INR fluctuation: a reflection of treatment inadequacy - or of prothrombin time inadequacy

1. INR fluctuation:a reflection of treatment inadequacy - or of prothrombin time inadequacy? 2011 Pall T. Onundarson, M.D Professor of Hematology, University of Iceland School of Medicine Chief, Dept. of Laboratory Hematology and Coagulation Disorders, Landspitali, Reykjavik, Iceland

2. The trouble with warfarin

3. Bad press � rat poison FDA�BLACK BOX� WARNING �Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR)...� ED VISITS FOR ADE�s Estimated 701, 547 ADEs per year. 17% require hospitalization Insulin (8%) or warfarin (6%): implicated in 14% of ADEs treated in ED. (JAMA 2006; 296. 1858-1866) Sounds like rat poison But are there better agents?Sounds like rat poison But are there better agents?

4. Warfarin/coumarins a love-hate relationship Love Well studied and effective Controllable dose by monitoring Therapeutic window well delineated � and can be adjusted to personal needs Standardized Easily reversed Hate Slow onset of effect Variable dose Mutations affecting metabolism and dose size INR fluctuates in many patients leading to frequent dose adjustments Serious bleeding complications Needlestick Work!

5. We have a dream of an ideal anticoagulant

6. The Ideal Anticoagulant Disadvantages � no routine monitoring � cannot titrate dose, ? Failure of therapy vs. non-compliance; no antidote; no monitoring/lab marker available to measure drug activity if needed ; renal/hepatic dosing; cost Disadvantages � no routine monitoring � cannot titrate dose, ? Failure of therapy vs. non-compliance; no antidote; no monitoring/lab marker available to measure drug activity if needed ; renal/hepatic dosing; cost

7. Are the new oral agents better than warfarin?

8.  Background Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. Full Text of Background... Methods In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran � 110 mg or 150 mg twice daily � or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Full Text of Methods... Results Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). Full Text of Results... Conclusions In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Background Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. Full Text of Background... Methods In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran � 110 mg or 150 mg twice daily � or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Full Text of Methods... Results Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). Full Text of Results... Conclusions In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.

9. Dabigatran versus Warfarin in Patients with Atrial FibrillationStuart J. Connolly, et al. The RE-LY studyN Engl J Med 2009; 361:1139-1151September 17, 2009 The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051).

10. 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 trialLars Wallentin et al on behalf of the RE-LY investigatorsThe Lancet, Volume 376, Issue 9745, 18-24 September 2010, Pages 975-983  So, what was the quality of warfarin management in the multicentric RE-LY study?So, what was the quality of warfarin management in the multicentric RE-LY study?

11.  Time to primary outcome in each quartile of centre's mean time in therapeutic range cTTR=centre's mean time in therapeutic range. Summary Background Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2�0�3�0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. Methods In the RE-LY trial, 18?113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2�0�3�0. Median follow-up was 2�0 years. For 18?024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. Findings The quartiles of cTTR for patients in the warfarin group were: less than 57�1%, 57�1�65�5%, 65�5�72�6%, and greater than 72�6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0�89) or 150 mg dabigatran (interaction p=0�20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0�71) or 150 mg dabigatran (interaction p=0�89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0�03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0�036 and p=0�0006, respectively) and total mortality (interaction p=0�066 and p=0�052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. Interpretation The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. Summary Background Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2�0�3�0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. Methods In the RE-LY trial, 18?113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2�0�3�0. Median follow-up was 2�0 years. For 18?024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. Findings The quartiles of cTTR for patients in the warfarin group were: less than 57�1%, 57�1�65�5%, 65�5�72�6%, and greater than 72�6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0�89) or 150 mg dabigatran (interaction p=0�20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0�71) or 150 mg dabigatran (interaction p=0�89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0�03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0�036 and p=0�0006, respectively) and total mortality (interaction p=0�066 and p=0�052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. Interpretation The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives.

12. Time to major bleeding event in each quartile of centre's mean time in therapeutic range cTTR=centre's mean time in therapeutic range. Summary Background Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2�0�3�0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. Methods In the RE-LY trial, 18?113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2�0�3�0. Median follow-up was 2�0 years. For 18?024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. Findings The quartiles of cTTR for patients in the warfarin group were: less than 57�1%, 57�1�65�5%, 65�5�72�6%, and greater than 72�6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0�89) or 150 mg dabigatran (interaction p=0�20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0�71) or 150 mg dabigatran (interaction p=0�89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0�03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0�036 and p=0�0006, respectively) and total mortality (interaction p=0�066 and p=0�052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. Interpretation The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. Summary Background Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2�0�3�0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. Methods In the RE-LY trial, 18?113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2�0�3�0. Median follow-up was 2�0 years. For 18?024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT00262600. Findings The quartiles of cTTR for patients in the warfarin group were: less than 57�1%, 57�1�65�5%, 65�5�72�6%, and greater than 72�6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0�89) or 150 mg dabigatran (interaction p=0�20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0�71) or 150 mg dabigatran (interaction p=0�89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0�03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0�036 and p=0�0006, respectively) and total mortality (interaction p=0�066 and p=0�052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. Interpretation The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives.

13. New Oral Anticoagulants:Rivaroxaban 2010 Primary efficacy Safety Outcome Does not report TTR in control arm N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. Oral rivaroxaban for symptomatic venous thromboembolism. EINSTEIN Investigators, Abstract BACKGROUND: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.). Does not report TTR in control arm N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. Oral rivaroxaban for symptomatic venous thromboembolism. EINSTEIN Investigators, Abstract BACKGROUND: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

15. Event free survival 97 vs 97.9% event free survival for 360 days Does not report TTR in control arm N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. Oral rivaroxaban for symptomatic venous thromboembolism. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Collaborators (483) Agnelli G, Berkowitz S, Bounameaux H, B�ller H, Cohen A, Gallus A, Lensing A, Misselwitz F, Peters G, Prins M, Raskob G, Schellong S, Bauersachs R, van Bellen B, Boda Z, Borris L, Brenner B, Brighton T, Chlumsk� Y, Davidson B, Decousus H, Eriksson H, Jacobson B, Kakkar A, Kwong YL, Lee LH, Meijer K, van der Meer J, Minar E, Monreal M, Piovella F, Sandset PM, Smith M, Tomkowski W, Verhamme P, Wang Y, Wells P, Brandjes D, Mac Gillavry M, Otten HM, Prins M, Carlsson A, Laporte S, Schulman S, Muehlhofer E, Tewes M, Whatton J, Mueller K, Beckmann H, Pap AF, Spadari G, Peters-Wulf C, Kubitza D, Muck W, Coughlin P, Chong B, Carroll P, Connors G, Baker R, Gallus A, Gan E, Leyden M, Crispin P, Ward C, Bianchi A, Leahy M, Brighton T, Blombery P, Campbell P, Dean M, Jackson D, Denaro C, Hirschl M, Baghestanian M, Mathies R, Pilger E, Marschang P, Vossaert R, Hainaut P, Motte S, Verhaeghe R, Verhamme P, Vandekerkhof J, Vleeschauwer P, de Leersnyder J, Demelenne J, Buche M, Vermassen F, Sprynger M, van Bellen B, Moreira R, Costa J, Sacilotto R, Silvestre J, Yoshida W, Panico M, Wolosker N, Kovacs M, Wells P, Wong T, Selby R, Geerts W, Blondal J, Chen Z, Zhang J, Wang Y, Liu C, Dong Y, Guo W, Wu D, Ying K, Li X, Jin B, Xu J, Jing Z, Liu Z, Jing Z, Kovarova K, Spacek R, Podpera I, Patek F, Vitovec M, Chlumsk� J, Mato�ka P, Husted S, Tuxen C, Hildebrandt P, Nielsen H, Decousus H, Aquilanti S, Pernod G, Lacroix P, Schmidt J, Brisot D, Quere I, Mottier D, Stephan D, Achkar A, Boccalon H, Simoneau G, Lorenzini JL, Trinh-Duc A, Mahe I, Elias A, Emmerich J, Meneveau N, Roy PM, Vital-Durand D, Constans J, Le Jeunne C, Agraou B, Ferrari E, Meyer G, Potel G, Parent F, Sevestre MA, Franke D, Schellong S, Petermann W, Beyer-Westendorf J, Diehm C, Baron Von Bilderling P, Hoffmann U, Hasslacher C, Landgraf H, Horacek T, Bauersachs R, Lindhoff-Last E, Heckmann F, Mondorf W, Espinola-Klein C, Haering HU, Kieback A, Taute BM, Eifrig B, Potratz J, Herrmann T, R�cken M, Tse E, Kov�cs A, Sipos G, Farkas K, Gurzo M, Boda Z, Riba M, Landi A, P�csv�rady Z, Parakh R, Ramakrishna P, Sudhindran S, Kamerkar D, Sembiring R, Soeharti C, Tambunan K, Sumantri R, Zeltser D, Elias M, Hoffman R, Lishner M, Gavish D, Hussein O, Lugassy G, Varon D, Inbal A, Zisman D, Schliamser L, Haran M, Ghirarduzzi A, Barone M, Beltrametti C, Imberti D, Prandoni P, Porreca E, Di Nisio M, Martinelli I, Siragusa S, Ageno W, Ambrosio G, Palareti G, D'Angelo A, Quintavalla R, Cattaneo M, Park KH, Cho WH, Sathar J, Meier K, van der Meer J, van Marwijk-Kooy M, Beeker A, Komdeur R, Kamphuisen PW, Groot M, Ten Cate H, Ockelford P, Simpson D, Harper P, Royle G, Beasley R, Smith M, Quist-Paulsen P, Sandset PM, Ghanima W, Tveit A, Abola M, Roxas D, Checinski P, Adamiec R, Kloczko J, Witkiewicz W, Tomkowski W, Wronski J, Musial J, Oszkinis G, Strzelczyk J, Szyber P, Jackowski M, Ng J, Tay C, Becker J, Isaacs R, Jacobson B, Adler D, Siebert R, van Zyl L, Wright N, van Marle J, Ellis G, Schmidt S, Villalta J, Garc�a-Bragado F, Sanchez J, Fontcuberta J, Eriksson H, Aagesen J, Jonson T, Sj�lander A, Mazzolai L, Bounameaux H, Banyai M, Frank U, Reinhardt W, Dorffler-Melly J, Asmis L, Chiu KM, Tsai W, Yu TJ, Angchaisuksiri P, Rojnuckarin P, Hunt B, Nokes T, Cohen A, Sekhar M, Dexter J, Lyons R, Nadar V, Krell K, Rehm J, Rathbun S, Spyropoulos A, Moll S, Chen D, Banish D, Joseph S, Rodgers G, Stevens S, Wright P, Botnick W, Albrecht C, Jaffer A, Kennedy M, Rodriguez W, Coughlin P, Chong B, Leyden M, Connors G, Gan E, Jackson D, Gallus A, Baker R, Bianchi A, Campbell P, Carroll P, Denaro C, McRae S, Blombery P, Dean M, Ward C, Crispin P, Marschang P, Hirschl M, Mathies R, Baghestanian M, Kyrle PA, Forstner K, Pilger E, Verhaeghe R, Verhamme P, Vossaert R, Motte S, Vermassen F, Sprynger M, Soffiatti R, van Bellen B, Panico M, Sacilotto R, Moreira R, Silvestre J, Zhang J, Wang C, Li X, Liu C, Chen Z, Wang Y, Jing Z, Wu D, Spacek R, Kovarova K, Vitovec M, Mato�ka P, Povolny J, Chlumsk� J, Patek F, Nielsen HK, Husted S, Hildebrandt P, Decousus H, Schmidt J, Aquilanti S, Pernod G, Lorenzini JL, Achkar A, Brisot D, Mottier D, Trinh-Duc A, Lacroix P, Quere I, Parent F, Potel G, Stephan D, Wahl D, Mahe I, Roy PM, Sevestre MA, Petermann W, Diehm C, Franke D, Harenberg J, Baron Von Bilderling P, Hasslacher C, von Schwaiblmair W, Sipos G, Kov�cs A, Farkas K, Gurzo M, P�csv�rady Z, Boda Z, Riba M, Parakh R, Kamerkar D, Ramakrishna P, Sudhindran S, Sembiring RJ, Elias M, Hoffman R, Zeltser D, Gavish D, Lishner M, Lugassy G, Zisman D, D'Angelo, Porreca E, Baresne M, Beltrametti C, Prandoni P, Cattaneo M, Di Minno G, Quintavalla R, Ambrosio G, Imberti D, Palareti G, Siragusa S, Sathar J, van der Meer J, Kamphuisen PW, van Marwijk Kooy M, Beeker A, Mol J, Simpson D, Ockelford P, Harper P, Smith M, Beasley R, Sandset PM, Ghanima W, Tveit A, Abola MT, Roxas DJ, Tomkowski W, Strzelczyk K, Adamiec R, Lewczuk J, Kloczko J, Musial J, Szyber P, Ng HJ, Tay JC, Jacobson B, Becker JH, Isaacs R, Siebert RS, Adler D, Ellis G, Wright N, van Marle J, van Zyl L, Redondo M, Villalta J, Fontcuberta J, de Diego I, Garc�a-Bragado F, Grau E, Eriksson H, Lapidus L, Jonson T, Sj�lander A, Aagesen J, Wallen T, Bounameaux H, Banyai M, Angchaisuksiri P, Rojnuckarin P, Luckit J, Cohen A, Sekhar M, Lyons R, Krell K, Rathbun S, Spyropoulos A, Wright P, Joseph S, Kennedy M, Moll S, Cymet T. Abstract BACKGROUND: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.). Does not report TTR in control arm N Engl J Med. 2010 Dec 23;363(26):2499-510. Epub 2010 Dec 3. Oral rivaroxaban for symptomatic venous thromboembolism. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Collaborators (483) Agnelli G, Berkowitz S, Bounameaux H, B�ller H, Cohen A, Gallus A, Lensing A, Misselwitz F, Peters G, Prins M, Raskob G, Schellong S, Bauersachs R, van Bellen B, Boda Z, Borris L, Brenner B, Brighton T, Chlumsk� Y, Davidson B, Decousus H, Eriksson H, Jacobson B, Kakkar A, Kwong YL, Lee LH, Meijer K, van der Meer J, Minar E, Monreal M, Piovella F, Sandset PM, Smith M, Tomkowski W, Verhamme P, Wang Y, Wells P, Brandjes D, Mac Gillavry M, Otten HM, Prins M, Carlsson A, Laporte S, Schulman S, Muehlhofer E, Tewes M, Whatton J, Mueller K, Beckmann H, Pap AF, Spadari G, Peters-Wulf C, Kubitza D, Muck W, Coughlin P, Chong B, Carroll P, Connors G, Baker R, Gallus A, Gan E, Leyden M, Crispin P, Ward C, Bianchi A, Leahy M, Brighton T, Blombery P, Campbell P, Dean M, Jackson D, Denaro C, Hirschl M, Baghestanian M, Mathies R, Pilger E, Marschang P, Vossaert R, Hainaut P, Motte S, Verhaeghe R, Verhamme P, Vandekerkhof J, Vleeschauwer P, de Leersnyder J, Demelenne J, Buche M, Vermassen F, Sprynger M, van Bellen B, Moreira R, Costa J, Sacilotto R, Silvestre J, Yoshida W, Panico M, Wolosker N, Kovacs M, Wells P, Wong T, Selby R, Geerts W, Blondal J, Chen Z, Zhang J, Wang Y, Liu C, Dong Y, Guo W, Wu D, Ying K, Li X, Jin B, Xu J, Jing Z, Liu Z, Jing Z, Kovarova K, Spacek R, Podpera I, Patek F, Vitovec M, Chlumsk� J, Mato�ka P, Husted S, Tuxen C, Hildebrandt P, Nielsen H, Decousus H, Aquilanti S, Pernod G, Lacroix P, Schmidt J, Brisot D, Quere I, Mottier D, Stephan D, Achkar A, Boccalon H, Simoneau G, Lorenzini JL, Trinh-Duc A, Mahe I, Elias A, Emmerich J, Meneveau N, Roy PM, Vital-Durand D, Constans J, Le Jeunne C, Agraou B, Ferrari E, Meyer G, Potel G, Parent F, Sevestre MA, Franke D, Schellong S, Petermann W, Beyer-Westendorf J, Diehm C, Baron Von Bilderling P, Hoffmann U, Hasslacher C, Landgraf H, Horacek T, Bauersachs R, Lindhoff-Last E, Heckmann F, Mondorf W, Espinola-Klein C, Haering HU, Kieback A, Taute BM, Eifrig B, Potratz J, Herrmann T, R�cken M, Tse E, Kov�cs A, Sipos G, Farkas K, Gurzo M, Boda Z, Riba M, Landi A, P�csv�rady Z, Parakh R, Ramakrishna P, Sudhindran S, Kamerkar D, Sembiring R, Soeharti C, Tambunan K, Sumantri R, Zeltser D, Elias M, Hoffman R, Lishner M, Gavish D, Hussein O, Lugassy G, Varon D, Inbal A, Zisman D, Schliamser L, Haran M, Ghirarduzzi A, Barone M, Beltrametti C, Imberti D, Prandoni P, Porreca E, Di Nisio M, Martinelli I, Siragusa S, Ageno W, Ambrosio G, Palareti G, D'Angelo A, Quintavalla R, Cattaneo M, Park KH, Cho WH, Sathar J, Meier K, van der Meer J, van Marwijk-Kooy M, Beeker A, Komdeur R, Kamphuisen PW, Groot M, Ten Cate H, Ockelford P, Simpson D, Harper P, Royle G, Beasley R, Smith M, Quist-Paulsen P, Sandset PM, Ghanima W, Tveit A, Abola M, Roxas D, Checinski P, Adamiec R, Kloczko J, Witkiewicz W, Tomkowski W, Wronski J, Musial J, Oszkinis G, Strzelczyk J, Szyber P, Jackowski M, Ng J, Tay C, Becker J, Isaacs R, Jacobson B, Adler D, Siebert R, van Zyl L, Wright N, van Marle J, Ellis G, Schmidt S, Villalta J, Garc�a-Bragado F, Sanchez J, Fontcuberta J, Eriksson H, Aagesen J, Jonson T, Sj�lander A, Mazzolai L, Bounameaux H, Banyai M, Frank U, Reinhardt W, Dorffler-Melly J, Asmis L, Chiu KM, Tsai W, Yu TJ, Angchaisuksiri P, Rojnuckarin P, Hunt B, Nokes T, Cohen A, Sekhar M, Dexter J, Lyons R, Nadar V, Krell K, Rehm J, Rathbun S, Spyropoulos A, Moll S, Chen D, Banish D, Joseph S, Rodgers G, Stevens S, Wright P, Botnick W, Albrecht C, Jaffer A, Kennedy M, Rodriguez W, Coughlin P, Chong B, Leyden M, Connors G, Gan E, Jackson D, Gallus A, Baker R, Bianchi A, Campbell P, Carroll P, Denaro C, McRae S, Blombery P, Dean M, Ward C, Crispin P, Marschang P, Hirschl M, Mathies R, Baghestanian M, Kyrle PA, Forstner K, Pilger E, Verhaeghe R, Verhamme P, Vossaert R, Motte S, Vermassen F, Sprynger M, Soffiatti R, van Bellen B, Panico M, Sacilotto R, Moreira R, Silvestre J, Zhang J, Wang C, Li X, Liu C, Chen Z, Wang Y, Jing Z, Wu D, Spacek R, Kovarova K, Vitovec M, Mato�ka P, Povolny J, Chlumsk� J, Patek F, Nielsen HK, Husted S, Hildebrandt P, Decousus H, Schmidt J, Aquilanti S, Pernod G, Lorenzini JL, Achkar A, Brisot D, Mottier D, Trinh-Duc A, Lacroix P, Quere I, Parent F, Potel G, Stephan D, Wahl D, Mahe I, Roy PM, Sevestre MA, Petermann W, Diehm C, Franke D, Harenberg J, Baron Von Bilderling P, Hasslacher C, von Schwaiblmair W, Sipos G, Kov�cs A, Farkas K, Gurzo M, P�csv�rady Z, Boda Z, Riba M, Parakh R, Kamerkar D, Ramakrishna P, Sudhindran S, Sembiring RJ, Elias M, Hoffman R, Zeltser D, Gavish D, Lishner M, Lugassy G, Zisman D, D'Angelo, Porreca E, Baresne M, Beltrametti C, Prandoni P, Cattaneo M, Di Minno G, Quintavalla R, Ambrosio G, Imberti D, Palareti G, Siragusa S, Sathar J, van der Meer J, Kamphuisen PW, van Marwijk Kooy M, Beeker A, Mol J, Simpson D, Ockelford P, Harper P, Smith M, Beasley R, Sandset PM, Ghanima W, Tveit A, Abola MT, Roxas DJ, Tomkowski W, Strzelczyk K, Adamiec R, Lewczuk J, Kloczko J, Musial J, Szyber P, Ng HJ, Tay JC, Jacobson B, Becker JH, Isaacs R, Siebert RS, Adler D, Ellis G, Wright N, van Marle J, van Zyl L, Redondo M, Villalta J, Fontcuberta J, de Diego I, Garc�a-Bragado F, Grau E, Eriksson H, Lapidus L, Jonson T, Sj�lander A, Aagesen J, Wallen T, Bounameaux H, Banyai M, Angchaisuksiri P, Rojnuckarin P, Luckit J, Cohen A, Sekhar M, Lyons R, Krell K, Rathbun S, Spyropoulos A, Wright P, Joseph S, Kennedy M, Moll S, Cymet T. Abstract BACKGROUND: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. METHODS: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. In parallel, we carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism. The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study. RESULTS: The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin-vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001). The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11). CONCLUSIONS: Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation. (Funded by Bayer Schering Pharma and Ortho-McNeil; ClinicalTrials.gov numbers, NCT00440193 and NCT00439725.).

16. Pall�s Conclusion:  No health benefit of dabigatran over adequate warfarin treatment if TTR is >65% Hardly a relevant difference with rivaroxaban Efficacy and safety benefit of new agents over warfarin may be limited to centers with poorer management of warfarin Other side effects, antidote and prize must be an issue Warfarin is not yet moribund The inevitable question...The inevitable question...

17. Can treatment with warfarin be improved?

18. Volume 352, Issue 9139, 7 November 1998, Pages 1505-1509Multicentre randomised study of computerised anticoagulant dosage multicentre randomised study of computerised anticoagulant dosageL Poller ProfDSca, , CR Shiach MDb, PK MacCallum MDc, AM Johansen MDd, AM M�nster MDe, A Magalh�es MDf, J Jespersen DSce and on behalf of the European Concerted Action on Anticoagulation. Background The demand for anticoagulant treatment is increasing. We compared the benefits of computer-generated anticoagulant dosing with traditional dosing decided by experienced medical staff in achieving target international normalised ratios (INRs). Methods In five European centres we randomly assigned 285 patients in the stabilisation period and stabilised patients to the computer-generated-dose group (n=137) or traditional-dose group (n=148). Centres had a specialist interest in oral anticoagulation but no previous experience with computer-generated dosing. The computer program calculated doses and times to next visit. Our main endpoint was time spent in target INR range (Rosendaal method). Findings For all patients combined, computer-generated dosing was significantly beneficial overall in achieving target INR (p=0�004). The mean time within target INR range for all patients and all ranges was 63�3% (SD 28�0) of days in the computer-generated-dose group compared with 53�2% (27�7) in the traditional-dose group. For the stabilisation patients alone, computer-generated doses led to a non-significant benefit in all INR ranges (p=0�06), whereas in the stable patients the benefit was significant (p=0�02). Interpretation The computer program gave better INR control than the experienced medical staff and at least similar standards to the specialised centres should be generally available. Clinical outcome and cost effectiveness remain to be assessed. Background The demand for anticoagulant treatment is increasing. We compared the benefits of computer-generated anticoagulant dosing with traditional dosing decided by experienced medical staff in achieving target international normalised ratios (INRs). Methods In five European centres we randomly assigned 285 patients in the stabilisation period and stabilised patients to the computer-generated-dose group (n=137) or traditional-dose group (n=148). Centres had a specialist interest in oral anticoagulation but no previous experience with computer-generated dosing. The computer program calculated doses and times to next visit. Our main endpoint was time spent in target INR range (Rosendaal method). Findings For all patients combined, computer-generated dosing was significantly beneficial overall in achieving target INR (p=0�004). The mean time within target INR range for all patients and all ranges was 63�3% (SD 28�0) of days in the computer-generated-dose group compared with 53�2% (27�7) in the traditional-dose group. For the stabilisation patients alone, computer-generated doses led to a non-significant benefit in all INR ranges (p=0�06), whereas in the stable patients the benefit was significant (p=0�02). Interpretation The computer program gave better INR control than the experienced medical staff and at least similar standards to the specialised centres should be generally available. Clinical outcome and cost effectiveness remain to be assessed.

19. Quality of warfarin managementDAWN� based AMC improves time in range compared to cardiologist dosing Int J Lab Hematol. 2008;30(5):382-9. Warfarin anticoagulation intensity in specialist-based and in computer-assisted dosing practice. Onundarson PT, Einarsdottir KA, Gudmundsdottir BR. Int J Lab Hematol. 2008 Oct;30(5):382-9. Warfarin anticoagulation intensity in specialist-based and in computer-assisted dosing practice. Onundarson PT, Einarsdottir KA, Gudmundsdottir BR. Source Department of Laboratory Hematology and Hemostasis Center, University of Iceland Medical School, Landspitali University Hospital, 101 Reykjavik, Iceland. pallt@landspitali.is Abstract The efficacy and safety of oral anticoagulation (OA) with vitamin K antagonists depends on maintaining anticoagulation intensity, measured as international normalized ratio (INR), within defined target ranges. We assessed the quality of our current software-assisted warfarin dosing in the year 2006 in 941 unselected consecutive patients on stable OA with atrial fibrillation (AF), venous thromboembolism (VTE) and prosthetic heart valves (PHV) by comparing it to our previous cardiologist-based dosing practice in 1992 when a study was carried out on 241 comparable patients. Over 14 years, the time within target range increased in all three anticoagulated groups, i.e. in AF patients from 46% to 81%, in VTE patients from 62% to 84% and in patients with PHV from 40% to 64%. Only 1% of the treatment time is now spent at INR < 1.5 compared to 7% previously (P < 0.0001) and 0.4% of the treatment time at INR > 4.0 presently compared to 2.8% in the past (P < 0.0001). INR-targets are better achieved with the current software-assisted dosing practice and extreme low and high values are less common than previously. The results provide indirect evidence suggesting that both efficacy and safety has improved with the current practice. Int J Lab Hematol. 2008 Oct;30(5):382-9. Warfarin anticoagulation intensity in specialist-based and in computer-assisted dosing practice. Onundarson PT, Einarsdottir KA, Gudmundsdottir BR. Source Department of Laboratory Hematology and Hemostasis Center, University of Iceland Medical School, Landspitali University Hospital, 101 Reykjavik, Iceland. pallt@landspitali.is Abstract The efficacy and safety of oral anticoagulation (OA) with vitamin K antagonists depends on maintaining anticoagulation intensity, measured as international normalized ratio (INR), within defined target ranges. We assessed the quality of our current software-assisted warfarin dosing in the year 2006 in 941 unselected consecutive patients on stable OA with atrial fibrillation (AF), venous thromboembolism (VTE) and prosthetic heart valves (PHV) by comparing it to our previous cardiologist-based dosing practice in 1992 when a study was carried out on 241 comparable patients. Over 14 years, the time within target range increased in all three anticoagulated groups, i.e. in AF patients from 46% to 81%, in VTE patients from 62% to 84% and in patients with PHV from 40% to 64%. Only 1% of the treatment time is now spent at INR < 1.5 compared to 7% previously (P < 0.0001) and 0.4% of the treatment time at INR > 4.0 presently compared to 2.8% in the past (P < 0.0001). INR-targets are better achieved with the current software-assisted dosing practice and extreme low and high values are less common than previously. The results provide indirect evidence suggesting that both efficacy and safety has improved with the current practice.

20. What are the current major limitations of warfarin? Dose size at initiation Fluctuating INR: frequent dose changes frequent monitoring Fluctuating INR is caused by: Food and drugs Prothrombin time?

21. Coumarin effect and it�s monitoring Vitamin K inhibition Gamma carboxylation of ii, vii, ix and x prevented T1/2 �Common wisdom� Reduction in all VKD factors is equally important for the anticoagulant effect of coumarins Confounding effect of factor VII during initiation �Must reduce all vit K dependent factors to be anticoagulated�

22. 1935-1984: Presumption: ii, vii, ix and x contribute equally to antithrombotic effect Prothrombin times measure activity of II, VII and X (not IX) the clotting times obtained are equally sensitive to reduction in coagulation factors II, VII or X. �General wisdom��General wisdom�

23. Monitoring tests Armand Quick PT (1935) sensitive to reduced factors ii, vii, x i (fibrinogen), v Paul A. Owren Owren PT (P&P test) (1951) diluted test sample adsorbed bovine plasma mixed with patient plasma sensitive to reduced factors ii, vii, x Not i, v Thrombotest (1959) ii, vii, ix and x

24. Do individual VKD factors influence clot formation in vivo equally? Shouting in the desert 1984-2011... Shouting in the desert...Shouting in the desert...

25. Blood. 1984 Aug;64(2):445-51.Comparison of the native prothrombin antigen and the prothrombin time for monitoring oral anticoagulant therapy.Furie B, Liebman HA, Blanchard RA, Coleman MS, Kruger SF, Furie BC. We have measured the fully carboxylated (native) prothrombin antigen and the undercarboxylated (abnormal) prothrombin antigen in patients treated with sodium warfarin using specific immunoassays to evaluate a new approach for monitoring oral anticoagulant therapy. Plasma and serum samples (391) were assayed for the prothrombin time, native prothrombin antigen, and abnormal prothrombin antigen. The results were correlated with the presence of bleeding or thromboembolic complications at the time of phlebotomy. The native prothrombin antigen correlated with the occurrence of complications in 95% of samples. Of 13 samples from patients with bleeding complications, 13/13 (100%) had a native prothrombin of 12 micrograms/mL or lower. Of seven samples from patients with thromboembolic complications, 6/7 (86%) had a native prothrombin of 24 micrograms/mL or greater. By comparison, a prothrombin time index of 1.5 to 2.5, 1.5 to 2.2, 1.5 to 2.0, or 1.3 to 1.8 identified 6/20 (30%), 9/20 (45%), 11/20 (55%), or 12/20 (60%) patients at risk, respectively. Although the prothrombin time index did correlate with the presence of bleeding complications, the native prothrombin antigen correlated closely with the presence of bleeding and thromboembolic complications. According to these results, the native prothrombin antigen, maintained in a range of 12 to 24 micrograms/mL by regular adjustment of the warfarin dosage, may be associated with a reduced risk of complications due to excessive or insufficient warfarin therapy. On the basis of these preliminary data, we recommend that the native prothrombin antigen be considered to monitor warfarin therapy. We have measured the fully carboxylated (native) prothrombin antigen and the undercarboxylated (abnormal) prothrombin antigen in patients treated with sodium warfarin using specific immunoassays to evaluate a new approach for monitoring oral anticoagulant therapy. Plasma and serum samples (391) were assayed for the prothrombin time, native prothrombin antigen, and abnormal prothrombin antigen. The results were correlated with the presence of bleeding or thromboembolic complications at the time of phlebotomy. The native prothrombin antigen correlated with the occurrence of complications in 95% of samples. Of 13 samples from patients with bleeding complications, 13/13 (100%) had a native prothrombin of 12 micrograms/mL or lower. Of seven samples from patients with thromboembolic complications, 6/7 (86%) had a native prothrombin of 24 micrograms/mL or greater. By comparison, a prothrombin time index of 1.5 to 2.5, 1.5 to 2.2, 1.5 to 2.0, or 1.3 to 1.8 identified 6/20 (30%), 9/20 (45%), 11/20 (55%), or 12/20 (60%) patients at risk, respectively. Although the prothrombin time index did correlate with the presence of bleeding complications, the native prothrombin antigen correlated closely with the presence of bleeding and thromboembolic complications. According to these results, the native prothrombin antigen, maintained in a range of 12 to 24 micrograms/mL by regular adjustment of the warfarin dosage, may be associated with a reduced risk of complications due to excessive or insufficient warfarin therapy. On the basis of these preliminary data, we recommend that the native prothrombin antigen be considered to monitor warfarin therapy.

26. Randomized prospective trial comparing the native prothrombin antigen with the prothrombin time for monitoring oral anticoagulant therapyFurie B, Diuguid CF, Jacobs M, Diuguid DL, Furie BC, New England Medical Center, BostonBlood. 1990 Jan 15;75(2):344-9 Abstract Patients with indications for anticoagulation were randomized to be monitored by the native prothrombin antigen (therapeutic range, 12 to 24 micrograms/mL) or the prothrombin time index (therapeutic range, 1.5 to 2.0). Of the prothrombin time group (N = 80), seven (8.8%) had bleeding or thrombotic complications, with a complication rate of 9.5%/patient-year. In the native prothrombin antigen group (N = 76), one subject (1.3%) had a bleeding complication. The complication rate per patient-year was 1.5%. These results indicate an 85% reduction in the complication rate of the native prothrombin antigen group compared with the complication rate of the prothrombin time group. This difference is statistically significant by the Fisher exact test (P = .037) and by Kaplan Meier survival analysis (P = .040). This study suggests that the use of the native prothrombin antigen assay has the potential to decrease the complications associated with anticoagulation therapy with warfarin sodium. ATHUGA REF Monitoring a single factor was better than warfarin using PT-ratio 1.5-2.0 (high sensitivity thromboplastin, no INR calculation at the time) The dosage of the anticoagulant warfarin sodium is based upon the prolongation of the prothrombin time into an optimal therapeutic range. We have developed a new assay for the native prothrombin antigen that measures the fully gamma-carboxylated prothrombin using a radioimmunoassay. Based on preliminary data that indicated that the native prothrombin antigen predicted both bleeding and thrombotic complications more accurately than the prothrombin time in patients anticoagulated with warfarin sodium, we have performed a randomized prospective trial comparing the complication rate in warfarin-treated patients monitored with the native prothrombin antigen or the prothrombin time. Patients with indications for anticoagulation were randomized to be monitored by the native prothrombin antigen (therapeutic range, 12 to 24 micrograms/mL) or the prothrombin time index (therapeutic range, 1.5 to 2.0). Of the prothrombin time group (N = 80), seven (8.8%) had bleeding or thrombotic complications, with a complication rate of 9.5%/patient-year. In the native prothrombin antigen group (N = 76), one subject (1.3%) had a bleeding complication. The complication rate per patient-year was 1.5%. These results indicate an 85% reduction in the complication rate of the native prothrombin antigen group compared with the complication rate of the prothrombin time group. This difference is statistically significant by the Fisher exact test (P = .037) and by Kaplan Meier survival analysis (P = .040). This study suggests that the use of the native prothrombin antigen assay has the potential to decrease the complications associated with anticoagulation therapy with warfarin sodium. ATHUGA REF Monitoring a single factor was better than warfarin using PT-ratio 1.5-2.0 (high sensitivity thromboplastin, no INR calculation at the time) The dosage of the anticoagulant warfarin sodium is based upon the prolongation of the prothrombin time into an optimal therapeutic range. We have developed a new assay for the native prothrombin antigen that measures the fully gamma-carboxylated prothrombin using a radioimmunoassay. Based on preliminary data that indicated that the native prothrombin antigen predicted both bleeding and thrombotic complications more accurately than the prothrombin time in patients anticoagulated with warfarin sodium, we have performed a randomized prospective trial comparing the complication rate in warfarin-treated patients monitored with the native prothrombin antigen or the prothrombin time. Patients with indications for anticoagulation were randomized to be monitored by the native prothrombin antigen (therapeutic range, 12 to 24 micrograms/mL) or the prothrombin time index (therapeutic range, 1.5 to 2.0). Of the prothrombin time group (N = 80), seven (8.8%) had bleeding or thrombotic complications, with a complication rate of 9.5%/patient-year. In the native prothrombin antigen group (N = 76), one subject (1.3%) had a bleeding complication. The complication rate per patient-year was 1.5%. These results indicate an 85% reduction in the complication rate of the native prothrombin antigen group compared with the complication rate of the prothrombin time group. This difference is statistically significant by the Fisher exact test (P = .037) and by Kaplan Meier survival analysis (P = .040). This study suggests that the use of the native prothrombin antigen assay has the potential to decrease the complications associated with anticoagulation therapy with warfarin sodium.

27. Thromb Haemost. 1989 Sep 29;62(2):788-91.The relative importance of the factors II, VII, IX and X for the prothrombinase activity in plasma of orally anticoagulated patients.Xi M, B�guin S, Hemker HC.Department of Biochemistry, University of Limburg, Maastricht, The Netherlands. The individual importance of each of the four vitamin K-dependent clotting factors on the generation of prothrombinase activity in the plasma of orally anticoagulated patients has been investigated. Addition of purified factors VII, IX or X to plasma from deeply anticoagulated patients (International Normalized Ratio 2.8-4.8) did not influence the amount of prothrombinase activity or the amount of thrombin formed. Only the prothrombin level in the plasma determines the course of thrombin generation. Addition of increasing amounts of purified factor II, VII, IX or X to plasmas deficient in respectively factor II, VII, IX or X showed that the prothrombinase activity increases linearly with the concentration of factor II added and that the concentration below which the factors VII, IX and X start to have a measurable effect on prothrombinase activity are 5%, 20%, and 30%, respectively. Half maximal prothrombinase activity was found at about 1% factor VII, 5% factor IX and 8% factor X respectively. From these observations we conclude that primarily the variation in factor II level determines thrombin generation and hence presumably the antithrombotic effect of oral anticoagulant therapy. It therefore seems likely that, for the control of oral anticoagulant therapy, tests that reflect factor II activity would be suitable. 1989 Thrombin generation using S2238... FII >>> X > IX >>>> VII1989 Thrombin generation using S2238... FII >>> X > IX >>>> VII

28. Circulation. 1993 Aug;88(2):454-60.Comparison of native prothrombin antigen with the prothrombin time for monitoring oral anticoagulant prophylaxis.Kornberg A, Francis CW, Pellegrini VD Jr, Gabriel KR, Marder VJ.Department of Medicine, University of Rochester School of Medicine and Dentistry These results indicate that the NPA concentration more accurately reflects the antithrombotic effect of warfarin than does prothrombin time and may be superior in monitoring prophylactic oral anticoagulation. Phlebographic studyPhlebographic study

29. �J. Clin. Invest. 92(5): 2131-2140 (1993). doi:10.1172/JCI116814. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors.A Zivelin, L V Rao and S I Rapaport Department of Medicine, University of California, San Diego 92093. Immunodepletion of plasma factor X or prothrombin, but not of factor VII or factor IX, protected otherwise normal rabbits against tissue factor-induced coagulation. Next, we determined the effect upon the protection in warfarin-treated rabbits of selectively restoring factor X or prothrombin before infusing tissue factor. When either factor was selectively restored, warfarin's protective effect was abolished. Moreover, selective restoration of prothrombin sensitized warfarin-treated rabbits to coagulation more severe than observed in nontreated control rabbits. One may extrapolate from these data that depression of both factor X and prothrombin are required for warfarin's clinical antithrombotic efficacy and that depression of plasma prothrombin is particularly important. We have evaluated the contribution of depression of individual procoagulant vitamin K-dependent clotting factors to the ability of warfarin to protect rabbits against tissue factor-induced coagulation. Mean activities of individual procoagulant factors were determined, in assays with rabbit substrates, for a group of rabbits achieving a protective degree of anticoagulation with warfarin. Values were: factor VII, 12%; factor IX, 7%; factor X, 14%, and prothrombin, 13%. The effect upon tissue factor-induced coagulation of selective immunodepletion of each factor to a comparable level was then evaluated. Immunodepletion of plasma factor X or prothrombin, but not of factor VII or factor IX, protected otherwise normal rabbits against tissue factor-induced coagulation. Next, we determined the effect upon the protection in warfarin-treated rabbits of selectively restoring factor X or prothrombin before infusing tissue factor. When either factor was selectively restored, warfarin's protective effect was abolished. Moreover, selective restoration of prothrombin sensitized warfarin-treated rabbits to coagulation more severe than observed in nontreated control rabbits. One may extrapolate from these data that depression of both factor X and prothrombin are required for warfarin's clinical antithrombotic efficacy and that depression of plasma prothrombin is particularly important. We have evaluated the contribution of depression of individual procoagulant vitamin K-dependent clotting factors to the ability of warfarin to protect rabbits against tissue factor-induced coagulation. Mean activities of individual procoagulant factors were determined, in assays with rabbit substrates, for a group of rabbits achieving a protective degree of anticoagulation with warfarin. Values were: factor VII, 12%; factor IX, 7%; factor X, 14%, and prothrombin, 13%. The effect upon tissue factor-induced coagulation of selective immunodepletion of each factor to a comparable level was then evaluated. Immunodepletion of plasma factor X or prothrombin, but not of factor VII or factor IX, protected otherwise normal rabbits against tissue factor-induced coagulation. Next, we determined the effect upon the protection in warfarin-treated rabbits of selectively restoring factor X or prothrombin before infusing tissue factor. When either factor was selectively restored, warfarin's protective effect was abolished. Moreover, selective restoration of prothrombin sensitized warfarin-treated rabbits to coagulation more severe than observed in nontreated control rabbits. One may extrapolate from these data that depression of both factor X and prothrombin are required for warfarin's clinical antithrombotic efficacy and that depression of plasma prothrombin is particularly important.

30. Prothrombin restoration in warfarin treated rabbitsZivelin et al JCI 1993 Restoration of prothrombin led to consumption of fibrinogen, factor V and factor VIII

31. Oral Anticoagulation ThresholdsKE Brummel, SG Paradis, RF Branda, KG Mann(Circulation 2001;104:2311-17) �Patients with similar INRs show significant individual variability* in their tissue factor coagulation response**, suggesting different risks...� *Intra-individual, inter-individual **including clotting time, formation of TAT complexes

32. So... Prior evidence suggests that measuring factors II or X may better indicate clottability and anticoagulation in patients on warfarin than the prothrombin time does which included factor VII

33. ROTEM STUDY Rotational Thromboelastometry� Weight of each VKD factor in a ROTEM modelWeight of each VKD factor in a ROTEM model

34. ROTEM parameters Whole blood (300 �l, anticoagulated with citrate) is placed into the disposable cuvette using an electronic pipette. A disposable pin is attached to a shaft which is connected with a thin spring (the equivalent to Hartert�s torsion wire in thrombelastography) and slowly oscillates back and forth. The signal of the pin suspended in the blood sample is transmitted via an optical detector system. The test is started by adding appropriate reagents. The instrument measures and graphically displays the changes in elasticity at all stages of the developing and resolving clot. The typical test temperature is 37�C, but different temperatures can be selected, e.g. for patients with hypothermia[8]. In contrast to thrombelastography with its pendulum-like principle, the design of the TEM viscoelastic detection system (figure 1) makes it quite robust and insensitive against mechanical shocks or vibrations.

35. Aim and Method We evaluated the effect of selective in vitro depression of individual vitamin K dependent (VKD) coagulation factors (and their restoration) on ROTEM Coagulation activated in plasma by adding trace amount thromboplastin (1:17,000 dilution f.c.)

36. ROTEM and VKD coagulation factors

37. ROTEM parameters in relation to PP percent coagulant activity in 65 samples from patients on stable anticoagulation with warfarin. 

38. ROTEM clotting time (CT), Maximum velocity (MaxVel) and maximum clot firmness (MCF) in relation to progressive reduction of individual vitamin K dependent coagulation factors in PPP

39. Conclusions of ROTEM experiments ROTEM parameters correlated poorly with the Owren prothrombin time in anticoagulated patients� plasma ROTEM clotting time (CT, initiation phase), ROTEM maximum velocity (Max Vel, propagation phase) ROTEM MCF (stabilization phase) were affected markedly more by mildly and moderately low concentrations of factors II or X than by identical FVII or factor IX concentrations FVII only mattered once << 5 U/dL

40. Hypothesis Hypothesis: �The combined measurement of factors ii and x alone on fibrin formation reflects clotting better in anticoagulated patients on coumarins than the current PT based methods which include factors ii, vii and x� The PT can be �Fiix�-ed

41. Fiix- prothrombin time Stuart-prothrombin time

42. �Fiix � PT�(Stuart-prothrombin time)* Measurement of fibrin formation rate (clotting time) in coumarinized plasma that is made only deficient in factors II and X, ie the clotting rate is in relation to deficiency in ii and x only Fiix-method/ idea: Addition of factor II and X deficient plasma to patient sample in order to correct for all other factor deficiencies Coagulation then activated by thromboplastin (eg. PT reagent) Alternative test possibilities

43. Owren�s PT (P&P) versus Fiix-PT P&P test Patient plasma dilution* 1/7 Volume 50 �l of dilution STA-SPA+ reagent (Thromboplastin (rabbit brain) + adsorbed bovine plasma free of FII, VII, IX and X + CaCl2) Volume 100 �l Fiix test Patient plasma 1/7 dilution* Volume 80 �l of dilution Human plasma free of FII and FX immunodepleted, Volume 25 �l Thromboplastin Neoplastin CI plus� ie standard PT reagent from Stago (rabbit brain) reagent + CaCl2 Volume 70 �l

44. Fiix-PT measurements using different dilutions and plasma ratios

45. Calculation In both tests, ISI is calculated (measured) from international standard (Decks 99) and INR calculated: INR = (Patient�s clotting time/mean normal clotting time)ISI

46. Fiix-�INR� (Fiix-NR) vs INR

47. Sequential VKD- factor measurements in relation to the INR in two individuals

48. Planned prospective randomized and blinded trial Single center (Landspitali Reykjavik) Dosing by DAWN and AMC staff based on blinded �INR� Followed for 1200 patients years Primary endpoints TE Bleeding events Surrogate endpoints: TTR number of tests ATHUGA hva� er ��tla�ur fj�ldi �falla?ATHUGA hva� er ��tla�ur fj�ldi �falla?

49. The End