Xarelto and the New Orals

Xarelto and the New Orals in the ER Peter L. Gross MD M.D., MSc M.Sc., FRCP(c) Associate Professor Thrombosis and Atherosclerosis Research Institute McMaster University Thrombosis Clinic Director, Juravinski Site at HHS peter.gross@taari.ca pgross@mcmaster.ca

Disclosures Peter Gross Grants/Research Support: nil Speakers Honoraria: Bayer, Pfizer, Leo Equity Holder: nil UNLABELED/UNAPPROVED USES UNLABELED/UNAPPROVED USES DISCLOSURE: yes

Learning Objectives Discuss the new oral anticoagulants and their presence in the ER Review the practical management of the new oral anticoagulants in the ER setting Interpret the data for use in patient management

Approach for the talk Patients coming into the ER on the New Orals Bleeding on the New Orals New Orals for treatment of VTE, possibly initiated in the ER

Agenda Indications for New Orals in Canada Introduction to the new orals Approach to bleeding on the new orals New Orals for VTE treatment in ER

Patients coming into the ER on the New Orals

Approved indications for new orals in Canada Indications Drugs and Dosages Dabigatran Rivaroxaban Apixaban Thromboprophylaxis 150 mg or 220 mg 10 mg daily for 14 2.5mg BID for 14 after elective hip or knee replacement daily for 14 days for knees and 30 days for hips days for knees and 30 days for hips days for knees and 30 days for hips Non valvular atrial fibrillation Venous thromboembolism Acute coronary syndromes 150 mg BID or 110 mg BID (for age >75) CrCl >30mL/min Pending 20 mg daily or 15 mg daily if CrCl between 30 49 DVT treatment. 15 mg BID for 21 days then 20 mg daily Pending Studies ongoing No studies Pending Studies ongoing

CCS 2012 Recommendations : Anticoagulation for Stroke Prevention in AF Patients Stratify all patients for risk of stroke (CHADS2) CHADS2 = 0 CHADS2 = 1 CHADS2 2 Increasing stroke risk OAC* OAC No antithrombotic ASA OAC* *ASA is a reasonable alternative in some as indicated by risk/benefit No additional risk factors for stroke Either female sex or vascular Age 65 or combination of female sex and vascular When OAC therapy is indicated, most patients disease disease should receive e dabigatran, rivaroxaban, aban or apixaban (pending approval). Skanes AC, et al. Can J Cardiol. 2012;28:125-136.

XI XII HK PK X Tissue Factor VIIa IX IXa XIa XI XIIa X V Va Xa VIIIa VIII Fibrinogen Prothrombin prothrombinase Thrombin Activated Protein C XIII Fibrin monomer Fibrin polymer XIIIa Cross-linked fibrin polymer

Warfarin XI XII HK PK X Tissue Factor VIIa IX IXa XIa XI XIIa X V Va Xa VIIIa VIII Fibrinogen Prothrombin prothrombinase Thrombin Activated Protein C XIII Fibrin monomer Fibrin polymer XIIIa Cross-linked fibrin polymer

LMWH XI XII HK PK X Tissue Factor VIIa IX IXa XIa XI XIIa X V Va Xa VIIIa VIII Fibrinogen Prothrombin prothrombinase Thrombin Activated Protein C XIII Fibrin monomer Fibrin polymer XIIIa Cross-linked fibrin polymer

hirudins, argatroban, melagatran, dabigatran etc XI XII HK PK X Tissue Factor VIIa IX IXa XIa XI XIIa X V Va Xa VIIIa VIII Fibrinogen Prothrombin prothrombinase Thrombin Activated Protein C XIII Fibrin monomer Fibrin polymer XIIIa Cross-linked fibrin polymer

fondaparinux, rivaroxaban, apixaban etc XI XII HK PK X Tissue Factor VIIa IX IXa XIa XI XIIa X V Va Xa VIIIa VIII Fibrinogen Prothrombin prothrombinase Thrombin Activated Protein C XIII Fibrin monomer Fibrin polymer XIIIa Cross-linked fibrin polymer

New Oral Agents key Pharmaco facts Rivaroxaban Dabigatran Time to Cmax (hrs) 2.5 to 4 2.3 2.9 Half life (hrs) 5.7 9.2 14 17 (varies with CrCl) Renal clearance 33% (of active drug) 80% (50% of metabolized inactive drug) Hepatic clearance 33% (of total) 20% Prodrug No Yes Bioavailability 80% (66% with 20 mg tab) 5% Potential for drug drug CYP3A4 and Proton pump inhibitors interactions P glycoprotein inhibitors (possibly basic foods) Renal cut off (AFib) Dose reduce at 50 ml/min Avoid at less than 30 ml/min Antidote? No No Safe in pregnancy? No No Dose reduce at 50 ml/min Avoid at less than 30 ml/min Can you monitor? Affects PT Affects aptt and Thrombin time Will rviia work?? No Prothrombin complexes correct lab abnormality Yes No

Bleeding on the New Orals

A note on testing/rivaroxaban There is no data correlating any lab test of rivaroxaban levels to any clinical outcome (thrombosis or bleeding) PT (prothrombin time) goes up (to 13 to 25 secs with Neoplastin reagent) 2 to 4 hours after the dose (peak), Then returns to normal, before the drug is fully gone. but this is variable and has not been correlated with events/efficacy other PT reagents, not as good, no INR correlation lti So an abnormal PT means rivaroxaban has been taken recently. Other tests are coming Similar to anti Xa level

A note on testing/dabigatran There is no data correlating any lab test of dbi dabigatran levels l to any clinical i l outcome (thrombosis or bleeding) In the absence of such a test, t do not measure levels! l A normal thrombin time means that the drug is gone. This has taken days to occur, even in patients with normal CrCl. Some centres allow surgery if the aptt is normal, not prospectively studied.

Non emergency bleeding Hold the drug, wait for clearance Where is the lesion? Can it be fixed? GI bleed oscopy Hematuria urology etc

Emergency bleeding Assess and monitor vital signs intervene as required with lifesaving therapies Consider transfer to intensive i care setting, fluids Alert other health care professionals including radiology, endoscopy, and surgery as required Measure coagulation (i.e., INR and aptt), blood count and renal function reassess periodically if bleeding continues.however, normal results do not mean that drugs are fully eliminated. Stop the anticoagulant Consider charcoal l(dabigatran) Address bleeding using interventional procedures Consider administration of non specific pro hemostatic agents Antifibrinolytics amicar, tranexamic acid DDAVP Prothrombin complex concentrates (octaplex, beriplex) Activated prothrombin complex concentrates (FEIBA) rfviia rfviia Consider modalities that may remove the anticoagulant Hemodialysis that rivaroxaban is highly protein bound decreases the potential utility of dialysis. Dabigatran should be dialyzable. Might enter from third spaces. There are no clinical reports.

Reversal with prothrombin complex concentrates? Volunteers, Cofact 50U/kg Rivaroxaban: YES Eerenberg et al., Circulation 2011

Reversal with prothrombin complex concentrates? Dabigatran: No

Will rviia work? Rivaroxaban and Apixaban rviia reduced fondaparinux induced prolongations of thrombin generation and ETP (Bijsterfeld et al., Circ. 2002) Dabigatran rviia did not alter melagatan induced prolongations of thrombin generation and ETP, or inhibition of platelet activation (Woltz et al., Thromb Haemostas 2004)

FEIBA for Dabigatran bleeding CCM, 2011

Discontinuation before surgery Dabigatran From McMaster Hematology Clinical Protocol Website Renal function (CLCR, ml/min) Estimated half life of effect (a) (hours) Timing of discontinuation after last dose of dabigatran before surgery Bleeding Risk Standard Risk High Risk (b) >80 13 (11 22) 24 hours 2 to 4 days 50 to 80 15 (12 34) 24 hours 2 to 4 days 30 to 50 18 (13 23) At least 48 hours 4 days <30 (c) 27 (22 35) 2 to 5 days > 5 days a Data from renal impairment study in healthy volunteers (REF), geometric mean (range). b Types of surgery associated with a high risk of bleeding (or in major surgery where complete hemostasis may be required) include but is not limited to cardiac surgery, neurosurgery, abdominal surgery or those involving a major organ. Other procedures such as spinal anesthesia may also require complete hemostatic function. Other important determinants of bleeding risk include advancing age, co morbidities (e.g. major cardiac, respiratory or liver disease) and concomitant use of antiplatelet therapy. c Dabigatran etexilate is contraindicated for use in these patients. CLCR = creatinine clearance.

Discontinuation before surgery Rivaroxaban At least 24 hours prior to procedure. 2 to 4 days prior to a major procedure depending on clinical circumstances. From Xarelto product monograph

Approach for the talk New Orals for New Orals for treatment of VTE, possibly initiated in the ER

New option for DVT treatment

VTE treatment rivaroxaban DVT treatment EINSTEIN (open label) Rivaroxaban 15 mg BID (21 days) then 20 mg daily v. LMWH then warfarin Recurrent VTE, non inferior 2.1% v 3.0% (0.44 1.04) major bleeding and any bleeding no difference Buller et al., NEJM 2010 Approved in Canada

EINSTEIN DVT: study design Randomized, open label, event driven, non inferiority study 88 primaryefficacy outcomes needed Treatment period: 3, 6 or 12 months Confirmed symptomatic DVT without symptomatic PE Day 1 Day 21 N=3,449 R Rivaroxaban Rivaroxaban 15 mg bid 20 mg od Enoxaparin (1.0 mg/kg) bid for at least 5 days, plus VKA target INR 2.5 (INR range 2 3) 30-day observatio on period

Patient flow Rivaroxaban Enoxaparin/VKA Randomized 1,731 1,718 (n=3,449) 1,731 Intention-to-treat population 1,718 1,718 Safety population* 1,711 34 (2%) Withdrawal of consent 67(4%) 15 (1%) Lost to follow-up 18 (1%) *As treated Bauersachs et al. N Engl J Med 2010;363(26):2499-510

Patient characteristics Rivaroxaban (n=1,731) Enoxaparin/VKA (n=1,718) Males (%) 57 56 Age, mean (years) 56 56 Creatinine clearance (%) <50 ml/min 7 8 50 <80 ml/min 23 23 80 ml/min 69 68 Patients with previous VTE (%) 19 19 Patients with active cancer (%) 7 5 Intended treatment duration (%) 3 months 12 12 6 months 63 63 12 months 25 25 Pre-treatment for maximum 48 hours with LMWH, heparin/fondaparinux (%) 73 71 ITT population 1. Bauersachs et al. N Engl J Med 2010;363(26):2499-510

Primary efficacy outcome analysis Rivaroxaban (n=1,731) Enoxaparin/VKA (n=1,718) n (%) n (%) First symptomatic recurrent VTE 36 (2.1) 51 (3.0) Recurrent DVT 14 (0.8) 28 (1.6) Recurrent DVT + PE 1 (<0.1) 0 (0) Non-fatal PE 20 (1.2) 18 (1.0) Fatal PE/unexplained death where PE cannot be ruled out 3 (0.2) 6 (0.3) p<0.001 for non-inferiority (one-sided) 0.68 0.44 1.04 p=0.076 for superiority (two-sided) 0 1.00 Hazard ratio ITT population 1. Bauersachs et al. N Engl J Med 2010;363(26):2499-510 2.00

Primary efficacy outcome: time to first event Cumu ulative eve ent rate (%) 40 4.0 Enoxaparin/VKA (n=1,718) 3.0 Rivaroxaban (n=1,731) 2.0 1.0 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of subjects at risk Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1,220 400 369 363 345 309 266 Enox/VKA 1,718 1,616 1,581 1,553 1,368 1,358 1,186 380 362 337 325 297 264 1. Bauersachs et al. N Engl J Med 2010;363(26):2499-510

Mean percentage of time in therapeutic range Mean Duration of enoxaparin treatment 8 days INR above 2 at discontinuation of LMWH 80.8% The time in therapeutic range (TTR) of the Warfarin arm was 54% during the first month to 66% of the time during month 10 Safety population

Principal safety outcome analysis First major or clinically relevant non-major bleeding Rivaroxaban Enox/VKA (n=1,718) (n=1,711) HR (95% CI) n (%) n (%) p value 139 (8.1) 138 (8.1) 0.97 (0.76 1.22) p=0.77 Major bleeding 14 (0.8) 20 (1.2) 0.65 (0.33-1.30) Contributing ti to death 1 (<0.1) 5 (0.3) In a critical site 3 (0.2) 3 (0.2) p=0.21 Associated with fall in Hb 2 g/dl and/or transfusion of 2 units Clinically relevant non-major bleeding 10 (0.6) 12 (0.7) 126 (7.3) 119 (7.0) Safety population 1. Bauersachs et al. N Engl J Med 2010;363(26):2499-510

Principal safety outcome: time to Cum mulative ev vent rate (% %) 14 first event 12 p=0.77 for noninferiority 10 8 6 4 2 Enoxaparin/VKA (n=1,711) Rivaroxaban (n=1,718) 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of subjects at risk Rivaroxaban 1,718 1,585 1,538 1,382 1,317 1,297 715 355 338 304 278 265 140 Enox/VKA 1,711 1,554 1,503 1,340 1,263 1,238 619 338 321 287 268 249 118 1. Bauersachs et al. N Engl J Med 2010;363(26):2499-510

VTE treatment rivaroxaban PE treatment EINSTEIN PE, NEJM, April 2012 Same regimen, 4832 pts, randomized, open label 13% had limited PE (likely subsegmental) Recurrent VTE, non inferior, 2.1% v 1.8% (0.75 1.68) Major and clin relevant non major bleeding (R v L/W) 10.3%. V. 11.4% (0.76 1.07) Major bleeding (R v L/W) 1.2% v. 2.2% (0.31 0.79) Approval is pending

Implications of new DVT treatment indication Great compliance is important. Transition to the daily dose should occur at Day 22. If the DVT is severe there is utility in continuing i LMWH longer, thus reassess very symptomatic patients. Convenience over Warfarin should not govern decision of anticoagulation.

Convenience over Warfarin should not govern decisions i about anticoagulation i This does not alleviate the necessity to firmly establish a diagnosis of DVT. Not a scar from an old clot, or a calf vein clot, or a superficial vein This does not remove the question of how long someone should be on anticoagulation. Provoked or unprovoked, patient preference

Possible future indication ACS treatment rivaroxaban ATLAS ACS ACS 2 TIMI 51, Mega et al., NEJM Nov 2011 Pts with ACS, stabilized (up to 7d), randomized to placebo, rivaroxaban 25mg 2.5 BID, or riv 5 mg BID Regimen CV Death Any Death TIMI Bleeding placebo 10.7% 4.5% 0.6% Riv 2.5 BID 9.1% * 2.9% * 1.8% * Riv 5 BID 8.8% * 4.4% 2.4% *

Thanks! Questions? Skull Rock, Joshua Tree Nat. Park. CA, USA