New Oral Anticoagulants in treatment of VTE, PE DR.AMR HANAFY (LECTURER OF CARDIOLOGY ) ASWAN UNIVERSITY

New Oral Anticoagulants in treatment of VTE, PE DR.AMR HANAFY (LECTURER OF CARDIOLOGY ) ASWAN UNIVERSITY

Fact VTE is deadly! It nibbles after it bites! The 30-day mortality rates for first-time DVT or pulmonary embolism 2 3.0% and 31%, respectively

Rationale Anticoagulant therapy remains the mainstay of medical therapy for DVT because it(s) Is noninvasive, Treats most patients (approximately 90%) with no immediate demonstrable physical sequelae of DVT, Has low risk of complications, and outcome data demonstrate an improvement in morbidity and mortality.

Targets of Older Anticoagulants Xll UFH LMWH ATIII Xl lx VIIIa VII TF Fondaparinux ATIII Va X II I VK Argatroban Vitamin K antagonists Fibrin Clot Bivalirudin UFH = unfractionated heparin; LMWH = low molecular-weight heparin; VK = vitamin K; ATIII = antithrombin III. Adapted from Ansell J. J Thromb Haemost. 2007;5(suppl 1):60-64. Hirsh J et al. Circulation. 2007;116:552-560. Hirsh J et al. J Am Coll Cardiol. 2003;41:1633-1652.

What s wrong with traditional anticoagulants??? Traditional anticoagulants have 2 major limitations: - Narrow therapeutic window of adequate anticoagulation without bleeding - Highly variable dose-response, requiring monitoring by lab testing These limitations have provided impetus for development of other antithrombotic agents>>>>noval oral anticoagulants(noacs).

Targets of NOACs Xll Xl lx VIIIa X VII TF Factor Xa inhibitors Focus of clinical trials VTE prevention and treatment Stroke prevention in AF Rivaroxban Va II I Direct thrombin inhibitors Dabigatran Apixaban Edoxaban Fibrin Clot Inhibition *Dabigatran was approved for VTE prophylaxis in Canada, the EU, and Columbia in 2008. Adapted from Ansell J. J Thromb Haemost. 2007;5(suppl 1):60-64. Turpie AGG. Arterioscler Thromb Vasc Biol. 2007;27:1238-124 National Institutes of Health - ClinicalTrials.gov. - last accessed July 2013

Indications 1. Prevention of venous thromboembolism in a patient undergoing total hip or knee replacement 2. Prevention of stroke or systemic embolism in patients who have non-valvular atrial fibrillation and has one or more risk factors for developing stroke or systemic embolism 3. Rivaroxaban for the prevention of recurrent venous thromboembolism and for the treatment of deep vein thrombosis and pulmonary embolism.

Features of NOAC Features to consider - Faster onset - Shorter ½ life - Less drug-drug interactions - No need for monitoring with NOACs(except in liver and renal disease) - Allows predictable anticoagulation with no need for dose adjustments

Journal.pone.0144856 December 30, 2015

Journal.pone.0144856 December 30, 2015

J Plos one. 2015; 0144 856

All NOACs showed similar efficacy to standard treatment All NOACs showed non-inferiority in bleeding risk Apixaban showed superiority in bleeding risk J Plos one. 2015; 0144 856

Pharmacokinetics

Renal function impact on NOAC half lives Renal function impact on NOAC half lives

Rivaroxaban Highly selective direct Factor Xa inhibitor with oral bioavailability and Take with food Effects last approximately 12 hour. but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible Extremes in weight do not influence Does not require parenteral anticoagulation prior to initiation Renal and hepatic impairment Cr Cl < 30: avoid use Moderate-severe hepatic impairment: avoid use Predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) With flat dose response across an eightfold dose range (5 40 mg) ONE TABLET..ONE DOSE ONCE A DAY

Rivaroxaban Dosing DVT/PE treatment: 15mg BD x 21 days followed by 20mg OD 10 mg: Prevention of venous thromboembolism(vte) in adult patients undergoing elective hip or knee replacement surgery. 15 mg / 20 mg: Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation Treatment of DVT and PE, and prevention of recurrent DVT and PE in adults. Reduction in risk of recurrence: 20mg OD

Rivaroxaban Discontinuation for surgery or other procedures Stop rivaroxaban at least 24 hours before procedure Restart rivaroxaban after surgery/procedure as soon as adequate hemostasis is established Switching to rivaroxaban From warfarin to rivaroxaban: Discontinue warfarin and start rivaroxaban as soon as INR is below 3.0 From anticoagulant other than warfarin to rivaroxaban: Start rivaroxaban 0 to 2 hours prior to next scheduled evening administration of the drug and omit administration of the other anticoagulant From unfractionated heparin continuous infusion to rivaroxaban: Stop infusion and start rivaroxaban at the same time

Apixaban Highly selective, orally bioavailable, and reversible direct inhibitor of free and clotbound factor Xa IDosing DVT treatment: 10mg BD x 7 days followed by 5mg BD Does not require parenteral anticoagulation prior to initiation Reduction in risk of recurrence: 2.5mg BD Renal impairment CrCl < 30: use with caution Decrease dose to 2.5 mg PO BD in patients with any 2 of the following characteristics: Age 80 years Weight 60 kg Serum creatinine 1.5 mg/dl Surgery/procedures Discontinue at least 48 hr before elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding

DVT or PE Treatment EDOXABAN Indicated for treatment in patients who have been initially treated with a parenteral anticoagulant for 5-10 days >60 kg: 60 mg PO OD 60 kg: 30 mg PO OD Renal impairment (DVT/PE) >50 ml/min: No dosage adjustment required 15-50 ml/min: 30 mg PO OD

Hepatic impairment Mild (Child-Pugh A): No dose adjustment required Moderate-to-severe (Child-Pugh B/C): Not recommended; Transition to edoxaban From warfarin or other vitamin K antagonists (VKAs): Discontinue warfarin and start edoxaban when INR 2.5 From oral anticoagulants other than warfarin or other VKAs: Discontinue current oral anticoagulant and initiate edoxaban at the time of the next scheduled dose of the previous oral anticoagulant From low molecular weight heparin (LMWH): Discontinue LMWH and initiate edoxaban at the time of the next scheduled administration of LMWH From unfractionated heparin: Discontinue heparin infusion and initiate edoxaban 4 hr later

Dabigatran Direct thrombin inhibitor Treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days CrCl >30 ml/min: 150 mg PO BD CrCl 30 ml/min or on dialysis: not indicated Prevention of VTE in hip/knee replacement surgery dose: 220 mg PO OD

Discontinuation for surgery and other interventions Discontinue dabigatran 1 to 2 days (CrCl 50 ml/min) or 3 to 5 days (CrCl <50 ml/min) before invasive or surgical procedures because of the increased risk of bleeding Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required

NOAC Parenteral needed Weight adj Unique Reversal Rivaroxaban No No Take with food Andexanat alfa Apixaban No ~ No Pregnancy B Andexanat alfa Edoxaban Yes Yes CrCl > 95: avoid No Dabigatran Yes No GI upset Praxbind, dialyzable

Contraindications for NOACs Known hypersensitivity to ingredients of NOAC Clinically significant active bleeding Renal impairment <30ml/min Hepatic disease (child pugh C) Recent high risk bleeding lesion (eg. ICH < 6 months) Pregnancy or breast feeding Recent stroke, surgery, GI bleed or ulcer Recent fibronolytic therapy <10days Concomitant warfarin therapy

Dosing Total hip / knee replacement (VTE prophylaxis) Dagibatran Rivaroxaban Apixaban Crcl > 50ml / min 220mg once daily 10mg once daily Crcl 30 50ml / min 150mg once daily 10mg once daily 2.5mg once daily Crcl 15-30ml / min contraindicated contraindicated

Switching anticoagulants Switching from Switching to Instructions LMW Heparin NOACs When next dose of LMW Heparin is due Heparin NOACs Immediately when heparin ceased Warfarin NOACs Start once INR < 2 Dagibatran LMW heparin / UFH No bolus required. Start 12 hrs after last dose Rivaroxaban / Apixaban LMW heparin / UFH No bolus required. Start 24 hrs after last dose NOACs Warfarin Continue NOAC and give warfarin 5 mg Stop NOAC once INR 2 on 2 consecutive days

What do we do when patients bleed?

Management of bleeding Seek early haematology advice Dagibatran: Measure: CBC, Urea &E,lectrolyte, Live FT, coagulation profile, Haemoclot and dabigatran level normal aptt suggests bleeding not due to dabigatran

Management of bleeding (Initial Ix) Rivaroxaban / Apixaban: Measure: CBC, U&E, LFT, coagulation profile, anti-xa and rivaroxaban level normal PT suggests rivaroxaban level not high tests are currently inconclusive for apixaban

Management of bleeding (mild) Mild bleeding - - local haemostatic measures - delay or discontinue NOAC as required

Management of bleeding (clinically significant) reduction in Hb >20 g/l or requiring RBC transfusion > 2 units Stop NOAC therapy Give oral charcoal if NOAC ingested < 2 hours ago Maintain adequate hydration to aid drug clearance Local haemostatic measures: mechanical compression Transfusion support: RBC transfusion as per Hb level Consider platelet transfusion if on antiplatelet therapy or if platelets < 50 x 109/L Consider radiological and surgical interventions to identify and treat source of bleeding

Prescribing a new oral anticoagulant 1. Detailed History EXCLUSION Criteria: -Known hypersensitivity to NOAC preparation -Pregnant or breastfeeding -Stable warfarin therapy -Prosthetic heart valve -Recent stroke

Prescribing a new oral anticoagulant 2. Lab tests FBC, EUC, LFTs Contraindications: -Poor renal function (CrCl 30 ml/ min, apixaban: 15 ml/min) -Liver disease (e.g. ALT > 3x upper limit of normal) -Hb 100 g/l (assess risk vs. benefit)

Prescribing a new oral anticoagulant 3. Assess bleeding risk -Disorder of haemostasis -Recent surgery ( 1 month ago) -GI bleed 12 months ago -Ulcer 30 days ago -Fibrinolytic treatment last 10 days -Dual antiplatelet therapy

Prescribing a new oral anticoagulant 4. Consider contaminant medications Rivaroxaban / Apixaban -Systemic azole antifungals (except fluconazole) -HIV-protease inhibitors Dabigatran -Systemic azole antifungals (except fluconazole) -Dronedarone -Simultaneous initiation with verapamil -Cyclosporin and Tacrolimus

NOAC endorsement by evidence based guidelines: CHEST 2016 ACCP Based on less bleeding with NOACs and greater convenience for patients and healthcare providers, we now suggest that a NOAC is used in preference to VKA for the initial and long-term treatment of VTE in patients without cancer. (Grade 2B) Kearon C et al Antithrombotic Therapy for VTE Disease: CHEST Guideline, Chest 2016;149:315-352

Take home massage Venous thromboembolism (VTE) is a common disease associated with high risk for recurrences, death, and late sequelae, accounting for substantial health care costs. NOCAs were noninferior and probably safer than conventional anticoagulation therapy Oral anticoagulant that can be administered in fixed doses, without laboratory monitoring and dose adjustment, is a landmark change in the treatment of VTE