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Tracy Minichiello, M.D.Professor of Medicine
University of California, San FranciscoChief, SF VA Anticoagulation & Thrombosis Service
Thrombosis & AnticoagulationCases & Controversies
Workshop
Disclosures
I have nothing to disclose
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TOPICS Catheter related thrombosis Calf vein thrombosis Management of subsegmental PE IVC filters When to restart anticoagulation after a
bleeding event Anticoagulation in dialysis patients with
AFIB Duration of anticoagulation for VTE
CASE #1 A 55 year old woman being treated for osteomyelitis of the spine develops right upper extremity swelling. U/S reveals a DVT in the subclavian and axillary vein. She has a PICC line in that arm. She needs 4 more weeks of antibiotics.You start anticoagulation. Do you need to pull the line? a. Yesb. No
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Kucher N. N Engl J Med 2011
Upper Extremity DVT
Remove catheter (after 3-5 days of anticoagulation if possible) if:InfectionMalfunctionAC contraindicatedAC failedCath not needed
Upper Extremity DVT
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Diagnostic Algorithm Upper Extremity DVT
Risk factor points
Catheter in place 1Localized pain 1Unilateral edema 1Other dx as likely -1
Kleinjan A et al. Ann Intern Med 2014
Score ≤1 UEDVT unlikelyScore ≥ 2 UEDVT likely
IF UEDVT likely-got u/s. 42% had DVTIf UEDVT unlikleyd-dimerd-dimer negative 0% DVT; d-dimer positive-got u/s-11% had DVT
CASE #1 A 55 year old woman being treated for osteomyelitis of the spine develops right upper extremity swelling. U/S reveals a DVT in the subclavian and axillary vein. She has a PICC line in that arm. She needs 4 more weeks of antibiotics.You start anticoagulation. Do you need to pull the line? a. Yesb. No
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CASE #2
A 45 year old man presents with moderate calf pain and swelling for 5 days since he was kicked playing soccer. Ultrasound shows DVT in the posterior tibeal vein. Does he need anticoagulation?
a) Yesb) No
NEW CHEST GUIDELINESIn patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial anticoagulation (Grade 2C).
Kearon et al CHEST 2012
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ISOLATED DISTAL DVTant/post tibeal, peroneal
TREATMENTLOW RISKu/s 1-2 weeks and
treat only if extends proximally
HIGH RISKtreatment same as proximal DVT
HIGH RISK + d-dimer severe symptoms cancer VTE history no reversible provoking
factor hospitalized near proximal veins > 5 cm long, mult
veins, > 7 mm
CASE #2
A 45 year old man presents with moderate calf pain and swelling for 5 days since he was kicked playing soccer. Ultrasound shows DVT in the posterior tibeal vein. Does he need anticoagulation?
a) Yesb) No
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Case #3A 65 year old man with history of HTN and hyerlipidemia is admitted with a new PE. He is on ASA and statin. He is started on LMWH and bridged to warfarin.You:A) stop his aspirin now that he is on warfarin due to concerns of increased risk of bleedingB) continue ASA for primary prophylaxis
Date of download: 10/21/2012Copyright © 2012 American Medical
Association. All rights reserved.
Risk of Bleeding With Single, Dual, or Triple Therapy With Warfarin, Aspirin, and Clopidogrelin Patients With Atrial Firillation
Hansen M et al. Arch Intern Med. 2010
warfarin + asa= 2xwarfarin + asa + clopidigrel=3x
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NEW CHEST GUIDELINES
“For patients taking warfarin we suggest AVOIDING concomitant antiplatelet therapy except where benefit is likely to be greater than harm: valves, ACS, stents, CABG” (2C)
Holbrook A et al. CHEST 2012 (Suppl);Anand S et al JAMA 1999l
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Risk of myocardial infarction/coronary death (A), thromboembolism (B), bleeding (C), and all-cause death (D).
Lamberts M et al. Circulation. 2014;
MI/coronary death
thromboembolism
bleeding
All cause-death
→
→
Case #3A 65 year old man with history of HTN and hyerlipidemia is admitted with a new PE. He is on ASA and statin. He is started on LMWH and bridged to warfarin.You:A) stop his aspirin now that he is on warfarin due to concerns of increased risk of bleedingB) continue ASA for primary prophylaxis
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Case #4aA 77 yo man had undergoes ORIF of the right hip. On POD#2 he becomes tachycardic to the 110s. Pain is well controlled and HGB is stable. O2 sat is normal. On POD#3 he is still tachycardic with normal ECG and normal troponin. No signs infection. The hospitalist orders a CTa to rule out PE. It shows an isolated subsegmentalPE. Do you treat this?
Case #4b
A 77 yo man undergoes CABG. On POD#2 he becomes tachycardic to the 110s. Pain is well controlled and HGB is stable. O2 sat is normal. On POD#3 he is still tachycardic with normal ECG and normal troponin. No signs infection. The hospitalist orders a CTa to rule out PE. It shows an isolated subsegmental PE. Do you treat this?
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Which of these patients do you anticoagulate?
Case #4a Case #4b Both Neither
Isolated Subsegmental PE
Definition: PE shown on CT angiography that occurred in a subsegmental branch but no larger order of vessels. The subsegmental PE may involve one or more than one subsegmental branch
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Subsegmental PE The multi-row detector CTPA is highly
sensitive and specific for PE, including relatively smaller emboli confined to subsegmental pulmonary arteries
Identification of thrombus in subsegmentalarteries has increased from 4.7% with the single detector to 15% with multi-row detector CTPA.
SSPE are frequent on pulmonary angiography in patients with a low probability ventilation-perfusion (V/Q) scan for suspected PE.
Carrier J Thromb Hemostas 2012
“Dots are not Clots” One of the normal lung functions is to
remove small emboli Many small PE may be part of “normal”
existence : DVT usually absent in ISSPE
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Management of Subsegmental PE
Stein et al Clinical and Applied Thrombosis/Hemostasis 2012
• 105 untreated patients.DVT excluded in all with 3 months follow up. No fatal recurrences at 1-3 months.
• 121 treated patients.7% had major bleeding
Witholding Anticoagulation for Isolated Subsegmental PE
No DVT Autopsy studies show DVT LE 97% only 3% pelvic
veins Limitations of testing-sensitivity 92% if symptomatic
55% if not u/s should be done 3 or 4 times over a 10- to 14-
day period to detect a new proximal deep-vein thrombosis before it leads to important recurrent PE
Adequate pulmonary reserve A major risk factor for VTE that is no longer
present (surgery trauma) and no continuing risk factor
No central line/No AFIB Reliable follow up
Stein et al Clinical and Applied Thromb/Hemostasis 2012/Raskob Blood 2013
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Outcomes in SSPE vs Proximal PE vs no PE
Den Exter et al. Blood 2013
Reconciling the Conflicting Findings
All the patients in the Stein study had ultrasound to rule out DVT. den Exterdid not assess this
Almost 20% of patients from den Extercohort had active malignancy
Up to 11% of SSPE subsequently reviewed by senior radiologist were reinterpreted as negative. interobservervariability for dx of SSPE is high (den Exter did not have independent radiology review)
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What to do?
Treat isolated subsegmental PE if no absolute contraindication or not VERY high risk for bleeding
If absolute contraindication or high bleeding risk withholding anticoagulation is likely a safe alternative provided neg DVT/adequate reserve/ serial u/s possible/no ongoing risk factor and no AFIB/central line/reliable follow up
Coming soon
Ongoing cohort study (NCT 01455818) of withholding anticoagulant therapy in patients with subsegmental PE who have negative results by serial ultrasonography for deep-vein thrombosis
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Which of these patients do you anticoagulate?
Case #4a Case #4b Both Neither
CASE # 5
A 68 year old woman falls and fractures her hip. She is in CHF on admission so OR time is delayed. On HD #3 she becomes acutely short of breath and is found to have PE and DVT. How do you manage her anticoagulation perioperatively?
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Anticoagulation for VTEUse UFH preferentially
Immediate risk of bleeding
Renal Failure Extremes of weight Massive PE,submassive
PE when considering thrombolysis
CHEST 2012
LMWH preferred agent for acute treatment VTE
IVC Filters
PREPIC STUDY GROUP, Circulation 2005; Decousus NEJM 1998
Filter No Filter
PE@ 12 days
1% 5%
DVT @ 2 years
20% 11%
PE@ 2 years
3.4%(ns) 6.3%
PREPIC STUDY PREPIC 8 yr FOLLOW UP
DVTHR 1.52
PEHR 0.32
No survival benefit
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IVC filter market projected change from 2006 to 2012
Friedell et al Annals of Vascular Surgery 2012
IVC Filters
Most “retrievable” IVC filters are not removed, in real-world practice Recent meta analysis found only 1/3
devices actually retrieved Filter complications are serious:
fracture, embolization, thrombosis
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IVC Filter IndicationsIndication for IVC Filter Placement
ACCP( 1)
AHA (2)
British Committee for Standards in Hematology (3)
Thrombosis Interest Group of Canada (4)
Acute VTE and contraindication to anticoagulation
YES YES YES YES If proximal DVT present
VTE despite anticoagulation
NO YES MAYBE High intensity oral anticoagulation or LMWH should be considered prior to placement of filter
NO Anticoagulation should be intensified or alternative agent started. IVC filter will not prevent progression
Preoperatively in patients who have had recent VTE (within one month) and must have anticoagulation interrupted for surgery
____ ___ YES (VTE within 4 weeks prior to surgery)
YES (VTE within 2 weeks prior to major surgery)
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IVC Filter Indications
Indication for IVC Filter Placement
ACCP( 1)
AHA (2)
British Committee for Standards in Hematology (3)
Thrombosis Interest Group of Canada (4)
Proximal DVT in patient with poor cardiopulmonary reserve
____ YES ___ There is no agreement on definition of poor reserve
Free-floating thrombus
____ ___ NO NO
Thrombolysis with proximal DVT
____ ___ NO NO
Primary prophylaxis in selected high risk patients (surgical, trauma etc)
NO ___ ____ NO
ACCP 2012 and IVC Filters
The ACCP recommends placement of an IVC filter for patients with acute proximal DVT(leg) or PE who have a contraindication to anticoagulation. (Grade 1B, strong recommendation with moderate quality evidence)
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ACCP 2012 and IVC Filters The ACCP recommends not placing IVC filters in
patients with acute PE who are being treated with anticoagulant therapy (Grade 1B, strong recommendation based on moderate strength evidence).
“Among patients with hemodynamic compromise in the International Cooperative Pulmonary Embolism Registry, insertion of an IVC filter was associated with a reduction of early recurrent PE (0%) and death (HR0.12). Consequently, our recommendation against insertion of an IVC filter in patients with acute PE who are treated with anticoagulants may not apply to this select subgroup of patients.”
Case #676 y/o man with AFIB CHADS2=3 on anticoagulation with warfarin is admitted with UGIB. INR is 3.2. He requires 3u PRBCs and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. When should his anticoagulation be restarted?a) Neverb) In one weekc) In one monthd) Let the primary provider deal with this one
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Is it safe to restart anticoagulation after a GI
bleed? Retrospective cohort of 1,329 patients on
AC for AFIB who developed GIB Restarting warfarin was associated with ↓
TE ( [HR], 0.71; p = 0.01) and ↓mortality (HR, 0.67; p < 0.0001), but not recurrent GIB.
Patients who restarted warfarin within 7 days of GIB had a higher risk of recurrent GIB.
There was no difference between rebleeding rates resuming warfarin after one week compared to after one month
Quereshi Am J Cardiol 2013
Recurrent GIB:Warfarin restart vs no
Quereshi Am J Cardiol 2013
Freedom from GIB(↑GIB if restart day 1-7)
Freedom from TE
mortality
For each figuredotted line: restartedsolid line: not restarted HR TE 0.71HR mortality 0.67
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Qureshi Amer J of Cardiol 2014
Outcomes stratified by duration of warfarin
interruption
----< 7 days___ no warfarinIncr GIB restart w/in 7d
Freedom from GIB
Is it safe to restart anticoagulation after a GI
bleed?442 patients with warfarin-associated GIB included in the analyses. Warfarin therapy resumption after the GIB was associated with a lower risk for thrombosis (HR 0.05) & death (HR 0.31) without significantly increasing the risk for recurrent GIB (HR 1.32)
WITT et al Arch Intern Med. 2012
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90 day Follow up
WITT et al Arch Intern Med. 2012
↑ GIB (ns)-none fatalHighest risk time day 1-7
% alive
% without recurrent GIB
% without thrombosis
Nearly 50% of pts with GIB on ASA also
↓ TE 0.4% vs 5.5% -3 fatalIf resumed within 14 days no thrombosis
Case #676 y/o man with AFIB CHADS2=3 on anticoagulation with warfarin is admitted with UGIB. INR is 3.2. He requires 3u PRBCs and FFP. EGD shows peptic ulcer disease. He is started on high dose PPI therapy, bx for H Pylori done. When should his anticoagulation be restarted?a) Neverb) In one weekc) In one monthd) Let the primary provider deal with this one
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Case #7A 65 year old man with DM, HTN and ESRD on HD is admitted to your service with SOB and new AFIB with RVR. He is in AFIB throughout his hospital stay. His ECHO shows EF of 50% diastolic dysfunction a moderately enlarged RA and no valvular disease. You: Start him on warfarin Continue his ASA therapy
Warfarin use and the risk for stroke in patients with atrial fibrillation undergoing dialysis.
Shah M et al. Circulation. 2014;129:1196-1203
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Warfarin use and the risk for bleeding in patients with atrial fibrillation undergoing
dialysis.
Shah M et al. Circulation. 2014;129:1196-1203
What Do the Guidelines Say?
2015 Canadian Cardiovascular Society –no longer recommends warfarin for dialysis patients with AFIB
2011 KDIGO does not advise warfarin for CKD stage 4/5 including dialysis
2014 AHA/ACC for patients with CHADS-vasc-≥2 CrCl < 15 or dialysis it is reasonable to prescribe warfarin
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Case #7A 65 year old man with DM, HTN and ESRD on HD is admitted to your service with SOB and new AFIB with RVR. He is in AFIB throughout his hospital stay. His ECHO shows EF of 50% diastolic dysfunction a moderately enlarged RA and no valvular disease. You: Start him on warfarin Continue his ASA therapy
CASE # 8
A 33 year old woman diagnosed with left lower extremity DVT 3 months ago maintained on warfarin present with complaints of pleuritic chest and shortness of breath. A CT angio of the chest reveals new bilateral segmental pulmonary emboli.
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CASE #8
She reports compliance with her warfarin therapy and has an INR of 2.5 at the time of admission. She is admitted to your service for recurrent VTE. How do you manage this?
VTE Despite Anticoagulation
Medication adherence Antiphospholipid antibody syndrome Cancer DIC/Trousseaus Heparin-induced thrombocytopenia Myeloproliferative disorder Antithrombin deficiency Structural defect
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VTE Despite Anticoagulation
Warfarin failureTransition to LMWH then transition to
warfarin with higher target OR continue LMWH
LMWH failureChange to BID dosingIncrease dosing by 20%Follow anti-Xa levels
Management Algorithm of Recurrent VTE in Cancer
Lee A Y Y et al Blood 2013;122:2310-2317
©2013 by American Society of Hematology
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Case #5a:How long will you recommend this patient stay on
anticoagulation? 55 yo man with unprovoked PE?
a) 3 monthsb) 6 monthsc) 12 monthsd) Indefinitely
Case #5b:How long will you recommend this patient stay on
anticoagulation? 68 yo woman with provoked PE ?
a) 3 monthsb) 6 monthsc) 12 monthsd) Indefinitely
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Risk of VTE Recurrence After Cessation of VTE
Risk factor 1st yr Next 5 yrs
Distal DVT 3% (6%) <10%
Major-transient
3% 10%
Minor-transient
5-6% 15%
Unprovoked At least 10% 30%
Recurrent > 10% > 30%
Kearon, Blood 2005
Guidelines for Duration of Anticoagulation for VTE
Indication
8th ACCP guidelines
2012AHA 2010
British Hematology2011
First episode of VTE secondary to a transient risk factor
3 months (Grade 1B).
3 months (Class I Level A) 3 months
First episode of idiopathic (unprovoked) VTE
At least 3 months, prefer long-term treatment if risk/benefit ratio ok (Grade 2B).
At least 6 months, consider indefinite(Class I Level A)
At leastmonths;considerlong term if risk
benefit favors (2B)
Recurrent VTE Long term(Grade 1B).
IndefiniteClass I Level A).
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D-dimer and Recurrent VTE
D-dmer + D-dimer -Prolong(18 months)
D-dimer @ 1 month after AC stopped
15% 6.2%
Annals 2008(one year)
Systematic review
8.9 3.5%
Prolong II(one year)
d-dimer q 2 months after 1st negative d-dimer
27% 2.9%
Cosmi et al(18 months)
d-dimer & RVO
9-12% 0-5%
Verhovsek et al Ann Intern Med 2008;Cosmi et al Blood 2010;Palareti NEJM 2006;Cosmi Thromb Haemost 2011
Clinical Scores to Predict Recurrence
Kyrle et al Thromb Haemost. Dec 2012
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Clinical presentation predicts likelihood and type
of recurrence Distal (calf vein thrombosis)
Low risk of recurrence/PE Proximal- nearly 5 fold increased
recurrence risk over distal PE vs. DVT
Patients presenting with PE are 3x more likely to suffer recurrent PE than those presenting with DVT
Baglin T et al J Thromb Haemost. 2010
Individual Bleeding Risk on Anticoagulation
Bleeding Risk Factors Age > 75 Previous GI bleed
with no reversible cause
Previous bleed on warfarin
Renal/hepatic failure Antiplatelet therapy Cancer
Case fatality rate VTE Case fatality rate of
recurrent VTE highest in 1st 3-6 months-11%
Case fatality rate of recurrent VTE decreases after 3-6 months to 3.6%
Carrier Ann Intern Med 2010
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Duration of AnticoagulationUnprovoked VTE
ding
riskConsider
indefinite
tx(esp
PE,
male,
thrombophilia)patient
preference
cal
prediction
rule:<1
and
wants
to
stop
anticoagulation-ok
sure
D-dimer
at
30days,if
low
okIf
elevated
consider
Restarting
tx
High
bleed
riskElderlyBleed
on
ACSTOP
AC
IF DVT get u/s. measure d-dimer . If d-dimer + continue AC
Case #5a/b:How long will you recommend these patients stay on
anticoagulation? 55 yo man with unprovoked PE?
a) 3 monthsb) 6 monthsc) 12 monthsd) Indefinitely
68 yo woman with provoked PE ?
a) 3 monthsb) 6 monthsc) 12 monthsd) Indefinitely
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Aspirin for Prevention of Recurrent VTE.
Becattini C et al. N Engl J Med 2012; Brighton TA et al N Engl J Med 2012
WARFASA :VTE 6.6%v 11.2 %↓VTE 40%ASPIRE: ns ↓ VTE 26% underpowered;↓ Vascular events by 34%
When trials combined: 32% ↓VTE
Take Home Points
Catheter-associated VTE does not mandate catheter removal and requires 3 months of anticoagulation once catheter is removed
Risk stratify each patient to determine IF calf vein thrombosis needs treatment
Analyze risks and benefits of anticoagulation in each case of islolated subsegmental PE
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Take Home Points
Risk benefit of concomitant use of ASA plus warfarin should be assessed in each patient
Risk benefit of warfarin for stroke prevention in AFIB in dialysis patients should be assessed individually in each patient
Provide guidance on duration of anticoagulation for VTE event at time of discharge
Take Home Points
Consider ASA for secondary prevention of recurrent VTE in patients with unprovoked events who are not candidates for ongoing anticoagulation
Work with GI specialists during hospitalization for warfarin associated GIB to determine safe time to restart anticoagulation in patients after GIB
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Take Home Points
Consider risk benefit if IVC filter If retrievable IVC filter placed, at
discharge arrange retrieval of temporary device or dedicated follow up appt to address retrieval time