Venous thromboembolism (VTE) Can Biomarkers Help to Guide Duration of Therapy After VTE? New Chest Guidelines 2016

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1 Venous thromboembolism (VTE) Can Biomarkers Help to Guide Duration of Therapy After VTE? Marlene Grenon, MD Associate Professor of Surgery University of California San Francisco UCSF Vascular Surgery Symposium 2016 VTE is the 3 rd most frequent CV disease 1 case per 1000 person-years Most frequent site is DVT in the legs 1/3 of patients suffering from a 1 st episode of VTE develop recurrence within 10 years Management options are changing: LMWH-> Vit K antagonist direct oral anticoagulants Abuldstrom et al, Heart 2003; Ferreieres et al, Am J Cardiol 1995; Ellkjaer et al, Stroke 1997; Kyrle et al, Lancet 2005; Naess et al, J Thromb Haemost 2007; Shulman et al, J Thromb Haemost New Chest Guidelines 2016 Non-vitamin K antagonist oral anticoagulants (NOACs) are suggested over warfarin for initial and long-term treatment of VTE in patients without cancer. Since publication of the 9th edition, new studies show that NOACs are as effective as VKA therapy with reduced risk of bleeding and increased convenience for patients and health-care providers. How Long to Treat with Anticoagulants? VTE (proximal DVT or PE) provoked by surgery: Recommend 3 months VTE (proximal DVT or PE) provoked by non-surgical transient risk factor (e.g. estrogens, pregnancy, leg injury, flight > 8 hrs): Suggest 3 months Unprovoked VTE (proximal DVT or PE): Suggest at least 3 months, then reevaluate for risk/benefit Recurrent VTE Suggest extended treatment (no stop date) over 3 months ***consider bleeding risk in decision Chest

2 Can Biomarkers Aid in Deciding on the Treatment Duration? Decrease risk of VTE recurrence Decrease risk of bleeding from anticoagulation D-Dimers Endogenous Thrombin potential CRP and other inflammatory markers Clotting Factor VIII Fibrin degradation product Small protein fragment present in the blood after clot degraded by fibrinolysis Name because it contains two crosslinked D fragments of the fibrin protein D-Dimers For diagnosis of DVT D-Dimers Sensitivity 96% but low specificity (40%) and PPV (48%) Associated with an increased risk of recurrent VTE Relative risk 2.19, 95% CI At 2 years: <250 ng/ml (3.7%) vs > 250 ng/ml (11.5%) Rectenwald et al, Thromb Haemost 2005; Wakefiled et al, Art Thromb Vasc Biol patients with first unprovoked DVT D-dimer testing 1 month after the discontinuation of anticoagulation. Normal d-dimer level -> not resume anticoagulation Abnormal d-dimer level -> randomly assigned either to resume or to D/C tx ** testing for antiphospholipid antibody + antithrombin deficiency-> if positive: excluded from further analysis Study outcome: composite of recurrent venous thromboembolism and major bleeding Average follow-up of 1.4 years 2

3 Patients with an abnormal d-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. Recurrence of DVT- Vienna Prediction Model 30% risk of recurrence over 10 years D-Dimers may be useful in guiding the decision on duration Patients with an abnormal d-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous of thromboembolism, oral anticoagulation which is reduced for secondary by the resumption VTE prophylaxis of anticoagulation. Eichinger et al, Vasc Med

4 Recurrence of DVT- Vienna Prediction Model Recurrence of DVT- Vienna Prediction Model Eichinger et al, Vasc Med 2010 Eichinger et al, Vasc Med 2010 Endogenous Thrombin Potential Thrombin generation test thrombin potential endogenous thrombin potential Information about the catalyst of the main reaction transformation of fibrinogen into fibrin Calculates free thrombin generation The power of thrombin = The man hours of thrombin activity HC Beguin, CRIM, Netherlands = The area Under the TG-curve = Endogenous Thrombin Potential (ETP) 4

5 Member of selectin family of cell adhesion molecules, stored in the alpha granules of platelets and Weibel- Palade bodies of ECs receptor (PSGL-1) expressed in platelets and mediates plateletendothelium interaction, fibrin formation and thrombus growth Important molecule in hemostasis and thrombosis Elevated in acute DVT and recurrent DVT LETS Study (Leiden Thrombophilia Study) Elevated s 6 months after DVT compared to controls (odds ratio 2.1, CI ) Elevated in acute DVT and recurrent DVT LETS Study (Leiden Thrombophilia Study) Elevated s 6 months after DVT compared to controls (odds ratio 2.1, CI ) reflects a pro-thrombotic state but clinical applicability of measurements need to be standardized and investigated in interventional trials. Blann et al, Vr J Haem 2000; Ay et al, Clin Chem 2007; Kyrle et al, Thromb Hemo

6 Inflammatory cytokines: CRP Small amount of studies Inflammatory cytokines: Others IL 1-B, IL6, IL8, IL10, IL 12p70, TNF CRP: sensitivity 77% specificity 66% Reviewed in Fox et al, Thromb Hemo 2005 and Pabinger et al, Art Thromb Vasc Biol 2009 Reviewed in Fox et al, Thromb Hemo 2005 and Pabinger et al, Art Thromb Vasc Biol 2009 Inflammatory cytokines: Others IL 1-B, IL6, IL8, IL10, IL 12p70, TNF Clotting Factor VIII + Other Clotting Factor VIII: Small number of studies Genetically determined ABO blood group system May be predictor BUT interventional trials needed Increased inflammatory cytokines may not constitute an independent risk marker for future VTEfurther research needed Reviewed in Fox et al, Thromb Hemo 2005 and Pabinger et al, Art Thromb Vasc Biol 2009 Other biomarkers also needing further investigations: E-Selectin Micro-Particles 6

7 Conclusion Can Biomarkers Help to Guide Duration of Therapy After VTE? YES Ongoing data support the use of biomarkers to predict recurrence risk + guide length/modality of treatment Most promising: D-Dimers, ETP More data needed:, E-Selectin, Micro- Particles Updated Vienna Model time prediction 7