LMWH Low Molecular Weight Heparin vs Warfarin in Cancer Patients with Recurrent VTE Venous ThromboEm

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LMWH(Low Molecular Weight Heparin)
-vs-Warfarin in Cancer Patients withRecurrent
VTE (Venous ThromboEmbolism)

• By
• Robert Pohlmeyer
• Jan 14 2003

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Outline of talk goals

• Case presentation
• A description of how cancer patients differ from
  non-cancer patients in risk of VTE and bleeding.
• Treatment options for recurrent VTE.
• Advantages of LMWH-vs-other TX options.
• Mechanisms of actions of UFH (unfractionated
  heparin) LMWH and warfarin.
• Evidence demonstrating the advantages of
  LMWH-vs-Warfarin in cancer patients with
  recurrent presentation.
• Summary

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Case Presentation

• 41 yo male with stage 4 Colon cancer (known liver
  Mets) status post resection and chemotherapy
  (irinotecan/5FU/leucovorin). Course has been
  complicated by a pulmonary embolism treated with
  chronic warfarin. Patient presented to the ED
  with complaints of left lower extremity swelling
  and pain. INR was 3.1 and doppler ultrasound
  revealed a DVT.

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Why does this patient have a recurrent VTE

• Are cancer patients different from non-cancer
  patients in the development of VTE and recurrence
  of events
• And if so what evidence supports this and what is
  the proposed mechanism
• What is the best way to treat this recurrence

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Haemostasis 199929(suppl1)pages 91-97

• Clinical reviews have demonstrated an increase in
  clinically apparent VTE in 26 of patients with
  cancer. Specifically in mucinous carcinomas
  particularly of those in lung pancreas and
  gastrointestinal tract. Proposed etiologies of
  the increase in VTE is thought to be disturbances
  in both the haemostatic and fibrinolytic systems.
  Also cancer patients have increased
  immobility increased surgical procedures
  increased placement of central venous catheraters
  and treatment with chemo/hormonal therapies all
  of which may contribute to VTE formation.
• Also cancer patients spent more time outside the
  therapeutic INR range despite weekly monitoring.

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Management of Venous Thromboembolism in Cancer
Patients. Oncology March 2000

• Cancer patients remaining on therapeutic levels
  of warfarin still have a two fold greater risk of
  VTE recurrence than non-cancer patients.

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Incidence of RecurrentThromboembolic and
Bleeding. Journal of Clinical Oncology 9/00

• Retrospective analysis of two large randomized
  trials. Specifically the Columbus study 97 and
  the Tasman Study 96. Both of which compared
  initial anticoagulation with either UFH or LMWH
  followed by oral warfarin.
• This study then combined these two populations
  (1299) and then subdivided them into malignancy
  (261) and no malignancy (1038).
• These groups were then examined with regards to
  recurrent VTE and major bleeding events (defined
  as an overt hemorrhage decrease in hgb by 2
  grams requiring a PRBC transfusion or a
  retroperitoneal/intracranial hemorrhage.

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Incidence of recurrent VTE

• Cancer pts were again noted to be outside the
  therapeutic INR range. They were only in the 2-3
  range approximately 50 of the time. This
  corresponded to a risk of recurrent VTE that was
  three times the non-cancer patients. Most of
  these events occurred when the INRconsistent with the non-cancer group.

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Incidence of Major Bleeding

• The surprising finding was that the cancer group
  had a six fold increased risk of major bleed
  compared to the non-cancer patients. Here the
  INR was not a factor as the cancer group with the
  highest bleeding had an INRgroup had a predisposition to bleeding.

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Possible treatment options in our case patient
with recurrent VTE.

• Placement of a Greenfield filter.
• Dose adjusted UFH to keep the PTT 1.5-2.5 the
  normal range.
• Increase the dose of warfarin for a goal INR of
  3.5-4.0.
• Conversion of warfarin to subcutaneous LMWH.

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Disadvantage of a Greenfield filter

• Still require anticoagulation.
• Increase the risk of lower extremity deep venous
  thrombosis secondary to sluggish blood flow.
• Over time still have a risk for PE as clot can
  form on the filter itself.

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Advantages of LMWH-vs-UFH

• Binds less to plasma proteins/plts/endothelial
  cells and thus has better bio-availability and a
  longer half life.
• IV access not needed.
• Dont need to monitor the PTT because medicine is
  weight based.
• May be given either once a day or twice a day
  with the same efficacy.
• Less incidence of Heparin Induced
  Thrombocytopenia.
• Faster regression of the thrombus.

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Effects of LMWH on thrombus regression.NEJM
March 1 2001

• Head to Head comparisons via repeat venography
  demonstrated faster regression in the LMWH group.
• Specifically LMWH had a 42 reduction -vs- UFH
  33 reduction at 14 days and a 53-vs-40 at 21
  days.

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Review of the coagulation cascade and points of
inhibition.
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Mechanism of action of UFH

• Heparins are long chain molecules which can form
  tertiary complexes allowing them to inactivate
  IIa/thrombin (which is why the PTT increases) as
  well as factor Xa. It also accelerates the
  activity of antithrombin III (AT III) which aids
  in thrombolysis.

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Mechanism of action of LMWH

• LMWH is partial depolymerization of UFH resulting
  in fragments approximately 33 the size of the
  parent compound.
• This is much more selective and works mostly on
  Xa and ATIII with not much effect on thrombin.
  Thus it doesnt effect the PTT.
• Instead must use specific anti-factor Xa assays.

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Mechanism of action of warfarin
A vitamin K antagonist which prevents the hepatic
post-translational carboxylation of factors 2
7 9 and 10.
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Evidence for using LMWH in warfarin-failure
thromboembolic disease.

• Extended outpatient therapy with LMWH for
  treatment of recurrent VTE despite warfarin
  therapy.
• American Journal of Medicine Sept 2001
• Study design Retrospective Review
• Purpose Determine the optimal management of
  patients who have recurrent VTE despite treatment
  with warfarin.
• Methods Review of patient records in 3 tertiary
  hospitals in England from 6/96-8/98

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Results continued

• All 878 patients were initially treated with
  either LMWH or UFH and started of warfarin. The
  LMWH/UFH was then continued until the INR was
  2.
• There were 32 patients during the 2 years
  reviewed with recurrent VTE.
• 25 of these patients were initially treated with
  LMWH and 7 with UFH.
• 20 of the 32 patients (63) had known cancer at
  the time of recurrence and later another patient
  was diagnosed with cancer.
• At the time of recurrence 23 (72) of the
  patients had a INR2 and all the patients INR was
  1.5
• Average time to recurrence was 18 weeks with
  (SD33)

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Results 32 of the 878 patients were found to had
recurrence during the 2 years reviewed.
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Treatments

• These 32 patients were then treated with
  Dalteparin 200u/kg.
• 7 patients were treated with this for 4-6 wks
  then converted back to warfarin.
• 5 patients received 10-12 weeks prior to
  conversion back.
• 16 patients received this until death
• 1 patient received 36 weeks.
• The other 3 patients developed recurrent VTE on
  Dalteparin and required the dose be increased.
  There were not any recurrences on the higher
  dose.
• No major bleeding episodes occurred on the
  Dalteparin.

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Study limitations

• Retrospective study although it would be
  difficult to do an Randomized Clinic Trial (RCT)
  on these cancer patients with recurrent VTE
  despite warfarin as it would require multiple
  centers to recruit enough patients to have enough
  power. (the ability to detect a difference if
  one does exists).
• Not blinded and therefore susceptible to
  selection bias.
• 3 patients had recurrence despite being on the
  lower dose of LMWH.
• Patients were not standardized to how long they
  would receive the LMWH.
• Study done outside the US.

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Conclusions

• Most of the recurrent VTE occurred in cancer
  patients.
• Other etiologies for recurrence included 3
  Protein C def 1 Factor V Leiden 1 lupus
  anticoagulant 3 post-op.
• All patients had an INR1.5 and 23 had an
  INR2.0 and thus had warfarin failure.
• The lower dose Dalteparin was effective in
  preventing recurrence in 29 patients but did
  require the higher dose in 3 patients.
• There were no major bleeding episodes in patients
  while on the Dalteparin.
• Therefore LMWH may be a more effective safe
  and convenient option in cancer patients with
  recurrent VTE and warfarin resistance.

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Evidence for using LMWH in warfarin-failure
thromboembolic disease.

• Comparison of LMWH and Warfarin for the Secondary
  Prevention of VTE in Patients Cancer.
• Arch Intern Med Aug 2002
• Study Design RCT
• Purpose Compare warfarin head to head with LMWH
  in patients with cancer and acute VTE.
• Methods 146 patients were randomized from 25
  centers in France between 4/95 and 3/99.
  Patients were treated with the assigned therapy
  for 3 months. Patients assigned to the warfarin
  group (75 patients) had weekly INR with a goal of
  2.0-3.0. The LMWH group (71 patients) were
  treated with 1.5mg/kg given once daily. Patients
  had anti-factor Xa levels checked on days
  2103060 and 90 however no dose adjustments
  were made.

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Some of the Exclusion Criteria

• History of HIT
• Pregnancy
• History of iodine allergy
• Fibrinolytic therapy in the last 3 days
• Already on warfarin for 5 days
• Major PE with resulting Shock
• Life expectance of
• Surgery planned in the next 3 months
• Severe liver dysfunction with PT17
• Renal dysfunction with CR2

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End Points

• Primary Treatment Failure defined as either a
  recurrent VTE or a major bleed.
• Secondary 3 and 6 month mortality bleeding
  HIT recurrent VTE during the 6 month follow up.
• All patients analysis was done using an
  intention-to-treat model.
• 8 patients were excluded from final analysis (4
  from each group) Specifically 2 were lost to
  follow up 3 withdrew consent 3 died and didnt
  have autopsy.

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Baseline Characteristics
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Baseline Characteristics
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Results

• Patients in the warfarin group were only in the
  2-3 range 41 of the time.
• Major bleeding occurred in 12 (16) of the
  warfarin group -vs- 5 (7) in the LMWH group.
• 6 patients (8) in the warfarin group died
  secondary to bleeding vs- 0 in the LMWH.
• The 5 patients who bled in the LMWH group all had
  Cr1.85

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Charts
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Study limitations

• 66 of cancer patients who presented with VTE
  met exclusion criteria and thus were not eligible
  for the study. Therefore it is unclear if this
  information can be applied to all cancer
  patients.
• Small study population.
• Open-label trial i.e. no blinding therefore can
  have selection bias.
• Done outside the US.
• This study did use weekly INR checks and
  adjustments by the patients primary physician but
  did not have a warfarin clinic.

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Conclusions

• The warfarin group 16 bleeding risk was higher
  than other studies which have tended to be
  approximately 13. This may have been due to the
  fact that the patients were only in the 2-3 range
  41 of the time-vs- 50 in other studies.
• 8 of the 12 had INR 3 or at the time of their
  bleed 3 of 12 had INRresult of their bleed.
• During the 3 month trial 15 patients (21.1) in
  the warfarin group had either a major bleed or
  recurrent VTE-vs- 7 patients (10.5) in the LMWH
  group.
• This was significant with a P value.04

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Summary of advantages of LMWH over warfarin

• Avoids warfarin resistance i.e.. development of
  recurrent VTE while on warfarin.
• NO documented evidence that increasing the
  INR3.5 decreases the likelihood of recurrent
  VTE but does increase the risk of bleeding.
• Not influenced by dietary habits.
• Doesnt have all the medical interactions (Direct
  displacement increased or inhibited hepatic
  metabolism antibiotics which decrease gut flora
  and thus vit k ).
• No lag time between administration and effective
  levels.
• Frequent lab draws not required.
• No increase in vascular calcification.
• Possible anti-tumor effect of heparins.

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Case Presentation Review

• 41 yo male with stage 4 Colon cancer (known liver
  Mets) status post resection and chemotherapy
  (irinotecan/5FU/leucovorin). Course has been
  complicated by a pulmonary embolism treated with
  chronic warfarin. Patient presented to the ED
  with complaints of left lower extremity swelling
  and pain. INR was 3.1 and doppler ultrasound
  revealed a DVT.

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Case Conclusion

• Our patients warfarin was discontinued and he
  was started on lovenox at 1.5 mg/kg sc once
  daily.
• Annals of Internal Med in 2/2001 demonstrated
  that once a day and twice a day lovenox were
  equally effective. In the cancer patient
  sub-group there was a trend towards the twice a
  day dose however it wasnt statically
  significant. More research is needed to look
  specifically at this question.

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Duration of treatment post VTE in a cancer
patient.

• Overall there is not a consensus statement.
• General practice is to treat these patients as
  long as they have persistent disease or are
  receiving anti-neoplastic therapies.
• Once disease is non-detectable and treatment has
  been stopped for 3-6 months then therapy can be
  stopped.

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Take Home lessons

• Remember roughly 1 in 4 cancer patients will
  develop a VTE at some point.
• Cancer patients with recurrent VTE despite
  warfarin treatment and normal renal function
  would benefit to conversion of LMWH.
• Currently Lovenox 1.5 mg/kg once a day is thought
  to be as effective as the 1 mg/kg twice daily
  but more research is needed for the cancer
  subgroup.
• If you want to see if the patient is therapeutic
  on that dose check an Anti-factor Xa level. This
  should be between 0.5-0.8.
• Remember to dose LMWH based on the patients
  ideal weight especially in the very obese
  patient.
• For example in the infamous words of Brent Powers
  beware the BIGGONS!

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Just for SHOW-BOATWhich conference is 1

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