A healthy, non-smoking, 35 y/o female presented
  w/ a proximal DVT. Her only RF was using OCPs.
  Thrombophilia w/u is negative. She has completed
  LMWH?coumadin (3mo) without complications. What
  now?
• A 62 y/o male presented with an idiopathic
  proximal DVT and left PE treated with
  LMWH?coumadin (6mo). His PMH includes CAD, DM,
  HTN, and OA. Thrombophlia and malignancy workup
  is unrevealing. He completes 6 months of
  coumadin without complications. What now?

3
we finished the treatment course!?!?

• Will they clot again?
• If they do, could it be fatal?
• What about just keeping them on coumadin?
• Whats the risk of recurrent VTE vs. significant
  bleeding?

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objectives

• Review the risks of bleeding while on vitamin K
  antagonists (VKAs)
• Provide data on the risks of recurrent VTE, and
  particularly, fatal PE after completion of
  recommended durations of anticoagulation in pts
  with VTE and the absence of non-modifiable RFs
  (malignancy, high-risk thrombophilia, permanent
  immobility)
• Compare mortality rates of recurrent VTE and
  continued VKA use

5
2004 Chest Guidelines - DVTs

• For patients with a first episode of DVT
  secondary to a transient (reversible) risk
  factor, we recommend long-term treatment with a
  VKA for 3 months over treatment for shorter
  periods (Grade 1A).1
• For patients with a first episode of idiopathic
  DVT, we recommend treatment with a VKA for at
  least 6 to 12 months (Grade 1A). 1

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DVTs cont.

• We suggest that patients with first-episode
  idiopathic DVT be considered for indefinite
  anticoagulant therapy (Grade 2A).1
• In patients who receive indefinite anticoagulant
  treatment, the risk-benefit of continuing such
  treatment should be reassessed in the individual
  patient at periodic intervals (Grade 1C).1

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what about PEs?

• Given the dearth of studies in patients with PE
  alone, many of the recommendations about
  long-term treatment of patients with PE are
  derived from clinical trials of patients who
  largely had DVT and as a result, the
  recommendations about the long-term treatment are
  the same as for DVT.1

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What happens after stopping coumadin?
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so, in one slide or less, how risky is coumadin?

• Lets suppose, a pt w/ a consistently controlled
  INR (2-3) has a 1-3 risk per year of bleeding.
  a good guess5
• Case fatality of major bleeding is estimated at
  96
• Therefore, annual risk of death is the product of
  bleeding risk and case fatality (0.18). (NNH
  555)

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shall we compare to recurrent VTE?

• The Risk for Fatal Pulmonary Embolism after
  Discontinuing Anticoagulant Therapy for Venous
  Thromboembolism by Douketis et al.
• An inception cohort following gt2000 patients as
  they stopped VKAs after appropriate duration who
  initially had VTE. The outcomes were recurrent
  VTE

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how it worked . . .
where
DVT PE DVT PE
outcomes Nonfatal DVT Recurrent nonfatal
PE Definate/probable fatal PE Possible fatal PE
2054 Pts w/ VTE stop VKAs at end of treatment
course
Monitored
etiology
Idiopathic Secondary
secondary associated w/ surgery, leg trauma/fx,
childbirth, bedridden gt1mo 2/2 medical illness,
pregnancy, hormonal therapy, rheumatologic illness
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details

• Design induction cohort comprised of patients
  from a cohort (1628)2 and RCT (424)3
• Who were they? Consecutive pts w/ DVT, PE, or
  both for the first time. Excluded if had a
  condition requiring lifelong anticoagulation
  (malignancy, permanent immobility, high-risk
  thrombophilia). Included when they had
  discontinued gt 3 months of therapy

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details

• The included cohort study of VTE and gt3 mo Tx
• The included RCT comparison on 6wks and 6mos of
  Tx, using only the 6mo group
• Outcomes
• Nonfatal DVT (U/s or venography)
• Recurrent nonfatal PE (by V/Q or CTA)
• Definite/probable fatal PE
• Possible fatal PE (sudden death of undetermined
  cause)

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definite/probable/possible

• Dx of fatal PE problematic
• Clinician bias/diagnostic suspicion in sudden
  death if a hx/o VTE
• Attributing all sudden deaths in pts with
  previous VTE would overestimate the risk
• Definite fatal PE confirmed at autopsy
• Probable death preceded immediately nonfatal
  PE/DVT
• Possible sudden death that couldnt be explained
  by anything other than PE
• Definite/Probable linked together in study to
  more conservative risk estimate. Possible then
  included to provide the range of risk

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follow-up

• Cohort q6mo w/ phone or clinic visit for a
  maximum of 120 months
• RCT clinic visits at 3 and 6 mo in first year
  and then every 12 mo for maximum of 120 months

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pg 769
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how likely is fatal PE?

• Average f/u 52 months
• 501/2052 pts had a clinical outcome
• 340 DVTs
• 116 nonfatal PE
• 27 possible fatal PE
• 18 definate/probable fatal PE
• 42 lost to followup/resumed ACT for reasons other
  than VTE

pg 770
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if VTE occurs, what are fatal?
Case fatality fatal event / total number of
events
pg 770
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examining across time
pg 771
20
across time cont
pg 772
21
any clues as to who will die?
pg 772
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applicability

• Do/will I see patients like this? Yes
• Does this information potentially change my
  decision making process? Yes
• Are the results valid?
• Long term follow-up
• Clinically relevant outcomes
• Biases/confounders?
• Where could I use more information
• Risk w/ comorbidities (DM, CVD, COPD, etc)
• By design, we did not define optimal duration of
  VKA, but what happened after . . .
• We didnt define number needed to help patients
  with VTE, but number needed to harm those who
  stop using anticoagulation

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but what do I apply?

• Were now informed of the risks associated in
  discontinuation of VKAs in specific VTE
  populations
• We can compare risk of this group with the risk
  of continuing VKAs for longer

24
in stopping Tx for VTE, what is the NNH?

• Recurrence risk of VTE per year is 105
• Case-fatality 4-9 in recurrent VTE
• Therefore product of recurrence risk and
  case-fatality gives likelihood of a fatal event
  per year (0.4-0.9)
• NNH 111-250
• Reminder, NNH for continued coumadin 555!!

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so . . . .

• Both continuing and stopping VKAs have real but
  small risks of death
• While the risk might be higher with
  discontinuation, other factors must be considered
• In the end, this helps us to better inform
  patients in the decision making process
• Idiopathic VTE presenting as a PE in an older
  adult is likely the most concerning demographic

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A dilemma no more?

• A healthy, non-smoking, 35 y/o female presented
  w/ a proximal DVT. Her only RF was using OCPs.
  Thrombophilia w/u is negative. She has completed
  LMWH?coumadin (3mo) without complications. What
  now?
• A 62 y/o male presented with an idiopathic
  proximal DVT and left PE treated with
  LMWH?coumadin (6mo). His PMH includes CAD, DM,
  HTN, and OA. Thrombophlia and malignancy workup
  is unrevealing. He completes 6 months of
  coumadin without complications. What now?

27
references

• Buller et al. Antithrombotic Therapy for Venous
  Thromboembolic Disease. Chest 2004 126401S-428S
• Prandoni, P. The Risk of Recurrent Venous
  Thromboembolism After Discontinuing
  Anticoagulation in Patients with Acute Proximal
  Deep Venous Thrombosis or Pulmonary Embolism.
  Hematologica. 2007 92199-205
• Schulman, S. A Comparison of Six Weeks with Six
  Months of Oral Anticoagulant Therapy After a
  First Episode of Venous Thromboembolism. NEJM.
  1995 3321661-1665.
• Levine MN, et al. Hemorrhagic Complications of
  Anticoagulant Treatment. Chest 2004
  126287S-310S
• Linkins, LA. Clinical Impact of Bleeding in
  Patients Taking Oral Anticoagulant Therapy for
  Venous Thromboembolism. Ann Intern Med.
  2003139893-900
• Douketis, JD. Comparison of Bleeding in Patients
  With Nonvalvular Atrial Fibrillation Treated With
  Ximelagatran or Warfarin. Arch Intern Med.
  2006166853-859
• Douketis, JD. The Risk for Fatal Pulmonary
  Embolism after Discontinuing Anticoagulant
  Therapy for Venous Thromboembolism. Ann Intern
  Med. 2007147766-774.