New Oral Anticoagulants Who Gets What for Atrial Fibrillation and Venous Thromboembolism?

Transcription

1 New Oral Anticoagulants Who Gets What for Atrial Fibrillation and Venous Thromboembolism? Kathryn Hassell, MD Professor of Medicine, Division of Hematology University of Colorado Denver

2 Disclosures No financial or commercial conflicts of interest No intended off-label discussion

3 Objectives Describe the basic characteristics of new oral anticoagulants (OACs) Recognize potential candidates for new anticoagulants for atrial fibrillation and treatment of venous thrombosis

4 Outline of Presentation Discuss the properties of new oral anticoagulants (new OACs) Compare/contrast with older anticoagulants Mechanisms and reversibility Review the pivotal trials for atrial fibrillation and venous thromboembolism Glean important and pertinent clinical lessons Consider ways to decide who gets what

5 Anticoagulant Mechanisms of Action VII Warfarin Fondaparinux Heparin LWMH Rivaroxaban Apixaban Dabigatran Adapted from Eriksson, Ann Rev Med 62:41, 2011

6 Another way to look at it Heparin blocks most activated factors Low molecular weight heparin blocks two activated factors: Xa and thrombin (IIa) Newer agents block only one factor: Anti-Xa agents Fondaparinux (Arixtra) s.q. daily Rivaroxaban (Xarelto) p.o. every 24 hrs Apixaban (Eliquis) p.o. every 12 hrs Anti-IIa agents Argatroban i.v. Bivalirudin i.v, Dabigatran (Pradaxa) p.o. every 12 hrs Warfarin doesn t block ANY activated factors

7 Yet another way to look at it COOH = carboxyl groups placed by vitamin K Factors II, VII, IX, X COOH Factors circulate folded until they are activated during a prothrombotic stress Protein unfolds with activation, revealing COOH, used to adhere to build a clot

8 Warfarin: Fewer Sticky Factors Prothrombotic stimulus No COOH COOH

9 Heparins/New Oral Anticoagulants: Inhibition of Activated Factors Prothrombotic stimulus COOH

10 New OACs: Like drinking your LMWH LMWH Inhibit activated factors No vitamin K impact Weight-adjusted dose Dependent on renal clearance No medication interactions No monitoring needed Irreversible Injections (ouch) Very expensive NEW ORAL AGENTS Inhibit activated factors No vitamin K impact Fixed dose Dependent on renal clearance (not apixaban) Few medication interactions No monitoring needed (can t) Irreversible Oral 5-10x cheaper than LMWH

11 Potential Drug Interactions Dabigatran: affected by pgp inhibitors or inducers Not excluded from clinical trials PI notes quinidine contraindicated; use caution with: strong inhibitors like verapamil, clarithomycin and others strong inducers (rifampin, St. John s wort) reduced effect May be impacted by degree of renal insufficiency

12 Potential Drug Interactions Rivaroxaban: affected by combined pgp and CYP3A4 Studies excluded subjects on strong inhibitors (e.g. HIV meds), strong inducers (e.g. rifampin, phenytoin) Package insert (PI) advises avoiding or increasing rivaroxaban dose if using carbamazepine, phenytoin, rifampin, St. John s wort May be impacted by degree of renal insufficiency

13 Potential Drug Interactions Apixaban: affected by combined pgp and CYP3A4; per package insert: For patients receiving >2.5 mg twice daily, decrease dose of by 50% when coadministered with strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin) For patients receiving 2.5 mg twice daily, avoid coadministration with strong dual inhibitors Avoid concomitant use of strong dual inducers of CYP3A4 and P-gp (e.g., rifampin, carbamazepine, phenytoin, St. John s wort) May be impacted by degree of renal insufficiency

14 Potential Drug Interactions pgp + CYP3A inhibitors: itraconazole, ketoconzole, clarithromycin, azithromycin cyclosporin, dronedarone verapamil, diltiazem, dronedarone lopinavir/ritonavir, conivaptan amiodarone, captopril, carvedilol, felodipine, quinidine pgp inducers: carbamazepine, phenytoin, rifampin, tipranavir/ritonavir, St. John s wort CYP3A inhibitors: voriconazole (strong), cimetidine (weak)

15 New Oral Anticoagulants: Measurement Monitoring Common assays (aptt, prothombin time) insensitive and inconsistently affected INR is a lab parameter created ONLY for warfarin Other measures may better reflect drugs Ecarin clotting time (ECT): dabigatran Chromogenic factor Xa actvity level (as done for people with a lupus anticoagulant): rivaroxaban, apixaban Even if drug effect can be measured, not the same as what results correlated with outcomes in the studies

16 New Oral Anticoagulants: Effect on INR Dabigatran: therapeutic concentration (NOT clinical outcomes) correlates with INR range of Stangier, Clin Pharmacokinet 47:285, 2008

17 New Oral Anticoagulants: Effect on Protime Itself Rivaroxaban: therapeutic concentrations (NOT clinical outcomes) associated with PT seconds Kubitza D, et al. Clin Pharmacol Ther 2005;78:

18 New Oral Anticoagulants: Effect on aptt Dabigatran: therapeutic concentrations (NOT clinical outcomes) associated with aptt seconds Eriksson BI, et al. J Thromb Haemost 2004;2: Liesenfeld L-H, et al. Br J Clin Pharmacol 2006;62:

19 New Oral Anticoagulants: Effect on Coagulation Assays Rivaroxaban, Apixaban: anti-xa, so how about an anti-xa ( heparin ) assay? Relatively linear, with some scatter Expected range unknown, no clinical correlations Barrett Thromb Haemost 104:1263, 2010

20 New Oral Anticoagulants: Pharmacological Properties Attribute Dabigatran Etexilate Absorption 6.5% Better in acidic environment (tartaric acid added) Sl delayed high-fat diet Rivaroxaban 66-80% Slightly delayed by food Apixaban 66% Not affected by food T max h h h Half-Life 7-17 h h 8-15 h Metabolism Converted to active drug by esterases in plasma or liver Metabolized by CYP3A4 (18%) and CYP212 (14%) Metabolized by CYP3A4,1A 1/2 Elimination 80% renal 66% renal 30% renal Reversibility?Factor VIIa conc May be dialyzed?apcc conc?apcc conc Giorgi. Expert Opin Pharmacother 12:567, 2011

21 Renal Clearance Warfarin: not impacted by renal function Dabigatran, rivaroxaban: GFR 60 ml/min best Mean GFR in studies ml/min Very few subjects had lower GFR Will not detect drug accumulation no monitoring Apixaban: only 25% cleared really Likely to be better tolerated with lower GFR Subgroups defined in pivotal trial for reduced dose (2.5 mg bid instead of 5 mg bid) 80 yrs, Cr 1.5, wt 60 kg Bauersachs, Thromb Res 129:107, 2012

22 Drug Clearance in the Elderly Dabigatran (150 mg bid dosing) Healthy elderly ( 75 yrs): up to 2x exposure after 6 dys Risk of major bleeding higher in subjects 75 yrs Doubled risk if >80 yrs and CrCl ml/min Recommended dose of 75 mg bid based on modeling Rivaroxaban (20 mg/day dosing) Healthy elderly (>75 yrs): AUC but not max level Similar safety & efficacy in subjects >75 yrs No differences with mild-moderate renal impairment 15 mg/day (instead of 20) used for CrCl ml/min Bauersachs, Thromb Res 129:107, 2012

23 Principles Regarding Bleeding Anticoagulation doesn t cause bleeding Bleeding occurs when a vessel ruptures Anticoagulation doesn t weaken vessels Most people who bleed to death aren t on anticoagulation Outcome Placebo Apixaban 2.5 mg po bid Apixaban 5.0 mg po bid Bleeding 22 (2.7%) 27 (3.5%) 35 (4.3%) Major 4 (0.5%) 2 (0.2%) 1 (0.1%) Risk of major bleeding, including intracranial, does not correlate with history of falls Donze, Am J Med 125:773, 2012

24 Anticoagulants and Bleeding Risk of major bleeding %/year Warfarin: the most reversible form of oral anticoagulation Fresh frozen plasma immediate repletion of factors, temporary effect Vitamin K p.o. or i.v. production of functional factors within 6-12 hrs New agents: active anticoagulation (e.g. binds activated factors) no benefit with FFP/Vit K No proven way to reverse anticoagulation Twice-daily (e.g. dabigatran or apixaban) may be preferred with shorter effective half-life

25 Vitamin K and Warfarin With excessive anticoagulation, can use vitamin K to drop INRs: INR Drop By Time Interval 1 mg i.v hrs 1 mg s.q hrs mg p.o hrs Guidelines (and experience) advise AGAINST subcutaneous vitamin K for patients on oral anticoagulation

26 Reversal of New OACs FIX THE HOLE that s bleeding Decrease quantity of drug Activated charcoal if thought to still be in stomach Dabigatran may be dialyzed Bypass the drug effect Prothrombin complex (PCC), factor VIIa concentrates anecdotally successful Recent study suggested apcc may work best for anti- Xa (rivaroxaban) but not anti-thrombin (dabigatran) No increased risk of mortality or morbidity (even in >75 y.o.) related to bleeding with new agents DeLoughery, Am J Hem 86:586, 2011 Eerenberg, Circulation 124:1508, 2011 Sardar, J Am Geriat Soc 62:857, 2014

27 New OACs: Interruption of Therapy Dabigatran (per package insert) If CrCl>50 ml/min, hold 1-2 days If CrCl<50 ml/min, hold 3-4 days Ecarin clotting time may be a marker of activity aptt approximates activity (??), INR unreliable Rivaroxaban (per package insert) Hold for at least 24 hours Apixaban (per package insert) Hold for at least 24 hours, 48 for interventions with higher bleeding risk

28 New OACs: Interruption of Therapy Bridging with LMWH?? Per package insert: Dabigatran: interruption has been associated with risk of stroke and thrombotic events consider administration of other anticoagulant Rivaroxaban: events occurred when moving from the drug back to warfarin during clinical trials consider administration of other anticoagulant Apixaban: bridging not recommended Similar half-life to LMWH, no clear theoretical reasons to bridge

29 New OACs: Switching Drugs On warfarin, going to a new OAC Hold warfarin for ~2-3 days Remember, the lower the daily warfarin dose, the longer it takes to clear the system If in doubt, check an INR before starting the new OAC Start new drug once INR is at/below desired range (e.g. <2, <2.5, <3) Remember, new OACs fully therapeutic within 2-3 hours

30 New OACs: Switching Drugs On a new OAC, going to warfarin New drugs affect INR, so need to hold for hours before it can be used to measure warfarin May see some effect even at very low drug concentrations If worried about thrombotic risk, start LMWH in place of new drug while making the transition Discontinue LMWH once INR >2.0 (or into desired range) for 24 hours

31 New OACs and Adherence Onset of activity within 2-3 hours Rapid return to therapeutic benefit Loss of activity within hours Missed doses may really be missed no lingering effect as is true with warfarin Once-daily may be easier to remember Cannot assess drug levels: drug failure or failure to take the drug? PT/INR, aptt insensitive No data regarding anti-xa levels (rivaroxaban, apixaban)

32 New OACs: Different than Warfarin WARFARIN Production of dysfunctional factors Changes the body Effect through vitamin K Multiple medication interactions Dose adjusted Can/must be monitored Can be used in renal failure Reversible NEW ORAL AGENTS Inhibition of activated factors No effect unless factors active No vitamin K (diet) impact Few medication interactions Fixed dose No monitoring (can t) Dependent on renal clearance (not apixaban) Irreversible

33 New Oral Anticoagulants (OACs) Indication Dabigatran Etexilate (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Atrial fibrillation 150 mg bid 20 mg/dy 5 mg bid renal fctn (GFR) CrCl 15-30: 75 mg bid Acute VTE 5-10 days of LMWH, then 150 mg bid CrCl 15-30: 15 mg/dy 15 mg bid x 21 days, then 20 mg/day 2.5 mg bid 10 mg bid x 7 days, then 5 mg bid Wittkowsky, J Thromb Thrombolysis 29:182, 2010; Giorgi, Expert Opin Pharmacother 12:567, 2011; DeLoughery, Am J Hem 86:586, 2011 FDA Approved

34 Statistical vs. Clinically Relevant (?) Pause for Perspective p< p< Stroke ICH 0 Stroke ICH New Drug Old Drug New Drug Old Drug

35 New OACs: Atrial Fibrillation Comparator: warfarin Consider time in therapeutic range (TTR) Usual thrombotic outcomes (%/year): noninferiority design Composite of stroke, systemic embolism Usual hemorrhagic outcomes: Major bleeding Clinically relevant, non-major bleeding Typical duration of study: 2 years EXCLUDES valvular disease/artificial heart valves

36 Percentage/Year Dabigatran vs. Warfarin for A Fib: RE-LY Subjects: 18,113 Mean age: 71 yrs Mean CHADS: 2.1 Mean CrCl: NR % ASA use: 39% Dosing: Dabigatran: 110 mg bid or 150 mg bid Warfarin: INR 2-3 Primary Outcome: Stroke/systemic embolism Warfarin TTR: 64% p< Stroke / Embolism Connolly, NEJM 361:1139, Death Major Bleeding Dabigatran 150 mg bid ICH Warfarin - Side effect of dyspepsia in 11.8% vs. 5.8% GI bleeding 1.5% vs. 0.9% (p<.001) - CrCl>30 ml/min to be on study - No differences noted in patients on amiodarone, H 2 -receptor antagnoists, proton pump inhibitors * *p<.05

37 Percentage/Year Rivaroxaban vs. Warfarin for A Fib: ROCKET-AF Subjects: 14,264 Median age: 73 yrs Mean CHADS: 3.47 Median CrCl: 67 ml/min % on ASA: 35% Dosing: Rivaroxaban: 20 mg q dy Warfarin: INR 2-3 Primary Outcome: Stroke/systemic embolism Warfarin TTR: 55% Stroke Embolism Death Rivaroxaban Patel, NEJM 365:883, Major Bleeding Warfarin *p= ICH 0.7 -Use of CYP3A4 or P-glycoprotein inhibitors prohibited -As treated safety population 1.7% vs. 2.2% favoring rivaroxaban (p=.02) -No difference across INR ranges *

38 Percentage/Year Apixaban vs. Warfarin for A Fib: ARISTOTLE Subjects: 18,206 Median age: 70 yrs Mean CHADS: 2.3 CrCl <50 ml/min: 16% % on ASA: 31% Dosing: Apixaban: 5 mg bid or 2.5 mg bid (renal/age) Warfarin: INR 2-3 Primary Outcome: Stroke/systemic embolism Warfarin TTR: 66% p= Granger, NEJM 365:981, Thrombosis Death Major Bleeding Apixaban Warfarin *p< ICH -Excluded creat >2.5 mg/dl, CrCl<25 ml/min -Interaction between bleeding and -diabetes: apixaban=warfarin if DM -renal function: apixaban better than warfarin with severe renal failure * * 0.8

39 Meta-Analysis of New Agents for A Fib Three RCTs including 44, 563 subjects RE-LY (Dabigatran) ROCKET AF (Rivaroxaban) ARISTOTLE (Apixaban) As compared to warfarin: Stroke, Systemic Embolism Vascular Mortality All-Cause Mortality 0.78 ( ) 0.87 ( ) 0.88 ( ) Major Bleeding ICH GI Bleeding 0.88 ( ) 0.49 ( ) 1.25 ( ) Miller, Am J Cardiol, amjcard

40 ACCP 2012 Guidelines for A Fib CHADS 2 score One point each for: - CHF - Hypertension - Age 75 - Diabetes mellitus - Stroke/TIA history (2 pts) Score 0 1 Therapy Nothing or ASA mg Oral anticoagulant (OAC) or ASA+clopidogrel (if not OAC candidate) If OAC: favor dabigatran over warfarin Rivaroxaban or apixaban instead of warfarin? You, Chest 141(Suppl):e531S, 2012

41 New OACs: Treatment of VTE Usual comparator: LMWH warfarin Warfarin goal INR 2-3; remember TTR Usual outcomes: Recurrent VTE Bleeding Usual duration of therapy 3-6 months Extension studies (compared to placebo or warfarin) for up to 2 years

42 Percentage Dabigatran vs. Warfarin for VTE: RE-COVER Subjects: 2564 Mean age: 55 yrs Isolated PE: 21% History of VTE: 25% Weight: 85 (38-175) kg Est CrCl: 105 ml/min Dosing: Dabigatran 150 mg bid Warfarin INR 2-3 Primary Outcome: VTE/related death Warfarin TTR: 60% Primary Outcome Dabigatran All-Cause Death NEJM 361:2342, 2009 Warfarin *p= Major Bleed Clin Rel Bleed Treated for a mean of 3 days with standard therapy before randomization More dyspepsia with dabigatran (2.9 vs. 0.6, p<0.001) 2% were cancer patients *

43 Percentage Rivaroxaban vs. Warfarin for VTE: EINSTEIN DVT Subjects: 3445 Mean age: 55 yrs Isolated PE: 0.6% History of VTE: 19% Thrombophilia: 7% Weight>100 kg: 14% CrCl<50 ml/min: 7.5% Dosing: Rivaroxabn: 15 mg bid x 3 wks, then 20 mg/day LMWH+Warfarin INR 2-3 Primary Outcome: VTE Warfarin TTR: 58% Rivaroxaban *p<.001 non-inferior * Thrombosis Death Major Bleeding NEJM 363:2499, 2010 Warfarin All Bleeding -Excluded -CrCl <30 ml/min -strong CYP3A4 inhibitors (e.g. HIV meds) or inducers (e.g. carbamazepin, dilantin)

44 Percentage Rivaroxaban vs. Warfarin for VTE: EINSTEIN-PE Subjects: 4817 Mean age: 57 yrs Unprovoked: 64% History of VTE: 19% Thrombophilia: 5% Weight>100 kg: 14% CrCl<50 ml/min: 8% Dosing: Rivaroxabn: 15 mg bid x 3 wks, then 20 mg/day LMWH+Warfarin INR 2-3 Primary Outcome: VTE Warfarin TTR: 62.7% Rivaroxaban *p<.003^ *non-inferiority * Warfarin Thrombosis Death Major Bleeding NEJM 366:1278, All Bleeding -Excluded -CrCl <30 ml/min -strong CYP3A4 inhbiitors (e.g. HIV meds) or inducers (e.g. carbamazepine, dilatin) ^

45 Percentage Apixaban vs. Warfarin for VTE: AMPLIFY Subjects: 5395 Mean age: 57 yrs Unprovoked: 90% History of VTE: 16% Thrombophilia: 2.5% Weight>100 kg: 19% CrCl<50 ml/min: 6% Dosing: Apixaban: 10 mg bid x 7 dys, then 5 mg bid LMWH+Warfarin INR 2-3 Primary Outcome: VTE Warfarin TTR: 61% Apixaban *p<.003^ *non-inferiority * Thrombosis Death Major Bleeding NEJM 369:799, 2013 Warfarin ^ ^ All Bleeding -Excluded -CrCl <25 ml/min or serum Cr >2.5 mg/dl -potent CYP3A4 inhibitors -Cancer: 2.6%

46 New OACs: Treatment of VTE Recurrent thrombosis: equal to warfarin Bleeding: maybe less than warfarin Population included some Thrombophilias Wt >100kg Relatively few with renal insufficiency Exception is apixaban, which is minimally renally cleared

47 Management of VTE: ACCP 2012 Acute Management: active anticoagulation Subcutaneous LMWH Intravenous or subcutaneous UFH Fondaparinux Rivaroxaban?, Apixaban? Kearon, Chest 141:e419S, 2012

48 Management of VTE: ACCP 2012 Transition to chronic phase of anticoagulation Initiation of VKA (warfarin) on first day (if not using rivaroxaban or apixaban?) Continue LMWH/UFH until INR stable and 2.0 for at least 24 hours Treatment with LMWH/UFH for at least 5 days Switch to dabigatran? Kearon, Chest 141:e419S, 2012

49 Cost Effectiveness Drug costs ~AWP (not the same as copay/coverage) Warfarin: $ /day Enoxaparin (prophylaxis): $30-40/day Enoxaparin (treatment): $50-100/day New Agents: $4-$8/day Cost-effectiveness of therapy depends on CHADS score for dabigatran in atrial fibrillation CHADS score 0: ASA CHADS score 1-2: warfarin, if INR stable (TTR>57%) and low bleeding risk CHADS score 3: dabigatran, unless INR very stable (TTR>75%) Shah, Circulation 123:2562, 2011

50 Other Scenarios: Cancer In patients with DVT or PE, and cancer, per ACCP: LMWH over VKA CLOT study Lee, NEJM 349:146, 2003 If not treated with LMWH, ACCP recommends VKA over rivaroxaban or dabigatran ( too few patients ) Kearon, Chest 141:e419S, 2012

51 Other Scenarios: Antiphospholipid Antibody Syndrome RAPS Study (Cohn, UK) Rivaroxaban vs. warfarin for 3 months Study characteristics: Population: thrombotic APS SLE, single episode VTE Endpoint: endogenous thrombin potential at 4 months If successful, will endorse clinical use (!) No plans for clinical outcomes study However, we routinely use LMWH if concerned about warfarin and this was never studied, either Remember, new OACs act like LMWH

52 Agent Selection Who Gets What? New OACs Instead of LMWH Basically similar properties irreversible, unmonitored - except new agents require: Better (e.g. >60 ml/min) renal function, probably Awareness of potentially interacting meds Ability to take p.o. medication Arguably, new agents are at least as efficacious and safe, easier to administer and cheaper

53 Agent Selection Who Get s What? New OACs Instead of Warfarin Normal renal function; low risk for rapid progression to renal insufficiency Low bleeding risk: unlikely to need reversal Patients with unstable INRs: new agents likely costeffective in addition to safety/efficacy advantage Adherence: missed dose will be missed! However, immediate return to adequate anticoagulation once dosing resumed Drug monitoring not needed to assess adherence, interpret clinical events Not on potentially interacting drugs

54 Agent Selection Who Gets What? Warfarin Instead of New Anticoagulants: Renal insufficiency (GFR<60? <30?), ESRD High bleeding risk: most easily reversed Patients with stable INR: most cost-effective Difficulty with adherence: least harm with missed dose History of multiple events (bleeding or clotting) Can measure INR to assess degree of anticoagulation relative to event (INR too high or too low) On medications that may interact with new anticoagulants, especially those that inhibit drug clearance and in patient with fluctuating mild-moderate renal insufficiency

55 Agent Selection Who Get s What? New Anticoagulants Instead of Warfarin Normal renal function, low risk for rapid progression to renal insufficiency Low bleeding risk: unlikely to need reversal Patients with unstable INRs: new agents likely costeffective in addition to safety/efficacy advantage Adherence: missed dose will be missed! However, immediate return to adequate anticoagulation once dosing resumed Drug monitoring not needed to assess adherence, interpret clinical events Not on potentially interacting drugs