Sektion CAMPUS INNENSTADT Med. Klinik und Poliklinik IV NOAC s across indications Ulrich Hoffmann, M.D. Division of Vascular Medicine University Hospital Munich, Germany
Disclosure Speaker name: Ulrich Hoffmann I have the following potential conflicts of interest to report: x Consulting & lecture fees (Bayer Health Care, Boehringer, Pfizer, BMS, Daiichi Sankyo, Leo, Aspen) Employment in industry Stockholder of a healthcare company Owner of a healthcare company Other(s) I do not have any potential conflict of interest
Pharmacology of NOAC s Dabigatran 1 Rivaroxaban 2,3 Apixaban 4 Edoxaban 5 9 Target Molecule IIa (Thrombin) Xa Xa Xa Bioavailability, % 3 7 80 50 62 Hrs to C max 1 3 2 4 3 4 1 2 Halflife, hrs. 12 17 5 13 12 10-14 Renale Clearance, % 80 33 27 35* Transporter P-gp P-gp P-gp P-gp CYP-Metabolism, % None 32 % < 32 % < 4 % Proteinbinding, % 35 92 95 87 40 59 Dose regimen bid qd bid. qd CYP: Cytochrom P450; P-gp: P-glycoprotein *of the dosage applied 1.Pradaxa [Packungsbeilage]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 2013 2. Xarelto [Packungsbeilage]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2011 3. Weinz et al. Drug Dispos Metab 2009;37:1056 1064 4. ELIQUIS Zusammenfassung der Merkmale des Arzneimittels. Bristol Myers Squibb/Pfizer EEIG, Vereinigtes Königreich 5. Matsushima et al. Am Assoc Pharm Sci 2011; Abstract; 6. Ogata et al. J Clin Pharmacol 2010;50:743 753 7. Mendell et al. Am J Cardiovasc Drugs 2013;13:331 342; 8. Bathala et al. Drug Metab Dispos 2012;40:2250 2255 9. Giugliano et. al. Am J Cardiovas Drugs; e-pub ahead of print
NOACs in nonvalvular Atrial Fibrillation Compared to warfarin Better efficacy 51 % lower rate of hemorrhagic stroke 10 % lower mortality Better safety 52 % lower rate of intracranial bleeding 4 Ruff et al. Lancet. 2014;383:955-62 (Metaanalysis of all phase III studies).
NOAC s in Venous Thromboembolism Compared to LMWH/Wafarin Non inferior efficacy Better safety 40 % reduction of major bleedings Safety (major bleeding) 5 Nick van Es et al., Blood 2014;124:1968-1975
Concepts tested in Phase III VTE Trials Single-drug approach Rivaroxaban (Xarelto ) 2 x 15 mg 3 weeks 1x 20 mg Rivaroxaban Apixaban (Eliquis ) 2x 10 mg 1 week 2x 5 mg Apixaban 2x2.5 mg Apixaban after 6 mo Switching Dabigatran (Pradaxa ) LMWH 1 week 2x 150 mg Dabigatran Edoxaban (Lixiana ) LMWH 1 week 1x 60 mg Edoxaban
EINSTEIN CHOICE LONG-TERM SECONDARY VTE PREVENTION STUDY Official study title: Reduced-dosed Rivaroxaban and Standard-dosed Rivaroxaban Versus ASA in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism in Patients With Symptomatic Deep-vein Thrombosis and/or Pulmonary Embolism Objective: efficacy and safety of reduced-dosed rivaroxaban, standard-dosed rivaroxaban versus ASA for the long-term secondary prevention of recurrent symptomatic VTE in patients with symptomatic DVT and/or PE Rivaroxaban 20 mg od Day 1 n~950 Population: DVT and/or PE after 6 12 months of anticoagulation* N~3,300 R Rivaroxaban 10 mg od n~950 ASA 100 mg od n~950 12-month treatment duration 1 month observation period Short design: Multicentre, randomized, double-blind, doubledummy, active-comparator, event-driven, superiority study Indication: VTEx FPFV: Q1-14 LPLV: Q4-16 *Completed 6 12 months (±1 month) with interruption of anticoagulation 1 week at randomization www.clinicaltrials.gov/ct2/show/nct02064439 Weitz JI et al. Thromb Haemost 2015
ATLAS ACS 2-TIMI 51 EFFICACY AND SAFETY ENDPOINTS Event rate % Standard medical therapy ASA Standard medical therapy Death from any cause HR=0,68 (0,53-0,87) Nicht TIMI ACVB-assoziierte non-cabg major Fatal bleedings schwere bleedings TIMI Blutungen* HR 3,46 (2,08-5,77) Mega et al. N Engl J Med 2012;366:9 19.
COMPASS CAD/PAD STUDY Official study title: A Randomized Controlled Trial of Rivaroxaban for the Prevention of Major Cardiovascular Events in Patients With Coronary or Peripheral Artery Disease (COMPASS - Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) Objective: efficacy and safety of rivaroxaban, low-dose rivaroxaban plus ASA or ASA alone for reducing risk of MI, stroke or cardiovascular death in CAD or PAD Rivaroxaban 2.5 mg bid + ASA 100 mg od ± pantoprazole 40 mg od Population: Documented CAD or PAD N~21,000 1:1:1 30-day run-in, ASA 100 mg R Rivaroxaban 5.0 mg bid + ASA 100 mg od ± pantoprazole 40 mg od ASA 100 mg od ± pantoprazole 40 mg od Final follow-up visit # 30-day washout period* Final washout period visit Short design: Randomized, double-blind, controlled trial Indication: CAD/PAD Start: Q2-13 LPLV: Q1-18 *Patients treated according to local standard of care; # 30 days of the required pre-specified Angiologie number - Gefäßzentrum of events having occurred www.clinicaltrials.gov/show/nct01776424
VOYAGER PAD STUDY Objective: Efficacy and Safety of Rivaroxaban for the Reduction of Thrombotic Vascular Events in Subjects with PAD Undergoing Peripheral Revascularization Procedures Rivaroxaban 2.5 mg bid + ASA 100 mg od Population: Patients with symptomatic PAD undergoing peripheral revascularization N~6500 R 1:1 Event-driven study 30 days Safety Follow-up Day 1 ASA 100 mg od Efficacy Cut-off Date Study End Mean treatment duration per patient: ~30 months Short design: Randomized, multicenter, prospective, double-blind, double-dummy, parallel-group, placebo-controlled, event-driven Indication: PAD FPFV: Q2-2015 LPLV: Q1-2019 www.clinicaltrials.gov/ct2/show/nct02504216
NOAC s across indications Ongoing non-cardiac phase III vascular studies Cerebrovascular Acute nondisabling cerebrovascular events Embolic stroke of undetermined source VTE Long term prevention of VTE (prophylactic dosage) Cancer related venous thromboembolism VTE in children Thrombembolism in anti-phospholipid AB Syndrome Medically ill patients at risk for VTE PAD Major CV events in CAD and PAD patients Thrombotic vascular events in PAD patients undergoing peripheral artery interventions 11
Thank you for your attention 12
Sektion CAMPUS INNENSTADT Med. Klinik und Poliklinik IV NOAC s across indications Ulrich Hoffmann, M.D. Division of Vascular Medicine University Hospital Munich, Germany