New Developments

in

VTE Treatment

GPCME meeting, August, Dunedin

Dr Mark Smith

Haematologist

CDHB Christchurch

Disclosures:

• Accommodation at this meeting funded by Boehringer

• Investigator in phase III studies of Rivaroxiban, Dabigatran, Edoxaban

Clotting factor production & Warfarin effect

Clotting Protein Structure and Inhibitory Drugs

Lane DA et al. Blood 2005;106:2605-2612

ThrombinFactor Xa

Rivaroxaban (Bayer-Schering)

Edoxaban (Daiichi Sankyo)

Apixaban (BMS, Pfizer)

Dabigatran (Boehringer)

Pathway to clot

XII

XI

I (fibrin clot)

II

X

VII

IX

VIII

V

Pathway to clot

XII

XI

I (fibrin clot)

II

X

VII

IX

VIII

V

Pathway to clot

XII

XI

I (fibrin clot)

II

X

VII

IX

VIII

V

Pathway to clot

XII

XI

I (fibrin clot)

II

X

VII

IX

DabigatranAnti-thrombin

VIII

VProteins C & S

Rivaroxiban

Pathway to clot

XII

XI

I (fibrin clot)

II

X

VII

IX

DabigatranAnti-thrombin

VIII

VProteins C & S

Rivaroxiban

NOAC v warfarin

Photo: Art Widak, Dublin,

Ireland

Efficacy

Safety

NOAC v warfarin

Van Der Hulle et al. J Thromb Haemostat. 2014;12:320-328

Efficacy

Safety

Major BleedingDabigatran or Warfarin

• 1121 major bleeds in 1034 patients in 5 phase III studies

• 27,419 patients

• Dabigatran bleeds:

• 627 of 16,755 (3.74%) (warfarin 4.07%)

• Older (75 years v 71 years)

• lower CrCl (53 v 62)

• more use of aspirin (32 v 24%)

Majeed et al. Circulation. 2013;128:2325-2332

NOAC safety in renal failure:

9 Phase III studies, NOAC v warfarin, n=12,272

Lega et al. J Thromb Haemostat. 2014;12:337-343

Efficacy

Lega et al. J Thromb Haemostat. 2014;12:337-343

Safety

NOAC safety in renal failure:

9 Phase III studies, NOAC v warfarin, n=12,272

Routine Clinical Practise Experience

• Patient selection from Hutt Hospital and two primary

care practices, July 2011 – April 2012

• n=92

• At median of 8 months, 70% still taking Dabigatran

• Different from RE-LY at 12 months (p=0.0002)

• Commonest reason for discontinuation GI side effects

• Majority stopped within a few days

• SAE rate for Dabigatran low

Thorne et al. Int Med J. 2014;44:261-65

GI symptomsno antidote

renal function

MI

GP referral:

Male, 46 yearsDuration of anticoagulation?

• Right leg DVT 2013, provoked, 3/12 Rivaroxiban

• Heterozygous FV Leiden

• Now presents with recurrent right leg DVT

provoked by flight from Japan

• Duration of anticoagulation?

GP referral:

Male, 57 yearsDuration of anticoagulation?

• PE February 2014, unprovoked

• Past history:

• High grade lymphoma 1972

• GORD, HTN, chronic fatigue

• Meds:

• Quetiapine, omeprazole, cilazapril, bendrofluazide,

citalopram

• Uncertain if thrombophilia screen done, to help

with decision about long tem anticoagulation

• Duration of anticoagulation?

Eichinger S et al. J Am Heart Assoc 2014;3:e000467

Cumulative VTE recurrence rate after first unprovoked VTE(95% confidence interval)

Male, 48 yearsAdjusting anticoagulation to fit lifestyle

• Motorbike enthusiast

• Pulmonary Embolism 2013, unprovoked

• Duration of anticoagulation?

Male, 48 yearsAdjusting anticoagulation to fit lifestyle

• Motorbike enthusiast

• Pulmonary Embolism 2013, unprovoked

• Duration of anticoagulation?

• Recommended life long warfarin• Declined, stopped warfarin after 6 months

• MVA Jan 2014 (2 months after stopping warfarin)

• Is it safe to remain off anticoagulation?

• Is there a role for D-dimer testing?

Is there a role for D-dimer testing?

Cosmi et al. BLOOD 2010;115:481-488

GP referral:

Female, 42 yearsDuration of anticoagulation?

• Female, 42 years, mother of two (6 and 2 years)

• PE 2013, unprovoked (on OCP)

• Past history:• Polycystic Ovary Syndrome

• Meds:• OCP, spironolactone, metformin, nattokinase (a Japanese soy

extract remedy purported to have fibrinolytic activity)

• ACCP estimated risk:• 10% clot recurrence over 2 years

• Duration of anticoagulation?

• Was the use of estrogen relevant?

Risk of recurrence of estrogen-associated VTE:

a prospective cohort study

Eischer et al. J Thrombosis Haemostasis 2014;12(5):635-640

Anticoagulant

stopped

17%

7%

18%

14%

HRT

D-dimer after first unprovoked VTE:

clot recurrence rate

• Methods: patients <75 years (n=410, 51 years, 44% females), D-dimer while on anticoagulants, and 1 month after stopping.

• Results: 318 remained off anticoagulant therapy; recurrence rate: 5.6% per year

Kearon et al, ISTH 2013

D-dimer after first unprovoked VTE:

clot recurrence rate

• Methods: patients <75 years (n=410, 51 years, 44% females), D-dimer while on anticoagulants, and 1 month after stopping.

• Results: 318 remained off anticoagulant therapy; recurrence rate: 5.6% per year

• Males: 8.2% per year

• Females: 3.9% per year (initial VTE not associated with estrogens)

• Females: 0% per year (initial VTE associated with estrogens)

Kearon et al, ISTH 2013

D-dimer after first unprovoked VTE:

clot recurrence rate

• Methods: patients <75 years (n=410, 51 years, 44% females), D-dimer while on anticoagulants, and 1 month after stopping.

• Results: 318 remained off anticoagulant therapy; recurrence rate: 5.6% per year

• Males: 8.2% per year

• Females: 3.9% per year (initial VTE not associated with estrogens)

• Females: 0% per year (initial VTE associated with estrogens)

• Conclusion: negative D-dimer does not justify stopping anticoagulants after 3-7

months in men

• Risk of recurrent VTE in women low enough to justify stopping anticoagulants

after 3-7 months.

Kearon et al, ISTH 2013

5 year recurrence rate calculation:from 3 weeks after end of anticoagulation (baseline) by use of sex, location of venous

thromboembolism, and d‐dimer

Eichinger S et al. J Am Heart Assoc 2014;3:e000467

http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-

software/recurrent-vte/

Annual recurrence rate calculation:DASH score: D‐dimer, Age, Sex and Hormone use

Tosetto et al. J Thrombosis and Haemostasis 2012;6:1019-1025

Optional additional slides: 1

• Female, 74 years• Atrial fibrillation

• Systolic murmur

• Echo shows:• Mild-moderate AS

• Mild-moderate MR

• Trivial TR

• Should a NOAC be prescribed?

• “Valvular AF”:• Prosthetic mitral valve

• Mitral stenosis

NEJM 2013

Optional additional slides: 2

Optional additional slides: 3

• What is the landscape for SVT?

• 171 cases annually (incidence 0.64%)

• Concomitant DVT: 24%

• Concomitant PE: 5%

Frappe et al. J Thrombosis and Haemostasis 2014;12:831-8

Optional additional slides: 4

• Association between thyroxine and VTE:

• High FT4 associates with increased clot factors

• Natural anticoagulants unchanged

• High FT4 associates with increased clot risk

• Clinical hyperthyroidism: OR of 17%

Debij et al. J Thrombosis and Haemostasis 2014;12:839-46

New Developments in VTE TreatmentSummary:

• NOACs are safe and effective

• Beware vulnerable patients:

• >75 years, < 50kg, CrCl < 30ml/min (ABC)

• Concurrent aspirin use

• Clot recurrence risk is influenced by:

• Clot provocation (including OCP), gender, d-dimer, age

• Relevance of thrombophilia testing:

• Consider for age less than 40 years

• Consider for pregnancy loss

Pregnancy matters

• 42 Argentine males from couples with unexplained recurrent pregnancy loss

• FV Leiden compared to male controls

• 16% v 3%, OR 6.5% (95% CI 2-20)

Udry et al. J Thrombosis Haemostasis 2014;12(5):666-9

Thank you

Enjoy your meeting

Enjoy Dunedin…