ic5 - selection and management of anticoagulants for stroke prevention in AF (SPAF) Flashcards
what is the difference between valvular and non valvular AF
valvular AF includes moderate to severe mitral stenosis, prosthetic heart valves
non valvular AF is AF with other valvular heart lesions
compare the agents used for valvular vs non valvular AF
use VKA for valvular, use DOACs for non valvular
should OAC be used for SPAF
yes if mCHA2SD2-VASc score is not = 0 for males and not = 1 for females
what is the preferred OAC for SPAF
DOAC > VKA
compare the scorings for CHA2SD2-VASc and mCHA2SD2-VASc
CHA2SD2-VASc:
congestive HF [+1]
HTN [+1]
Age (>75) [+2]
DM [+1]
prev stroke or TIA or thromboembolism [+2]
vascular disease (prev MI or PAD or aortic plate) [+1]
65-74 [+1]
female [+1]
mCHA2SD2-VASc:
congestive HF [+1]
HTN [+1]
DM [+1]
prior stroke/ TIA [+2]
vascular disease [+1]
65-74 [+1]
Age (>75) [+2]
what is meant by time in therapeutic range (TTR)
it means the time spent in therapeutic INR range
consider factors favouring DOACs vs factors favouring warfarin
factors favouring warfarin: pts who have at least 6/10 INR in therapeutic range, pts with moderate to severe hepatic or renal impairment, pts unable to tolerate s/e of DOACs (epigastric discomfort), pts with clinically significant ddi to DOACs
factors favouring DOACs: pts w less than 6/10 INR in therapeutic range when on warfarin, pts reluctant for more freq monitoring or no access, warfarin has narrower therapeutic index thus req more freq monitoring, warfarin assoc with greater deterioration of renal func, warfarin assoc with neuropathy and vascular calcification, DOACs have simpler dosing and safer bc lesser major bleeding, DOACs have significantly lesser ddi
what scoring is used to measure bleeding risk and what are the scoring componnets
HASBLED (max score of 9)
HTN [1]
abnormal renal func (dialysis, transplant, SCr >200mcmol/L) [1]
abnormal liver func (cirrhosis, bilirubin >2x, AST or ALT or ALP >3x)
stroke (hx of) [1]
bleeding (hx of and risk) [1]
labile INR (>6/10 above target or high or unstable INR) [1]
elderly (>65) [1]
drugs (antiPLT, NSAIDs etc) [1]
alcohol (>8u/w) [1]
is HASBLED scoring correlated with actual bleeding
no
what are the tx goals for AF
ABC
avoid stroke -> identify low risk pt, offer stroke prevention if at least one risk factor (or based on mCHA2SD2-VASc), decide on OAC
better sx control
cardiovascular and other comorbs or risk factors
what is LAA occlusion and is it more beneficial than anticoagulants
watchman device inserted into left atrium but anticoagulants better efficacy
list examples of antithrombotics
antithrombotics comprises of both antiPLT and anticoagulants
antiPLT: [PO] aspirin, dipyridamole, P2Y12i like clopidogrel and ticagrelor [IV] glycoprotein IIb/IIIa inhibitor like eptifibatide
anticoagulant: [PO] DOACs like dabigatran and rivaroxaban and apixaban, VKA like warfarin [IV] heparin (LMWH like enoxaparin and UFH)
compare the dosing between OACs for SPAF
dabigatran: [for SPAF] 150mg BD, 110mg BD older than 80, high risk bleeding or if concom PGPi [CrCl 30-50] same as SPAF [CrCl 15-30] c/i [CrCl <15] c/i
rivaroxaban: [for SPAF] 20mg QD [CrCl 30-50] 15mg QD [CrCl 15-30] caution [CrCl <15] c/i
apixaban: [for SPAF] 5mg BD, 2.5mg BD if any two of following - older than 80, weight below 60kg, SCr more than 1.5mg/dL or 132.6mmol/L [CrCl 30-50] same as SPAF [CrCl 15-30] 2.5mg BD [HD] same as SPAF
edoxaban: [for SPAF] 60mg QD, 30mg QD if any of the following - CrCl 30-50, weight below 60kg, concom verapamil or quinidine or dronedarone [CrCl 30-50] 30mg QD [CrCl 15-30] 30mg QD [CrCl <15] not rec
warfarin: individualised dosing
what eqn do you use to estimate renal func for dosing of OAC and what is the eqn
cockroft-gault eqn
CrCl = [(140-age)(BW)]/[SCr(72)(88.4)] (0.85 if female)
**note SCr in micromol/L (/88.4) to convert to mg/dL
what are the diff BW and when are they used in the cockroft-gault eqn
TBW for underweight
IBW for normal weight
adjBW for obese (0.4 x TBW)
calc range of CrCl for obese and morbidly obese using TBW and IBW
typically use TBW to calc dosing of DOAC
would CrCl be of higher or lower value than GFR and why
CrCl would be of higher value because Cr is being secreted by proximal tubule (in addition to being filtered by glomerulus)
what is the CKD-EPI eqn mostly used for and for whom might using GFR be less accurate in estimating kidney function
calc GFR to classify CKD
for DM with high GFR, pregnancy, unusual body mass (obese, severely malnourished, amputee etc)
how to stage CKD
GFR cat [CKD stage] {GFR value}
G1 [1] {>90}
G2 [2] {60-89}
G3a [3] {45-59}
G3b [3] {30-44}
G4 [4] {15-29}
G5 [5] {<15}
what are some special populations to take note when choosing antithrombotics and what are the considerations for these special populations
elderly: apixaban
BW 60-120kg: lower BW requires dose adjustments for apixaban and edoxaban, higher BW use rivaroxaban and apixaban
what is the frequency for monitoring and follow up
first follow up in 1 month
after first follow up: q4m if >75yo or frail OR q”CrCl/10”m if CrCl <60ml/min OR immediately in case of intercurrent conditions esp if potential impact on renal or hepatic func
what should be checked during regular follow up
bleeding events, s/e, adherence (inform about monitoring for minor bleedings eg. gum bleed epistaxis), changes in co-medication (OTC), blood sampling q12m or as per TCU interval, reassess HASBLED or CHA2SD2-VASc score, assessing optimal DOAC and correct dosing
which DOACs are cyp450, P-gp, BCRP and OATP substrates
cyp450: rivaroxaban (50%), apixaban (20-25%)
P-gp: dabigatran, rivaroxaban, apixaban, edoxaban
BCRP: rivaroxaban, apixaban
OATP: dabigatran (weak), rivaroxaban, edoxaban (weak)
what are the types of ddi to note for DOACs and list specific examples for each type
abx:
[macrolides] P-gp inhibition and 3A4 inhibition
[rifampicin] P-gp induction, BCRP induction, 3A4 induction **NO DOAC
ASM:
[CBZ] P-gp induction, 3A4 induction **NO DOAC, WARFARIN OK
[PB] 3A4 induction, possible P-gp induction **NO RIVAROXABAN
[PHT] 3A4 induction, P-gp induction **NO RIVAROXABAN
[VPA] 3A4 induction/ inhibition and P-gp induction/ inhibition **NO DOAC
herbals:
[st john’s wort] P-gp induction, BCRP induction, 3A4 induction **NO DOAC, WARFARIN OK
[ginger] anticoagulation/ antiPLT effect **CAUTION
[ginko] P-gp inhibition, anticoagulation/ antiPLT effect **CAUTION
[ginseng] anticoagulation/ antiPLT effect **CAUTION
[green tea] P-gp inhibition, anticoagulation/ antiPLT effect **CAUTION
consider how to swap from VKA to DOAC, DOAC to VKA, UFH to DOAC and DOAC to UFH
VKA to DOAC: daily VKA and therapeutic INR -> stop VKA -> if INR 3 and above postpone DOAC, if INR 2 and below start DOAC immediately, if INR 2-2.5 start DOAC immediately, if INR 2.5-3.0 recheck INR in 1-3 days (** ensure daily INR <2.5 before switching from VKA to DOAC)
DOAC to VKA: daily DOAC -> continue DOAC (half dose for epoxaban) and start VKA -> recheck INR 3-5d before starting VKA and if INR 2 and below continue DOAC, if INR more than 2, stop DOAC and repeat INR 1 day after stopping DOAC
UFH to DOAC: UFH -> stop UFH -> start DOAC 2-4h after stopping UFH
DOAC to UFH: daily DOAC -> start UFH 12h (if DOAC taken BD) or 24h (if DOAC taken QD) after last DOAC intake
do you monitor INR for DOACs
no bc coagulation assays (aPTT, PT, ACT, TT) are often deranged by DOACs
what is the estimates for expected plasma levels of DOACs when treating for AF
dabigatran: [peak] 50-300 [trough] 50-100
rivaroxaban: [peak] 150-300 [trough] 10-100
apixaban: [peak] 100-300 [trough] 30-200
edoxaban: [peak] 100-300 [trough] 10-40
how to manage bleeding when on DOAC
mild bleeding: delay or discontinue dose, reconsider concom medications, reconsider choice of DOAc and dosing
non life threatening major bleed: supportive measures (mechanical compression, surgical hemostasis, endoscopic hemostasis, fluid replacement/ RBC or PLT substitution, consider adjunct tranexamic acid, tx of factors or comorbs contributing to bleeding)
life threatening or bleeding into critical sites: [dabigatran] idarucizumab 5g IV [rivaroxaban, apixaban, edoxaban] indexanet alpha first line if not prothrombin complex concentrates (PCC)
what is the post bleeding management after bleeding while taking a DOAC
discuss impact of bleeding on patient’s consideration of risks and benefits of anticoagulation, assess risk of repeat bleeding, reevaluate modifiable bleeding risk factors, review correct choice and dosing of DOAC, reinitiate anticoagulation in the absence of absolute c/i
what are the gold standard and reversal agents for reversal of dabigatran, rivaroxaban and apixaban
dabigatran: gold standard is to withhold 1-2days if normal renal func and non life threatening bleed, if urgent reversal needed give idarucizumab (praxibind)
rivaroxaban and apixaban same as dabigatran but can also consider PCC but likely ineffective
what are the types of unplanned invasive procedure when taking DOACs
acute emergency procedure which refers to need to operate within mins
urgent procedure which refers to need to operate within hrs
expedite procedure which refers to need to operate within days
if got time to hold off and reverse drug then assess bleeding risk, if high risk then hold off but if not high risk then may not need to hold off
what is the process like for acute emergency, urgent and expedite procedures in the event of an unplanned invasive procedure whilst taking DOAC
acute emergency: blood sampling (full coagulation panel) -> reversal of NOAC if necessary -> operate -> repeat coag panel -> intervention as per results
urgent procedure: blood sampling (full coag panel) -> possible to defer surgery for 12-24h? -> if yes then defer and repeat coag panel (-> consider if there is residual effect -> if no operate -> intervention as per results) if no then reversal of DOAC -> operate -> repeat coag panel -> intervention as per results
expedite procedure: blood sampling (full coag panel) -> can defer surgery for planned interventions -> if no then can defer surgery for 12-24h -> if yes then defer and repeat coag panel (-> consider if there is residual effect -> if no then operate -> intervention as per results) if no then reversal of DOAC -> operate -> repeat coag panel -> intervene as per results
**if residual effect still present, consider deferring surgery for another 12-24h again (flow chart)
what does full coagulation panel include
aPTT, PT, anti-FXa, dTT etc
how to determine the time required to hold off DOAC and when to resume full dose of DOAC
based on drug half life and renal impairment
for dabigatran: [CrCl 80 and above] at least 24h for low risk, at least 48h for high risk [CrCl 50 and above] at least 36h for low risk, at least 72h for high risk [CrCl 30 and above] at least 48h for low risk, at least 96h for high risk (note use of dabigatran c/i for CrCl <30)
for rivaroxaban and apixaban: [CrCl 80 and above] at least 24h if low risk, at least 48h if high risk [CrCl 50 and above] at least 24h if low risk, at least 48h if high risk [CrCl 30 and above] at least 24h if low risk, at least 48h if high risk [CrCl 15 and above] at least 36h if low risk, at least 48h if high risk [CrCl <15] c/i for use
to perform procedure at trough of DOAC and to resume full dose DOAC on same day or latest next day
for pts with older age, renal insufficiency and other concom medications that may contribute to accumulation, consider stopping drug 12-24h earlier and resume full dose of DOAC 48h if low risk, 72h if high risk
which enantiomer of warfarin is more active
S-enantiomer
what is the moa of warfarin
blocks VKOR encoded by VKORC1 gene and thus inhibit the conversion of oxidised vitK epoxide to its reduced form of vitK hydroquinone
what is the role of reduced vitK
serves as a cofactor for gamma glutamate carboxylase
what is the metabolism path for warfarin
S-warfarin metabolised by 2C9 and genetic polymorphism of 2C9 can incr warfarin metabolism
what are the factors contributing to interindividual differences in warfarin response
clinical and env factors (age, height, weight, race, gender, medicines, diet, smoking, alcohol) 10%
genetic polymorphisms (in 2C9 and VKORC1) 41%
other new factors (new common and rare genetic variants, pharmacomicrobiomic factors, pharmacoepigentic factors) 49%
what are the components that are vitK dependent and thus targeted by warfarin and what are their half lives
factor II (42-74h)
factor VII (4-6h)
factor IX (24-30h)
factor X (27-48h)
protein C (9h)
protein S (60h)
factor II has longest half life, factor VII has shortest half life
how long does factor II take roughly to impact INR
may take >96h to reach level for INR =2
what are the ddi mechanisms for warfarin
- absorption from gut (gut produces vitK called menadione which can be affected if there is disruption of gut bacteria)
- protein binding (eg. NSAID use)
- cyp450 enzyme inhibition or induction
- transporter enzymes
- concom antiPLT
- concom abx
- concom metronidazole (part of PPI) -> need 35% dose reduction
- concom amiodarone (for arrhythmia) -> 30-35% dose reduction bc 3A4 and 1A2 inhibitor (note amiodarone has long half life of 105d thus reversal of effects after discontinuation may take weeks)
how might febrile states affect INR and warfarin and what should be done
febrile states may incr INR due to incr in turnover of clotting factors thus repeat INR in 3-5d after starting warfarin
consider daily INR if sepsis or admitted
list common abx and their enzyme type and for which enzyme
2C9 inhibitor: metronidazole, co-trimoxazole, fluconazole, voriconazole
3A4 inhibitor: fluconazole, voriconazole, ketoconazole, itraconazole, ciprofloxacin, clarithromycin, erythromycin
2C9 inducer: rifampicin, ritonavir
3A4 inducer: rifampicin
which enzymes are important for each type of warfarin enantiomer
S-warfarin: 2C9, 3A4
R-warfarin: 3A4, 2C19, 1A2
when should loading doses for warfarin given
if there is existing clot
what are the likely factors to affect the maintenance doses of warfarin
BSA, age, weight, race, target INR, current thrombosis, current amiodarone use, smokers
PGx (esp for dose extreme pts of less than 21 and more than 49mg/w)
when should warfarin be preemptively adjusted
cotrimoxazole adjust by 25-50%
ciprofloxacin decr by 20-30%
metronidazole decr by 35%
amiodarone decr by 30-50%
what is the monitoring parameters for warfarin and when to consider switching to DOACs but what to note if switch to DOAC
INR target of 2-3 with TTR at least 70% (2.5-3.5 if valvular heart disease with mechanical heart valve)
switch to DOAC if low TTR but ensure good adherence bc DOAC shorter half life and not routinely measured
how long should warfarin be used for based on different indications (DVT/PE, SPAF, valvular heart disease, bioprosthetic heart valve, left ventricular thrombus, mechanical heart valve)
DVT/PE target INR 2-3 for 3m (extended if recurrent or presence of persistent risk factor)
SPAF target INR 2-3 for lifelong
valvular heart disease target INR 2-3 for lifelong
bioprosthetic heart valve target INR 2-3 for 3-6m after surgery
left ventricular thrombus target INR 2-3 for 3m (must repeat TTE to document resolution before stopping)
mechanical heart valve target INR 2.5-3.5 for lifelong
what are the drug-lifestyle interactions of warfarin
alcohol binge can cause blips in INR due to 450 inhibition
chronic alcoholism can decr INR bc 450 induction
sudden incr in physical activity can decr INR bc incr warfarin metab
smoking can decr INR bc 450 induction
what are the drug-disease interactions for warfarin
liver related diseases: decr clotting factors synthesis and decr wafarin metab -> incr INR
fever: incr clotting factors turnover -> incr INR
fluid retention: decr gut absorption -> decr INR
thyroid diseases: hyperthyroidism -> incr turnover of clotting factors -> incr INR VS hypothyroidism -> decr clotting factor turnover -> decr INR
what is the reversal agent for warfarin
vitamin K, fresh frozen plasma, PTT (if urgent reversal needed)
what is the disadvantage of giving high levels of vit K
pose as a risk for resistance when trying to re-anticoagulate patient (resistance last for up to 3w which poses as a high thrombogenic risk)
what are the differences in route and dosing of vitK given when trying to reverse warfarin
if INR 4.5-10, give PO vitK 1-2mg
if major bleeding and INR >1.5, give IV vitK5-10mg
if minor bleeding, assess bleeding risk vs thromboembolic risk then consider withholding warfarin and/or giving PO vitK 1-2mg or IV 1mg as necessary
what are the important counselling points for warfarin
tablet ID and non interchangeability of brand
moa of warfarin
indication for tx (discuss about INR and the need to come back for freq monitoring)
compliance (note dates of missed dosing) and risk of TEE
target range and necessity of blood tests and TCUs
ddi (Rx and non Rx)
who should know of tx (GP, dentist, pharmacists)
diet (avoid binging on vitK rich foods, impt to maintain as per normal diet)
alcohol
illnesses (fever, N/V/D) before next TCU
precautions (sports, cuts, accidents)
possible s/e (watch for sx of bleeding)
importance of carrying emergency ID around
pregnancy/ breastfeeding
storage
what is the r/s between INR and PT
INR = (patient PT/ normal PT) ^ISI where ISI is different for different tissues used
what are examples of some vitK rich foods
dark green leafy veges (broccoli, brussel sprouts, lettuce, spinach, watercress), beef or pork liver, salad dressing, mayo, green tea, chrysanthemum tea, herbal tea
