anticoagulation management after a clot vte_bristol_180418.pdf · rivaroxaban day 1 day 21...
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Anticoagulation management after a clot
Professor DA FitzmauriceUniversity of Warwick
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What this presentation covers
• Background• Current treatment• New agents• Duration of treatment
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VTE risk
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VTE risk
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Aims of treatment
• To prevent extension• To prevent embolisation• To allow stabilisation and recanalisation• To prevent recurrence• To prevent long term effects (PTS, PH)
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Current Treatment
• Initial treatment with UFH, LMWH, SP• No placebo controlled trials• Minimum 5 days (average 7)• LMWH drug of choice for cancer patients
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Current Treatment
• Combined with warfarin (VKA)• Treatment phase 3-12 months• One placebo controlled trial (PE pts, Barritt
and Jordan 1960)• Duration of therapy?
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Current Treatment –What’s the problem?
• INR monitoring• Which LMWH – HIT??• Bleeding versus recurrence• Duration of therapy
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Einstein
....not him
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Rivaroxaban EINSTEIN phase III: study designs
15 mg bid
Confirmed acute
symptomatic DVT without symptomatic
PEN=3,449
Rivaroxaban
Day 1 Day 21
Enoxaparin 1.0 mg/kg bid for at least 5 days, followed
by VKA to start ≤48 hours, target INR range 2.0–3.0Confirmed acute symptomatic PE with or without symptomatic
DVT
EINSTEIN DVT1 and EINSTEIN PE2 (non-inferiority studies)Treatment period of 3, 6 or 12 months
20 mg od
N=4,833
Rivaroxaban
R
30-d
ay o
bser
vatio
n af
ter
trea
tmen
t ces
satio
n
Confirmed symptomatic
DVT or PE completing 6 or 12 months
of rivaroxaban or VKA
Rivaroxaban 20 mg od
PlaceboDay 1
N=1,197
EINSTEIN Extension1 (superiority study)Treatment period of 6 or 12 months
R
30-d
ay o
bser
vatio
n af
ter
trea
tmen
t ces
satio
n
The EINSTEIN investigators, 1. N Eng J Med 2010;363:2499-2510 & 2. N Eng J Med 2012;366:1287-1297
L.GB.01.2013.1379 Jan 2013
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Einstein DVT- results
• 3449 pts (1731 Rivaroxaban)• Rivaroxaban 36 (2.1%) vs 51 (3%) recurrent
events• Major bleeding 8.1% in both
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Einstein PE
As per DVT study4,833 ptsNon-inferior
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EINSTEIN PE: Major bleeding 3.0
2.5
2.0
1.5
1.0
0.0
0.5
0 30 60 90 120 150 180 210 240 270 300 330 360
Cum
ulat
ive
even
t rat
e (%
)
Time to event (days)
RivaroxabanN=2412
Enoxaparin/VKAN=2405
Number of patients at risk
Rivaroxaban 2412 2281 2248 2156 2091 2063 1317 761 735 700 669 659 350
Enoxaparin/VKA 2405 2270 2224 2116 2063 2036 1176 746 719 680 658 642 278
The EINSTEIN investigators, N Eng J Med 2012;366:1287-1297
Safety population
L.GB.01.2013.1379 Jan 2013
Rivaroxabann/N (%)
Enoxaparin/VKAn/N (%)
HR (95% CI)p-value
26/2412 (1.1)
52/2405(2.2)
0.49 (0.31–0.79) p=0.003
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Einstein - Conclusion
Rivaroxaban• Non-inferior acutely compared with
standard therapy• Superior in terms of secondary prevention
compared with placebo but some excess bleeding
• Pre-specified joint analysis suggest superiority of rivaroxaban
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Einstein
A new era?
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NOAC VTE trials
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Length of Treatment
• 1st episode of idiopathic VTE should be treated with warfarin at an INR of 2.0 to 3.0 at least three months
• the optimal length of time and optimal degree of anticoagulation are not known
• Baglin T et al. JTH 2012 Duration of anticoagulant therapy after a first episode of unprovoked pulmonary embolus or deep vein thrombosis: guidance from the scientific and standardization committee of the international society on thrombosis and haemostasis.
• Boutitie F et al. BMJ 2011; 342:d3036 Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials.
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Risk of recurrent VTE based on history of index event
Cambridge cohort Baglin et al Lancet 2003; 362: 523–26
Unprovoked
Non-surgical risk factor
Post-surgery
Risk of recurrence after unprovoked VTE 30-40% after 5-10 years
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Length of Treatment – balance of risksThrombosis vs bleeding
• Risk benefit analysis • Patients values and preferences in regard to
such risks and benefits • The potential benefit of extending
anticoagulation to six (or more) months may be offset by a higher risk of bleeding and the greater cost and inconvenience of the longer duration of treatment
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2012 ACCP Guidelines
Recommendations based upon the perceived balance between
• the number of deaths from recurrent VTE prevented by continued anticoagulation
versus • the number of fatal bleeding episodes
associated with continued anticoagulation
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Risk of rVTE after discontinuation of anticoagulation
Risk or rVTE 1st year Thereafter
1st VTE provoked by surgery
1% 0.5%
1st VTE provoked by a nonsurgical factor
5% 2.5%
1st unprovoked VTE 10% 5%
2nd episode unprovoked VTE
15% 7.5%
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Risk of major bleeding if anticoagulation is continued
Risk factors Risk category During 1st 3 months Thereafter/yr
None LOW 1.9% 0.9%
1 INTERMEDIATE 3.2% 1.6%
Ø2 HIGH 12.8% > 6.5%
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BLEEDING• Warfarin in top 10 drugs largest number of serious adverse
event reports submitted to the United FDA
• Anticoagulants also ranked first in 2003 and 2004 in the number of total mentions of death for drugs "causing adverse effects in therapeutic use"
• a common cause of emergency department visits
• "black box" warning re warfarin's bleeding risk
• Related to the degree of anticoagulation as well as the presence in the patient of pre-existing risk factors for bleeding.
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Thrombotic recurrence risk group
LOW bleeding risk group
INTERMEDIATE bleeding risk group
HIGH bleeding risk group
1st VTE provoked by surgery
Discontinue(strong)
Discontinue(strong)
Discontinue(strong)
1st VTE provoked by a nonsurgical factor or 1st
unprovoked distal DVT
Discontinue(weak)
Discontinue(weak)
Discontinue(strong)
1st unprovoked proximal DVT or PE
Continue(weak)
Continue(weak)
Discontinue(strong)
2nd episode unprovoked VTE
Continue(strong)
Continue(weak)
Discontinue(weak)
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ISTH guidance 2012 – unprovoked VTE
• In favour of long term a/c (>3-6 months)– Male– Moderate to severe PTS– Ongoing dyspnoea– Satisfactory a/c control– Elevated D-dimer 3-4 weeks after stopping (using
study validated assay)
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Issues to consider
• Patient information and counselling– Estimated risk of recurrence– Bleeding risk– Patient values and preferences
Age, comorbidities, quality of life issues
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Amplify-Ext: Apixaban for VTE
N Eng J Med 2013;368:699-708
Apixaban 2.5mg bd
Apixaban 5mg bd
Placebo
Recurrent VTE 1.7% 1.7% 8.8%Major bleeding 0.2% 0.1% 0.5%Non-major bleeding
3.2% 4.3% 2.3%
n= 829
n = 840n = 813
Symptomatic VTE or death
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Amplify-Ext: Apixaban for VTEMajor or Clinically RelevantNon-major Bleeding
N Eng J Med 2013;368:699-708
Apixaban 2.5mg bd
Apixaban 5mg bd
Placebo
Recurrent VTE 1.7% 1.7% 8.8%Major bleeding 0.2% 0.1% 0.5%Non-major bleeding
3% 4.2% 2.3%
n= 829n = 840
n = 813
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Length of Treatment
Who is truly low risk of recurrence?
Who is truly high risk of bleeding?
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Other issues
• Stockings• HRT/OCP• Aspirin• Travel• Hospital Admission
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Conclusion
• New agents now available• Optimal length of time of anticoagulation are
not known (low risk of recurrence)• Cost?• New care pathways• Warfarin here for a while yet