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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