NOACs (new oral anticoagulants): are we ready for a wide use after stroke?

YES

G e o r g e N t a i o s

U n i v e r s i t y o f T h e s s a l y, L a r i s s a , G r e e c e

2013 Joint meeting BNS-BSC

Leuven, Belgium

23/11/2013

Disclosures• Support to attend conferences: Bayer; Sanofi-Aventis; Pfizer; Lundbeck;

Boehringer-Ingelheim; Galenica; Elpen; Bristol Myers Squibb.

• Honoraria: Quintiles; CHUV; Medtronic.

• Speaker fees: Sanofi

• Scholarships: European Stroke Organization; Hellenic Society of Atherosclerosis.

• Participation in trials– National coordinator (Greece) for the ENOS trial.– Sub-investigator (AMGEN, 20110118).

Don’t forget my INR !

Courtesy of Patrik Michel, adapted from Hylek et al. NEJM 1996; 335:540-6

INR1.0

5

3.0 4.0 5.0 6.0 7.0

Odd

s ra

tio

10

15

20

2.0

Target INR 2.5 (range 2-3)

Ischemic stroke

Intracranial hemorrhage

Baker W, et al. J Manag Care Pharm 2009;15:244-52

Reduced Vitamin K Oxidised Vitamin K

Vitamin K oxide reductase

WARFARINS R

CYP1A1CYP1A2CYP3A4CYP2C9

Inactive precursor

Active Clotting Factor

- Diet

Why is it so difficult ?

Reduced Vitamin K Oxidised Vitamin K

Vitamin K oxide reductase

WARFARIN

S R

CYP1A1CYP1A2CYP3A4CYP2C9

Inactive precursor

Active Clotting Factor

- Diet- Drugs

AbciximabAcetaminophen

Alcohol(acute and chronic)

AllopurinolAminodarone

AminoglutethimideAmobarbital

Anabolic steroidsAspirin

AzathioprineButabarbital

ButalbitalCarbamazepineCefoperazone

CefotetanCefoxitin

CeftriaxoneChenodiol

Chloral hydrateChloramphenicolChlorpropamideChlorthalidoneCholestyramine

CimetidineCiprofloxacin

ClarithromycinClofibrate

Corticotropin

Cortisone

Coumadin

Cyclophosphamide

Danazol

Dextran

Dextrothyroxine

Diazoxide

Diclofenac

Dicloxaxillin

Diflunsial

Disulfram

Doxycycline

Erythromycin

Ethacrynic acid

Ethchlorvynol

Fenoprofen

Fluconazole

Fluorouracil

Gemfibrozil

Glucagon

Glutethimide

Griseofulvin

Haloperidol

Halothane

Heparin

Ofloxacin

Olsalazine

Omeprazole

Oxaprozin

Oxymetholone

Paraldehyde

Paroxetine

Penicillin G

Pentobarbital

Pentoxifylline

Phenobarbital

Phenylbutazone

Phenytoin

Piperacillin

Piroxicam

Prednisone

Primidone

Propafenone

Propoxyphene

Propranolol

Propylthiouracil

Phytonadione

Quinidine

Quinine

Ranitidine

Rifampin

Ibuprofen

Ifosamide

Indomethacin

Influenza virus vaccine

Itraconazole

Ketoprofen

Ketorolac

Levamisol

Levothyroxine

Liothyronine

Lovastatin

Mefenamic

Meprobamate

Methimazole

Methyldopa

Methylphenidate

Methylsalicylate

Miconzale

Metronidazole

Miconazole

Moricizine HCl

Nafcillin

Nalidixic acid

Naproxen

Neomycin

Norfloxacin

Secobarbital

Sertaline

Simvastatin

Spironolactone

Stanozolol

Streptokinase

Sucralfate

Sulfamethizole

Sulfamethoxazole

Sulfinpyrazone

Sulfinpyrazone

Sulfisoxazole

Sulindac

Tamoxifen

Tetracycline

Thyroid hormone

Ticacillin

Ticlopidine

t-PA

Tolbutamide

Trazodone

Trimethoprim-sulfamethoxazole

Urokinase

Valproate

Vitamin C

Vitamin E

Reduced Vitamin K Oxidised Vitamin K

Vitamin K oxide reductase

WARFARIN

S R

CYP1A1CYP1A2CYP3A4CYP2C9

Inactive precursor

Active Clotting Factor

- Diet- Drugs- Polymorphisms

Estimated warfarin daily dose (mg)

based on patient age and genotype

20 25 30 35 40 45 50 55 60 6570 75 80 85 90

Age (years) CYP2C9*1 CYP2C9*2 CYP2C9*3

6.5 (2.9, 10.2)6.3 (2.7, 9.9)6.0 (2.5, 9.6)5.8 (2.2, 9.3)5.5 (2.0, 9.0)5.3 (1.8, 8.8)5.0 (16, 8.5)4.8 (1.3, 8.2)4.5 (1.1, 7.9)4.3 (0.9, 7.7)4.0 (0.6, 7.4)3.8 (0.4, 7.2)3.5 (0.9, 6.9)3.3 (-0.2, 6.7)3.0 (-0.5, 6.5)

5.8 (1.9, 9.8)5.6 (1.8, 9.4)5.3 (1.6, 9.0)5.1 (1.5, 8.7)4.8 (1.3, 8.3)4.6 (1.1, 8.0)4.3 (1.0, 7.7)4.1 (0.8, 7.4)3.8 (0.5, 7.1)3.5 (0.3, 6.8)3.3 (0.1, 6.5)3.0 (-0.2, 6.3)2.8 (-0.5, 6.0)2.5 (-0.8, 5.8)2.3 (-1.1, 5.6)

5.5 (1.3, 9.8)5.3 (1.2, 9.4)5.0 (1.1, 9.0)4.8 (1.0, 8.6)4.5 (0.8, 8.3)4.3 (0.7, 7.9)4.0 (0.5, 7.5)3.8 (0.3, 7.2)3.5 (0.1, 6.9)3.3 (-0.1, 6.6)3.0 (-0.3, 6.4)2.8 (-0.6, 6.1)2.5 (-0.8, 5.9)2.3 (-1.1, 5.7)2.0 (-1.5, 5.5)

Thrombosis & Anticoagulation Research Group

“… lower initiation doses should be considered

for patients with certain genetic variations in

CYP2C9 and VKORC1 enzymes …”

FDA 2007

Kimmel, et al. NEJM 2013, online early

45.2% 45.4%

Verhoef, et al. NEJM 2013, online early

61.6%

60.2%

Pirmohamed, et al. NEJM 2013, online early

67.4%

60.3%

Anti-VKAs’ limitations

• Narrow therapeutic window • Frequent INR monitoring• Frequent dose adjustments• Unpredictable dose response• Drug and food interactions• Slow onset/offset of action

Baker W, et al. J Manag Care Pharm 2009;15:244-52

Anti-VKAs’ limitations

• Narrow therapeutic window • Frequent INR monitoring• Frequent dose adjustments• Unpredictable dose response• Drug and food interactions• Slow onset/offset of action

Guigliano, et al. NEJM 2013, online first

Guigliano, et al. NEJM 2013, online first

AcenocoumarolWarfarin

Dabigatran

RivaroxabanApixabanEdoxaban

Ntaios G, et al. Stroke 2012; 43: 3298-3304

Ntaios G, et al. Stroke 2012; 43: 3298-3304

Ntaios G, et al. Stroke 2012; 43: 3298-3304

Ntaios G, et al. Stroke 2012; 43: 3298-3304

Ntaios G, et al. Stroke 2012; 43: 3298-3304

Ntaios G, et al. Stroke 2012; 43: 3298-3304

Ntaios G, et al. Stroke 2012; 43: 3298-3304

Ntaios G, et al. Stroke 2012; 43: 3298-3304

NOAC’s limitations (?)

Eerenberg, et al. Circulation 2011; 124:1573-9

- Patients with renal function impairment

- Patients with mechanical valves

- Can not monitor drug effect and titrate dose

- No specific antidote

- Their short half-life makes them dangerous in non-adherent patients

- Not better than warfarin for high TTRs

Majeed, et al. Circulation 2013; 128:2325-32

Wallentin L, et al. Lancet 2010; 376:975–83

Wallentin L, et al. Lancet 2010; 376:975–83

Baker W, et al. J Manag Care Pharm 2009;15:244-52

- Patients with renal function impairment

- Patients with mechanical valves

- Can not monitor drug effect and titrate dose

- No specific antidote

- Their short half-life makes them dangerous in non-adherent patients

- Not better than warfarin for high TTRs

- Bleeding rates in real-life were higher than in RCTs

NOAC’s limitations (?)

“We believe that the large number of reported cases of bleeding associated with dabigatran provides a salient example of stimulated reporting.”

“Bleeding rates associated with dabigatran are not higher than those with warfarin, a finding that is consistent with the results of RE-LY.”

Southworth M, et al. NEJM 2013; 368:1272-4

“We believe that dabigatran provides an important health benefit when used as directed.”

Novel oral

anti-

coagulants

- Reduce stroke or systemic embolism

- Reduce ICH

- Reduce major hemorrhage

- Steady dose

- Limited drug & no food interactions

- No INR monitoring

NOAC’s limitations vs. Warfarin

NOACs (new oral anticoagulants): are we ready for a wide use after stroke?

YES

THIS IS ALREADY HAPPENING !

Kirley K, et al. Circ Cardiovasc Qual Outcomes. 2012;5:615-621

Xu J, et al. CMAJ 2013

NOAC…