Non-vitamin K Oral Anticoagulants in atrial fibrillation ...
Atrial Fibrillation & Anticoagulants
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Transcript of Atrial Fibrillation & Anticoagulants
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?