All things thrombosis Julie Wang - PowerPoint Presentation

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All things thrombosis

Julie WangThrombosis Fellow

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VTE is chronic disease

Recurrence rate after initial VTE up to 24.6% after 5 yearsClinical need to identify individuals at increased risk of recurrent VTE

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VTE terminologyProvoked – surgery

3% recurrence at 5 yearsMinimally provoked – non-surgical transient risk factor –

oestrogen

, pregnancy, flight>8hrs

15% recurrent at 5 years

Unprovoked

30% recurrence at 5 years

Cancer-associated

15% annualized risk recurrence

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Other deep veins

Superficial femoral vein

Gastrocnemius

Soleal

Peroneal

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Duration of anticoagulation - proximal DVT and PEProximal = Above or involving popliteal vein

Minimum period is 3 months for all patientsAfter 3 months for unprovoked DVT/PE Assess risk/benefit of indefinite therapy

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Ref3

Risk factors for recurrent VTE

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Ref2

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DASH score

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MethodsRetrospective analysis of medical records at single institutionPatients with discharge diagnosis of DVT/PE between January 2013 and June 2015 D-dimer assay

Innovance D-dimer; Normal <500ng/mLPresence of residual thrombus defined by reporting radiologist

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Total reviewed patientsN = 443

Post-AC D-dimer

tested

N = 101

No post-AC D-dimer testing

N = 342

Male

N = 41

Female

N = 60

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ResultsMedian follow up 10 months (0 – 50 months)Median time to D-dimer testing 45 days after stopping anticoagulation (6-318 days)

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RR 5.0

, 95%CI 1.7-14.5;

p=0.003

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Anticoagulation was recommenced for 11 patients with elevated D-dimer>1000ng/mL = 8 patients

500-1000ng/mL = 3 patientsPatients with recurrent VTE = 0

Bleeding complications = 0

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Table 1 – VTE recurrence stratified by D-dimer

D-dimer (

ng

/mL)

Pts

with recurrent VTE

Pts

without anticoagulation recommenced

Recurrence rate

Relative risk (compared to patients with normal D-dimer)

>1000

4

4

100%

16.3

(95%CI 6.3-42;

p<0.0001

)

500-1000

7

21

33.3%

5.4

(95%CI 1.8-16.7;

p=0.0033

)

<500

4

65

6.2%

 

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Table 2 – months to recurrent VTE stratified by D-dimer

D-dimer (

ng

/mL)

Pts

with recurrent VTE

Pts

without anticoagulation recommenced

Recurrence rate

Mean

months to recurrent VTE from stopping anticoagulation

>1000

4

4

100%

4.8

500-1000

7

21

33.3%

6.6

<500

4

65

6.2%

 

13

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Table 4 – Effect of D-dimer & residual thrombus on risk of recurrent VTE

D-dimer = DD

No. patients

Patients with recurrent VTE

Recurrence rate

Normal DD &

NO

residual thrombus

45

1

2.2%**

Normal DD & residual thrombus

20

3

15%

High DD & residual thrombus

15

4

26.7%

High DD &

no

residual thrombus

18

6

33.3%

Normal DD & no residual thrombus

vs

rest of patients

p =

0.006

;

RR 0.09

(CI 0.01

–

0.67 p=0.02)

3 patients did not have repeat imaging

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Conclusions

Highest risk of VTE recurrence in those with D-dimer >1000ng/ml –

long term anticoagulation should be considered.

D-dimer 500-1000ng/ml confers intermediate risk

–

age-adjustment may further risk stratify.

Patients with normal D-dimer <500ng/ml without any residual thrombus have significantly lower risk of thrombus recurrence.

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RIETE score

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Choice of anticoagulantNOAC is now preferred over warfarin as:Efficacy is non-inferior to warfarin in multiple large RCTsLower risk of bleeding,

esp intracranialConvenient to takeNo direct comparison between NOACs but indirectly, efficacy appears similar

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Dabigatran

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Rivaroxaban, Apixaban

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Approved and Funded Indications

Non-valvular

AF

Acute DVT

Secondary DVT

Acute PE

Post-TKR/THR

Dabigatran

Rivaroxaban

Apixaban

Phase 3 data

PBS Funding

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Drug characteristics

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RELY

ROCKET-AF

ARISTOTLE

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NOAC Bleeding Rates – Real-world data

Lip et al

Int

J

Clin

Pract

2016;1-12

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Lab AssaysNo routinely available assays for degree of anticoagulation.

Currently available coagulation testing imperfect.No clinical correlation yet.Indications for testing:Bleeding or overdose

Before surgery or invasive procedure -

esp

if drug taken in previous 24

hr

or renal failure, or thrombolysis for stroke.

Renal failure

+/- Adherence

Time of last drug dose important

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APTT - Dabigatran

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Thrombin time vs plasma dabigatran

TT (seconds)

)

Dabigatran

concentration (

ng

/

mL

)

Hapgood J et al. Thromb Hemost 2013

60ng/mL

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Haemoclot assayModified TTCitrate plasma

Diluted with saline Diluted pool plasmaAdd thrombin

Van

Ryn

J.Thromb

Hemost

2010;103:1116-22

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Assessing Dabigatran levelsTCT (thrombin clotting time) – available at TNH 24/7Haemoclot

(dilute TCT) = drug level - Not done here – turnaround time ~24hPT and INR – not useful

APTT normal TCT normal = minimal/no drug

APTT normal TCT prolonged = likely low drug levels

Both prolonged = significant drug activity

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Lab AssaysRivaroxaban

Prolongs the PT if high levels of drug.Normal PT

≠

no rivaroxaban.

PT on rivaroxaban

≠

PT on warfarin.

Ignore the INR.

Rivaroxaban

anti-

Xa

= drug level

APTT not useful.

Apixaban

Apixaban

anti-

Xa

= drug level

PT, INR, APTT not useful

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But… What do they mean?No defined therapeutic range, no “safe” range.

Some idea of peak and trough levels from phase 2 trials, but wide 95% CI.Short half life – timing of testing matters.

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Tran et al, 2014

Management of Bleeding

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Idarucizumab

Antidote to the DTI – monoclonal antibody which binds to dabigatran with a 350x affinity

Neutralises

activity of free and thrombin-bound dabigatran

Rapid, complete and sustained reversal

Idarucizumab

produced immediate and complete reversal of anticoagulant effects of dabigatran without

procoagulant

effects in:

Young, healthy volunteers with normal renal function

Elderly volunteers 65 – 80 years of age

Volunteers aged 45 – 80 years with mild or moderate renal impairment

2x 2.5g bolus IV repeated 15minutes apart

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On the horizon…ANNEXA-A – andexanet

alfaRecombinant inactivated factor Xa

– decoy with a high affinity for factor

Xa

inhibitors

Phase III – bolus, followed by infusion

Rapid reduction in anti-

Xa

activity and sustained as long as the infusion was continued

Aripazine

(PER977)

Mode of action unclear

Inhibits LMWH,

fondaparinux

, direct

Xa

inhibitors and dabigatran

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Drug interactions

Tran et al, 2014

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Perioperative management

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Who I would put on a NOAC…

Outpatients.CrCl >30 mL/min.

LFTs not significantly deranged ?3xULN

Few other comorbidities.

Adherent.

Difficult warfarin control (<65% TTR?).

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Who I wouldn’t put on a NOAC…

Absolute contraindicatedCrCl <30 (very cautious if <50)

Mechanical heart valve

Antiphospholipid syndrome

Pregnant/Lactating

Mod-severe liver disease

Relative contraindications

Extremes of age and weight

Active malignancy – lack of powered RCTs

 individual case based assessment + involvement with haematologist

Non-adherent with warfarin. “Falls risk” or anyone “unsafe” for warfarin.

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Key Points for NOACs

NOAC is non-inferior to warfarin in non-valvular AF and VTEIt is

not appropriate

to use NOACs in patients with renal impairment, or in the very elderly or very frail.

There are

no antidotes

at present for

Xa

inhibitors – these are very early in clinical development. No effective reversal agents.

Normal coagulation parameters (PT/APTT) may not be affected by NOACs. Drug levels can be tested, but interpretation is difficult.

Adherence

is extremely important – rapid offset and loss of anticoagulation if renal function normal.

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NOAC iGuidance

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Isolated distal DVTNot great evidence and unclear guidelines33% of symptomatic if untreated will extend into popliteal vein; risk extension lower in muscular veins (soleus, gastroc

)Risk of PE in distal DVT 50% of proximal DVTRisk of recurrence 50% of proximal DVT/PE

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Isolated distal DVTSuggested risk factors for extensionPositive D-Dimer>5cm length, multiple veins involved

Close to proximal veinsUnprovokedActive cancerHistory of VTEInpatient status

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Isolated distal DVTIf elect to anticoagulate – full dose anticoagulation as per proximal DVT

Duration is uncertain – 6 weeks? 3 months?

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NOACs not PBS approved for SVT

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VTE and cancerLMWHRCTs have shown LMWH more effective than warfarin in active cancerMore reliable if difficulty with oral therapy

eg vomitingEasier to withold if thrombocytopenia or invasive procedures

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NOACs in Cancer

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Recurrent VTEs whilst on anticoagulationIs there really a recurrent thrombus? –

compare closely current and previous ultrasounds. ?post-thrombotic syndromePotential causesAdherence to therapy

Subtherapeutic

INR? NOAC interacting with another drug?

Cancer

Antiphospholipid

syndrome

Oestrogen

therapy

Switch to LMWH if on oral therapy

If already on LMWH consider higher dose

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When to do thrombophilia testing Give estimated risk factors for hereditary/acquired factorsChanged in era of NOAC?

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RCPA RecommendationsRCPA recommends to follow the recommendations of the College of American Pathologists and perform specific thrombophilia testing in the patient groups

Additionally, testing for

antiphospholipid

antibodies is considered appropriate for patients with VTE, particularly if the VTE is idiopathic, associated with autoimmune disease or in the absence of a family history of venous thrombosis

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When to test? FVL and PT 20102A mutation are PCR based – can test anytime. Other tests - Not during acute thrombosis or pregnancy – wait at least 6 weeks.

Heparin lowers AT activity and antigen levelsAffects LAC (clot-based) assay

delay 5 days after heparin is stopped

Warfarin

reduces the vitamin K–dependent factors, (Protein C and S.) - may take 6 weeks to normalise.

rarely, may increase AT levels (in deficient

pt

)

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A general approachOnly test if it will change management (eg

deciding on duration of anticoagulation, planning for future prophylaxis, family testing in the case of inherited thrombophilias). Testing for inherited thrombophilia (FVL, PT mutation, AT deficiency, PC and PS deficiencies): for patients with an unprovoked or recurrent clots and family history of VTE.

Testing for acquired thrombophilia (lupus anticoagulant,

anticardiolipin

antibodies, B2G1 antibodies): for patients with an unprovoked or recurrent clots, young females, clot during pregnancy, or history of miscarriages/ pregnancy complications.

Patients with unusual clots (cerebral sinus thrombosis,

splachnic

vein thrombosis): test for all of the above, and others

eg

PNH screen, JAK 2.

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Useful referencesAntithrombotic therapy for VTE disease: CHEST guideline, CHEST (2016)Tran et al, New oral anticoagulants – a practical guide on prescription, laboratory testing and peri‐procedural/bleeding management.IMJ;

44:2014.