Perioperative management of antithrombotic drugs: New anticoagulants

Transcription

1 Perioperative management of antithrombotic drugs: New anticoagulants Steen Husted Medical-Cardiological Department Aarhus University Hospital Denmark ESC 2010

2 Perioperative anticoagulation: Risk of bleeding Risk of thromboembolism

3 Evaluating the risk of perioperative bleeding and thromboembolism Important for the risk of bleeding: 1) Patient characteristics hemorrhagic tendency, previous bleeding, previous stroke, high age, reduced renal function etc. 2) Type and intensity of antithrombotic treatment 3) Type of surgery Important for the risk of thromboembolism: 1) Patient co-morbidity 2) Indication for antithrombotic treatment 3) Type of surgery

4 Type of patient: Venous thromboembolism and cardioembolism Low-risk patients - Biological artificial heart valve or mitral valve surgery (>3 mo.) - Venous thromboembolic event (>3 mo.) - Atrial fibrillation without high risk factors* or with no more than one moderate risk factor** - Previous venous thromboembolic event in a patient with mild thrombophilia Anticardiolipin antibodies without lupus anticoagulants Heterozygous for Factor V Leiden or prothrombin variant *previous ischemic stroke, TIA or systemic embolism, artificial heart valve ** left ventricle systolic dysfunction (EF < 30%) and/or heart insufficiency, age >75 year, hypertension, diabetes mellitus.

5 Type of patient: Venous thromboembolism and cardioembolism High-risk patients - Mechanic artificial heart valve - Biologic artificial heart valve or mitral valve surgery (<3 mdr.) - Recent venous thromboembolic event (<3 mo.) - Atrial fibrillation with at least one high risk factor* or at least two moderate risk factors** - Previous venous thromboembolism in patient with severe thrombophilia Lupus anticoagulants Antithrombin deficiency Protein C or protein S deficiency Combined thrombophilic risk fators Homozygous for Faktor V Leiden or prothrombin variant Cancer *previous ischemic stroke, TIA or systemic embolism, artificial heart valve ** left ventricle systolic dysfunction (EF < 30%) and/or heart insufficiency, age >75 year, hypertension, diabetes mellitus.

6 Type of patient: Atherothrombosis Low-risk patients 1) > 12 months after ACS and without angina 2) > 12 months after PCI with stent 3) > 3 months after stroke/tci 4) Intermittent claudication

7 Type of patient: Atherothrombosis High-risk patients 1) 1-12 months after ACS with stable angina 2) 1-12 months after PCI with BMS 3 ) 6-12 months after PCI with DES 3) 1 week-3 months after stroke/tci

8 Type of patient: Atherothrombosis Very high-risk patients 1) <1 month after ACS with angina 2) <1 month after PCI with BMS 3 ) <6 month after PCI with DES 3) <1 week after stroke/tci

9 Bleeding risk category Low-risk patients Diagnostic endoscopy Cataract surgery Oral surgery/dental extraction Arthrocentesis Cutaneous surgery Hernia repair Scrotal surgery Coronary angiography

10 Bleeding risk category High-risk patients Major intraabdominal surgery Major vascular surgery Major orthopedic surgery Prostatectomy or bladder surgery Heart valve replacement Coronary artery bypass graft surgery Major intrathoracic surgery Major cancer surgery Pacemaker Insertion/implantation Biopsy in non-compressible tissue Puncture in non-compressible artery Epidural and spinal anesthesia Very high-risk patients Neurosurgical procedures Retinal surgery

11 Bridging therapy with low-molecularweight heparin (LMWH) Stop anticoagulant therapy preoperatively Start therapeutic LMWH 2-4 days before procedure with last dose 24 hours before Postprocedural start of anticoagulant therapy on day 1,2 or 3 dependent on hemostasis Standard LMWH prophylaxis administered periprocedural Douketis JD et al., Arch Intern Med 2004;164:1319, Kovacs MJ et al. Circulation 2004;110:1658; Douketis JD et al., Chest 2008 ;133:S299

12 Dose of LMWH used for bridging LMWH-type Daily dose Enoxaparin (Klexane ) 1 mg/kg x 2 Tinzaparin (Innohep ) 90 IE/kg x 2 Dalteparin (Fragmin ) 100 IE/kg x 2

13 Adapted from Weitz & Bates, J Thromb Haemost 2005; Ahrens I et al, Thromb Haemost 2010 New anticoagulants ORAL PARENTERAL TTP889 TF/VIIa TFPI (tifacogin) X IX Rivaroxaban Apixaban Edoxaban Betrixaban Eribaxaban LY YM150 TAK-442 Dabigatran etexilate AZD0837 IXa VIIIa Va Xa II IIa AT APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux Biotinylated idraparinux DX-9065a Otamixaban Fibrinogen Fibrin

14 Adapted from Weitz & Bates, J Thromb Haemost 2005; Ahrens I et al, Thromb Haemost 2010 New anticoagulants ORAL PARENTERAL TTP889 TF/VIIa TFPI (tifacogin) X IX Rivaroxaban Apixaban Edoxaban Betrixaban Eribaxaban LY YM150 TAK-442 Dabigatran etexilate AZD0837 IXa VIIIa Va Xa II IIa AT APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idraparinux Biotinylated idraparinux DX-9065a Otamixaban Fibrinogen Fibrin

15 Apixaban Small molecule, potent reversible inhibitor of factor Xa l Inhibits both prothrombinase-bound and free factor Xa Good oral bioavailability No food effects observed Multiple routes of elimination (25% renal) T 1/2 approximately 9 to 14 hours No monitoring No antidote Gross PL, Weitz JI. Arterioscler Thromb Vasc Biol. 2008;28:

16 Apixaban Clinical Program Overview ADVANCE-1 Trial ADVANCE-2 Trial ADVANCE-3 Trial ADOPT Trial ARISTOTLE Trial AVERROES Trial APPRAISE -1 Trial ADVOCATE Trial Phase III trial for VTE prevention in knee replacement 3000 patients Finished Phase III trial for VTE prevention in knee replacement 3000 patients Finished Phase III trial for VTE prevention in hip replacement 4000 patients Finished Phase III trial in acutely ill medical patients 6,500 patients Phase III atrial fibrillation Double blind design versus warfarin 18,000 patients Inclusion finished february 2010 Phase III atrial fibrillation Double blind design versus aspirin 5,600 patients Inclusion finished 2009 Phase II ACS 1,800 patients Published Circulation 2009 Phase II VTE prevention in cancer 160 patients ACS=acute coronary syndrome; VTE=venous thromboembolism

17 Perioperative apixaban Bleeding risk low Bleeding risk high Thrombosis risk low Stop apixaban for 24 hours Stop apixaban for 48 hours* Thrombosis risk high Stop apixaban for 24 hours Stop apixaban for 48 hours* *Restart apixaban 1-3 days postop. dependent on hemostasis. Standard LMWH prophylaxis used until then.

18 Rivaroxaban (Xarelto ) Small molecule, potent reversible inhibitor of factor Xa Good oral bioavailability T 1/2 approximately l 5-9 h in younger patients l h in elderly patients Metabolized by the liver Renal clearance l 66% excreted by kidneys No monitoring No antidote Gross PL, Weitz JI. Arterioscler Thromb Vasc Biol. 2008;28:

19 Rivaroxaban Clinical Program Overview RECORD-1-4 Registered for thrombosis prophylaxis in knee and hip surgery EINSTEIN ROCKET AF ATLAS 2 TIMI51 MAGELLAN Phase III VTE treatment and long-term secondary prevention 7500 patients Phase III atrial fibrillation 14,000 patients Phase III ACS 15,000 patients Phase III medically ill patients 8,000 patients ACS=acute coronary syndrome; AF=atrial fibrillation; VTE=venous thromboembolism

20 Perioperative rivaroxaban Bleeding risk low Bleeding risk high Thrombosis risk low Thrombosis risk high Stop rivaroxaban for 24 hours Stop rivaroxaban for 24 hours Stop rivaroxaban for 48 hours* Stop rivaroxaban for 48 hours* *Restart rivaroxaban 1-3 days postop. dependent on hemostasis. Standard LMWH prophylaxis used until then.

21 Dabigatran etexilate (Pradaxa ) Dabigatran Active site of thrombin molecule Thrombin Rapid oral absorption and biotransformation of prodrug to active drug Mainly renal excretion Not metabolised T ½ hours (CrCl >50 ml/min) and 27 hours (CrCl <30 ml/min) Low potential for food/drug interactions No coagulation monitoring required Fixed dosing and predictable response Clinical data demonstrates efficacy with bid dosing No antidote

22 Dabigatran etixilate clinical program: Overview Completed Primary VTE Prevention Registered for thrombosis prophylaxis in knee and hip surgery VTE Treatment VTE Secondary Prevention Stroke Prevention in Patients with AF Secondary Prevention of Cardiac Events in Patients with ACS Ongoing N=2600 N=2600 N=2000 N=1800 N=18,000 N=1800 ACS=acute coronary syndrome; AF=atrial fibrillation; VTE=venous thromboembolism

23 Perioperative dabigatran etexilate Bleeding risk: Renal function (CrCl ml/min) >80 >50 to <80 Half-life (hours) 13 (11-22) 15 (12-34) Low bleeding risk Dabigatran discontinuation before surgery 24 hours 24 hours High Bleeding risk Dabigatran discontinuation before surgery 2-4 days 2-4 days >30 to <50 <30 18 (13-23) 27 (22-35) at least 48 h. 2-5 days 4 days >5 days Van Ryn J et al., Thromb Haemost 2010;103:1116

24 Perioperative dabigatran etexilate Thrombosis risk: Renal function (CrCl m/min) Bleeding risk: Low High bleeding risk bleeding risk Low thrombosis risk High thrombosis risk >30 <30 >30 <30 Stop dabigatran for 1-2 days Stop dabigatran for 4-5 day Stop dabigatran for 24 hours Stop dabigatran for 4-5 days with LMWH bridging* *Dabigatran restarted 1-3 days postop. dependent on hemostasis. Standard LMWH prophylaxis used until then. Stop dabigatran for 4-5 days* Stop dabigatran for 4-5 days with LMWH bridging* Van Ryn J et al., Thromb Haemost 2010;103:1116

25 Idraparinux/Idrabiotaparinux Novel, synthetic pentasaccharide T ½ 80 hours Administered sc once weekly s.c. Dosage must be reduced in patients with renal insufficiency Does not require monitoring The biotinylated version inactivated by avidin sc=subcutaneously; VTE=venous thromboembolism Gross PL, Weitz JI. Arterioscler Thromb Vasc Biol. 2008;28:

26 Idrabiotaparinux: Clinical Phase 3 Program Overview Trial Disease and patient segment Status CASSIOPEA Management of PE Enrolling Clinical study assessing SSR126517E injections once-weekly in pulmonary embolism therapeutic approach. EQUINOX International, randomized, double-blind, double-dummy, parallel group study. Bioequipotency study of SSR126517E and Idraparinux in patients with deep venous thrombosis of the lower limbs and study of the neutralizing effect of SSR29261 on the SSR126517Einduced Anti-Xa activity Management of DVT Enrollment completed BOREALIS- AF SSR126517E against warfarin in Patients with atrial fibrillation Prevention of ischemic stroke in atrial fibrillation Study stopped prematurely

27 Avidin : Product profile l Heterologous tetrameric glycoprotein extracted from hen egg whites l High affinity for biotin (Kd=10-15 ) AT Xa l Increased biotinylated idraparinux clearance via a specific, immediate action Biotin arm Avidin Idraparinux Indication: Neutralization of the anticoagulant activity of biotinylated idraparinux (SSR126517E)

28 PK profile of circulating idrabiotaparinux (SSR126517) and debiotinylated active metabolite (SSR115771) in VTE dose regimen 3 mg idrabiotaparinux sc weekly for 6 months SSR SSR Plasma Conc (µm) Time (Months)

29 Reversal of anticoagulant activity at short notice in case of bleeding, overdose, or urgent invasive procedure Two weeks after the last idrabiotaparinux injection there is a negligible amount of circulating biotinylated idraparinux. Therefore there is no rationale to administer avidin beyond 2 weeks after end of treatment with idrabiotaparinux. Avidin indicated at any time from randomization up to 2 weeks following the last injection of idrabiotaparinux. Because of low concetrations of active matabolite avidin alone is sufficient during the first 2 months of treatment with idrabiotaparinux as a first approach for neutralizing anti-xa activity.

30 Reversal of anticoagulant activity for planned invasive procedure Recommended time to wait between the last weekly injection and the procedure (i.e. the time needed to reach a level of inhibition of factor Xa close to the level observed 7 days after a single injection of idrabiotaparinux): 3 weeks for an idrabiotaparinux treatment duration of 2 months or less 2 months for idrabiotaparinux treatment duration of more than 2 months.

31 Reversal of anticoagulant activity at short notice in case of bleeding, overdose, or urgent invasive procedure The use of procoagulant factors (i.e. fresh frozen plasma, prothrombin complex concentrates; or recombinant activated factor VII the latest having been shown to shorten idraparinuxinduced thrombin generation times in healthy subjects), should be considered before procedures with a risk of life threatening bleeding, or of bleeding with potential serious consequences (e.g. closed space surgery such as eye surgery, needle biopsy of deep structures,lumbar puncture).

32 Perioperative idrabiotaparinux (Idbiop) Conclusion: Avidin should be used with last injection of Idbiop within 2 weeks Alternatively if possible in elective cases a treatment pause of 3 weeks with less than 2 months of therapy and 2 months with more than 2 months of therapy with Idbiop Procoagulants should be used in case of urgent intervention with avidin from 2 months after the first and to 2 weeks after the last Idbiop injection and alone from 2 weeks to two months after the last injection Perioperative LMWH should be used both when avidin and when procoagulants have been used Idbiop can be restarted postop. on day 1-3 dependent on hemostasis