New Developments in VTE Treatment

Transcription

1 Disclosures: Accommodation at this meeting funded by Boehringer Investigator in phase III studies of Rivaroxiban, Dabigatran, Edoxaban New Developments in VTE Treatment GPCME meeting, August, Dunedin Dr Mark Smith Haematologist CDHB Christchurch

2 Clotting factor production & Warfarin effect

3 Clotting Protein Structure and Inhibitory Drugs Factor Xa Thrombin Rivaroxaban (Bayer-Schering) Dabigatran (Boehringer) Edoxaban (Daiichi Sankyo) Apixaban (BMS, Pfizer) Lane DA et al. Blood 2005;106:

4 Pathway to clot XII VII XI IX VIII X V II I (fibrin clot)

5 Pathway to clot XII VII XI IX VIII X V II I (fibrin clot)

6 Pathway to clot XII VII XI IX VIII X V II I (fibrin clot)

7 Pathway to clot XII VII XI IX Proteins C & S Anti-thrombin VIII X V II Rivaroxiban Dabigatran I (fibrin clot)

8 Pathway to clot XII VII XI IX Proteins C & S Anti-thrombin VIII X V II Rivaroxiban Dabigatran I (fibrin clot)

9 NOAC v warfarin Efficacy Safety Photo: Art Widak, Dublin,

10 NOAC v warfarin Efficacy Safety Van Der Hulle et al. J Thromb Haemostat. 2014;12:

11 Major Bleeding Dabigatran 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:

12 NOAC safety in renal failure: 9 Phase III studies, NOAC v warfarin, n=12,272 Efficacy Lega et al. J Thromb Haemostat. 2014;12:

13 NOAC safety in renal failure: 9 Phase III studies, NOAC v warfarin, n=12,272 Safety Lega et al. J Thromb Haemostat. 2014;12:

14 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 MI renal function no antidote GI symptoms Thorne et al. Int Med J. 2014;44:261-65

15 GP referral: Male, 46 years Duration 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?

16 GP referral: Male, 57 years Duration of anticoagulation? PE February 2014, unprovoked Past history: Meds: High grade lymphoma 1972 GORD, HTN, chronic fatigue Quetiapine, omeprazole, cilazapril, bendrofluazide, citalopram Uncertain if thrombophilia screen done, to help with decision about long tem anticoagulation Duration of anticoagulation?

17 Cumulative VTE recurrence rate after first unprovoked VTE (95% confidence interval) Eichinger S et al. J Am Heart Assoc 2014;3:e000467

18 Male, 48 years Adjusting anticoagulation to fit lifestyle Motorbike enthusiast Pulmonary Embolism 2013, unprovoked Duration of anticoagulation?

19 Male, 48 years Adjusting 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?

20 Is there a role for D-dimer testing? Cosmi et al. BLOOD 2010;115:

21 GP referral: Female, 42 years Duration 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?

22 Risk of recurrence of estrogen-associated VTE: a prospective cohort study HRT 17% 7% 18% 14% Anticoagulant stopped Eischer et al. J Thrombosis Haemostasis 2014;12(5):

23 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

24 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

25 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

26 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

27 Annual recurrence rate calculation: DASH score: D dimer, Age, Sex and Hormone use Tosetto et al. J Thrombosis and Haemostasis 2012;6:

28 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

29 Optional additional slides: 2 NEJM 2013

30 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

31 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

32 New Developments in VTE Treatment Summary: 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

33 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

34 Thank you Enjoy your meeting Enjoy Dunedin