New Oral Anticoagulants Overview. Renee Mistovich, DO Updated 5/6/14

Transcription

1 New Oral Anticoagulants Overview Renee Mistovich, DO Updated 5/6/14

2 3 New Agents Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis)

3 Outline FDA approvals/indications Clinical Trials For Stroke Prevention Atrial fibrillation Guidelines for stroke prevention/atrial fibrillation Clinical Trials for DVT/PE Current Guidelines for DVT/PE with New anticoagulants Contraindications/ Precautions Dosing and considerations with renal failure; hepatic failure, geriatric population/ medication interactions Conversion to/from warfarin and parenteral anticoagulants Perioperative Considerations Reversal Agents? Cases and Discussion points

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5 Dabigatran (Pradaxa) Direct thrombin (factor IIa) inhibitor 10/2010- FDA approved for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation 4/2014- FDA approved for treatment of DVT and PE in patients initially treated with parenteral anticoagulant for 5-10 days and to reduce risk of recurrence of DVT/PE in patients who have been previously treated

6 Rivaroxaban (Xarelto) Factor Xa inhibitor 11/2011; FDA approved for prevention of stroke and systemic embolism for nonvalvular atrial fibrillation 7/2011; FDA approved for DVT prophylaxis after total knee or hip arthroplasty 11/2012; FDA approved for treatment of DVT/PE and to reduce risk of recurrence of DVT/PE in extended treatment

7 Apixaban (Eliquis) Factor Xa inhibitor 12/2012: FDA approved for prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation 3/2014: FDA approved for DVT prophylaxis following hip or knee arthroplasty

8 Clinical Trials - Atrial Fibrillation Major Clinical Trials for New Oral Anticoagulants That led to FDA Approval for stroke prevention in nonvalvular atrial fibrillation

9 Dabigatran Clinical Trials RE-LY RELY Trial Open-label, randomized, noninferiority trial 18,113 pts randomly assigned to dabigatran 110 mg bid or 150mg bid (blinded) or to adjusted-dose warfarin (unblinded) Exclusion criteria included pt s with severe valvular heart disease, increased bleeding risks (recent GI bleed, ICH, recent surgery), Active liver disease, CrCl < 30ml/min Primary outcome stroke or systemic embolization Primary safety outcome- major hemorrhage Primary analysis test whether either dose of dabigatran (110mg bid or 150mg bid) was noninferior to warfarin NEJM 2009) (Connolly,

10 Dabigatran RE-LY Results Both doses of dabigatran were noninferior to warfarin to prevent stroke or systemic embolism in nonvalvular afib (P<0.001) The 150mg bid dosing of dabigatran was superior to warfarin (P<0.001) 150mg dabigatran was superior to 110 mg dose to reduce risk of stroke or systemic embolism (P=0.005) (Connolly, NEJM 2009)

11 RE-LY 110 mg dabigatran was superior to warfarin in regards to major bleeding (P=0.003) 150mg dabigatran was noninferior to warfarin in regards to major bleeding Rates of total bleeding (intracranial bleeding, life threatening bleeding, and major or minor bleeding), were higher in warfarin group compared to both dabigatran groups - subset rates of GI hemorrhage were higher in both dabigatran groups however ***Also Dyspepsia was only side effect significantly more common with pradaxa compared to warfarin. *** (Connolly, NEJM 2009)

12 Dabigatran Based on RE-LY, the FDA approved the Dabigatran 150mg bid for prevention of stroke or systemic embolism in patients with atrial fibrillation (the 110 mg dose is not approved) - It was determined that the irreversible effects of strokes and systemic emboli have greater clinical significance than nonfatal bleeding - there was also inability to identify any subgroup in the trial in which the lower dosing would not represent a disadvantage Since dabigatran is cleared by kidneys; FDA also approved a dose of dabigatran 75 mg bid for patients with creatinine clearance ml/min -this recommendation is based on extrapolated pharmacokinetics and pharmacodynamics, over efficacy and safety data (Beasley, NEJM 2011)

13 Dabigatran RE-ALIGN Trial Randomized Phase II study to Evaluate the Safety and pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement Included patients with aortic or mitral valve replacement within past 7 days and those who had undergone valve replacement at least 3 months earlier Randomly assigned to dabigatran or warfarin Study terminated early due to excess of thromboembolic and bleeding events in dabigatran group (Eikelboom, NEJM 2013)

14 Rivaroxaban Clinical Trials ROCKET AF Randomized double blind trial >14,000 pt with nonvalvular afib received either rivaroxaban 20 mg daily or dose-adjusted warfarin (pt w/ CrCl ml/min received 15mg rivaroxaban daily) Primary analysis was to determine whether rivaroxaban was noninferior to warfarin for primary end point of stroke or systemic embolism Intention to treat analysis assessed for superiority Primary safety end point is major and nonmajor clinically relevent bleeding (Patel, NEJM 2011)

15 ROCKET AF In primary analysis and intention-to-treat analysis; rivaroxaban was noninferior to warfarin. In intention to treat population, there was no significant difference between groups in superiority analysis Rates of major and nonmajor clinically relevant bleeding were similar between the two study groups Fatal or bleeding at critical anatomical site (intracranial) was less in rivaroxaban group Bleeding from GI tract was higher in rivaroxaban group (Patel, NEJM 2011)

16 Apixaban- Clinical Trials For afib - ARISTOTLE Randomized, double-blind trial; 18,201 pts Compared apixaban 5mg bid (or 2.5mg bid in select patients) with warfarin (dose adjusted) in pts with afib and at least one risk factor for stroke Primary outcome is ischemic or hemorrhagic stroke or systemic embolism Trial designed for noninferiority with secondary objectives of testing for superiority with respect to primary outcome and the major bleeding rates and death from any cause (Granger, NEJM 2011)

17 ARISTOTLE Primary outcome (stroke or embolism) was 1.27% per year in apixaban group and 1.60% per year in warfarin grp (P<0.001 for noninferiority and P= 0.01 for superiority) Major bleeding 2.13% per year in apixaban grp and 3.09% per year in warfarin grp (P<0.001) Rate of hemorrhagic stroke was 0.24% per year in apixaban group and 0.47% per year in warfarin grp (P<0.001) In patients with afib, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding and resulted in lower mortality. (Granger, NEJM 2011)

18 Summary of Trial Results Dabigatran 150 mg bid and Apixaban 5mg bid showed superiority for prevention of CVA and systemic embolism in pts with nonvalvular afib Rivaroxaban 20mg daily showed noninferiority compared to warfarin in prevention of CVA or systemic embolism Dabigatran 150mg bid and Rivaroxaban 20mg daily showed noninferiority for major bleeding events overall (both had less ICH s and higher rates of GI bleeding compared to warfarin) Apixaban showed superiority in regards to bleeding events including GI bleeds, compared to warfarin.

19 Summary Trial Results Dabigatran (RE-LY) Rivaroxaban (ROCKET AF) Superiority for CVA prevention compared to warfarin 150mg bid dosing Noninferiority for CVA prevention compared to warfarin 20mg daily Superiority to total bleeding events compared to warfarin Noninferiority for total bleeding events compared to 150mg bid dosing (had higher GI bleeding event) 20 mg daily (had higher GI bleeding events) Apixaban (ARISTOTLE) 5mg bid 5 mg bid (included lower GI bleeding event rates)

20 Summary of Trials Mean age Dabigatran (pts had at least 1 risk factor) Mean CHADS2 TTR time in therapeutic range for INR Major side effects compared to warfarin 65% dsypepsia Rivaroxaban (pts had at least 2 risk factors) 55% / Apixaban (pts had at least 1 risk factor) 66% /

21 Guidelines For Use in Atrial Fibrillation American College of Cardiology Foundation/ American Heart Association/ Heart Rhythm Society (Circulation 2014) American Heart Association/ American Stroke Association (Stroke 2012) American College of Chest Physicians (CHEST 9 th ed. 2012)

22 2014 ACC/ AHA/ HRS (Circulation)- Class I For pt s with nonvalvular afib with prior stroke, TIA, or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include warfarin (INR 2-3) (level of evidence A), dabigatran (level of evidence B), rivaroxaban (level of evidence B), or apixaban (level of evidence B). For patients with nonvalvular afib unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin or factor Xa inhibitor (dabigatran, rivaroxaban or apixaban) is recommended (level of evidence C). (January, Circulation 2014)

23 2014 ACC/ AHA/ HRS (Circulation)- Class I Re-evaluation of the need for and choice of antithrombotic therapy at periodic intervals is recommended to reassess stroke and bleeding risks (level of evidence C). Renal function should be evaluated prior to initiation of direct thrombin inhibitors or factor Xa inhibitors and should be re-evaluated when clinically indicated and at least anually (level of evidence B) (Jaunuary, Circulation 2014)

24 2014 ACC/ AHA/ HRS (Circulation) Class IIa recommendation: For pts with nonvalvular AF and a CHA2DS2-VASc score of 2 or greater and who have end stage CKD (CrCl < 15 ml/min) or are on HD, it is reasonable to prescribe warfarin (INR 2-3) for oral anticoagulation (level of evidence B) Class IIb recommendation: For pt s with nonvalvular AF and moderate to severe CKD with CHA2DS2-VASc scores of 2 or greater, treatment with reduced doses of direct thrombin or factor Xa inhibitors may be considered (eg dabigatran, rivaroxaban, apixaban), but safety and efficacy have not been established (level of evidence C) (Jaunuary, Circulation 2014)

25 2014 ACC/ AHA/ HRS (Circulation)- Class III Class III: No benefit The direct thrombin inhibitor, dabigatran, and the factor Xa inhibitor, rivaroxaban, are not recommended in patients with AF and end stage CKD or on HD because of lack of evidence from clinical trials regarding the balance of risks and benefits (level of evidence C) Class III: Harm The direct thrombin inhibitor, dabigatran, should not be used in pts with AF and a mechanical heart valve (level of evidence B) (January, Circulation 2014)

26 Guidelines - American Heart Association/ American Stroke Association (Stroke 2012) The following are indicated for prevention of first and recurrent stroke in pts with nonvalvular atrial fibrillation: Warfarin (Class I, level A evidence) Dabigatran (Class I, level B) Apixaban (Class I, Level B) Rivaroxaban (Class IIa, level B) The selection of antithrombotic agent should be individualized on basis of risk factors, cost, tolerability, pt preference, drug interactions, INR therapeutic range if pt on warfarin (Furie, Stroke 2012)

27 Guidelines - American Heart Association/ American Stroke Association (Stroke 2012) for Dabigatran - recommends Dabigatran 150 mg bid as efficacious alternative to warfarin for prevention of first and recurrent stroke in pts with nonvalvular atrial fibrillation and at least 1 additional risk factor for stroke and creatinine clearance > 30 ml/min. (Class 1, level of evidence B) - the use of Dabigatran 75mg bid in patients with AF and at least 1 additional risk factor for stroke, who have a low CrCl (15-30 min/ml) may be considered, but its safety and efficacy have not been established (Class IIb, Level of Evidence C) - Dabigatran is not recommended in pts with CrCl < 15min/ml (Class III, Level of Evidence C) (Furie, Stroke 2012)

28 Guidelines- American Heart Association/ American Stroke Association (2012) for Rivaroxaban - In patients with nonvalvular AF who are at moderate to high risk of stroke (prior hx TIA/CVA or systemic embolims or 2 or more risk factors), rivaroxaban 20mg/day is reasonable as an alternative to warfarin (Class IIa, level B evidence) - In pts with renal impairment and nonvalvular afib at moderate to high risk stroke, with a CrCl of ml/min, then 15mg of rivaroxaban daily may be considered; however safety and efficacy not established (Class IIb, level C evidence) - Rivaroxaban should not be used for CrCr < 15ml/min (Class III, C) (Furie, Stroke 2012)

29 Guidelines- American Heart Association/ American Stroke Association (2012) for Apixaban Apixaban 5 mg twice daily is a relatively safe and efficacious alternative to warfarin in patients with nonvalvular afib deemed appropriate for Vitamin K antagonists who have at least 1 additional risk factor and no more than 1 of the following: age 80 YO or greater, wt < 60kg or creatinine > 1.5 (class I, level B) Although safety and efficacy not established, apixaban 2.5mg bid may be considered as alternative to warfarin in pts with nonvalvular afib deemed appropriate for VKA who have at least 1 risk factor and 2 of following; age > 80, wt < 60kg or creatinine > 1.5 (class II b, level C) Apixaban should not be used if CrCl is < 25 ml/min (Furie, Stroke 2012)

30 American College of Chest Physicians Antithrombotic Guidelines (CHEST 9 th ed 2012) For patients with AF, including pt s with paroxysmal AF, who are at intermediate or high risk of stroke (CHADS2 of 1 or more) Dabigatran 150mg bid is suggested over dose adjusted VKA therapy (target INR 2-3) - Grade 2 B This recommendation excludes patients with valvular disease, stable coronary artery disease, patients with ACS or recently undergone coronary stenting with BMS or DES In pts with hx of ischemic CVA or TIA and afib, including PAF, dabigatran 150mg bid is suggested over adjusted dose VKA therapy w/ INR goal 2-3. Grade 2 B (Guyatt, CHEST 2012)

31 American College of Chest Physicians did not comment on Rivaroxaban or Apixaban as these drugs were not approved yet by FDA at time of writing.

32 DVT/PE Studies Rivaroxaban (Xarelto) was FDA approved in 2012 and Dabigatran (Pradaxa) was FDA approved in 2014 for treatment of acute venous thromboembolism and prevention of recurrent thromboembolism Apixaban study showed noninferiority to warfarin in DVT study, though currently not FDA approved NEJM 2013) (Schulman, NEJM 2009, 2013; Agnelli,

33 Rivaroxaban For DVT EINSTEIN program for acute treatment of DVT and extended treatment DVT Open label, randomized, noninferiority study compared oral rivaroxaban alone (15mg bid x 21 days, then 20mg daily) with lovenox/warfarin therapy for 3,6, or 12 months In parellel, double-blind randomized superiority trial comparing rivaroxaban alone (20mg daily) to placebo for 6-12 months tx (pt s already completed 6-12 months tx for DVT) (Bauersachs NEJM 2010)

34 EINTSTEIN - DVT Rivaroxaban had noninferior efficacy with respect to primary outcome (recurrent thromboembolism) (P<0.001) Safety outcome (major bleeding or clinically relevant nonmajor bleeding) was similar in both groups In continued treatment study, rivaroxaban had superior efficacy compared to placebo for recurrent thromboembolism (P< 0.001) The principle safety outcome of major bleeding occurred in 0.7% of rivaroxaban group and none in placebo Clinically relevant, nonmajor bleeding was 5.4% in rivaroxaban grp to 1.2% in placebo (mucosal) Suggests acceptable benefit- to- risk profile (Bauersachs NEJM, 2010)

35 EINSTIEN PE Randomized, open label, noninferiority trial in patients with acute symptomatic PE (+/- DVT) compared rivaroxaban (15mg bid x 21 days and then 20mg daily) to lovenox/warfarin for 3,6 or 12 months Primary efficacy outcome was symptomatic recurrent venous thromboembolism Principle safety outcome was major or clinically relevant nonmajor bleeding (Buller, NEJM 2012)

36 EINTSTEIN PE Rivaroxaban was noninferior to standard therapy (P=0.003) for initial and long term treatment of PE Bleeding rates were similar in two groups with increased major bleeding in warfarin group NEJM 2012) (Buller,

37 Dabigatran for DVT RE-COVER and RE-COVER II trials Randomized, double-blind, noninferiority trials >2,500 pts with acute VTE - received initial parental anticoagulation for median of 9 days Compared oral dabigatran 150mg bid to warfarin (dose adjusted for INR 2-3) Primary outcome - 6 month incidence of recurrent, symptomatic, objectively confirmed VTE and related deaths Safety endpoints - bleeding events, ACS, other adverse events and results of LFTs. Results - dabigatran was noninferior to warfarin for tx of VTE; with similar major bleeding events and similar safety profile; dabigatran had slightly lower nonmajor bleeding events

38 Dabigatran for extended VTE treatment Two double blinded, randomized trials RE-MEDY active control study- compared dabigatran 150mg bid to warfarin (dose adjusted for INR 2-3) for median of 18 months RE-SONATE placebo control study- compared dabigatran 150mg bid to placebo for median of 6 months Both studies for patients who already completed at least 3 initial months of therapy

39 Active control study showed dabigatran to be noninferior to warfarin in preventing recurrent or fatal VTE Active control study showed few major bleeding events and significantly few clinically relevant nonmajor bleeding events in dabigatran group compared to warfarin Placebo control study showed dabigatran superior to placebo in reducing rate of recurrent VTE, though had significantly higher risk of major or clinically relavant nonmajor bleeding There was a higher rate of acute coronary events with dabigatran than with warfarin, with no significant difference in these events between dabigatran and placebo There is also other conflicting evidence showing increase risk ACS in pts treated with dabigatran in other trials

40 American College of Chest Physicians DVT/PE Guidelines-2012 In pts with DVT/PE of the leg and no cancer, we suggest VKA therapy over LMWH for long-term therapy.(grade 2C) For pts with no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long term therapy (Grade 2 C) In pts with DVT leg and cancer,suggest LMWH over VKA(grade 2B). If not treated with LMWH, then suggest VKA over dabigatran or rivaroxaban. (grade 2B) *** Remarks: Treatment of VTE with dabigatran or rivaroxaban may have better clinical outcomes and be less burdensome to pts; when ACCP guidelines were prepared, postmarketing studies of safety unavailable and thus above is weak recommendation to favor VKA or LMHW over new agents *** (Guyatt, CHEST 2012)

41 Black Boxed Warnings- post marketing Digatraban, Rivaroxaban and Apixaban should not be stopped abruptly or prematurely discontinued as this could cause increase thrombotic events, including stroke Consider addition of alternative anticoagulant when discontinuing for reasons other than pathological bleeding or completion of course of therapy Spinal or epidural hematomas, including subsequent paralysis may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients who are anticoagulated (Uptodate/ Lexicomp- 2013; Digabatran, Rivaroxaban, Apixaban [package insert], accessed 11/2013)

42 Contraindications Dabigatran contraindicated in patients with mechanical prosthetic heart valves based on RE-ALIGN trial (pts more likely to have stroke, MI, valve thrombosis and bleeding/pericardial effusion) Dabigatran was not studied in patients with bioprosthetic heart valves and use in this populations is not recommended. Rivaroxaban and Apixaban are not studied in pt s with prosthetic valves and use is not recommended here Anaphylaxis and major bleeding risks Not recommended in pregnancy or breast feeding; was not tested in this population, category C (apixaban is category B) (Uptodate, Lexicomp 2013; Dabigatran, Rivaroxaban, Eliquis [package insert] accessed 11/2013)

43 Dabigatran Dosing considerations- Renal Nonvalvular atrial fibrillation: Function - CrCl > 30 ml/min; no dosing adjustment (150mg bid) - CrCl ml/min; 75mg bid - (of note, pts w/ CrCl < 30 were excluded from RE-LY and per ACCP, this is contraindicated here ) - CrCl < 15, use not recommended (including hemodialysis patients) DVT/PE: - CrCl > 30 ml/min: no dosage adjustment necessary - CrCl < 30 ml/min: no dosage recommendations provided; these pts were excluded from clinical trials (avoid use with ESRD on HD) 11/2013) (Updodate/Lexicomp Dabigatran [package insert] accessed

44 Rivaroxaban Dosing Considerations - Renal Function Nonvalvular afib: - CrCl > 50 ml/min: no dosage adjustment necessary (20mg daily) - CrCl ml/min: 15mg once daily with evening meal - CrCl< 15 ml/min: avoid use (avoid in ESRD on HD) For DVT/PE: - CrCl 30 ml/min: no dosage adjustment (15mg bid x 21 days and then 20 mg daily) - CrCl < 30 ml/min: avoid use (including patients on HD) (Uptodate/Lexicomp 2014 Rivaroxaban [package insert]; accessed 11/2013)

45 Apixaban Dosing Considerations- Renal Impairment For Nonvalvular Afib: Standard dosing is 5mg bid Use 2.5mg bid dosing if 2 or more of the following: serum creatinine 1.5 mg/dl, age 80 YO, and body wt 60 kg - if CrCl < 25 ml/min; no recs as has not been studied AHA/ ASA recommends to avoid use ESRD on hemodialysis: 5mg bid; reduce dose to 2.5mg bid if age 80 or body wt 60 kg (Uptodate/Lexicomp 2014; Apixaban [package insert] 2013)

46 Considerations- Hepatic Impairment For all 3 drugs; In US, no dose adjustment provided for hepatic impairment; especially if mild Child-Pugh Class A Dabigatrain: The 2011 ACCF/AHA/HRS guidelines do not recommend in pts with advanced liver disease Rivaroxaban: Avoid use with Moderate to severe impairment: (Child-Pugh class B or C) and pts with hepatic disease associated with coagulopathy Apixaban: moderate (Child-Pugh class B): use w/ caution; no dosage adjustment provided (limited clinical experience in these pts); Avoid use in Child-Pugh Class C (Updodate/Lexicomp 2014; Dabigatran, Rivaroxaban, Apixaban [package insert] accessed 11/2013)

47 Considerations- Geriatric Increased risk of bleeding has been observed, particularly in elderly pts with low body weight or w/ concomitant renal impairment Dabigatran and Rivaroxaban; No dose adjustments for age; adjust dose based on creatinine clearance as noted in previous slides; for dabigatrain use extreme caution or avoid if pts > 80 YO For apixaban, if pt is 80 YO or greater AND either weighs < 60 kg or has serum creatinine > 1.5 mg/dl, then reduce dose to 2.5 mg bid Mean ages ranged for afib trials and for VTE trials (Updodate/Lexicomp 2014; Dabigatran, Rivaroxaban, Apixaban [package insert]; acessed 11/2013)

48 Medication Interactions All 3 drugs have interactions with P-glycoprotein inducers/ inhibitors Rivaroxaban and Apixaban are also metabolized by the CYP3A4 system (Dabigatran is not) - watch with diltiazem, clarithromycin, azithromycin, erythromycin P-gp Inducers rifampin P-gp Inhibitors ketoconazole, dronedarone, amiodarone, verapamil Other drugs that increase risk of bleeding (ASA, NSAIDs, plavix, effient, pletal, coumadin, SSRIs) (Updodate/Lexicomp 2013; Dabigatran, Rivaroxaban, Apixaban [package insert]; accessed 11/2013)

49 Conversion From Warfarin discontinue warfarin - initiate dabigatran when INR < initiate rivaroxaban when INR < Initiate apixaban when INR < 2.0 (Uptodate/Lexicomp 2014; Dabigatran, Rivaroxaban, Apixaban [package insert], accessed 11/2013)

50 Conversion to Warfarin- All 3 drugs affect INR Dabigatran: start time is adjusted based on CrCl - CrCl > 50 ml/min: start warfarin 3 days before stopping dabigatran - CrCl ml/min: initiate warfarin 2 days before hand - CrCl ml/min: initiate warfarin 1 day before hand - CrCl < 15 ml/min: no recommendations Rivaroxaban: initiate warfarin and a parenteral anticoagulant 24 hours after discontinuation of rivaroxaban or when next dose is due (other approaches to conversion may be acceptable) Apixaban: if continuous anticoagulation necessary, discontinue apixaban and begin both a parenteral AC w/ warfarin when next dose apixaban is due; d/c parental AC when INR is acceptable range (apixaban affects INR) (Uptodate/Lexicomp 2014; Dabigatran, Rivaroxaban, Apixaban [package insert]; 2013)

51 Conversion from parenteral AC For dabigatran, rivaroxaban and apixaban - initiate 2 hours prior to time of the next scheduled dose of the parenteral anticoagulant or at the time of discontinuation of continuously parenteral drug (IV heparin) (Uptodate/Lexicomp 2014; Dabigatran, Rivaroxaban, Apixaban [package insert] accessed 11/2013)

52 Conversion to Parenteral AC Dabigatran: wait 12 hours (CrCl 30 ml/min) or 24 hours (CrCl < 30 ml/min) after last dose dabigatran before initiating parenteral anticoagulant Rivaroxaban: initiate heparin gtt or other anticoagulant 24 hours after discontinuation of rivaroxaban Apixaban: d/c anticoagulant and begin the other at next scheduled dose (Uptodate/Lexicomp, 2014; Dabigatran, Rivaroxaban, Apixaban [package insert] 2013)

53 Perioperative For dabigatran: if CrCl 50 ml/min, then d/c 1-2 days prior to surgery -if CrCl < 50 ml/min, then d/c 3-5 days prior - consider earlier d/c if major surgery, spinal puncture or epidural catheter placed Rivaroxaban : no specific evidence; 24 hrs prior to surgery generally recommended Apixaban: hold 24 hours prior if low risk surgery or bleeding site would be noncritical; hold 48 hrs if surgery has moderate to high risk unacceptable or critical bleeding Post op- resume when adequate hemostasis achieved AHA/ACC/HRS 2014 Guidelines: for elective surgery, holding newer oral anticoagulants for 1 day prior to surgery is generally sufficient for patients with normal renal function; the need for complete hemostasis (major surgery; spinal surgery) will need longer period of discontinuation of 48 hrs for pts w/ normal renal function (AHA/ACC/HRS 2014; Uptodate 2013, OhioHealth Prescribing Guidelines)

54 Perioperative Bridging? Rapid onset (2-3 hrs) and offset of drugs in general obviates need for bridging with other anticoagulants There are ongoing studies to assess the safety of this Consider bridging with heparin or lovenox preoperatively if stopping drug 4-5 days ahead of time for renal failure Consider bridging post op with low dose heparin or LMWH if pt underwent major surgery and/or cannot tolerate PO meds Must take into account that full anticoagulation is achieved promptly when restarting newer oral anticoagulants and reversal agents not readily available (AHA/ACC/HSR 2014 guidelines; Uptodate 2013)

55 Reversal Dabigatran Dabigatran d/c for active pathological bleeding- short half life makes discontinuation usually sufficient to reverse any excessive AC activity If severe bleeding; 3-4 units FFP Dabigatran can be dialyzed if renal impairment If emergent, aptt and thrombin time (TT) are most useful qualitative methods to monitor AC effects; if w/in normal range, then suggest little dabigatran activity Kcentra (PCC) and Vit K are not appropriate (OhioHealth Prescribing Guidelines 2012)

56 Reversal Rivaroxaban and Apixaban D/c drug short half life usually sufficient to reverse excessive AC activity FFP may be used if severe If PT elevated- Consider Prothrombin Complex Concentrate (Kcentra) - 50 units /kg For Rivaroxaban, If emergent, aptt and PT are most useful qualitative methods for monitoring AC effects of rivaroxaban (OhioHealth Prescribing Guidelines 2012; Anticoagulant Reversal Guidelines for Patients with Spontaneous Intracerebral Hemorrhage; Riverside Methodist Hospital Emergency Department 2013)

57 Case #1 70 YO F w/ pmhx of HTN and CKD, p/w new onset afib with RVR. After successful rate control with a BB and anticoagulation with heparin, pt underwent successful cardioversion. A TEE was neg for thrombus and showed normal EF, no valvular disease. CrCl is 41 ml/min, INR 1.0, LFTs are normal. CHA2DS2- VASc is 3 and it is determined pt should be on anticoagulation. Patient does not wish for coumadin. She does not want to bother with INRs and has hx of medication noncompliance in past, though agreeable to take a new AC medication. She has no clinically significant hx of major bleeding. Her weight is 80kg. What are considerations in choosing new oral agent? How should she be switched from heparin to new oral med? (Spinler, Circulation 2012)

58 Case #1- Discussion Based on Creatinine clearance (41 ml/min)- there would be no change in dose for Pradaxa or Eliquis (given her normal wt and age < 80). She would require reduced dose of Xarelto (15mg daily) since CrCl is < 50ml/min. History of noncompliance makes Pradaxa and Eliquis riskier meds given they are twice daily dosing and Xarelto is only once daily dosing. Xarelto should be taken with largest meal of day for best absorption and regular food intake should be reviewed. She is on no meds that would interact with either drug. (Spinler, Circulation 2012)

59 Case #1- Discussion Given her CKD; it is recommended that she has outpatient serum creatinine measured every 6 months If patient is hospitalized in future with acute illness and has acute on chronic kidney disease, then cessation of oral anticoagulant is recommended and replaced with SC lovenox/ heparin until renal function stable The pt s pharmacy and insurance company should be contacted to identify pt s copay and required prior authorizations Heparin infusion should be discontinued at the same time the new oral anticoagulant is administered (Spinler Circulation 2012)

60 Case #2 76 YO F p/w weakness and dehydration; found to have UTI. Pt has hx of frequent UTIs resulting in weakness, dehydration and often times resulting in acute renal failure. She is admitted and given IVFs and antibiotics for UTI. Her BUN/Cr is 35/2.0 on admission and this resolved by hospital day #3 w/ IVFs. Other labwork is normal. During hospitalization she is noted on telemetry to have paroxysmal atrial fibrillation that is rate controlled and she is asymptomatic. This is new diagnosis. TTE only shows left atrial enlargement; otherwise unremarkable. CHA2DS2-VASc is 4.

61 Case #2 Pmhx: HTN, GERD and hx PUD (no hx GI bleeding); she has no hx of clinically significant bleeding in past Home meds: lisinopril, protonix Wt is 110 kg - after discussion with patient about her atrial fibrillation; it is determined that is she an appropriate candidate for anticoagulation. -What are considerations for this patient for choosing an oral anticoagulant between coumadin and new agents?

62 Case #2 - Discussion - Despite resolution of pt s renal failure; she has hx of frequent UTIs/dehydration and AKI; in addition she is on lisinopril in this context which makes using an new anticoagulant more risky; esp Pradaxa which is mostly renally cleared - Her age alone is not a contraindication, though there has been tendency towards bleeding in elderly pts in clinical trials, esp due to increased risk renal failure - With Pradaxa; The RELY trial showed that dyspepsia/ GI symptoms were largest side effect of the drug; this patient has PUD and may be at risk for GI bleeding as well (Eliquis is only study drug w/out increase in GI bleeds compared to warfarin)

63 Case #3 A 65 YO M w/ pmhx of HTN and diabetes mellitus p/w new onset afib w/ RVR. An ischemic workup is negative. A TEE shows no thrombus and a normal EF; he does have moderate MR on his TEE. He asks about starting a new anticoagulant and prefers not to take warfarin. Based on labwork and medical hx, he is determined a candidate for one of new oral anticoagulants. Do his TEE results change this? What is definition of nonvalvular afib?

64 Case #3 Nonvalvular atrial fibrillation is defined as atrial fibrillation that occurs in the absence of rheumatic mitral valve disease (mitral stenosis), mitral valve repair or prosthetic heart valve (Uptodate Fuster 2011) Mitral regurgitation is generally considered protective against intracardiac thrombi in chronic afib due to enhanced turbulence and decreased stasis in left atrium. (Uptodate 2013) Pts enrolled in clinical trials included valvular lesions without HF like MVP, non-rheumatic MR or aortic valve lesions. (Uptodate 2013)

65 Case #4 93 YO F w/ hx of afib, hx PE in 2003, HTN p/w dyspnea; found to have large bilateral PE causing right heart strain. She is hemodynamically stable. She had been off AC due to prior hx fall risk, though this improved once she had epidural steroid injections for chronic back pain. She was not tpa candidate due to age; she was started on heparin gtt. Renal and hepatic function are normal No hx of GI bleeding in past What is best AC regimen? Coumadin or Xarelto or (Pradaxa)?

66 Case #4 Pt was seen by cardiology and xarelto was recommended ; based on convenience of dosing and lack of INR draws, normal labs Later, upon further investigation, pt revealed that she has hx some type of hemorrhage in her eye that was related to retinal vein occlusion (after discussion w/ ophthalmologist) in past; specifics are uncertain. It was determined that pt should be on coumadin given bleeding hx and no readily reversible agent. She had just received her first dose of xarelto this am when should first dose of coumadin be started and IV heparin/lovenox?

67 Case #4 First dose of warfarin should be given 24 hrs after last dose xarelto or when next dose is due. Wt based lovenox injection or IV heparin should be started at the same time for bridging. Given that the pt received xarelto this am, when will the INR be reliable to interpret warfarin s effects?

68 Case #4 The INR was 1.8 the following day#2 (after receiving xarelto in am and warfarin in pm day#1) The next day, #3, the INR was 1.3 and this was determined to be reliable (2 days after xarelto dose)

69 Case 5 60 YO M w/ pmhx of HTN, CVA, DM-II and A-fib on coumadin presents with left sided weakness; found to have acute embolic CVA. His INR was 1.3 on admission and he reports difficulty achieving therapeutic range as outpatient. After it was deemed safe to start full AC per neuro, he is started on heparin gtt and coumadin is restarted. He remains in the hospital for several days due to development of pneumonia and during this time it is determined he may benefit from one of the new anticoagulants. By this time is INR is 2.5. How do you convert from warfarin to pradaxa? To xarelto? To eliquis?

70 Case #5 Discontinue warfarin and start dabigatran when INR < 2.0 Discontinue warfarin and start rivaroxaban when INR < 3.0 Discontinue warfarin and start apixaban when INR < 2.0 (It is important to ensure that his low INR is not related to noncompliance as missing doses of new AC meds is dangerous given short half lives)

71 General Points to Take Away FDA approval for use of Dabigatran, Rivaroxaban and Apixaban for stroke prevention in nonvalvular atrial fibrillation (and for Rivaroxaban and Dabigatran for acute and extended treatment of DVT/PE) is based on a limited number of randomized control trials; making recommendation for use of these agents Level B evidence according to the ACC/AHA/HSR and AHA/ASA guidelines. The guidelines in the U.S. are continuously changing as there is much new information and ongoing studies coming out currently. The intention of this presentation is to evaluate the current information that is available, and gain a solid understanding of these new oral anticoagulants to allow us to make the most informed treatment decision for each individual patient.

72 References Connolly. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. The New England Journal of Medicine Sept. 2009; 361; Beasley. Anticoagulant Options- Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran. The New England Journal of Medicine May 2011; 364; Gage. Can We Rely on RE-LY? The New England Journal of Medicine Sept. 2009; 361; Eikelboom. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves. The New England Journal of Medicine Sept ; Patel. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. The New England Journal of Medicine Sept. 2011; 365; Granger. Apixaban versus Warfarin in Patients with Atrial Fibrillation. The New England Journal of Medicine Sept 2011; 365;

73 January ACC/AHA/HSR Guideline for the Management of Patients with Atrial Fibrillation: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation Mar 2014; Furie. Oral Antithrombotic Agents for the Prevention to Stroke in Nonvalvular Atrial Fibrillation: A Science Advisory for Healthcare Profressionals From the American Heart Association/American Stroke Association. Stroke August 2012; 43; Guyatt. Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST Feb, ; 13, 14, 22, 25, 29, 34, 38. Wann ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation (Update on Dabigatran): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation Nov. 2011; 123;

74 Schulman. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. New England Journal of Medicine Dec. 2009; 361; Schulman. Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism. New England Journal of Medicine Feb 2013; 368; Agnelli. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. The New England Journal of Medicine Aug 2013; 369; Bauersachs. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. The New England Journal of Medicine Dec 2010; 363; Buller. Oral Rivaroxaban for the Treatments of Symptomatic Pulmonary Embolism. The New England Journal of Medicine April 2012; 366; Dabigatran: Drug Information. UpToDate.com. 2014

75 Dabigatran Etexilate. Lexicomp Online Dabigatran [package insert]. Accessed Nov 2013 Rivaroxaban UpToDate.com Rivaroxaban Lexicomp Online Rivaroxaban [package insert]. Accessed Nov 2013 Apixaban UpToDate.com Apixaban Lexicomp Online Apixaban [package insert]. Accessed Nov 2013 Leung. Anticoagulation with direct thrombin inhibitors and factor Xa inhibitors. UpToDate.com Manning. Antithrombotic Therapy to Prevent Embolization in Atrial Fibrillation. UpToDate.com. Oct 2013.

76 Lip. Management of Anticoagulation before and after elective surgery. UpToDate.com. Oct Spinler. New Oral Anticoagulants for Atrial Fibrillation. Circulation 2012; 126; OhioHealth. Prescribing Guidelines Dabigatran (Pradaxa). June OhioHealth. Prescribing Guidelines Rivaroxaban (Xarelto). Dec OhioHealth. Anticoagulation Reversal Guidelines for Patients with Spontaneous Intracerebral Hemorrhage. Riverside Methodist Hospital Emergency Department. Oct 2013