EBM

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EBM

• R1/???
• 97.10.2

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PICO

• No27010858 69F ?X?
• Diagnosis Acute cerebral vascular accident
• P Patients with acute ischaemic stroke
• I Low-molecular-weight heparins or heparinoids
• C Standard unfractionated heparin
• O Outcome (re-stroke rate, side effects, ICH
  rate)

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The Search
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The Search
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Cochrane Review

• Low-molecular-weight heparins or heparinoids
  versus standard unfractionated heparin for acute
  ischaemic stroke (Review)
• Peter AG Sandercock, Carl Counsell, Mei-Chiun
  Tseng
• The Cochrane Collaboration and published in The
  Cochrane Library 16 July 2008

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Background

• The large scale RCTs
• Comparing unfractionated heparin(UFH) with
  control and heparinoid with placebo
• No evidence of improvement the overall outcome
  of patients with acuteischaemic stroke
• Any reductions in early recurrent ischaemic
  stroke or pulmonary embolism Were offset by
  similar-sized increases in intra and extracranial
  haemorrhages
• No difference in the proportion of patients dead
  or dependent
• Not support the routine use of any anticoagulant
  regimen - whether standard UFH,
  low-molecular-weight heparins (LMWHs),
  heparinoids, or oral anticoagulants - in patients
  with acute confirmed or presumed ischaemic stroke

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Background

• Heparin in low dose (5000IU of unfractionated
  heparin BID, SC)
• Prevention of deep venous thrombosis
• Systematic reviews RCTs
• Anticoagulant therapy significantly reduced the
  odds of DVT by about 66
• DVT rate44 (control) 15 (anticoagulants)
• Significant 36 reduction in the odds of PE with
  anticoagulants
• Intracranial haemorrhage and so worsen prognosis
• IST datasignificant risk of intra and
  extracranial haemorrhage with UFH.
• Dose related
• Risk remained statistically and clinically
  significant, even with the low-dose regimen
• Anticoagulant agent
• less potential for inducing haemorrhage
• Preventing DVT and PE.
• ischaemic stroke with high risk of venous
  thromboembolism/

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Background UFH LMWHs

• UFH
• Inhibit the coagulation cascade non-specifically
  at a number of different sites (by inhibiting
  factors IIa, IXa, Xa, XIa, XIIa)
• Inhibit platelet function
• Anticoagulant agents with more specific sites of
  action may be associated with lower risks of
  haemorrhage
• LMWHs and some heparinoids (heparin analogues)
• potent inhibitors of factor Xa with little direct
  antithrombin (IIa) activity and little
  antiplatelet activity
• Other heparinoids ((dermatan sulphate, pentosan
  polysulphate)
• Specific antithrombin activity
• Theoreticallyless bleeding than with UFHfor an
  equivalent antithrombotic effect
• In factmore powerful antithrombotic effect than
  UFH and a much longer half life
• More specific? Safe, Much longer half life?
  increasing hemorrhage ??

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Object

• To compare the effectiveness and safety of LMWHs
  and heparinoids with UFH in the treatment of
  patients with acute or presumed ischaemic stroke
• LMWHs or heparinoids might be associated with a
  lower incidenceof DVT and PE compared with UFH
• LMWHs or heparinoids might reduce the risk of
  early recurrent ischaemic strokes compared with
  UFH
• these benefits of LMWHs or heparinoids might lead
  to a reduction in death and disability compared
  with UFH
• these benefits may potentially be offset by
  increased fatal or disabling intracranial
  haemorrhage or by severe extracranial haemorrhage

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Criteia for considering studies for this review

• Types of studies
• Randomised controlled trials that use of LMWHs or
  heparinoids in the acute phase of ischaemic
  stroke was compared with standard UFH as control.
• Types of participants
• excluded trials more than 14 days, TIA ,
  hemorrhagic stroke
• Types of intervention
• UFHlow dose subcutaneous regimen or a high dose
  intravenous one
• LMWHs Fragmin/ Fraxiparine / enoxaparin/
  Logiparin/Innohep/ Fluxum/ Sandoparin/
  Clivarine/ Sandoz
• HeparinoidsOrgaran/ ermatan sulphate,mesoglycan,
  pentosan poly-sulphate
• By IV or SC
• Types of outcome measures
• DVT I125 fibrinogen scanning, doppler ultrasound
  or systematic X-ray contrast venography
• PEduring the scheduled follow-up period, or at
  autopsy
• died fromany cause, died of vascular causes (due
  to stroke including complications, cardiac,
  haemorrhagic, embolic, or other vascular causes)
• intracranial haemorrhage or haemorrhagic
  transformation confirm with CT or MRI

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Search methods for identification of studies

• The Cochrane StrokeGroupTrialsRegister
• The Cochrane Central Register of Controlled
  Trials
• MED MEDLINE (1966 to June 2007)
• EMBASE (1980 to June 2007)
• Nine trials involving 3137 people were included
• Dumas 1994, Hageluken 1992, Hillbom 1998, PREVAIL
  2007, PROTECT 2006, Stiekema 1988, TRACE 2004,
  Turpie 1992, Wong 2000
• Four trials compared a heparinoid (danaparoid
• four trials compared LMWHs ((enoxaparin or
  certoparin)
• one trial compared an unspecified
  low-molecular-weight heparin with standard
  unfractionated heparin

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Result - Effects of interventions

• 01.01 Deep venous thrombosis during treatment
  period
• Seven out of nine trials
• LMWH or heparinoid was associated with a
  significant reduction in DVT (odds ratio (OR)
  0.55, 95 (CI) 0.44 to 0.70, P lt 0.00001).
• Both the heparinoid (OR 0.52) the LMWH (OR
  0.56) associatedwith a lower incidence of
  DVTcompared wit UFH

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Result - Effects of interventions

• 01.02 Pulmonary embolism during follow up
• six out of nine trials
• There were too few PEs to provide reliable
  evidence on whether or not the observed trend in
  favour of LMWHor heparinoid (OR 0.57, 95 CI
  0.23 to 1.41) was merely due to the play of
  chance.

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Result - Effects of interventions

• 01.03 Death from all causes during follow up
• The number of deaths during the scheduled
  follow-up period was too small to provide a
  reliable estimate of any difference ((OR 0.98,
  95 CI 0.79 to 1.23)
• substantial harm (2 deaths per 100 patients
  treated) benefit (2 fewer deaths per 100
  patients treated)

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Result - Effects of interventions

• 01.04 Vascular death during follow up
• no significant difference in vascular death
  between danaparoid or LMWH and those allocated
  UFH (OR 1.15, 95 CI 0.72 to 1.85)

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Result - Effects of interventions

• 01.05 Any intracranial haemorrhage/haemorrhagic
  transformation of the cerebral infarct during
  treatment period
• no significant difference in any HTI
  (haemorrhagic transformation of the cerebral
  infarct) between LMWHor heparinoid
  andUFH(OR0.75, 95CI 0.46 to 1.23)

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Result - Effects of interventions

• 01.06 Symptomatic intracranial
  haemorrhage/haemorrhagic transformation of the
  cerebral infarct during treatment period.
• no significant difference in symptomatic HTI
  between LMWH or heparinoid and UFH(OR 0.73, 95
  CI 0.35 to 1.54)

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Result - Effects of interventions

• 01.07 Death from all causes during treatment
  period
• no significant difference (OR 1.06 95 CI 0.78 to
  1.46)

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Result - Effects of interventions

• 01.08 Extracranial haemorrhage during treatment
  period
• only 14 major extracranial haemorrhages (0.5 of
  all participants),
• the vast majority of which occurred in
  participants allocated to LMWH or danaparoid (OR
  3.79, 95 CI 1.30 to 11.06)
• no difference in minor bleeds in those allocated
  to LMWH or danaparoid compared to UFH (OR 0.91,
  95 CI 0.67 to 1.24).

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Result - Effects of interventions

• Effect on recurrent ischaemic stroke or recurrent
  stroke of unknown pathological type during
  treatment
• Only one trial (TRACE 2004)
• recurrent stroke was observed in 5/46 (10.9) of
  those allocated to LMWH or danaparoid, and 1/44
  (2.3) of those allocated to UFH, statistically
  non-significant difference.
• Effect on functional outcome
• three studies (Wong2000 TRACE 2004 PREVAIL
  2007)
• not reported in sufficient detail to be included
  in analysis.

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Discussion

• It is not yet clear that routine use of any
  anticoagulant treatment at all in acute stroke is
  beneficial.
• Aspirin has been shown to be effective in
  improving neurological outcome and preventing PE
  following ischaemic stroke and carries little
  risk of major haemorrhage
• LMWH or heparinoids yield greater protection
  against DVT than UFH
• Our conclusions differ from a recent non-Cochrane
  reivew of LMWHs versus UFH in ischaemic stroke?R
• Recommended more widespread use of LMWHs because
  of their benefit in terms of reducing venous
  thromboembolism.
• LMWHs were safe in this clinical, no
  statistically significant increase in haemorrhage
  and death compared to UFH
• ASA vs ASA LMWHor heparinoid for high risk of
  DVT PE ??

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Authors conclusions

• The criteria to identify those few patients that
  might benefit from the UFH, LMWHs, or heparinoid
  regimens tested in these trials have not been
  defined
• LMWH and heparinoids appear to be more effective
  at prevent DVT ((and possibly also PE) than UFH.
• However, their safety compare with UFH, has not
  reliably been established in stroke patient.

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Thanks for your attention!!