Νέα από του στόματος αντιπηκτικά. Γ. Μίχας Ειδικευόμενος Α Παθολογικής Κλινικής, Γ.Ν. Καλαμάτας

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1 Νέα από του στόματος αντιπηκτικά Γ. Μίχας Ειδικευόμενος Α Παθολογικής Κλινικής, Γ.Ν. Καλαμάτας

Atrial fibrillation is a common arrythmia In the FHS, the lifetime risk of atrial fibrillation (AFib) for adults age 40 is 26% for men and 23% for women 1 Prevalence of AFib

2 Atrial fibrillation is a common arrythmia In the FHS, the lifetime risk of atrial fibrillation (AFib) for adults age 40 is 26% for men and 23% for women 1 Prevalence of AFib in the US is estimated > 2.2 million adults 2 Prevalence increases steeply with age 2 1.Lloyd-Jones DM, et al. Circulation 2004;110: Go et al. JAMA 2001;285:2370-5

3 Prevalence of AFib in the US is expected to increase upwards of 5.3 million by 2050 Go et al. JAMA 2001;285:2370-5

4 AFib: a common but serious arrythmia AFib increases the risk of stroke 5-fold 1 The increase in risk of stroke is similar for paroxysmal, persistent and permanent AFib 2 Strokes associated with AFib are usually more severe than those from other causes, conferring an increased risk of morbidity, mortality and poor functional outcome 1 1. Savelieva et al. Ann Med 2007;39: Hart R et al. JACC 2000; 35:

5 Stroke prevention in AFib (SPAF) Currently approved medications are oral anticoagulants (vitamin K antagonists such as warfarin) and aspirin 1 Vitamin K antagonists are extremely effective in preventing stroke among AFib patients: 68% relative reduction versus placebo 1 1. Arch Intern Med 1994;154:

6 Limitations of vitamin K antagonists Narrow therapeutic window Wide variation in metabolism, with numerous food and drug interactions Need for regular coagulation monitoring and dose adjustment Slow onset/offset

7 No warfarin 65% Warfarin for AFib Limitations Lead to Inadequate Treatment Adequacy of Anticoagulation in Patients with AFib in Primary Care Practice INR above target 6% INR in target range 15% Subtherapeutic INR 13% Samsa GP, et al. Arch Intern Med 2000;160:967.

8 ACTIVE W Failure of clopidogrel/asa to prevent stroke, embolism, MI or vascular death compared to OAC Lancet 2006; 367:

9 Therefore, there is a need for novel approaches to stroke prevention in AFib with new antithrombotic agents

10 ORAL TTP889 Rivaroxaban Apixaban LY YM150 DU-176b Betrixaban TAK 442 Dabigatran New Anticoagulants X Fibrinogen TF/VIIa VIIIa Xa IIa IXa Adapted from Weitz & Bates, J Thromb Haemost 2007 II Va IX Fibrin AT PARENTERAL TFPI (tifacogin) APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux DX-9065a

11 XIIa Direct Thrombin inhibition XIa IXa Xa II Factor IIa (thrombin) VIIa Dabigatran Tissue factor

12 Original Article Dabigatran versus Warfarin in Patients with Atrial Fibrillation Stuart J. Connolly, M.D., Michael D. Ezekowitz, M.B., Ch.B., D.Phil., Salim Yusuf, F.R.C.P.C., D.Phil., John Eikelboom, M.D., Jonas Oldgren, M.D., Ph.D., Amit Parekh, M.D., Janice Pogue, M.Sc., Paul A. Reilly, Ph.D., Ellison Themeles, B.A., Jeanne Varrone, M.D., Susan Wang, Ph.D., Marco Alings, M.D., Ph.D., Denis Xavier, M.D., Jun Zhu, M.D., Rafael Diaz, M.D., Basil S. Lewis, M.D., Harald Darius, M.D., Hans- Christoph Diener, M.D., Ph.D., Campbell D. Joyner, M.D., Lars Wallentin, M.D., Ph.D., and the RE-LY Steering Committee and Investigators N Engl J Med Volume 361(12): September 17, 2009

13 Study Overview In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism

14 Conclusion 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

15 Acute venous thromboembolism Incidence 1-2/1000 in the general population Recurrence is one of the major complications With full anticoagulation, risk of recurrence in the first 6-12 months 25%->3% Risk of recurrence remains 5-10% within the first year after the discontinuation of anticoagulation Standard of therapy: Heparin LMWH Warfarin

16 Original Article Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism Sam Schulman, M.D., Clive Kearon, M.D., Ajay K. Kakkar, M.D., Patrick Mismetti, M.D., Sebastian Schellong, M.D., Henry Eriksson, M.D., David Baanstra, M.Sc., Janet Schnee, M.D., Samuel Z. Goldhaber, M.D., for the RE-COVER Study Group N Engl J Med Volume 361(24): December 10, 2009

17 Study Overview In this comparative-effectiveness trial, the oral direct thrombin inhibitor dabigatran was shown to be as effective as warfarin in the prevention of recurrent venous thromboembolism Bleeding complications were similar Dabigatran therapy offers the advantage that monitoring of anticoagulation is not necessary

18 Conclusion For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring

Dabigatran 150 mg once daily for people older than 75/ those with creatinine clearance of 30-50 ml/min/ those taking

19 Dabigatran 150 mg once daily for people older than 75/ those with creatinine clearance of ml/min/ those taking verapamil or amiodarone/ 220 mg once daily in all other patients Rivaroxaban 10 mg once daily Apixaban 2.5 mg twice daily

20 XIIa Direct Factor Xa inhibition XIa IXa Fibrinogen Xa Factor II (prothrombin) Fibrin clot VIIa Rivaroxaban Apixaban YM150 DU-176b LY Betrixaban TAK 442 Tissue factor

21 Original Article Apixaban in Patients with Atrial Fibrillation Stuart J. Connolly, M.D., John Eikelboom, M.B., B.S., Campbell Joyner, M.D., Hans- Christoph Diener, M.D., Ph.D., Robert Hart, M.D., Sergey Golitsyn, M.D., Ph.D., Greg Flaker, M.D., Alvaro Avezum, M.D., Ph.D., Stefan H. Hohnloser, M.D., Rafael Diaz, M.D., Mario Talajic, M.D., Jun Zhu, M.D., Prem Pais, M.B., B.S., M.D., Andrzej Budaj, M.D., Ph.D., Alexander Parkhomenko, M.D., Ph.D., Petr Jansky, M.D., Patrick Commerford, M.B., Ch.B., Ru San Tan, M.B., B.S., Kui-Hian Sim, M.B., B.S., Basil S. Lewis, M.D., Walter Van Mieghem, M.D., Gregory Y.H. Lip, M.D., Jae Hyung Kim, M.D., Ph.D., Fernando Lanas-Zanetti, M.D., Antonio Gonzalez-Hermosillo, M.D., Antonio L. Dans, M.D., Muhammad Munawar, M.D., Ph.D., Martin O'Donnell, M.B., Ph.D., John Lawrence, M.D., Gayle Lewis, Rizwan Afzal, M.Sc., Salim Yusuf, M.B., B.S., D.Phil., for the AVERROES Steering Committee and Investigators N Engl J Med Volume 364(9): March 3, 2011

22 Study Overview In this trial, the factor Xa inhibitor apixaban was shown to reduce the risk of stroke or systemic embolism, as compared with aspirin, without a significant increase in the risk of major bleeding. Apixaban is an alternative to aspirin for patients who cannot take warfarin..

23 Conclusions In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage.

24 Original Article Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D., Jyotsna Garg, M.S., Guohua Pan, Ph.D., Daniel E. Singer, M.D., Werner Hacke, M.D., Ph.D., Günter Breithardt, M.D., Jonathan L. Halperin, M.D., Graeme J. Hankey, M.D., Jonathan P. Piccini, M.D., Richard C. Becker, M.D., Christopher C. Nessel, M.D., John F. Paolini, M.D., Ph.D., Scott D. Berkowitz, M.D., Keith A.A. Fox, M.B., Ch.B., Robert M. Califf, M.D., and the ROCKET AF Steering Committee, for the ROCKET AF Investigators N Engl J Med Volume 365(10): September 8, 2011

25 Study Overview In this trial, 14,264 patients with atrial fibrillation were randomly assigned to receive either rivaroxaban or warfarin. In a per-protocol, as-treated analysis, rivaroxaban was noninferior to warfarin with respect to the primary end point of stroke or systemic embolism.

26 Conclusions In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.

27 Original Article Apixaban versus Warfarin in Patients with Atrial Fibrillation Christopher B. Granger, M.D., John H. Alexander, M.D., M.H.S., John J.V. McMurray, M.D., Renato D. Lopes, M.D., Ph.D., Elaine M. Hylek, M.D., M.P.H., Michael Hanna, M.D., Hussein R. Al-Khalidi, Ph.D., Jack Ansell, M.D., Dan Atar, M.D., Alvaro Avezum, M.D., Ph.D., M. Cecilia Bahit, M.D., Rafael Diaz, M.D., J. Donald Easton, M.D., Justin A. Ezekowitz, M.B., B.Ch., Greg Flaker, M.D., David Garcia, M.D., Margarida Geraldes, Ph.D., Bernard J. Gersh, M.D., Sergey Golitsyn, M.D., Ph.D., Shinya Goto, M.D., Antonio G. Hermosillo, M.D., Stefan H. Hohnloser, M.D., John Horowitz, M.D., Puneet Mohan, M.D., Ph.D., Petr Jansky, M.D., Basil S. Lewis, M.D., Jose Luis Lopez-Sendon, M.D., Prem Pais, M.D., Alexander Parkhomenko, M.D., Freek W.A. Verheugt, M.D., Ph.D., Jun Zhu, M.D., Lars Wallentin, M.D., Ph.D., for the ARISTOTLE Committees and Investigators N Engl J Med Volume 365(11): September 15, 2011

28 Study Overview The oral direct factor Xa inhibitor, apixaban, was compared with warfarin in atrial fibrillation. Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and lowered mortality.

29 Conclusions In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

30 New and old anticoagulants Features Warfarin New agents Onset Slow Rapid Dosing Variable Fixed Food/drug interactions Many None or very few Monitoring Yes No Half life Long Short Antidote Yes No

31 Comparison of the New anticoagulants Mechanism of action Dabigatran Rivaroxaban Apixaban direct thrombin inhibitor (both free and clot-bound) direct factor Xa inhibitor Bioavailability 7.2% >80% >50% Peak concentration 1.5hrs 3hrs 3-4hrs Half life 14-17hrs 4-9hrs (up to 12hrs in patients >75yo) Metabolism Interaction Garcia D et al. Blood. 2010;115: activated by liver up to 80% excreted by kidney quinine/quinidine, verapamil 66% excreted by kidney very few direct factor Xa inhibitor 10-14hrs Partially by CYP3A4 25% excreted by kidney very few (does not inhibit or induce CYP enzymes)

32 Potential Concerns of Novel No antidotes Anticoagulants No methods assessing compliance No close clinical surveillance Reduced awareness of the therapy Cost

33 Cost Comparison of Anticoagulants Agents Cost daily (Canada) Cost daily (drugstore.com) Warfarin Enoxaparin $0.4 (not including INR monitoring) $12.38 for 30mg twice daily $8.20 for 40mg once daily $0.5 (presumed 5mg tablets daily, INR monitor excluded) $25 per 40mg syringe Fondaparinux $15.08 $140/7.5mg, $60/2.5mg Dabigatran $7.85 $14.6 Rivaroxaban N/A N/A Apixaban N/A N/A Canadian Agency for Drugs and Technologies in Health

34 Nonhemostatic Actions Triggered by the Tissue Factor and Common Activation Pathways in the Phenotypic Modulation of the Arterial Wall. Borissoff JI et al. N Engl J Med 2011;364:

35 MI was significantly more common with dabigatran than with warfarin..

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