Use of the New Oral Anticoagulants in Patients with Heart Failure, Valvular Disease and Renal Dysfunction

Transcription

1 22nd Annual Heart Failure 2018 an Update on Therapy Stroke Prevention Atrial Fibrillation: Use of the New Oral Anticoagulants in Patients with Heart Failure, Valvular Disease and Renal Dysfunction Tien M.H. Ng, Pharm.D., FHFSA, FCCP, BCPS AQ Cardiology Associate Professor of Clinical Pharmacy and Medicine Director, PGY2 Residency in Cardiology Vice Chair, Titus Family Department of Clinical Pharmacy School of Pharmacy and Keck School of Medicine University of Southern California 1

2 Comparable droughts in professional sports: Chicago Cubs 107 years Arizona Cardinals 70 years Toronto Maple Leafs 50 years Coumarin Synthetic Coumarin Dicoumarol Warfarin Rivaroxaban Edoxaban Dabigatran Apixaban Betrixaban New/Novel Oral Anticoagulants (NOAC) Non-Vitamin K Oral Anticoagulants (NOAC) Direct Oral Anticoagulants (DOAC) Target Specific Oral Anticoagulants (TSOAC)

3 FDA Approved Indications Indication Apixaban Dabigatran Edoxaban Rivaroxaban Betrixaban Prevention stroke and systemic embolism in NVAF x x x x Prophylaxis VTE knee or hip replacement surgery x x* x Treatment of DVT/PE x x x x Prevent recurrence of DVT/PE following initial therapy x x x Prophylaxis VTE acute medically ill x Prior to treatment, patients should have been treated with parental anticoagulant for 5 to 10 days * Hip replacement only

4 NOACs and Renal Dysfunction 4

5 CKD in AF CKD prevalence is increasing CKD increases risk of AF CKD increases risk of stroke/se in AF All cause mortality is higher in CKD Olsen. N Engl J Med 2012;367:

6 Pharmacokinetic Comparison Onset (Cmax) Offset (t 1/2 ) % renal clearance Drug interactions Warfarin Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Betrixaban (Bevyxxa) Days 1-3 h 2-4 h 3-4 h 1-2 h 3-4 h Days 40 h h 5-9 h 6-12 h 6-11 h h P-gp 2C8/9 (2C19, 1A2, 3A4) Food P-gp P-gp, ABCG2 3A4, 2J2 P-gp 3A4 P-gp 3A4 P-gp 6

7 My Approach Renal Function Bleeding Risk Borderline Unstable Drug Interactions Low Body Wt Advanced Age Lots Stroke Risk HD* Clcr Clcr Some High Low Avoid NOAC if possible Reduced Dose Avoid NOAC if possible * apixaban, rivaroxaban maybe OK apixaban Scr > RF; dabigatran exempted 7

8 My Approach Renal Function Bleeding Risk Borderline Unstable Drug Interactions Low Body Wt Advanced Age Lots Stroke Risk HD* Clcr Clcr Some High Low Avoid NOAC if possible Reduced Dose Avoid NOAC if possible * apixaban, rivaroxaban maybe OK apixaban Scr > RF; dabigatran exempted 8

9 Package Inserts NVAF Dose Adjustment Threshold (Clcr ml/min) Usual Dose (mg) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Scr 1.5* 80yo 60kg Edoxaban (Savaysa) Betrixaban (Bevyxxa) Renal Dose (mg) (*2 risk factors) CI Threshold (Clcr ml/min) <15 <15 HD: 15mg? HD: 5mg <15 or >95 <15 9

10 CKD in NVAF Studies Dabigatran Rivaroxaban Apixaban Edoxaban RELY ROCKET-AF ARISTOTLE ENGAGE-AF CKD % CKD defn* (Clcr ml/min) Renal Exclusion Criteria (Clcr ml/min) <50 < <30 * Calculated by Cockroft-Gault equation Dose Adjustment Threshold (Clcr ml/min) CI Threshold (Clcr ml/min) <25 or Scr>2.5mg/dL Scr 1.5* 80yo 60kg < <15 <15 HD: 5mg <15 or >95 10

11 CKD (Clcr or egfr between 15 and 60 ml/min) 12,545 AF participants from 5 studies (N=658 Clcr 15-30) N Effect Size 95% CI Quality of Evidence SSE 12, , 1.00 Moderate Ischemic CVA 8, , 1.36 Hem. CVA 8, , 0.97 Major Bleeding 12, , 1.04 Low All-cause Mortality 9, , 1.05 Moderate Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No.: CD

12 Single-dose PK studies: Clcr ml/min? *Cmax *AUC N Kubitza Br J Clin Pharmacol 2010;70: Rivaroxaban 10mg 26% 64% 8 Kooiman J. JACC 2016;67: Dabigatran 75mg BID Similar to PK predicted 16 * vs healthy volunteers 12

13 Hemodialysis Single-dose PK studies pre/post-hd: Wang X. J Clin Pharmacol 2015;56: Apixaban 5mg BID *Cmax *AUC inf N 10% 36% 8 Dias C. Am J Nephrol 2016;43: Rivaroxaban 15mg 18% 56% 8 DeVriese A. Am J Kid Dis 2015;66:91-8. Rivaroxaban 10mg = 66% 12 Multiple-dose PK studies pre/post-hd: DeVriese A. Am J Kid Dis 2015;66:91-8. Rivaroxaban 10mg x 7d Similar Day 1 vs Day * vs healthy volunteers

14 Similar PK = Similar Efficacy & Safety? Reduced renal function = higher risk group AntiXa activity and clinical events Any bleeding severity Bhagirath VC. TH Open 2017;1:e

15 Guidelines (AF and CKD) ACC/AHA/HRS 2014: Direct thrombin dabigatran and factor Xa inhibitor rivaroxaban are not recommended in patients with AF and end-stage CKD or on dialysis because of a lack of evidence from clinical trials regarding the balance of risks and benefits (III, LOE C) With moderate-to-severe CKD and CHA2DS2-VASc scores of 2, reduced doses of direct thrombin or factor Xa inhibitors may be considered (IIb, LOE C) ESC 2016: No recommendation EHRA 2015: Non-vitamin K antagonist oral anticoagulants seem to be a reasonable choice for anticoagulant therapy in AF patients with mild or moderate CKD. In the absence of clinical data or experience, NOAC therapy should be avoided in AF patients on haemodialysis or preterminal CKD (CrCl 15 ml/min, Stage V). In patients on NOACs, renal function needs to be monitored carefully, at least yearly 15

16 My Approach Renal Function Bleeding Risk Borderline Unstable Drug Interactions Low Body Wt Advanced Age Lots Stroke Risk HD* Clcr Clcr Some High Low Avoid NOAC if possible Reduced Dose Avoid NOAC if possible * apixaban, rivaroxaban maybe OK apixaban Scr > RF; dabigatran exempted 16

17 Deviating from the Package Insert Optum Labs Data Warehouse, N=14,865 NVAF (1,473 with renal indication for dose reduction) Reduced dose and Standard dose when not appropriate Renal Indication for Dose Per 100 PY Reduced Dose Standard Dose SSE Major Bleeding No Renal Indication for Dose Per 100 PY Reduced Dose Standard Dose SSE Major Bleeding Yao X, Noseworthy PA. J Am Coll Cardiol 2017;69:

18 Drug Interactions Taiwan National Health Insurance database N=91,330 NVAF prescribed NOAC (Jan 2012-Dec 2016) Approx. % increased adjusted incidence of major bleeding Amiodarone 36 Fluconazole 135 Rifampin 57 Phenytoin 93 Chang SH. JAMA 2017;318(13):

19 NOACs and Valvular Heart Disease 19

20 The Backstory Age-adjusted prevalence 2.5% (2-3X >65yo) Thrombotic risk reduction RE-ALIGN AHA Statistical Update 2018; Torn M. Arch Intern Med 2009;169:

21 What is NVAF? Mechanical valves Rheumatic mitral stenosis Non-rheumatic mod-sev mitral stenosis THROMBOTIC RISK Bioprosthetic valves Mitral valve repair Mitral regurgitation Aortic stenosis Aortic insufficiency TV, PV ENGAGE-AF ESC/EACTS ARISTOTLE ROCKET-AF RE-LY AHA/ACC EHRA (HRS/CASSA/APHRS/SOLEACE/SA HEART) 21

22 Valve Dz in NVAF Studies 22

23 Valve Dz in NVAF Studies Stroke/Systemic Embolism NOAC vs warfarin HR RE-LY 150mg ROCKET-AF ARISTOTLE ENGAGE-AF hd VHD No VHD P interaction Major Bleeding NOAC vs warfarin HR RE-LY 150mg ROCKET-AF ARISTOTLE ENGAGE-AF hd VHD No VHD P interaction NOAC vs warfarin HR RE-LY 150mg ROCKET-AF ARISTOTLE ENGAGE-AF hd VHD No VHD P interaction ICH

24 NOACs in Valve Dz meta VHD associated with higher rate of SSE, major bleeding, and all-cause death P=0.13 for interaction Renda G. JACC 2017;69:

25 NOACs in Valve Dz meta P=0.63 for interaction Cochran s Q p< for heterogeneity Renda G. JACC 2017;69:

26 NOACs in Valve Dz real world Optum Labs Data Warehouse, N=20,158 NVAF with VHD Bioprosthetic (N=24) Valve repairs (N=55) Rheumatic MS (N=74) Non-rheumatic MS (N=654) AS/AI/MR (N=19,351) /100 person-years NOAC Warfarin HR (95% CI) SSE (0.59, 0.98) Major Bleeding (0.72, 0.97) Noseworthy PA. Int J Cardiol 2016; 209:

27 NOACs and VHD Unanswered Questions Limitations Pooling study-level data Efficacy and safety differences by VHD type Moderate-severe MS Esp. non-rheumatic 27

28 Anticoagulation with a vitamin K antagonist (VKA) is indicated for patients with rheumatic mitral stenosis (MS) and AF (I, B-NR) It is reasonable to use a DOAC as an alternative to a VKA in patients with AF and native aortic valve disease, tricuspid valve disease, or MR and a CHA2DS2- VASc score of 2 or greater (IIa, C-LD) No changes in VKA recommendation for patients with mechanical heart valves 28

29 NOACs should be considered as an alternative to VKAs in patients with aortic stenosis, aortic regurgitation and mitral regurgitation presenting with AF (IIa, B) NOACs should be considered as an alternative to VKAs after the third month of implantation in patients who have AF associated with a surgical or transcatheter aortic valve bioprosthesis (IIa, C) The use of NOACs is not recommended in patients with atrial fibrillation and moderate to severe mitral stenosis (III, C) NOACS are contraindicated in patients with a mechanical valve (III, B) 29

30 30

31 AHA/ACC ESC/EACTS EHRA MS Other native VHD Bioprosthetic/ Repair III (rheumatic) IIa III (mod-sev) IIa - IIa (rheumatic or mod-sev) Mechanical III III 31

32 Rivaroxaban GALLILEO NOACs in TAVR Apixaban ATLANTIS JACC Int 2017 Edoxaban ENVISAGE-TAVI AF Anticoagulation with a VKA to achieve an INR of 2.5 may be reasonable for at least 3 months after TAVR in patients at low risk of bleeding (IIb, B-NR) Seeger J. JACC Int 2017;10:

33 NOACs, AF and Heart Failure 33

34 NOACs and Considerations in HF AF and HF co-exist in approx % of patients Coexistent AF+HF is associated with poorer outcomes Increased risk of SSE, bleeding, and mortality Associated with lower TTR on warfarin 1y HFrEF HFpEF No HF SSE Mortality Lip G. Eur J Heart Fail 2015;17:

35 HR (95% CI) HF Subset in NOAC AF Trials Dabigatran* RE-LY Rivaroxaban ROCKET-AF Apixaban ARISTOTLE Edoxaban* ENGAGE AF Heart Failure or Reduced LVEF, % HF Stroke/SE 0.75 ( ) 0.91 ( ) 0.55 ( ) 0.83 ( ) HF Major Bleeding 0.79 ( ) 1.05 ( ) 0.81 ( ) 0.79 ( ) HF Hem CVA 0.39 ( ) 0.38 ( ) 0.27 ( ) 0.40 ( ) * High dose; LVSD subgroup; ICH McMurray JJ. Circ HF 2013;6: Ferreira J. Eur J Heart Fail 2013;15; Van Diepen S. Circ HF 2013;6: Magnani G. Eur J Heart Fail 2016;18:

36 NOAC, AF and HF meta-analysis Savarese G. JACC HF 2016;4:

37 NOAC, AF and HF meta-analysis Favors NOAC Favors Warfarin P=0.23 P=0.09 P=0.99 P=0.32 Savarese G. JACC HF 2016;4:

38 COMMANDER-HF A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and Safety of Rivaroxaban With Placebo for Reducing the Risk of Death, Myocardial Infarction or Stroke in Subjects With Heart Failure and Significant Coronary Artery Disease Following an Episode of Decompensated Heart Failure EJHF 2015;17;

39 SUMMARY Renal function assessment and monitoring is a key component of optimizing the safety of NOACs Dose adjustment decisions for NOACs should incorporate a multifaceted assessment beyond the label VHD definitions and existing data has clarified the use of NOACs, although controversies remain NOACs maintain their efficacy and safety in patients with NVAF and HF. Future studies will determine whether they have a role in HF alone. 39