ic5 - selection and management of anticoagulants for stroke prevention in AF (SPAF)

Question 1

what is the difference between valvular and non valvular AF

Answer 1

valvular AF includes moderate to severe mitral stenosis, prosthetic heart valves

non valvular AF is AF with other valvular heart lesions

Question 2

compare the agents used for valvular vs non valvular AF

Answer 2

use VKA for valvular, use DOACs for non valvular

Question 3

should OAC be used for SPAF

Answer 3

yes if mCHA2SD2-VASc score is not = 0 for males and not = 1 for females

Question 4

what is the preferred OAC for SPAF

Answer 4

DOAC > VKA

Question 5

compare the scorings for CHA2SD2-VASc and mCHA2SD2-VASc

Answer 5

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]

Question 6

what is meant by time in therapeutic range (TTR)

Answer 6

it means the time spent in therapeutic INR range

Question 7

consider factors favouring DOACs vs factors favouring warfarin

Answer 7

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

Question 8

what scoring is used to measure bleeding risk and what are the scoring componnets

Answer 8

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]

Question 9

is HASBLED scoring correlated with actual bleeding

Answer 9

no

Question 10

what are the tx goals for AF

Answer 10

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

Question 11

what is LAA occlusion and is it more beneficial than anticoagulants

Answer 11

watchman device inserted into left atrium but anticoagulants better efficacy

Question 12

list examples of antithrombotics

Answer 12

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)

Question 13

compare the dosing between OACs for SPAF

Answer 13

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

Question 14

what eqn do you use to estimate renal func for dosing of OAC and what is the eqn

Answer 14

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

Question 15

what are the diff BW and when are they used in the cockroft-gault eqn

Answer 15

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

Question 16

would CrCl be of higher or lower value than GFR and why

Answer 16

CrCl would be of higher value because Cr is being secreted by proximal tubule (in addition to being filtered by glomerulus)

Question 17

what is the CKD-EPI eqn mostly used for and for whom might using GFR be less accurate in estimating kidney function

Answer 17

calc GFR to classify CKD

for DM with high GFR, pregnancy, unusual body mass (obese, severely malnourished, amputee etc)

Question 18

how to stage CKD

Answer 18

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}

Question 19

what are some special populations to take note when choosing antithrombotics and what are the considerations for these special populations

Answer 19

elderly: apixaban

BW 60-120kg: lower BW requires dose adjustments for apixaban and edoxaban, higher BW use rivaroxaban and apixaban

Question 20

what is the frequency for monitoring and follow up

Answer 20

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

Question 21

what should be checked during regular follow up

Answer 21

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

Question 22

which DOACs are cyp450, P-gp, BCRP and OATP substrates

Answer 22

cyp450: rivaroxaban (50%), apixaban (20-25%)

P-gp: dabigatran, rivaroxaban, apixaban, edoxaban

BCRP: rivaroxaban, apixaban

OATP: dabigatran (weak), rivaroxaban, edoxaban (weak)

Question 23

what are the types of ddi to note for DOACs and list specific examples for each type

Answer 23

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

Question 24

consider how to swap from VKA to DOAC, DOAC to VKA, UFH to DOAC and DOAC to UFH

Answer 24

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

Question 25

do you monitor INR for DOACs

Answer 25

no bc coagulation assays (aPTT, PT, ACT, TT) are often deranged by DOACs

Question 26

what is the estimates for expected plasma levels of DOACs when treating for AF

Answer 26

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

Question 27

how to manage bleeding when on DOAC

Answer 27

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)

Question 28

what is the post bleeding management after bleeding while taking a DOAC

Answer 28

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

Question 29

what are the gold standard and reversal agents for reversal of dabigatran, rivaroxaban and apixaban

Answer 29

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

Question 30

what are the types of unplanned invasive procedure when taking DOACs

Answer 30

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

Question 31

what is the process like for acute emergency, urgent and expedite procedures in the event of an unplanned invasive procedure whilst taking DOAC

Answer 31

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)

Question 32

what does full coagulation panel include

Answer 32

aPTT, PT, anti-FXa, dTT etc

Question 33

how to determine the time required to hold off DOAC and when to resume full dose of DOAC

Answer 33

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

Question 34

which enantiomer of warfarin is more active

Answer 34

S-enantiomer

Question 35

what is the moa of warfarin

Answer 35

blocks VKOR encoded by VKORC1 gene and thus inhibit the conversion of oxidised vitK epoxide to its reduced form of vitK hydroquinone

Question 36

what is the role of reduced vitK

Answer 36

serves as a cofactor for gamma glutamate carboxylase

Question 37

what is the metabolism path for warfarin

Answer 37

S-warfarin metabolised by 2C9 and genetic polymorphism of 2C9 can incr warfarin metabolism

Question 38

what are the factors contributing to interindividual differences in warfarin response

Answer 38

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%

Question 39

what are the components that are vitK dependent and thus targeted by warfarin and what are their half lives

Answer 39

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

Question 40

how long does factor II take roughly to impact INR

Answer 40

may take >96h to reach level for INR =2

Question 41

what are the ddi mechanisms for warfarin

Answer 41

1. absorption from gut (gut produces vitK called menadione which can be affected if there is disruption of gut bacteria) 2. protein binding (eg. NSAID use) 3. cyp450 enzyme inhibition or induction 4. transporter enzymes 5. concom antiPLT 6. concom abx 7. concom metronidazole (part of PPI) -> need 35% dose reduction 8. 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)

Question 42

how might febrile states affect INR and warfarin and what should be done

Answer 42

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

Question 43

list common abx and their enzyme type and for which enzyme

Answer 43

2C9 inhibitor: metronidazole, co-trimoxazole, fluconazole, voriconazole 3A4 inhibitor: fluconazole, voriconazole, ketoconazole, itraconazole, ciprofloxacin, clarithromycin, erythromycin 2C9 inducer: rifampicin, ritonavir 3A4 inducer: rifampicin

Question 44

which enzymes are important for each type of warfarin enantiomer

Answer 44

S-warfarin: 2C9, 3A4 R-warfarin: 3A4, 2C19, 1A2

Question 45

when should loading doses for warfarin given

Answer 45

if there is existing clot

Question 46

what are the likely factors to affect the maintenance doses of warfarin

Answer 46

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)

Question 47

when should warfarin be preemptively adjusted

Answer 47

cotrimoxazole adjust by 25-50% ciprofloxacin decr by 20-30% metronidazole decr by 35% amiodarone decr by 30-50%

Question 48

what is the monitoring parameters for warfarin and when to consider switching to DOACs but what to note if switch to DOAC

Answer 48

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

Question 49

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)

Answer 49

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

Question 50

what are the drug-lifestyle interactions of warfarin

Answer 50

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

Question 51

what are the drug-disease interactions for warfarin

Answer 51

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

Question 52

what is the reversal agent for warfarin

Answer 52

vitamin K, fresh frozen plasma, PTT (if urgent reversal needed)

Question 53

what is the disadvantage of giving high levels of vit K

Answer 53

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)

Question 54

what are the differences in route and dosing of vitK given when trying to reverse warfarin

Answer 54

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

Question 55

what are the important counselling points for warfarin

Answer 55

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

Question 56

what is the r/s between INR and PT

Answer 56

INR = (patient PT/ normal PT) ^ISI where ISI is different for different tissues used

Question 57

what are examples of some vitK rich foods

Answer 57

dark green leafy veges (broccoli, brussel sprouts, lettuce, spinach, watercress), beef or pork liver, salad dressing, mayo, green tea, chrysanthemum tea, herbal tea