Atrial Fibrillation & AnticoagulantsMargaret Jin, BScPhm, PharmD, MSc, CDEHamilton Family Health TeamMay 27, 2014

DisclosureI have no actual or potential

conflict of interest in relation to this presentation

OutlineCase PresentationCanadian Cardiovascular Society

2012 RecommendationsDabigatran (Pradaxa®)Rivaroxaban (Xarelto®) Apixaban (Eliquis®)SummaryQuestions

CaseMr. AF, a 70 y male with Hypertension

(BP=135/85) and history of GERD. He was just diagnosed with non-valvular permanent atrial fibrillation

Normal renal and liver functionCurrent meds:

◦ Ramipril 10mg once daily◦ Bisoprolol 5mg once daily◦ Amlodipine 5mg once daily◦ Rabeprazole 20mg once daily◦ No OTCs

Smokes 25 cigs/d x 55 years, drinks no alcoholODB drug planBP=Blood Pressure, GERD=GastroEsophageal Reflux Disease,

ODB=Ontario Drug Benefit, OTCs=Over-the-counters

Anticoagulation optionsWhat anticoagulant (if any),

would you give?◦None?◦Aspirin?◦Warfarin?◦Dabigatran?◦Rivaroxaban?◦Apixaban?

Assess Thromboembolic TherapyThree Steps1. Assess Thromboembolic Risk

a. CHADS2 Risk Criteria2. Assess Bleeding Risk

a. HAS-BLED Risk Criteria3. Assess Benefit vs. Risk

1. Assessing Thromboembolic RiskCHADS2 Risk Criteria Point

sCongestive Heart Failure(symptoms in the last 3 months)

1

Hypertension (diagnosis) 1Age ≥ 75 years 1Diabetes mellitus 1Stroke/Transient Ischemic Attack (prior)

2

What is Mr. AF’s CHADS2 score?

Recommended TherapyCHADS

2

Stroke Rate %/yr

Canadian Cardiology Society (CCS) 2012 Recommendations

0 1.9 No additional risk factors: No antithromboticFemale or vascular disease: ASA 75-325mg dailyAge ≥ 65 yrs or female & vascular disease: OAC

1 2.8 OAC preferredAlternatives: ASA 75-325mg daily

2 4 Oral anticoagulant (OAC)

When OAC is indicated, most patients should receive

dabigatran, rivaroxaban, or apixaban in preference to

warfarinCCS 2012

3 5.94 8.55 12.56 18.2

ASA=Acetylsalicylic Acid, OAC=oral anticoagulant

2. Assessing Bleeding Risk

HAS-BLED Risk Criteria Points

Hypertension (SBP > 160 mmHg) 1Abnormal renal (transplantation, dialysis, SCr > 200umol/L) or liver function (AST/ALT>3xULN, bilirubin>2xULN) (1 point each)

1 to 2

Stroke (caused by a bleed) 1Bleeding (hospitalization, decrease Hgb > 20g/L, transfusion)

1

Labile INRs (therapeutic range < 60%) 1Elderly (age > 65 years) 1Drugs (ASA/NSAID) or alcohol (≥8 drinks/week) (1 point each)

1 to 2ASA=acetylsalicylic acid, AST=aspartate aminotransferase, ALT=alanine

aminotransferase, Hgb=hemoglobin, INRs=international normalized ratios, NSAIDS=non-steroidal anti-inflammatory drugs, SCr=serum creatinine, ULN=upper limit of normal

What is Mr. AF’s HAS-BLED score?

HAS-BLED Score & Major BleedsHAS-BLED

ScoreMajor Bleeds

(%/yr)0 1.131 1.022 1.883 3.744 8.705 12.50

Major bleedIntracranial, hospitalization, decrease Hgb > 20g/L, +/- transfusion

NOTE: HAS-BLED Score & Major Bleed risk is only validated with warfarin

3. Assess Risk vs. Benefit – Mr. AFCHADS2 = 1 = 2.8%/yr Stroke rateHAS-BLED = 1 = 1.02%/yr Major bleedRisk of stroke > Major Bleed RiskRecommendation: Oral anticoagulants

◦Warfarin◦Dabigatran◦Apixaban◦Rivaroxaban

ODB – Limited Use for newer agents

Preferred by Canadian Cardiology Society 2012 guidelines

ODB=Ontario Drug Benefit

Ontario Drug Benefit – Limited UseFor the prevention of stroke and systemic embolism in at risk patients with non-valvular atrial fibrillation AND in whom:1. Anticoagulation is inadequate {at least

35% of the tests are outside of range} following a reasonable trial {at least 3 months} of warfarin; OR

2. Anticoagulation with warfarin is contraindicated or not possible due to inability to regularly monitor via INR testing (i.e., No access to INR testing services at a lab, clinic, pharmacy & home)

Mr. AFMr. AF is prescribed warfarin2 years later, Mr. AF’s wife died

and Mr. AF is unable to cope – started drinking

INR levels fluctuating over 3 months

Time for a new oral anticoagulant◦Dabigatran? (Oct 2010, LU April

2012)◦Rivaroxaban? (Dec 2012, LU Aug

2013◦Apixaban? (Jan 2012, LU July 2012)

LU=Limited Use

Oral anticoagulantsDirect thrombin inhibitor

DabigatranDirect thrombin inhibitorHalf-life: 12-17 hoursDose: 150mg bid

◦110mg bid if ≥ 80y or 75-79y with ≥ 1 bleeding risk factor*

Renal function◦CrCl<30mL/min contraindicated

No antidoteNo dosette/blisterpack or open

capsule*Bleeding RF = moderate renal impairment (30-50mL/min), P-gp inhibitor, NSAID, anti-platelets, congenital/aquired coagulation disorders, thrombocytopenia or functional platelet defects, active/recent ulcerative GI bleeding, recent biopsy or major trauma, recent intracranial hemorrhage, surgery (brain, spinal or opthalmic), bacterial endocarditis

Dabigatran – Drug InteractionsContraindicated

◦Dronedarone, ketoconazoleAvoid: rifampicin

◦Increase dabigatran concentration: P-gp inhibitors (i.e., amiodarone,

clarithromycin, cyclosporine, itra-, posa-conazole, quinidine, tacagrelor, tacrolimus, verapamil, etc)

◦Decrease dabigatran concentration P-gp inducers (i.e., carbamazepine, St. John’s

Wort, tenofovir) Antacids (H2RA, PPI, Al-Mg Hydroxide)

H2RA=Histamine2 Receptor Antagonist, P-gp=P-glycoprotein, PPI=proton pump inhibitor, Al-Mg=aluminum-magnesium

Dabigatran vs. Warfarin – RE-LYRCT, dabigatranblinded, warfarinopen-label

Intervention: ◦ Dabigatran 150mg bid vs. dabigatran 110mg bid

vs. warfarinINR 2-3

Inclusion: AF & ≥ 1 of the following:◦ Previous stroke/TIA, LVEF<40, NYHA class II-IV HF

within 6 months, ≥ 75y or 65-74y + DM, HTN or CAD

Exclusion: ◦ Severe heart-valve disorder, stroke within 14 days

prior or severe stroke within 6 months prior, CrCl<30mL/min, active liver disease, conditions that increase risk of bleed

AF=atrial fibrillation, CAD=coronary artery disease, CrCl=creatinine clearance, DM=diabetes mellitus, HF=heart failure, HTN=hypertension, LVEF=left ventricular ejection fraction, NYHA=New York Heart Association, RCT=randomized control trial, TIA=transient ischemic attack, y=year

NEJM 2009;361:1139-51

RE-LY resultsN=18,113 non-valvular AF pts at

risk of strokeCHADS2 mean = 2.1Mean time in therapeutic range

with warfarin was 64%Median follow up = 2 years

NEJM 2009;361:1139-51

RE-LY resultsDabigatran (both doses) vs. warfarin

◦ Less hemorrhagic stroke & intracranial bleeds◦ More dyspepsia◦ Trend for higher MI?◦ Higher discontinuation rate with dabigatran

Dabigatran 150mg bid vs. warfarin◦ Superior to warfarin for stroke/SE (NNT=88)◦ Superior for ischemic/hemorrhagic stroke◦ Increase GI bleeds (NNH=100)

Dabigatran 110mg bid vs. warfarin◦ Non-inferior to warfarin for stroke/SE◦ Less major bleeds (NNT=77)

NEJM 2009;361:1139-51

Would you give Mr. AF dabigatran?

Yes, maybe?Dabigatran

150mg bid superior to warfarin in stroke or systemic embolism

No, maybe not?He is on a PPI – potential

drug interaction – unclear about clinical significance (~14% of RE-LY study patients were on PPI)

To enhance the absorption of dabigatran, a low pH is required – dabigatran capsules contain dabigatran-coated pellets with a tartaric acid core

More GI bleedNo antidote

The Hamilton SpectatorFebruary 15, 2014Trials and errors? Mac, HHS sued over drug

safetyIn an unprecedented case, McMaster

University and Hamilton Health Sciences are facing lawsuits in the United States over the safety of the drug Pradaxa. As The Spectator's Steve Buist reports, the lawsuits allege that regulatory approval for the popular anticoagulant was partly based on tainted data from clinical trials led by Hamilton researchers.

http://www.thespec.com/news-story/4369907-trial-and-errors-mac-hhs-sued-over-drug-safety/

Oral anticoagulantsDirect thrombin inhibitor

RivaroxabanDirect Factor Xa InhibitorHalf-life: 5-9h (young) or 11-13h

(elderly)Dose: 20mg once daily

◦CrCl 30-49mL/min: 15mg once dailyRenal function

◦CrCl < 30mL/min not recommendedNo antidote

Rivaroxaban – Drug InteractionsContraindicated:

Itra- keto- posacon-azoles, ritonavirCYP 3A4 and P-gp inducers

(decrease rivaroxaban concentration)◦Carbamazepine, clarithromycin,

phenytoin, rifampin, St. John’s Wort

Rivaroxaban vs. WarfarinROCKET-AFRCT, double-blindedIntervention:

◦ Rivaroxaban 20mg od vs. warfarinINR 2-3

◦ Rivaroxaban 15mg od if CrCl 30-49mL/minInclusion:

◦ Persistent/paroxysmal AF on ≥ 2 episodes, risk of future stroke/TIA or systemic embolism OR CHADS2 score ≥ 2

Exclusion: ◦ Stroke within 14 days or TIA within 3 days, anemia

Hgb<100g/L, prosthetic heart valve, CrCl<30mL/min, active liver disease, conditions that increase risk of bleedAF=atrial fibrillation, CHADS2=Congestive heart failure, Hypertension, Age≥75,

Diabetes, Stroke/Transient Ischemic Attack, CrCl=creatinine clearance, Hgb=Hemoglobin, RCT=randomized control trial, TIA=transient ischemic attack, y=year

NEJM 2011;365:883-91

ROCKET-AFN=14,264 non-valvular AF pts at risk

of strokeCHADS2 mean = 3.5Mean time in therapeutic range with

warfarin was 55% (North American sites: 64%)

Median follow up per protocol = 590 days (1.6 years)

Median follow up intention-to-treat = 707 days (1.9 years)

NEJM 2011;365:883-91

ROCKET-AFRivaroxaban vs. warfarin

◦Rivaroxaban non-inferior to warfarin for stroke or systemic embolism

◦Potential Benefits: Less hemorrhagic stroke (NNT=333) and systemic

embolism (NNT=417) Less critical bleeding (NNT=167), less fatal bleeding

(NNT=250), less intracranial bleeding (NNT=250)◦Potential Harms:

More drop in Hgb ≥ 20g/L (NNH=143), more transfusions (NNH=200), more GI bleeds (NNH=100), more epistaxis (NNH=67), more hematuria (NNH=125)

NEJM 2011;365:883-91

Would you give Mr. AF rivaroxaban?

Yes, maybe?Rivaroxaban

20mg once daily non-inferior to warfarin in stroke or systemic embolism

Once daily dosing may be more attractive to Mr. AF

No, maybe not?CHADS2 score =

1More GI bleedNo antidote

Oral anticoagulantsDirect thrombin inhibitor

ApixabanDirect Factor Xa InhibitorHalf-life: 12 hoursDose: 5mg twice daily

◦2.5mg BID if pts with ≥ 2 of the following: Age ≥ 80, body weight ≤ 60kg, or Scr ≥ 133

umol/LRenal function

◦Excluded patients with CrCl < 25mL/min◦CrCl < 15mL/min not recommended

No antidote

Apixaban – Drug InteractionsContraindications

◦Itra- keto- posacon-azoles, ritonavirCYP 3A4 and P-gp inducers

(decrease apixaban concentration)◦Carbamazepine, clarithromycin,

phenytoin, rifampin, St. John’s WortP-gp inhibitors (increase apixaban

concentration)◦Amiodarone, dronedarone, quinidine,

verapamil

Apixaban vs. WarfarinARISTOTLERCT, double-blinded Intervention:

◦ Apixaban 5mg BID vs. warfarinINR 2-3

◦ Apixaban 2.5mg BID in pts with ≥ 2 of the following: Age ≥ 80y, body weight ≤ 60kg, or SCr ≥ 133umol/Lmg od

Inclusion: ◦ Permanent/persistent AF or flutter, ≥ 1 of the following

stroke risk factors: age≥75y, prior stroke/TIA/systemic embolus, HF or LVEF≤40%, DM or HTN

Exclusion: ◦ Stroke within 7 days, Hgb<90g/L, prosthetic heart valve,

renal insufficiency (CrCl<25mL/min or SCr>221umol/L), active liver disease, conditions that increase risk of bleed, required ASA > 165mg/d, treatment with both ASA+thienopyridine

NEJM 2011;365:981-92

ARISTOTLE ResultsN=18,201 non-valvular AF pts at

risk of strokeCHADS2 mean = 2.1Mean time in therapeutic range

with warfarin was 62.2%Median follow-up = 1.8 years

NEJM 2011;365:981-92

ARISTOTLE ResultsApixaban vs. Warfarin

◦Apixaban superior to warfarin for stroke and systemic embolism (NNT=167/1.8 years)

◦Potential Benefits: Decrease stroke (NNT=175), decrease

hemorrhagic stroke (NNT=238) and decrease mortality (NNT=132)

Decrease major bleed (NNT=67) Intracranial bleed (NNT=128)

Decreased d/c rates (NNT=45)

NEJM 2011;365:981-92

Would you give Mr. AF apixaban?Yes, maybe?Apixaban 5mg

twice daily superior to warfarin in stroke or systemic embolism

Decrease all cause mortality

No difference in GI bleeds compared to warfarin

No, maybe not?Twice daily?No antidote

Switching FROM Warfarin NOAC1. Check INR2. Stop warfarin3. Recheck INR in 2-4 daysStart dabigatran when INR < 2.0CPS

◦Thrombosis Canada ≤ 2.0Start rivaroxaban when INR ≤ 2.5CPS

◦Thrombosis Canada ≤ 2.0Start apixaban when INR < 2.0CPS

◦Thrombosis Canada ≤ 2.0

What if?Mr. AF’s renal function declined:

◦72y male, SCr=130umol/L, Ht=65 inches, Wt=65kg, CrCl=39.5mL/min

What would you give him if he could not take warfarin?◦Dabigatran 150mg or 110mg bid?◦Rivaroxaban 20mg or 15mg od?◦Apixaban 2.5mg or 5mg bid?

SummaryWarfarin advantages60+ years experienceVitamin K antidoteValvular/non-valvular

AFAllows for missed

doses?No dosage

requirements for renal dysfunction

Monitoring – up to every 3 months

Cost $40/month

Warfarin disadvantagesMany drug/food

interactionsSlow onsetPhysician/nurse/

pharmacist time?Seasonal

changes in INR?Monitoring?

SummaryNovel oral anticoagulantsAdvantagesLess Monitoring:

◦ SCr & CrCl at least annually

Fast onset

Disadvantages<2 years

experienceNo antidoteIf miss dose,

short half-life – quick “offset”

Renal function dose adjustments

Cost > $100/month

SummaryWarfarin is preferred in:

◦Mechanical or valvular AF◦If INR is stable on warfarin◦CrCl < 30mL/min◦Liver dysfunction◦Poor compliance (or maybe no OAC

is preferred)◦Morbidly Obese?

SummaryDabigatran 150mg bid preferred if

recent ischemic stroke on warfarinRivaroxaban or apixaban is preferred:

◦CrCl 30-50mL/min◦Dypepsia or upper GI bleed◦Recent acute coronary syndrome

Apixaban preferred if recent GI bleedRivaroxaban preferred if poor

compliance with twice daily dosing or request for a once-daily regimen

Questions?