Dr Eileen Merriman - GP CME north/Fri_Room7_1630... · Patients with PE and proximal DVT included Dalteparin 200 IU/kg for one month then 150 IU/kg daily for months 2-6 versus rivaroxaban

Dr Eileen MerrimanClinical Haematologist & Lead Thrombosis

Clinician Dept of Haematology

Waitemata DHB

16:30 - 17:25 WS #82: Case Studies on Venous Thromboembolism Using Direct Oral Anticoagulants

17:35 - 18:30 WS #94: Case Studies on Venous Thromboembolism Using Direct Oral Anticoagulants

(Repeated)

CASE STUDIES IN VENOUS

THROMBOEMBOLISM USING DIRECT ORAL

ANTICOAGULANTS

Dr Eileen Merriman

Haematologist

North Shore Hospital

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwj5hpjDkt_eAhUZWX0KHf_nDYgQjRx6BAgBEAU&url=https://www.cartoonstock.com/directory/h/haematologist.asp&psig=AOvVaw3jlYeg-vL7N2LY4Hb5gJc1&ust=1542671819486598

CA S E 1

Mrs MC, age 76 years

Bilateral extensive unprovoked PE

PHx: Hypertension, GORD

Creatinine clearance 56 ml/min

Weight 49kg

Suggested treatment?

CASE 1: TREATMENT

(a) Warfarin, INR 2-3

(b) Rivaroxaban 15mg BD for 3 weeks, then 20mg daily

(c) LMWH for 5 days then dabigatran 150mg BD

(d)LMWH for 5 days then dabigatran 110mg BD

Weitz J. Thromb Haemost 2010; 103:62-70.

WARFARIN – THE END OF AN ERA?

Adapted from Weitz J. Thromb Haemost 2010; 103:62-70.

IdaracizumabAndexanet alfa † Andexanet alfa†

† Not registered in New Zealand.

Schulman et al NEJM 2009; 361:2342-52

RECOVER I: Dabigatran versus warfarin for

acute VTE

The Einstein Investigators, NEJM 2010.

The Einstein-PE Investigators NEJM 2012

Significant reduction in

major bleeding

in rivaroxaban group; 1.1%

vs 2.2% in standard therapy

(VKA) group

(HR 0.49; 95% CI 0.31-0.79;

p=0.003)

Connolly et al. NEJM 2009; 361: 1139-51

CASE 1: TREATMENT





CA S E 1: TR E A T M E N T

But considering history of GORD…





CASE 2

Mr PW, age 85 years

Intracranial haemorrhage one year ago thought secondary to

hypertension

Now presents with idiopathic ileofemoral DVT


Treatment?

CASE 2: TREATMENT





DIRECT ORAL ANTICOAGULANTS AND ICH

Chatterjee et al. JAMA Neurol 2013; 70(12):1486-1490

DA B IG A T R A N A N D B L E E D IN G

Idaricuzimab (Praxbind): monoclonal antibody, provides immediate reversal of

dabigatran anticoagulant effect

Indicated in setting of life-threatening or uncontrolled bleeding, or when

emergency surgery or urgent procedures are required

Minor bleeding: use local haemostatic measures; delay next dose of dabigatran

or discontinue if appropriate

Pollack CV et al. NEJM 2017;377:431-41

RIVAROXABAN AND BLEEDING/REVERSAL

Xandexanet not commercially available in New Zealand

In general, manage as for bleeds on Clexane: reversal not usually

required due to short half life

If prothrombin ratio normal (at least in hospitals around

Auckland), then no/very little residual rivaroxaban

If <24 hours post dose rivaroxaban and critical site

surgery/procedure can also ask for anti-Xa assay to confirm

RIV A R O X A B A N A N D BL E E D IN G

Can use PCCs (e.g. prothrombinex) or FEIBA for life-threatening

bleeding, bleeding in a critical organ or need for urgent

intervention associated with bleeding

Four-factor PCCs given at approx 25U/kg shown effective in 69% of

patients in one study*

In vitro studies have shown FEIBA to be superior to PCCs in vivo

for restoration of haemostasis

Charcoal can be used if <6 hours post ingestion

Please contact haematologist on call for advice

*Blood. 2017 Oct 12;130(15):1706-1712

https://www.ncbi.nlm.nih.gov/pubmed/28835439

XA N D E X A N E T

Recombinant modified human factor Xa decoy protein

Bolus followed by continuous infusion

Recently published trial: 352 patients with acute major

bleeding within 18 hours after FXa inhibitor

administration

64% of enrolled patients had ICH; 26% GI bleeding

Excellent or good haemostasis in 82%

30-day mortality 14%; 30-day thrombotic events in 10%

(compared with 4.8% at 90 days in REVERSE-AD trial

with idarucizumab)

FDA approved in US with black box warning for

thrombotic events/sudden death

Connolly et al NEJM 2019; 380:1326-1335

CASE 2: TREATMENT





CA S E 3

Mrs MK, 93 years old

Bilateral extensive PE

Creatinine 93 micromol/L

Weight 45kg

Treatment?

CASE 3: TREATMENT





WHAT IS MRS MK’S CREATININE CLEARANCE?

Using Cockcroft-Gault: 23.73 ml/min

Dabigatran and rivaroxaban can only be used if CreCl ≥ 30 ml/min

CASE 3: TREATMENT





WH E N W O U L D N ’T Y O U U S E A DOAC*?

Mechanical heart valve

Antiphospholipid syndrome

Cre Cl <30ml/min

Poor compliance (shorter half-life less forgiving)

*DOAC = direct oral anticoagulant

CA S E 4

Mrs LM, age 42yr

Breast cancer; for mastectomy

Incidental finding of segmental PE on CT staging scan

Patient is asymptomatic (no shortness of breath or chest pain)


Treatment?

CASE 4: TREATMENT

(a) No treatment required as patient as patient is asymptomatic

(b) Clexane 1.5 mg/kg daily for one month then reduce to 1mg/kg

once daily

(c) Rivaroxaban 15mg BD for 3 weeks then 20 mg daily

(d) Warfarin with INR 2-3

(e) LMWH 1.5mg/kg daily for 5 days then dabigatran 150mg BD

CLOT TRIAL

Lee et al. NEJM 2003; 349(2):146-153

Lee et al. NEJM 2003; 349(2):146-153

RIVAROXABAN AND MALIGNANCY

Select-D Trial: multicentre, open-label randomised controlled pilot

trial

Patients with PE and proximal DVT included

Dalteparin 200 IU/kg for one month then 150 IU/kg daily for

months 2-6 versus rivaroxaban 15mg BD for 3 weeks then 20mg

once daily

Primary outcome = VTE recurrence over 6 months

203 assigned to each arm, 58% of whom had metastastic disease

Young et al. J Clin Oncol 36: 2017-2023


Major bleeding rate at 6 months: 4%(95% CI 2-8%) for dalteparin

versus 6% (95% CI 3-11%) for rivaroxaban


SE L E C T -D: BL E E D IN G

Most major bleeding events gastrointestinal (GI)

No CNS bleeds

Patients with oesophageal or gastro-oesophageal cancer tended to

experience more major bleeds with rivaroxaban than with

dalteparin – 4/11 (36%) versus 1 of 19 (11%)

More CRNMB* with rivaroxaban (13%) versus dalteparin (4%) ;

most GI or urologic

*Clinically relevant non-major bleeding Young et al. J Clin Oncol 36: 2017-2023

CASE 4: TREATMENT

(a) No treatment required as patient is asymptomatic

(b) Clexane 1.5 mg/kg daily for one month then reduce to 1mg/kg

once daily




CASE 5

Mr GJ, age 56 years

Oesophageal cancer, unresectable (stented)

Estimated life expectancy no greater than 3 months

Diagnosed with DVT femoral vein


Treatment?

CA S E 5: TR E A T M E N T

(a) No treatment required as patient is palliative

(b) Clexane 1.5 mg/kg daily for one month then reduce to

1mg/kg once daily




CASE 6

Ms ML, age 34 years

Admitted with swollen right leg; also severe vertigo past few days

Known triple positivity APL antibodies: aCL IgG 126 GPL, β2GP

156 G units (found during infertility work-up)

No previous history of thrombosis

CASE 6

USS right leg: extensive ileofemoral DVT

MRI: small recent infarcts right parietal lobe and cerebellar

hemisphere; white matter changes in right occipital lobe and both

cerebellar hemispheres

Diagnosis: antiphospholipid syndrome with arterial and venous

thrombosis

CASE 6: TREATMENT

(a) Aspirin 100mg daily

(b) Rivaroxaban 15mg BD for 3 weeks then 20 mg daily

(c) Warfarin with INR 2-3

(d) LMWH 1.5mg/kg daily for 5 days then dabigatran 150mg BD

Pengo et al Blood 2018; 132: 1365-1371

CASE 6: TREATMENT

(a) Aspirin 100mg daily

(b) Rivaroxaban 15mg BD for 3 weeks then 20 mg daily

(c) Warfarin with INR 2-3

(d) LMWH 1.5mg/kg daily for 5 days then dabigatran 150mg BD

CA S E 7

Mr MS, 43 year old, left femoral DVT one week after flight from

London to Auckland

Has now completed six months of treatment with rivaroxaban; still

on 20mg daily

Repeat USS left leg shows small amount residual thrombus

No residual leg symptoms

?Treatment from this point

CASE 7

(a) Stop treatment as provoked by air line travel

(b) Continue on rivaroxaban 20mg daily

(c) Reduce rivaroxaban to 10mg daily

(d) Refer for catheter directed thrombolysis of residual thrombus

AIR TRAVEL AND VTE

Risk very small

27 PE per million flights and 0.05% DVT through screening

ultrasounds; most DVT muscular vein (calf vein) thrombosis

Risk significantly increased for flights ≥6-8 hours

Most patients have pre-existing risk factors

Prolonged sitting in cramped quarters, hypoxia, low humidity

1626 consecutive patients who discontinued anticoagulation

after first episode of symptomatic proximal DVT or PE

Prandoni et al. Haematologica 2007;92:199-205

DU R A T IO N O F TR E A T M E N T

3-6 months for those with VTE provoked by

transient risk factors

For those with permanent risk factors such as

active cancer: indefinite anticoagulation

For first idiopathic proximal DVT or PE: ACCP

guidelines recommend extended treatment for

those with low to moderate risk of bleeding

Antiphospholipid syndrome and proximal DVT

or PE: indefinite treatment

Kearon et al Chest 2016; 149(2):315-52.

Primary efficacy outcome

occurred in 1.5% of patients

on 20mg rivaroxaban,

1.2% on 10mg rivaroxaban

and 4.4% on aspirin

NEJM 2017;376:1211-22

Rates of major bleeding

0.5% in 20mg rivaroxaban

group, 0.4% in 10mg riva

group and 0.3% in

aspirin group

EINSTEIN CHOICE

Trial

BCC8661BCC8661

CASE 7

(a) Stop treatment as provoked by air line travel

(b) Continue on rivaroxaban 20mg daily

(c) Reduce rivaroxaban to 10mg daily

(d) Refer for catheter directed thrombolysis of residual thrombus

SUMMARY

Venous thromboembolism (idiopathic) is a chronic illness

DOACs are at least as efficacious for VTE treatment/prevention and SPAF, with an improved safety profile

DOACs can be used in selected patients with cancer-associated thrombosis

DOACs contraindicated in patients with mechanical heart valves and antiphospholipid syndrome

Warfarin and dabigatran should be used in patients with significant risk factors for bleeding due to reversibility

https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=2ahUKEwjSl9D6mN_eAhWcgUsFHe0BChoQjRx6BAgBEAU&url=https://www.jsuttondesign.co.uk/a-kids-guide-to-cancer&psig=AOvVaw0xgHDIy9i-R0br0hbkiT8H&ust=1542673550736076

Documents

Dr Eileen Merriman - GP CME north/Fri_Room7_1630... · Patients with PE and proximal DVT included Dalteparin 200 IU/kg for one month then 150 IU/kg daily for months 2-6 versus rivaroxaban