+

Pearls in Thrombosis

Update for Family Physicians – A Case-Based Approach

Sudeep Shivakumar

April 6th, 2018

44th Annual Dalhousie Spring Refresher

+Conflict of Interest Disclosures

• Pharmaceutical Company Affiliations

• None

• Grants/Research Support

• None

• Speakers Bureau/Advisory Boards

• Pfizer Inc

• Bayer Inc

+Objectives

To discuss the acute treatment of DVT/PE, including the direct

oral anticoagulants (DOACs)

To briefly discuss perioperative management of DOACs

To discuss the duration of anticoagulation for DVT/PE

+Case

23 year old female, G0P0

Dalhousie student

Previously healthy

Notes right calf cramps when walking the dog

Over the next 3 days, also notes swelling of the calf

Over the next 2 days, entire right leg swells up

Presents to GP

+Case

No history of trauma, immobility or surgery

No recent travel

Did start oral contraceptive Alesse last month

No family history of DVT/PE

No previous history of DVT/PE

No symptoms of PE

No constitutional symptoms

Full PMHx, meds, allergies, social history

+Case

Exam shows:

HR 86 reg, BP 122/70, sats 99% room air, RR 22

Chest clear

CVS: Normal JVP, normal S1S2, no murmurs

Abdomen benign

Right leg red, warm, swollen with pitting edema, and ++ tender

Whole leg is swollen

Distal pulses are strong and present

+

+Case

Sent immediately to ED

CBC shows normal hemoglobin and platelets

Creatinine normal

Pregnancy test negative

Given dose of dalteparin 200 units/kg

Appointment for ultrasound next AM

+Case

Presents for U/S next morning

Confirms presence of extensive right leg DVT

Thrombus seen from popliteal vein to superficial femoral vein,

extending into iliofemoral system

Sent to Hematology clinic for management

+Case

Questions:

Which anticoagulant would you start her on?

How long would you treat her for?

+Venous thromboembolism

Deep venous thrombosis Pulmonary embolism

+Venous thromboembolism

Not uncommon

Incidence of 1st time VTE = 1.92 per 1000 person years

Major cause of morbidity and mortality

6% of deceased patients had evidence of massive pulmonary

embolism

1Cushman, Am J Med, 2004

2Dismuke, JAMA, 1986

+Pulmonary embolism

Untreated PE

Mortality rate of ~30%1

Most die within hours of diagnosis

Treated PE

Prospective NEJM study looked at 399 patients with newly

diagnosed PE

94% received conventional treatment

Only 2.5% (10 patients) died of PE

1Dalen, Prog Cardiovasc Dis, 1975

2Carson,NEJM, 1992

+Treatment of DVT/PE

Goals of treatment:

Short term:

Prevent the extension of thrombus

Prevents embolization of DVT

Reduce mortality for PE by reducing recurrent events

Relief of symptoms

Long term:

Prevent recurrent events

+Standard initial treatment?

Start with low molecular weight heparin

Enoxaparin 1.5 mg/kg subcut daily

Dalteparin 200 units/kg subcut daily

Tinzaparin 175 units/kg subcut daily

Round to prefilled syringe dose

Most patients can be taught to do self-injections

Start as soon as diagnosis suspected

First 24 hours most risky time for untreated PE

+Standard initial treatment?

Warfarin can be started on day 1

Lots of nomograms available

10mg orally for 2 days is safe in most patients

Do not stop LMWH until minimum 5 days, and 2 days overlap

with INR therapeutic (2-3)

Hypercoagulable state in first few days

+Case

She has a severe needle phobia

Has trouble even getting dalteparin injection in ED

Asks about other options

“What about that blood thinner I saw an ad on CNN?”

+Difficulties with warfarin use

Requires monitoring

Numerous drug and diet interactions

Narrow therapeutic range

Difficult to control – takes time to get in or out of the system

Role for new anticoagulants?

+An ideal oral anticoagulant…

No monitoring

Few interactions

Short onset/offset

Reversible

Efficacious

Safe

✓

✓

✓

✓

✓

✓

+Warfarin…

No monitoring

Few interactions

Short onset/offset

Reversible

Efficacious

Safe

X

X

X

✓

✓

✓

+The direct oral anticoagulants…

No monitoring

Few interactions

Short onset/offset

Reversible

As efficacious

As safe

✓

✓

✓

X

?

?

+New anticoagulants

Leung, The Hematologist, 2011

+New (direct) oral anticoagulants

Predictable pharmacokinetics

No need for monitoring

Less interactions with medications and food

Direct thrombin inhibitors

Dabigatran

Factor Xa inhibitors

Rivaroxaban

Apixaban

Extensively studied in atrial fibrillation (and now DVT/PE!)

+

+

+

+

Drug Inhibitor of LMWH

bridging

Recurrent VTE Bleeding

Rivaroxaban Factor Xa No Non-inferior Non-inferior

Dabigatran Direct

thrombin

Yes Non-inferior Non-inferior

Apixban Factor Xa No Non-inferior Decreased

PHARMACOKINETIC PROPERTIES AND

NEW ANTICOAGULANTS

PropertyNew Anticoagulants

Dabigatran Rivaroxaban Apixaban

Bioavailability

(F rel)6.5% 80% 80%

Peak action

(t max)1-3 hrs 1-3 hrs 1-3 hrs

Elimination

half-life (t ½)14-17 hrs

9-15 hrs 9-14 hrs

Route of

clearance80% renal 65% renal 25% renal

+Direct oral anticoagulants

As good and as effective as LMWH/warfarin for acute VTE

May be trend towards less bleeding

Specifically, less intracranial bleeding

May not have to use LMWH bridging (rivaroxaban, apixaban)

Caveats:

No antidote… except dabigatran

Still some drug interactions

Cost

Need adequate creatinine clearance (>30 mL/min)

Not known how they work in pregnancy - AVOID

+Dosing

Rivaroxaban*

15 mg BID x 3 weeks, then 20 mg daily

Apixaban*

10 mg BID x 1 week, then 5 mg BID

Dabigatran

LMWH x 10 days, then dabigatran 150 mg BID

All are around $3 per day

*Covered by Pharmacare for 6 months only

+Case

She goes on a DOAC and does well with it

However, she develops abdominal discomfort and weight loss,

and is referred to gastroenterology, who wish to perform upper

and lower endoscopy

How should her DOAC be managed for the procedure?

+Perioperative management of direct

oral anticoagulants

Based on three major factors:

Elimination half life of the drug

Renal function

Bleeding risk of surgery (and type of anaesthesia)

+PHARMACOKINETIC PROPERTIES AND NEW

ANTICOAGULANTS

Property

New Anticoagulants

Dabigatran Rivaroxaban Apixaban

Bioavailability

(F rel)6.5% 80% 80%

Peak action

(t max)1-3 hrs 1-3 hrs 1-3 hrs

Elimination

half-life (t ½)14-17 hrs

9-15 hrs 9-14 hrs

Route of

clearance80% renal 65% renal 25% renal

+Pre-op

+Perioperative management of new

anticoagulants

In practice (what we do)…

Stop all new agents 2 days before (last dose 3 days prior) if

creatinine clearance is adequate (>50 ml/min)

Based on the fact that all agents have elimination half lives <17

hours

Can stop 1 day prior for low bleeding risk surgery

+Post-op

Option to use low dose dabigatran or bridging LMWH is felt full dose NOAC to be delayed

+Case

6 months later, she has had significant improvement in leg

swelling and resolution of her pain

No signs of significant post-thrombotic syndrome

She leads an active lifestyle, and wants to get off blood

thinners

Aware of risk of recurrent events

Wants to play ultimate and soccer again!

Can she stop anticoagulation?

+Duration of anticoagulation

Provoked DVT/PE

3 months and then stop (grade 1B)

<1% per year risk of recurrent events

Unprovoked DVT/PE

3 months minimum (grade 2B – in Canada, most treat 6 months)

If high bleeding risk, consider stopping

If low bleeding risk, consider long term anticoagulation

Risk of recurrence ~12-15% in the first year

2nd unprovoked DVT/PE

Lifelong anticoagulation

Chest guidelines, 2012

+Summary

VTE is common and has a high mortality

DOACs have growing body of evidence for acute and long term

treatment of DVT/PE

Three agents currently approved

Duration of anticoagulation a controversial area

3 months and stop for provoked events

3-6 months and consider continuation for unprovoked events

+Thank you!