Warfarin as a new oral anticoagulant Improving stability and outcome - PowerPoint PPT Presentation

Warfarin as a new oral anticoagulant Improving stability and outcome of warfarin by monitoring factors II and X only Results of the Fiix-trial Páll T. Önundarson, M.D. Landspitali - The National University Hospital of Iceland and University of Iceland Faculty of Medicine

Coauthors

How to read data from randomized trials? • Who is the real messenger? • Inclusion/exclusion criteria • Control groups • Absolute rate vs proportional change • Hazard ratios

COI disclosure • Pall Onundarson and Brynja Gudmundsdottir: Hold a patent or the Fiix-prothrombin time –

A reminder: Warfarin is very efficacious! SUPERIORITY VS. NON-INFERIORITY NON-VALVULAR ATRIAL FIBRILLATION ANNUAL CEREBRAL INFARCTION RATE IN ATRIAL FIBRILLATION • Annual cerebral infarction rate reduced by 79% 5 • No anticoag (placebo) 4.3% Placebo 4.5 • Warfarin 0.9% 4 Warfarin 79% 3.5 improvement over placebo 3 10 percent 2.5 improvement over warfarin 2 20 percent 1.5 improvement over warfarin 1 40% improvement 0.5 over warfarin 0 CTE annual rate Ezekowitz, MD et al. NEJM 1992;327:1406-

The efficacy of VKA depends strongly on the quality of warfarin management Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial Lars Wallentin, et al and on behalf of the RE-LY investigators, The Lancet 2010; 376: 975-983 Stroke and systemic embolism incidence Major bleeding incidence in each quartile of centre's mean time in therapeutic range (cTTR): in each quartile of centre's mean time in therapeutic range (cTTR): 6

1990-2014: Marked improvement in warfarin control in the Western world Onundarson PT, Einarsdottir KA, Gudmundsdottir BR. • International standardization of PT Warfarin anticoagulation in Reykjavik in 1992 vs 2006. reporting (INR) Int J Lab Haematol. 2008;30(5):382-9 . • Anticoagulation Management Centers – Specialized staff based dosing instead of private physician • Computer software assisted dosing – Poller et al Lancet 1998 • Self monitoring Self dosing •

Warfarin/coumarins a love-hate relationship • Hate • Love – Slow onset of effect – Well studied and efficacious – Hard to predict initial dose – Controllable anticoagulation – Mutations affect intensity by monitoring metabolism and dose size » VKORC • Therapeutic window is well » CYP450 delineated – adjustable to personal – PT-INR fluctuates needs (titratability) in many patients leading to need for frequent testing and dose – Compliance is measurable adjustments – Immediately reversible – Serious bleeding complications • Immediately with PCC – Needlestick • (Hours FFP) • 12-16 hours vitamin K – Work! – Cheap

Can warfarin treatment be improved in 2015? Even if warfarin is very efficacious… …managing warfarin is trouble • Annual cerebral infarction rate in AF reduced 79% compared to placebo • Dose varies between patients – metabolism • Fluctuating unstable effect (INR) – frequent dose adjustments – frequent testing Ezekowitz, MD et al. NEJM 1992;327:1406-

Why does the effect of warfarin fluctuate? Rephrase: Why does the INR fluctuate ? Common wisdom; Drug problem Test problem: Prothrombin time? • Food interactions • Drug interactions • Compliance problems

Influence of VKA on VKD factors Activity reduced at different Are the VKD factors the same? rate Factor T ½ (hours) • Antithrombotic effect? II 72 VII 4 • How accurately does the PT- IX 18-24 INR reflect the X 24-48 antithrombotic effect? • How does the PT reflect risk of bleeding?

Traditional prothrombin time Undiluted thromboplastin and CaCl 2 80 A Quick Prothrombin time (seconds) 60 FII FX FVII FIX 40 20 0 0.1 1 10 100 Coagulation factor activity (%) Gudmundsdottir BR, Francis CW, Bjornsdottir A, Nellbring M, Onundarson PT . Thromb Res 2012;130:674-81

Correlation of PT/P&P with ROTEM clotting parameters in a dilute thromboplastin experiment 3000 25 80 C A B MaxVel (mm x 100/second) ROTEM CT (seconds) 20 R 2 = 0.08 60 R 2 = 0.11 MCF (mm x 100) 2000 R 2 = 0.27 15 40 10 1000 20 5 0 0 0 1 10 100 1000 1 10 100 1000 1 10 100 1000 Owren prothrombin time % (PP %) Owren prothrombin time % (PP %) Owren prothrombin time % (PP%) Gudmundsdottir BR, Francis CW, Bjornsdottir A, Nellbring M, Onundarson PT . Thromb Res 2012;130:674-81

ROTEM clotting time (CT), Maximum velocity Traditional (MaxVel) and maximum clot firmness (MCF) in relation to progressive reduction of individual prothrombin time vitamin K dependent coagulation factors in PPP Highly diluted thromboplastin Undiluted thromboplastin 15 A FII ROTEM MaxVel (mm x 100/second) FX FVII FIX 10 80 6 000 5 A A Quick Prothrombin time (seconds) FII 0 60 FX 0.1 1 10 100 FII Coagulation factor activity (%) FVII FX ROTEM CT (seconds) 4 000 FIX FVII FIX 40 2 000 20 0 0 0.1 1 10 100 0.1 1 10 100 Coagulation factor activity (%) Coagulation factor activity (%) Gudmundsdottir BR, Francis CW and Onundarson PT, Thromb Res 2012

The PT-INR is not a great indicator of thrombin generation or of the anti-thrombotic effect of VKAs The anti-thrombotic effect depends mainly The PT-INR associates poorly with: on reductions in FII and FX – but not FVII IIa generation • Thrombin generation correlates with FII and less with FX but poorly with factors VII and IX activity – KE Brummel, SG Paradis, RF Branda, KG Mann Circulation 2001;104:2311-17 – Xi M, Béguin S, Hemker HC. Thromb Haemost. 1989 Sep 29;62:788-91 • Induced DIC in rabbits is prevented by reduced FII and FX but not by reduced FVII – A Zivelin, LV Rao and SI Rapaport. J. Clin. Invest. 92: 2131-2140 (1993). • Monitoring warfarin with NPA – Monitoring native FII lead to 85% reduction in major events compared to PT monitoring – Furie B, Diuguid CF, Jacobs M, Diuguid DL, Furie BC. Blood. 1990 ;75:344-9 ROTEM clotting parameters in a dilute • ROTEM experiments with low TF concentration thromboplastin experiment – Gudmundsdottir BR, Francis CW, Bjornsdottir A, Nellbring M, Onundarson PT. Thromb Res 2012;130:674–81. – Gudmundsdottir BR, Francis CW, Bjornsdottir A, Nellbring M, Onundarson PT . Thromb Res 2012;130:674-81 6 000 15 A A FII 3000 25 80 C ROTEM MaxVel (mm x 100/second) A FX B FII FVII MaxVel (mm x 100/second) FX FIX ROTEM CT (seconds) FVII ROTEM CT (seconds) 20 R 2 = 0.08 4 000 FIX 10 60 R 2 = 0.11 MCF (mm x 100) 2000 R 2 = 0.27 15 40 10 5 2 000 1000 20 5 0 0 0 0 0 0.1 1 10 100 0.1 1 10 100 1 10 100 1000 1 10 100 1000 1 10 100 1000 Coagulation factor activity (%) Coagulation factor activity (%) Owren prothrombin time % (PP%) Owren prothrombin time % (PP %) Owren prothrombin time % (PP %)

Hypothesis: During VKA anticoagulation measuring the combined influence of only the stable FII and FX reflects clottability better than does the PT (INR) which is affected also by the short half-life FVII that has little influence on thrombus prevention but confounds VKA dosing

Fiix-PT: Fiixing the prothrombin time • Factor II and X (“F ii x”) deficient plasma added to pre-diluted patient sample – corrected for all factor deficiencies other than II and X in test plasma • Coagulation activated by undiluted thromboplastin and CaCl 2 (i.e. PT reagent) and clotting time measured • i.e. the clotting rate is in relation to deficiency of ii and x only (Fiix-PT) Gudmundsdottir BR, Francis CW, Bjornsdottir A, Nellbring M, Onundarson PT. Thromb Res 2012;130:674–81.

Sequential VKD- factor measurements in relation to the INR in two individuals The short T ½ of FVII explains the difference in INR and Fiix-INR 100 10 INR FII 9 FX Coagulation factor activity percentage FVII FiixINR 80 8 7 60 6 INR value 5 40 4 3 20 2 1 0 0 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 Days from warfarin initiation Gudmundsdottir BR, Francis CW, Bjornsdottir A, Nellbring Moa, Onundarson PT. Critical role of factors II and X during coumarin anticoagulation and their combined measurement with a new Fiix-prothrombin time. Thromb Res 2012;130(4):674–81.

The Fiix trial TESTING THE HYPOTHESIS A DOUBLE BLIND RANDOMIZED CLINICAL TRIAL

Grant application RANNIS (Icelandic Research Council Expert Panel Evaluation) • This referee does not advise to fund this trial. • If this idea ever occurred to a clotting specialist s(he) must have rejected it before making it public because of doubts on the scientific value” The applicants have insufficiently considered what the adverse effects of • their approach could be for the study population. • Moreover the theoretical and experimental background is shaky. • … it is an ostrich’s policy to think that phenomena that remain unobserved could not hurt the patient.