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All things thrombosis

All things thrombosis. Julie Wang Thrombosis Fellow. VTE is chronic disease. Recurrence rate after initial VTE up to 24.6% after 5 years Clinical need to identify individuals at increased risk of recurrent VTE. VTE terminology. Provoked – surgery 3% recurrence at 5 years

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All things thrombosis

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  1. All things thrombosis Julie Wang Thrombosis Fellow

  2. VTE is chronic disease • Recurrence rate after initial VTE up to 24.6% after 5 years • Clinical need to identify individuals at increased risk of recurrent VTE

  3. VTE terminology • Provoked – surgery • 3% recurrence at 5 years • Minimally 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

  4. Other deep veins • Superficial femoral vein • Gastrocnemius • Soleal • Peroneal

  5. Duration of anticoagulation - proximal DVT and PE • Proximal = Above or involving popliteal vein • Minimum period is 3 months for all patients • After 3 months for unprovoked DVT/PE • Assess risk/benefit of indefinite therapy

  6. Risk factors for recurrent VTE Ref3

  7. Ref2

  8. DASH score

  9. Methods • Retrospective analysis of medical records at single institution • Patients with discharge diagnosis of DVT/PE between January 2013 and June 2015 • D-dimer assay Innovance D-dimer; Normal <500ng/mL • Presence of residual thrombus defined by reporting radiologist

  10. Total reviewed patients N = 443 No post-AC D-dimer testing N = 342 Post-AC D-dimer tested N = 101 Male N = 41 Female N = 60

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

  12. RR 5.0, 95%CI 1.7-14.5; p=0.003

  13. Anticoagulation was recommenced for 11 patients with elevated D-dimer • >1000ng/mL = 8 patients • 500-1000ng/mL = 3 patients • Patients with recurrent VTE = 0 • Bleeding complications = 0

  14. Table 1 – VTE recurrence stratified by D-dimer

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

  16. Table 4 – Effect of D-dimer & residual thrombus on risk of recurrent VTE 3 patients did not have repeat imaging Normal DD & no residual thrombus vs rest of patients p = 0.006; RR 0.09 (CI 0.01 – 0.67 p=0.02)

  17. 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.

  18. RIETE score

  19. Choice of anticoagulant • NOAC is now preferred over warfarin as: • Efficacy is non-inferior to warfarin in multiple large RCTs • Lower risk of bleeding, esp intracranial • Convenient to take • No direct comparison between NOACs but indirectly, efficacy appears similar

  20. Dabigatran

  21. Rivaroxaban, Apixaban

  22. Approved and Funded Indications Phase 3 data PBS Funding

  23. Drug characteristics

  24. ROCKET-AF RELY ARISTOTLE

  25. NOAC Bleeding Rates – Real-world data Lip et al Int J ClinPract 2016;1-12

  26. Lab Assays • No 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

  27. APTT - Dabigatran

  28. Thrombin time vs plasma dabigatran TT (seconds)) Dabigatran concentration (ng/mL) 60ng/mL Hapgood J et al. Thromb Hemost 2013

  29. Haemoclot assay • Modified TT • Citrate plasma • Diluted with saline • Diluted pool plasma • Add thrombin Van RynJ.ThrombHemost 2010;103:1116-22

  30. Assessing Dabigatran levels • TCT (thrombin clotting time) – available at TNH 24/7 • Haemoclot (dilute TCT) = drug level - Not done here – turnaround time ~24h • PT and INR – not useful APTT normal TCT normal = minimal/no drug APTT normal TCT prolonged = likely low drug levels Both prolonged = significant drug activity

  31. Lab Assays • Rivaroxaban • 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

  32. 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.

  33. Management of Bleeding Tran et al, 2014

  34. 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

  35. On the horizon… • ANNEXA-A – andexanet alfa • Recombinant 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

  36. Drug interactions Tran et al, 2014

  37. Perioperative management

  38. 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?).

  39. Who I wouldn’t put on a NOAC… • Absolute contraindicated • CrCl <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.

  40. Key Points for NOACs • NOAC is non-inferior to warfarin in non-valvular AF and VTE • It 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.

  41. NOAC iGuidance

  42. Isolated distal DVT • Not great evidence and unclear guidelines • 33% 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 DVT • Risk of recurrence 50% of proximal DVT/PE

  43. Isolated distal DVT • Suggested risk factors for extension • Positive D-Dimer • >5cm length, multiple veins involved • Close to proximal veins • Unprovoked • Active cancer • History of VTE • Inpatient status

  44. Isolated distal DVT • If elect to anticoagulate– full dose anticoagulation as per proximal DVT • Duration is uncertain – 6 weeks? 3 months?

  45. NOACs not PBS approved for SVT

  46. VTE and cancer • LMWH • RCTs have shown LMWH more effective than warfarin in active cancer • More reliable if difficulty with oral therapy eg vomiting • Easier to withold if thrombocytopenia or invasive procedures

  47. NOACs in Cancer

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