VKA to NOACs Really? Kevin W. Yingling, R.Ph., M.D., FACP November 1, 2014

Transcription

1 VKA to NOACs Really? Kevin W. Yingling, R.Ph., M.D., FACP November 1, 2014

2 Presenter Comments Ease of Use vs. Easy to Use (Simplicity Factor) No PWOK (prescribing without knowledge) No one ever thanked me for using Warfarin, I have patients asking for Eliquis, Pradaxa, Xarelto Disclosure - I am a lumper, and splitter with evidence (as the evidence develops)

3 Objectives Define and implement practice important, unique PK and PD parameters for NOAC Define and implement practice important clinical trial outcomes for NOAC Define and implement data that directs practices for NOAC associated bleeding Explore practice questions related to NOAC therapy

4 NOAC Factor Xa Inhibitors (XaI) -xaban Direct Thrombin Inhibitor (DTI) -atran NOT YET Perfectxaban Perfectatran Rapid Onset Wide Therapeutic Window Similar Kinetics Minimal Interpatient Variability

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6 DTI Old vs. New Hirudin Dabigatran Parental Removed Irreversible, DTI Non-active, pro-drug, competitive and reversible DTI (tartaric acid) Agratroban, bivalirubin Ximelagatran Rivavoxaban Apixaban XaI Endoxaban Betrixaban

7 DTI and XaI (NOACs) Indications Post-op DVT prophylaxis orthopedic surgery Treatment VTE and PE Prevention stroke and systemic embolism in NVAF Prevention VTE after treatment for VTE and PE

8 VKA-Indicated Mechanical Values (phase II- RE-ALIGN stopped, NEJM 2013) Severe CKD (<30 ml/min) Dual anti-platelet therapy (TAT) Cost

9 FDA Status Approval Exclusivity Dabigatran October 2010 February 2018 Rivaroxaban July 2011 November 2015 Apixaban December 2012 December 2017 Edoxaban Pending Betrixaban Pending Market Data: Pradaxa Largest Share Eliquis Overtake in 2016 Market Value Billion

10 FDA staff recommends limited use of Daiichi's blood thinner Food and Drug Administration staff reviewers recommended approval of a 60 mg dose of Daiichi Sankyo Co's blood thinner (endoxaban) for some atrial fibrillation patients, but suggested limiting its use to those with abnormal kidney function. (Reuters Online, October 28, 2014)

11 Direct Thrombin Inhibitors vs. Vitamin K antagonists - NVAF Objectives efficacy, safety, bleeding, ADR, mortality 8 studies, 26,600 patients both doses dabigatran, ximelagatran Not inferior Vascular death and ischemic events (150 mg BVD superior) Fewer major bleeding events (fatal, nonfatal, ICH) ADR greater DTI (GI related) Mortality same (Cochrane Systematic Review, 2014)

12 Factor Xa Inhibitors vs Vitamin K Antagonist - NVAF Objectives efficacy, safety, bleeding, ADR, mortality 10 studies, 42,000 patients, 6 xaban drugs XaI reduced number of strokes/embolic events vs. warfarin Reduced number of major bleeding events Reduced number of ICH Limited data to support which XaI is more effective or safer (Cochrane Systemic Review, 2013; JAMA, 2014)

13 Inter-trial, Indirect Comparison NOAC RE-LY, ROCKET-AF, ARISTOTLE Lower risk stroke, embolism, hematologic stroke, all cause mortality vs. warfarin Major bleeding lower vs. warfarin ICH lower vs. warfarin No profound differences in NOACs Major bleeding less with apixaban and dabigatran (110 mg dose) (JACC 2012; 60: )

14 Generalized Outcome Data (example apixaban) 1000 patient years compared to warfarin Prevents 3 more strokes Avoids 10 major bleeds Prevents 4 deaths Valuable data Your decision

15 Generalized Outcome Data ICH NOAC use Compared to warfarin, all NOAC significantly reduce risk of ICH by half (risk ratio = 0.44) Compared to aspirin, Apixaban has similar risk for ICH (Averroes, Stroke 2012) Long term study, average therapy 2.3 years after RE-LY trial, or real world rates (registry), similar rates (0.25% %, per dosages), (Circ 2013)

16 Contraindications do not use Known hypersensitivity to ingredients in NOAC Clinically significant active bleed, Hb <100 g/l Disorder of haemostasis Renal impairment 30 ml/min (apixaban 15 ml/min) Hepatic disease (Child-Pugh C) Severe valvular disease or prosthetic heart valve1 Recent, high-risk bleeding lesion (e.g. ICH < 6 months) Pregnancy or breast-feeding Concomitant contraindicated medications Recent: stroke, surgery (< 1 month), GI bleed (< 12 months), ulcer (< 30 days) Recent fibrinolytic treatment ( 10 days) Concomitant warfarin therapy- see switching guidelines Precautions use with caution Renal impairment ml/min dose adjustment required, see dosing instructions Hepatic Impairment (Child-Pugh A-B) Weight 60 kg see dosing instructions Age 75 years see dosing instructions Concomitant medications see drug interactions Concomitant Anti platelet therapy History: ICH, intra-ocular, spinal, retroperitoneal or atraumatic intraarticular bleed

17 Key NOAC Pharmacokinetics DTI XaI t ½ (12-15) (6-14) Protein Bound 35% >90% Renal Clearance 80% 30% Onset (tmax) 2 3

18 Lab Contraindications CKD (CrCl 30 ; apixaban 15) Liver disease (ALT > 3 x normal, Pugh class B or C) Hemoglobin 10 gm (risk assessment)

19 Coagulation Parameter DTI XaI PT Minor Minor PTT Major Minor TT Major Normal Anti-Xa Normal Major

20 Compliance Concerns T ½ 12 hours, no drug no protection Compliance 70 80%, all drugs Low compliance NOAC = VKA Trial data for DTI and NVAF therapy more than 12 weeks (Circ 2013 ) VTE 13 vs. 14 % * NVAF 22% * Once vs. twice day dosing

21 Dabigatran and GI System Tartaric acid derivative Gastritis symptoms (25 35%) PPI use helps drug induced symptoms (6 7 % absorbed, better in acidic ph) PPI absorption 12.5%, not identified as significant Take 2 hours before antacids ( absorption up to 30%) Contraindications: GI bleed 12 months ago, ulcer 30 days FDA, based on study 134,000 Medicare patients, increased risk of major gastrointestinal bleeding (FDA, May 2014)

22 Rivaroxaban (Xarelto) Food increases absorption 39% Take with food

23 Contraindications Precautions Drug Interactions Example Dabigatran Etexilate Converted by plasma and liver enzymes Substrate P-gp Intestine wall interaction (6 7 % absorption) Increase levels if P-gp inhibited AUC x 2-3

24 Drug Interactions Strong P-gp Strong CYP 3A4 DTI XaI Inhibitor Yes Yes Inducer Yes Yes Inhibitor Yes Inducer Yes

25 P-glycoprotein ATP binding cassette (ABC) Permeability protein, MDR 1 (Multi-drug resistance protein 1) Intestine, liver, kidney, blood brain barrier Pumps xenobiotics (toxins and drugs) back to origin Drug efflux pump Potential medicine medicine interactions

26 Drugs and P-glycoprotein (P-gp) Inhibitors Inducers Substrates Amiodarone Rifampin Digoxin Verapamil Carbamazepine Dabigatran Diltiazem Phenytoin XaI drugs Quinidine Protease Inhibitors Ketoconazole/itraconazole Azithromycin/Clarithromycin

27 Digoxin and Verapamil At P-glycoprotein Interaction Site Liver and Kidney Increase digoxin level (lower volume distribution)

28 Ketoconazole and Dabigatran Interaction At P-glycoprotein Site Intestine Increase absorption dabigatran (only 6 7 %, drug back to intestine, %)

29 Dabigatran Rivaroxaban/Apixaban Contraindicated clinically significant increased plasma levels Potent P-gp inhibitors: Systemic azole antifungals (except fluconazole), cyclosporin, dronedarone, tacrolimus, simultaneous initiation with verapamil Potent P-gp and/or CYP3A4 inhibitors: Systemic azole antifungals (except fluconazole), HIV-protease inhibitors Caution avoid use or seek advice, dose change may be warranted Less potent P-gp inhibitors: amiodarone, clarithromycin, erythromycin, fluconazole, HIV protease inhibitors, quinidine, ticagrelor Less potent P-gp and/or CYP3A4 inhibitors: amiodarone, cyclosporin, clarithromycin, erythromycin, diltiazem, fluconazole, quinidine, tacrolimus, verapamil Potent P-gp/CYP3A4 inducers: carbamazepine, phenobarbital, phenytoin, rifampicin, St John s Wort Antiplatelet agents / anticoagulants: e.g. warfarin, clopidogrel, prasugrel, ticagrelor, heparins Some antidepressants: Selective serotonin (SSRI) or serotoninnoradrenaline(snri) reuptake inhibitors (WATAG)

30 Promising Drug with a Flaw Dabigatran - No antidote 542 deaths, more than any other 800 drugs monitored (New York Times, November 2, 2012)

31 Bleeding What to Ask? Timing is important Last Dose Kidney Function (Calc CrCl) Coag studies often done but very little value

32 No specific antidote NOAC Bleeding Short t ½, supportive care (4 t ½ = 0) No role FFP Expecting high quality data on role PCC, apcc, rfviia (invitro, volunteer, animal data) Gap in knowledge for reversal Hospital-wide protocol imperative consideration of hematology and nephrology consult

33 Consensus on Treatment of NOAC - ICH 221 board certified neurologists Dabigatran induced ICH >73 % reversal PCC (61%) FFP (53%) VFVII (24%) Hemolysis (24%) Platelet infusion (7%) No hemostatic agent effects the rate of elimination of the NOAC associated with bleeding event (Stroke Cardiovascular Disease, 2013)

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37 Supportive Measures Charcoal Demopressin platelet dysfunction Platelet transfusion on DAPT FFP only dilution coagulopathy Coiling or regional embolization

38 NOAC Bleeding Caveats Last Dose < 2 3 hours give oral charcoal Dabigatran Dialysis Option Major bleed Renal Function (<30) Drug Assay (>50 mcg/l) Thrombosis with PCC vs. FFP In Warfarin reversal 3.9 % to 2.8 % ( Eur Heart J, 2013 )

39 Intracranial Hemorrhage and NOAC On Drug, ICH % 2/3 ICH are intracerebral, 1/3 subdural 30 day mortality equal to warfarin associated ICH (36 43 % ) Predictors increasing age, history TIA (stroke, use antiplatelet therapy) ( Curr Cardiol Rep, 2014 )

40 Antidote (a Dabi-Fab) to Dabigatran Humanized Ab fragment (FAB) structural similarity to Thrombin, competitively binds Dabigatran Healthy volunteers, Dabigatran 220 mg BID x 3 days 5 minute infusion Immediate reversal of prolonged thrombin time Lasted 12 hours Idarucizumab breakthrough therapy by FDA, June 2014 Phase III trials underway

41 Antidote (PRT 06445) to XaI Recombinant, inactive, variant of factor Xa competes with native Xa for XaI Phase II proof of concept trial 9 patients, Apixaban 5 mg BID for 6 days Rapid reversal, 2 minutes > 90% reversal Lasted 2 hours ( Blood,2013 )

42 Portola Andexanet alfa Phase III trials safety and efficacy, apixaban Phase III met primary and secondary endpoints Immediate and significant reversal of anticoagulant activity apixaban Detailed data to be presented November 17, 2014 at AHA 2014 Scientific Section Now, Phase III trials with Andexanet and (3) xaban drugs

43 Urgent Surgery on NOAC Therapy If possible, delay surgery hours last dose Assess risk bleed vs. urgency Review options embolism, etc. If surgery, seek a hematologist's advice

44 Coagulation Testing Off NOAC No data on a cut off value for specific tests below which patient safe for elective or urgent surgery.

45 Planned Surgery or Ablation - NOAC 25% of anti-coagulated patients require temporary cessation within 2 years Implement pre-post operative guideline, no bridging Attention Dabigatran and CrCl Planned Surgery - NOAC DTI XaI Low Risk High Risk Low Risk High Risk CrCl > 80 > 24 > 48 > 24 > 48 CrCl > 36 > 72 > 24 > 48 CrCl > 48 > 96 > 24 > 48 CrCl > 36 > 48

46 Clinical Challenges Ischemic Stroke on NOAC No thrombolytic acutely t ½ 12 hours (4 = 0) 48 hours reconsider No drug for 48 hours, mechanical recanalization possible

47 Ischemic Stroke on NOAC Rule (no clinical study) restart NOAC TIA: 1 day Non-disability infarct: 3 days Moderate stroke: 6 days Large stroke: days TIA of cardioembolic origin, start as soon as possible ( Eur Heart J, 2013 )

48 Atrial Fibrillation and CAD Highly Personalized Approach Three Clinical Groups ACS in NVAF on NOAC Recent ACS and new NOAC NVAF with history CAD, no ACS for 1 year/1 month time metal stent/6 months DES (JACC 2012: 59: )

49 Patients with CKD CrCl <60 ml/min increased risk stroke and thromboembolism No long-term outcome data for use NOAC <30 ml/min Very little data use on dialysis, VKA best option If NOAC, close monitoring CrCl and in acute illness re-evaluation is necessary. (AHA, ACA; January 2014)

50 NOAC Black Box Warnings Rivaroxaban and Apixaban Discontinuing in patient with Atrial fibrillation Spinal / epidural hematoma Dabigatran Discontinuing in patient with atrial fibrillation

51 Dabigatran Association with Higher Risk of Acute Coronary Events Suggested first noted in RELY trial (0.8 vs. 0.6%) Seven trial reviewed Higher rate MI/ACS, 1.19% vs. 0.79% (RR 1.27) Low number events FDA post-marketing review, 134,000 medicare patients MI equal to warfarin (Archives Internal Medicine, 2012)

52 Prevention vs. Risk DAT & TAT (W,A,C) Lower stroke, TAT coronary events with increased bleeding RE-DEEM Dabigatran + DAPT, increased bleeding events ATLAS ACS-TMI 46 Rivaroxaban + DAPT, increased bleeding events APPRAISE 2 Apixaban to DAPT for ACS, increased bleeding (3.2 % - 1.2%) Await Pioneer AF-PCI and RE-DUAL PCI NOW Utilize Risk Score Match Stent to Patient Add PPI in select patients Offer TAT to lower stroke and stent thrombosis to informed patient, More data for warfarin.

53 Heparin Induced Thrombocytopenia Neither DTI or XaI had any effect or interaction with PF4 or anti-pf4/heparin antibodies No randomized trials nor anecdotal case reports on off label use NOAC in HIT

54 Anticoagulants of the Future TFPI tissue factor pathway inhibitors Factor VIII inhibitor monoclonal antibody, long t ½ - 3 weeks Thrombomodulin t ½ 2 3 days Factor 1Xa inhibitor CAD Trials Factor X1 inhibitor Preliminary, in vitro Factor X11a inhibitor Preliminary, in vitro

55 VKA to NOAC REALLY. NOAC are effective NOAC risk ICH One better than another indirect evidence is no Major bleeding occurs, less often (Dabigatran) Antidote not mandatory, Not available yet All NOAC short t ½ Personalized approach each patient NOAC use will increase (generic 2017)