Non- Valvular Atrial Fibrillation and Stroke Prevention: Which OAC Do I Choose. Warfarin vs the NOACs

Transcription

1 Non- Valvular Atrial Fibrillation and Stroke Prevention: Which OAC Do I Choose Warfarin vs the NOACs Dr. Lori McIntosh D.O. Board Certified Neurologist

2 Objectives Be able to list the current options of oral anticoagulation for prevention of stroke in non- valvular atrial fibrillation Understand the differences between warfarin and the NOACs Develop a rationale for choice of OAC in patient s with non- valvular atrial fibrillation

3 Atrial Fibrillation is the most common cardiac arrhythmia Overall stroke risk 5x Ages inc. 4.6% Ages inc. 20.2% ~ 69,165 cardioembolic ischemic strokes due to AFib annually 2,3 1. Gregory et al. JAMA. 2015;313:19: Sacco RL et al. Stroke. 2006;37: Freeman WD et al. Neurotherapeutics. 2011;8: Steger C et al. Eur Heart J. 2004;25: Gattellari M et al. Cerebrovasc Dis. 2011;32:

4

5 History (Warfarin) vs Modern Times

6 Anticoagulants historical development Oral Spoiled sweet clover Dicoumarol discovered Warfarin clinical use Warfarin / Vitamin K mechanism High / low dose Warfarin / INR Dabigatran Rivaroxaban Apixaban AZD0837 Ximelagatran clinical trials Warfarin clinical trials s 1970s s 1990s Heparin discovered Heparin clinical use Continous heparin infusion/ aptt LMWH discovered LMWH clinical trials Pentasaccharide clinical trials Injection

7 Vitamin K antagonist Warfarin Vitamin K antagonist Oral, i.v, rectal- bioavailability nearly complete Onset of action = hours T 1/2 =25 to 60 hours ( 40 hours), duration of action= 2 to 5 days Monitoring: PT(INR) Antidote: Vitamin K 1 (phytonadione), FFP

8

9 Advantages and Disadvantages of Warfarin 10/1/15 9

10 Multiple Food Interactions- Vitamin K reverses the signs of Warfarin Foods with High Vitamin K - dark, green leafy vegetables (spinach, broccoli, lettuce, cabbage) - fruits: kiwi, avocado, dried prunes, blueberries, blackberries - Green Tea ***Cranberry juice and alcohol increase the effects of Warfarin

11 Warfarin is subject to multiple interactions Drugs that may Increase INR macrolide antibiotics imidazole antifungals sulfamethoxazole/trimethoprim amiodarone statins some non-steroidal anti-inflammatory drugs, and some complementary medicines such as St John s wort Weight Loss or Weight Gain 10/1/15 11

12

13 The Ideal Oral Anticoagulant Ideally, an oral anticoagulant would: Require no remote monitoring Have little interaction with food or other drugs Offer a good safety profile with regard to bleeding risk Have similar efficacy to warfarin in reducing thromboembolic events Reach therapeutic levels within several hours Oral and/or IV administration Ability to inhibit free and clot bound thrombin Availability of an antidote

14 New OACs: Atrial Fibrillation Direct Thrombin inhibitors: Dabigatran (Pradaxa) Factor Xa inhibitors: Rivaroxaban (Xarelto) Apixaban (Eliquus) Edoxaban (Savaysa) Comparator: warfarin Consider time in therapeutic range (TTR) Usual thrombotic outcomes (%/year): non- inferiority 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

15

16 NOACs for Stroke Prevention in AF Dabigatran RE- LY Reported September 2009 Apixaban ARISTOTLE Reported September Rivaroxaban ROCKET AF Reported November 2010 Edoxaban ENGAGE AF- TIMI 48 Reported November 2013

17 NOAC Trials Baseline Characteristics RE- LY a (Dabigatran) ROCKET AF b (Rivaroxaban) ARISTOTLE c (Apixaban) ENGAGE AF- TIMI 48 d (Edoxaban) Number randomized 18,113 14,264 18,201 21,105 Age, years (range) 72 (±9) 73 (65-78) 70 (63-76) 72 (64-78) Female, % Paroxysmal AF, % VKA naive, % Aspirin use, % CHADS 2 0 to CHADS CHADS : 77 >4: 23 Prior heart failure, % a. Connolly SJ, et al. N Engl J Med. 2009;361: [8] ; b. Patel MR, et al. N Engl J Med. 2011;365: [9] ; c. Granger CB, et al. N Engl J Med. 2011;365: [10] ; d. Giugliano RP, et al. N Engl J Med. 2013;369: [11]

18 Stroke or systemic embolic events

19

20

21

22

23 Comparative Pharmacology Characteristic Rivaroxaban a Apixaban b Dabigatran c Edoxaban d Target Xa Xa Thrombin Xa Time to maximum concentration, h Renal clearance, % 33* Transporters P- gp P- gp P- gp P- gp Cytochrome P450 metabolism, % 32 <32 None <4 Bioavailability, % ~ Dosing Once daily Twice daily Twice daily Once daily *33% renally cleared; 33% excreted unchanged in urine.

24 NOACs in Renal Dysfunction US Labeling Dabigatran Rivaroxaban CrCl > 30 ml/min 150 mg 2 CrCl > 50 ml/min 20 mg 1 CrCl ml/min 75 mg 2 CrCl ml/min 15 mg 1 CrCl < 15 ml/min Not recommended CrCl < 15 ml/min Not recommended Apixaban Edoxaban 2 of the following: age 80 years, weight 60 kg, serum Cr 1.5 mg/dl 2.5 mg 2 CrCl > 50 to 95 ml/min 60 mg 1 CrCl ml/min 30 mg 1

25

26 Mabel 77 y/o female with a past medical history of: Hypertension Severe Renal Dysfunction (CrCl 21 ml/min) Osteoarthritis Decreased hearing Lives alone no tob/etoh

27 In the past 4 months, she reported 3 episodes of paroxysmal palpitations Each lasting about 30 sec, spontaneous resolution, precipitated in 1 case by heavy meal In ED, ECG documented atrial fibrillation that resolved in 15 minutes spontaneously. She also had elevated BP (170/95). She was DC d. At the cardiologist's office 5 days later, ECG again showed EF, asymptomatic, BP was 165/90 TTE showed mild left ventricular hypertrophy with normal volumes and preserved segmental wall motion and global systolic function (EF 65%) with left atrial enlargement and mild mitral regurgitation Diagnosis... Paroxysmal non- valvular atrial fibrillation

28 What would be the management of Mabel at this time? 1. Determine her CHA 2 DS 2 - VAS c score 2. Determine her CHA 2 DS 2 - VAS c and HAS- BLED 3. Determine her CHADS 2 score 4. Initiate an anticoagulant therapy Determine her CHA 2 DS 2 - VAS c and HAS- BLED

29

30

31 Mabel s CHA 2 DS 2 - VAS c score is 4 > 75 2 pts HTN 1 pt. Female 1 pt. Mabel s HAS- BLED score is 3 >65 1 pt. severe renal dysfunction 1 pt. HTN 1 pt. Should Mabel receive oral anticoagulant (OAC) therapy?

32

33 NOAC versus Warfarin

34

35 Which is the best treatment option for Mabel? 1. Warfarin, with INR of 2 to 3 target 2. Dabigatran 150 mg twice daily 3. Rivaroxaban 10 mg once daily 4. Edoxaban 30 mg once daily Edoxaban 30 mg once daily

36 Why edoxaban and not warfarin? Dabigatran is contraindicated with a CrCl less than 30 ml/min Apixaban and Edoxaban have best safety profile with less bleeding than warfarin Rivaroxaban has good safety profile but incidence of major bleeding observed is similar but not inferior to that of warfarin Edoxaban and rivaroxaban are once daily dosing Taking all this into consideration and the patient information.edoxaban 30 mg daily was the choice for this patient

37

38

39 New OACs: Different than Warfarin WARFARIN NEW ORAL AGENTS 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 Inhibition of activated factors No effect unless factors active No vitamin K (diet) impact Few medication interactions Fixed dose Decreased ICH Better mortality benefit Offer net clinical benefit (efficacy and safety) No monitoring (can t) Dependent on renal clearance (not apixaban) Irreversible

40

41 Candidate for NOAC Pts experiencing difficulty in controlling their INR despite the best effort available. Pts who are at high risk for warfarin complications. Pts who are at high risk for drug interactions. Pts who prefer a drug that is not interfering with lifestyle.

42 PATIENTS WITH AF WHO SHOULD STILL BE CONSIDERED FOR WARFARIN Patients with renal disease (Cr cl <30 ml/min). Mechanical valve prosthesis. Valvular AF. Patients suffered adverse events while taking a NOAC who still require anticoagulant therapy. Patients who have concerns about compliance with a twice daily dose. Patients who simply cannot afford the new agents should be treated with warfarin with INR

43 So which one would you choose???? Warfarin Rivaroxaban Edoxaban Apixaban Dabigatran