New Oral Antithrombotics and Their Emergent Reversal Part 1

New Oral Antithrombotics and Their Emergent Reversal Part 1 Christian Hamm, PharmD, BCPS christian.hamm@multicare.org Allison Massingill, PharmD allison.massingill@multicare.org 1

Disclosures No relevant financial relationships exist. 2

Objectives Introduce the new oral anticoagulants (NOACs): dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban Introduce the new oral antiplatelets: prasugrel, ticagrelor, and vorapaxar Describe the incidence, morbidity and mortality associated with oral antithrombotic-related bleeding Discuss contemporary reversal strategies for these drugs Explain associated costs and risks involved with the reversal agents 3

FDA approval history of anticoagulants edoxaban 2015 heparin 1939 warfarin 1954 enoxaparin & lepirudin 1998 dalteparin 1999 fondaparinux 2001 argatroban & bivalirudin 2000 rivaroxaban 2011 dabigatran 2010 apixaban 2012 4

What are some ideal properties in an anticoagulant? Safe (low bleeding risk) Effective (in reducing thromboembolic events) Rapid onset (avoid the need for bridging) Optimal duration of action (ideally once daily dosing) Minimal food/drug interactions Simple therapeutic monitoring Ability for rapid reversal 5

Which of the following are associated with reduced rates of intracranial bleedings compared with warfarin? dabigatran apixaban rivaroxaban edoxaban 6

Which of the following are associated with reduced rates of intracranial bleedings compared with warfarin? ALL OF THEM dabigatran: 0.3% dabigatran vs 0.7% warfarin apixaban: 0.3% apixaban vs 0.8% warfarin rivaroxaban: 0.8% rivaroxaban vs 1.2% warfarin edoxaban: 0.5% edoxaban vs 1% warfarin 7

Which of the following are superior to warfarin for the reduction of ischemic stroke in nonvalvular a fib? dabigatran rivaroxaban apixaban edoxaban 8

Which of the following are superior to warfarin for the reduction of ischemic stroke in nonvalvular a fib? dabigatran: 0.92% dabigatran vs 1.2% warfarin (P = 0.002) rivaroxaban: 2.1% rivaroxaban vs 2.4% warfarin (P < 0.001) apixaban: 1.19% apixaban vs 1.51% warfarin (P =0.01) edoxaban: 1.18% edoxaban vs 1.5% warfarin (P < 0.001) 9

Which of the following drugs require bridging with a LMWH for a fib? dabigatran rivaroxaban NONE apixaban edoxaban 10

Which of the following require bridging with a LMWH for DVT/PE treatment? dabigatran rivaroxaban apixaban edoxaban 11

Which of the following requires bridging with a LMWH for DVT/PE treatment? dabigatran rivaroxaban apixaban Both require 5 to 10 days of parenteral anticoagulation edoxaban 12

The Clotting Cascade http://earlstevens58.files.wordpress.com/2011/07/new-anti-coagulation-drugs.gif. Accessed October 10, 2014. 13

Where in the clotting cascade does dabigatran work?? http://earlstevens58.files.wordpress.com/2011/07/new-anti-coagulation-drugs.gif. Accessed October 10, 2014. 14

The Clotting Cascade http://earlstevens58.files.wordpress.com/2011/07/new-anti-coagulation-drugs.gif. Accessed October 10, 2014. 15

Dabigatran 1st oral direct thrombin inhibitor 1st new oral anticoagulant in over fifty years Stroke prevention in a fib: 150mg PO BID No need for bridging for a fib (time to peak 1 hour) For poor kidneys (CrCl 15-30 ml/min): 75mg PO BID DVT/PE treatment:150mg PO BID after 5-10 days of parenteral anticoagulation Drug interactions? Do not use with strong PGP inhibitor (eg, amiodarone, dronedarone, clarithromycin, cyclosporine, ritonovir, quinidine, tacrolimus, verapamil) and if CrCl < 50 ml/min 16 http://keepyourhearthealthy.files.wordpress.com/ 2011/02/pradaxa.jpg. Accessed Nov 10, 2014

Can I monitor dabigatran with a lab test? What if I order a PT or PTT? Both will be elevated at therapeutic doses But it can serve to know if the patient has some drug in the body What is Dilute Thrombin Time? developed to monitor direct thrombin inhibitors. Better sensitivity than PTT. Cost/Turnaround time similar to PTT. How is it used? Assure absence of drug prior to invasive procedures (e.g., LP, or chest tube placement) Assure absence of drug prior to use of thrombolytic therapy Less likely to be useful for: assessing compliance assessing possible over-anticoagulation in hemorrhage assessing possible under-anticoagulation in treatment failure Love J, Ferrell C, Chandler W. Monitoring direct thrombin inhibitors with a plasma diluted thrombin time. Thromb Haemost 2007; 98: 234-242. 17

Which of the following has a once daily dosing for atrial fib? dabigatran rivaroxaban apixaban edoxaban 18

Which of the following has a once daily dosing for atrial fib? dabigatran rivaroxaban apixaban edoxaban 19

Which of the following has a once daily dosing for DVT/PE treatment? dabigatran rivaroxaban apixaban edoxaban 20

Which of the following has a once daily dosing for atrial fib? DVT/PE treatment? dabigatran rivaroxaban apixaban edoxaban 21

Where in the clotting cascade does rivaroxaban work?? http://earlstevens58.files.wordpress.com/2011/07/new-anti-coagulation-drugs.gif Accessed October 10, 2014. 22

Where Does rivaroxaban work? http://earlstevens58.files.wordpress.com/2011/07/new-anti-coagulation-drugs.gif Accessed October 10, 2014. 23

Rivaroxaban First oral direct Factor Xa inhibitor Time to peak 2-4 hours. No need for bridging. Several indications: DVT prophylaxis in post-op knee and hip replacements (want to start 6-10 hours post-op):10mg PO daily x 10-14 days for knees and 10mg PO daily x 10-35 days for hips Stroke prevention in a fib: 20mg PO daily DVT/PE treatment: 15mg PO BID x 3 weeks then 20mg PO daily Drug interactions? worry about P-gp and 3A4 inhibitors, but no dose adjustment recommended 24 http://injurylawyer-news.com/wpcontent/uploads/xarelto-pill-bottle.jpg. Accessed November 11, 2014.

How do I monitor rivaroxaban with a lab test? What if I order a PT or PTT? Both will be elevated at therapeutic doses But it can serve to know if the patient has some drug in the body How about ordering a rivaroxaban drug level? If available. A fib VTE Tx VTE Prophy laxis Anti-Xa activity test used to extrapolate rivaroxaban concentrations. How is it used? Assure absence of drug prior to invasive procedures Peak level 160-360 ng/ ml 175-360 ng/ ml 91-196 ng/ ml Assure absence of drug prior to use of thrombolytic therapy Less likely to be useful for: Trough level 4-6 ng/ml 19-60 ng/ml 1.3-38 ng/ml assessing compliance assessing possible over-anticoagulation in hemorrhage assessing possible under-anticoagulation in treatment failure Francart S, Hawes E, Deal, A, et al. Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. Thromb Haemost 2014; 111: 1133 1140 http://depts.washington.edu/anticoag/home/content/uw-medicine-alternative-monitoringantithrombotic-agents#rivaroxaban Accessed October 12, 2014 25

Rivaroxaban case #1 GF is 69 yo M who presents to the ED with cc of fever, chills, nausea. History of DM2, NSTEMI with CABG three weeks prior. This AM he began coughing, with CP and SOB. He is also slightly altered - not oriented to month or year. Initial vitals are BP=153/62, HR = 110, RR = 20 O2Sat = 96% RA, Temp = 103 (oral) Home meds: aspirin, glipizide, HCTZ, glargine, lisinopril, metformin, metoprolol, ranitidine, simvastatin, tramadol, EKG today: unchanged from discharge three weeks ago Labs: CBC, CMP, troponin, UA, lactate - all normal; D-Dimer - not ordered CXR: normal CT ANGIO LUNG: Findings of a very small non-occlusive pulmonary embolism within a subsegmental branch in the anterior segment of the left upper lobe. Plan: CT surgery is paged -> start enoxaparin & warfarin -> ED doc puts in those orders -> After reviewing patient I cannot find any contraindications to rivaroxaban and call back CT surg to get enoxaparin/warfarin switched to rivaroxaban. Hopefully thereby decreasing hospital admission time and simplify drug therapy for the patient. 26

Rivaroxaban case #2 CF is a 61 yo M who is brought to the ED for heart palpitations and weakness. He began having malaise about two weeks ago, but after being in bed for two days now is seeking medical help. PMH: DVT& PE earlier this year (was on warfarin for 6 months) ECG: a fib with rapid ventricular response in the 180s, also with runs of non-sustained wide complex beats. Vitals: HR 187, Bp 104/85, RR 17, O2 Sat 98% on RA Patient is rushed to CT for CTA of his chest to r/o PE 27

Rivaroxaban case #2 CT demonstrates massive bilateral PE Doc asks me if this a good rivaroxaban candidate. What is your response? 28

Apixaban Direct Factor Xa inhibitor No need to bridge. Time to peak: 3-4 hours Several indications: DVT prophylaxis in post-op knee and hip replacements (start 12-24 hrs post-op) 2.5mg PO BID x 12 days for knees 2.5mg PO BID x 35 days for hips Stroke prophylaxis in nonvalvular a fib 5mg PO BID Reduce dose to 2.5mg PO BID if patient has any 2 of the following: age > 80, weight< 60kg or Scr > 1.5 DVT/PE treatment 10mg PO BID x 7 days then 5mg PO BID Drug interactions: dose reduce for concurrent dual strong P-gp and 3A4 inhibitors (e.., ketoconazole, ritonivir) Pregnancy category: B 29 http://drugwatch.amagllc.netdna-cdn.com/wp-content/ uploads/eliquis-5mg-box_bottle.jpg. Accessed

Apixaban case JH is a 84 yo F who presents to the ED with a cc of CP and her heart beating out of her chest. She has a hx of HTN, CKD stage 4. and OA. Her CP has been going on for several days now. Initial vitals: HR= 150, BP = 146/87, RR = 24, 02Sat = 93% RA, Temp 99 (oral) Home meds: ramipril, chlorthalidone, and ibuprofen CXR: normal Labs: CBC, CMP, TSH, troponin D-Dimer - all normal except for Scr of 1.8 (unchanged from baseline two months ago). EKG: a fib with rvr (rate of 150) Plan: new onset a fib -> cardiology consult. They recommend apixaban 5mg PO BID. She is > 80 and Scr > 1.5 -> call back cardiology to get dose reduced to 2.5mg PO BID 30

How do I monitor apixaban with a lab test? What if I order a PT or PTT? Both will be elevated at therapeutic doses But it can serve to know if the patient has some drug in the body How about ordering an apixaban drug level? If available. A fib VTE Tx VTE Prophy laxis Anti-Xa activity test to extrapolate apixaban concentrations. How is it used? Peak level 69-221 ng/ml 30-572 ng/ml 41-146 ng/ml Assure absence of drug prior to invasive procedures Assure absence of drug prior to use of thrombolytic therapy Less likely to be useful for: Trough level 34-230 ng/ml 11-335 ng/ml 23-109 ng/ml assessing compliance assessing possible over-anticoagulation in hemorrhage assessing possible under-anticoagulation in treatment failure Francart S, Hawes E, Deal, A, et al. Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. Thromb Haemost 2014; 111: 1133 1140 http://depts.washington.edu/anticoag/home/content/uw-medicine-alternative-monitoringantithrombotic-agents#rivaroxaban Accessed May 7, 2015 31

Edoxaban Direct Factor 10a inhibitor Indications: Atrial fib: No bridging necessary for afib. Time to peak ~ 3 hours. 60mg PO daily (for Cr Cl 50-95 ml/min) 30mg PO daily (for Cr Cl 15-50 ml/min) Contraindication: Do not use if Cr Cl > 95 ml/min (greater than, not less than) due to increased risk of stroke. In Engage AF-TIMI 48 study, patients had an increased rate of ischemic stroke with edoxaban 60mg daily compared to patients on warfarin. In these patients, another anticoagulant should be used. Raises question: perhaps this is best NOAC in a fib for patients with poor kidney function? DVT/PE treatment: 60mg PO daily after 5-10 days of parenteral anticoagulation (just like dabigatran for this indication) Dose reduce to 30mg PO daily if (Cr Cl 15-50ml/min or weight < 60kg or taking certain pg. inhibitors) 32

Direct 10a inhibitor Currently in Phase 3 Trial Betrixaban Trying to be first anticoagulant approved for both in hospital and post discharge VTE prevention in acute medically ill patients (such as CHF, stroke, infection, pulmonary disease.) Game changer. No longer will patients be getting enoxaparin or SQ heparin for DVT prophylaxis -> medical patients get an oral med First thrombosis study to identify those at highest risk for a DVT and most likely to benefit from betrixaban: targeting patients with an elevated D-Dimer levels and those over age > 75 Betrixaban for up to 35 days vs enoxaparin for up to 14 days. Simultaneous development by the drug company, Portolo, of a reversal agent for betrixaban called andexanet. This reversal agent also being studied to reverse rivaroxaban, apixaban, and edoxaban. 33 http://www.portola.com/clinical-development/betrixaban-fxa-inhibitor/ Accessed November 12, 2014

Shifting gears http://ftw.usatoday.com/2015/03/fast-and-furious-best-driver-power-rankings-paul-walker-vin-diesel Accessed 5/2/2015 34

The platelet It is a major therapeutic target It is of central importance to cardiovascular disease No other single cell is responsible for as much morbidity and mortality as the platelet Still searching for a magic bullet that selectively targets pathological thrombus formation without undermining hemostasis Can you name the various pathways drugs can block platelet aggreagation? http://www.uphs.upenn.edu/news/news_releases/2011/10/cardio_disease_evol/figure-1_kahn.jpg Accessed October 12, 2014 35

Platelet activation pathways 36 http://www.medscape.org/viewarticle/732209 Accessed May 4, 2015

FDA approval history of antiplatelets aspirin 1906 clopidogrel ticlopidine 1997 aspirin/ 2001 dipyridamole 1999 prasugrel 2009 vorapaxar 2014 ticagrelor 2011 37

What is clopidogrel non-responsiveness? A. I just made up the term B. defined as no clinically important change in platelet function after treatment as compared to baseline C. Only happens in Asians D. none of the above 38

What is clopidogrel non-responsiveness? A. I just made up the term B. defined as no clinically important change in platelet function after treatment as compared to baseline C. Only happens in Asians D. none of the above 39

Prasugrel Irreversible ADP (P2Y12) receptor antagonist Faster, more consistent, and greater extent of platelet inhibition as compared to clopidogrel Prodrug just like clopidogrel. Onset: < 30 min after load Indication: reduce thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) who are to be managed with PCI Dose: 60mg PO x 1 (within 1 hour of PCI) followed by 10mg PO daily in combination with aspirin 81-325mg PO daily want to continue on prasugrel for at least 12 months regardless of stent type Dose reduce to 5mg PO daily for patients < 60 kg 40 http://cxcontent.affino.com/acucustom/sitename/ DAM/011/Effient_Bottle_10mg30ct_Main.jpg. Accessed October 13, 2014

Prasugrel - continued Efficacy: Primary combined endpoint of cardiovascular death, non-fatal MI, and non-fatal stroke: ~ 10% in prasugrel group vs ~12% in clopidogrel group (NNT 83) Safety: Major bleeding (by TIMI definition) 2.4% in prasugrel group vs 1.8% in clopidogrel group (NNH 167) Who should definitely NOT get prasugrel? Contraindicated in patients with hx of TIA or stroke 6.5% of prasugrel patients suffered a stroke vs only 1.2% of clopidogrel patients (NNH 19) Wiviott S, Braunwald E, McCabe C, et al. Prasugrel versus clopidogrel in patients with acute coronary syndrome. N Eng J Med 2007; 357: 2001-2015. 41

Case - aspirin/clopidogrel LT is a 55 yo M who arrives in the ED with a chief complaint of L sided weakness onset a 0300 (now 1000am), L grip weaker than R, positive pronator drift, slurred speech, and L sided facial droop Hx of HTN, DM, and CVA - discharged from hospital 11 days ago for his first CVA. Home meds: Aspirin 81mg daily, clopidogrel 75mg daily, citalopram 40mg daily, glargine 60 units, regular insulin 10 units CC, metformin 1000mg BID, metoprolol 150mg BID, simvastatin 40mg bedtime Head CT: Positive for new ischemic stroke How should this patient be managed pharmacologically? 42

What maintenance dose of aspirin should be prescribed with ticagrelor? None. You re crazy. It is marketed to replace aspirin. 81mg - 325mg PO daily < 100mg PO daily > 100mg PO daily 43

What maintenance dose of aspirin should be prescribed with ticagrelor? None. You re crazy. It is marketed to replace aspirin. 81mg - 325mg PO daily < 100mg PO daily > 100mg PO daily 44

Ticagrelor Class: Cyclopentyltriazolopyrimidine, not a thienopyridine (like clopidogrel and prasugrel.) Yet still affects the P2Y12 receptor like the both of them. Onset: < 30 mins (not a prodrug, unlike clopidogrel and prasugrel) Faster, more consistent, and greater extent of platelet inhibition as compared to clopidogrel Indication: reduce thrombotic events in patients with ACS Dose: 180mg PO x 1 with aspirin 325mg followed by 90mg BID with aspirin 81mg daily (to start 12 hours after loading dose) Drug interactions: 3A4 inhibitors 45 http://www.drugdevelopment-technology.com/ projects/brilinta-treatment/images/1-brilintatreatment.jpg. Accessed October 15, 2014

Ticagrelor - continued Efficacy: primary combined endpoint of death from vascular causes, MI, or stroke. 9.8% in ticagrelor vs 11.7% in clopidogrel. (NNT 53) Safety: (TIMI definition) major non-cabg related bleeds 4.5% in ticagrelor vs 3.8% in clopidogrel (NNH 142) ICH: 0.3% ticagrelor, 0.2% clopidogrel (not stat sig) fatal ICH: 0.1% ticagrelor, 0.01% clopidogrel (stat sig) Contraindication: hx of ICH, severe hepatic impairment Side effect (counseling point): mild to moderate dyspnea - resolution usually within a week. 14% ticagrelor vs 8% (high?) clopidogrel. But only 0.9% ticagrelor required discontinuation vs 0.1% clopidogrel Wallentin L, Becker R, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Eng J Med, 2009; 361: 1045-1057. 46

Vorapaxar is being marketed as an alternative to what other anti-platelet agent? A. aspirin B. clopidogrel C. all of the above D. none of the above 47

Vorapaxar is being marketed as an alternative to what other anti-platelet agent? A. aspirin B. clopidogrel C. all of the above D. none of the above 48

Vorapaxar First in class protease activated receptor (PAR-1) antagonist It inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP-induced) platelet aggregation Indication: Reduce thrombotic cardiovascular events in patients with a hx of MI or PAD Dose: 2.08mg PO daily IN COMBINATION with aspirin AND/OR clopidogrel This means a patient can be on 3 anti-platelet agents! Dose adjustments: caution in hepatic/renal impairment - but no dose adjustment noted Drug interactions?: 3A4 substrate, avoid use with strong 3A4 inducers/inhibitors - but no dose adjustment noted. Also PGP inhibitor Onset of action: > 80% TRAP-induced platelet aggregation within 1 week Half-life: (long) 3-4 days http://images.ddccdn.com/pro/images/34d5e7aa-7c18-4046-ba13-3ec17b61c262/zontivity-08.jpg Accessed October 12, 2014. 49

Vorapaxar - continued Efficacy: Looked at patients with hx of MI or PAD over 3 years 1.7% absolute risk reduction of primary composite endpoint for CV death, MI, stroke, or urgent coronary revascularization -> NNT 59 (not that effective?) No experience using vorapaxar as the only anti-platelet agent. Must be used in combination with aspirin and/or clopidogrel Safety: (GUSTO definition) moderate to severe bleed absolute difference in bleeding between groups was 1.3% -> NNH 77 Two years into 3 year trial -> stopped enrolling patients with hx of stroke due to increased risk of ICH Contraindication: Do not use in patients with hx of stroke, TIA, or intracranial hemorrhage (ICH) 50

Take Home Points all new oral anticoagulants are at least non-inferior in efficacy to warfarin as well as being just as safe from a bleeding perspective. However, some risk factors for decreased efficacy/increased bleeding: low body weight (especially < 60 kg) decreased renal function (especially when CrCl ~ 30-50ml/min) increased age (perhaps as early as 65) drug interactions: strong CYP3A4 inhibitors/inducers; P-gp inhibitors active liver disease: avoid use in Child-Pugh B and C Anti-platelet agents: prasugrel and ticagrelor are more potent P2Y12 inhibitors as compared to clopidogrel, but at the expense of more bleeds; vorapaxar is an adjunctive agent to be used along with aspirin and/or clopidogrel Lu Y, Brandstad R, Karim R, et al. Considerations of clinical variables for choosing new anticoagulant alternatives to warfarin for the management of non-valvular atrial fibrillation. J Clin Pharm & Therapeutics, 2014; 39: 628-636. 51