Perioperative medication management

Question 1

:) How does aspirin work & what are the implications preoperatively?

Answer 1

irreversibly inhibits plt COX so may increase periop blood loss & haemorrhagic complications but may help prevent periop thromboembolic complications

Question 2

:) What’s the risk of pre-op aspirin withdrawal in CABG patients? what type of studies this from?

Answer 2

increased in-hospital mortality, observational studies

Question 3

:) What does POISE-2 tell us about periop aspirin & non cardiac surgery? What are the clinical implications of this? What is an issue with pt exclusion for this trial?

Answer 3

aspirin increases bleeding risk but doesn’t improve CV or mortality outcomes, sub-study showed no benefit at reducing AKI risk & no benefit for VTE prevention (but 2/3 of the pts also received VTE prophylaxis & there were low overall VTE rates).
Withold aspirin 7/7 in pts taking it for primary or secondary prevention prior to non-cardiac surgery (however if secondary prevention, discussion btwn cardiologist, neurologist, surgeon & pt) & recommence postop once surgical bleeding risk passed EXCEPT pts undergoing CABG, CEA, popliteal artery aneurysm repair or those who are 6/12 after a BMS or DES or those who are having cataract surgery/minor dental/dermatologic procedures.
Many neurosurgical, where bleeding may be highest risk of severe adverse outcomes, were not enrolled in POISE-2, so optimal strategy for periop aspirin for these pts unknown.

Question 4

:) What’s the benefit of aspirin for CABG? does dose matter? what can be given to attenuate risk?

Answer 4

A systematic review from the Antiplatelet trialist’s collaboration showed that anti-platelets (esp if given early) are associated with improved graft patency @ an average of 1 year after CABG, similar benefit with low- vs high-dose aspirin. Antacids & PPIs often given preoperatively to attenuate risk.

ACC/AHA 2021: If patients are already taking aspirin, continue up until the time of surgery to reduce ischaemic events (*unless redo OT or bleeding dyscrasias or other risks of sig bleeding). If pt is undergoing elective CABG but not already on aspirin, don’t initiate it <24hrs pre-op (no benefit).

Question 5

+ What does the ATACAS trial tell us about prep aspirin 1-2 hours prior to CABG (in pts who had newly commenced aspirin or who hadn’t been on it for at least 5 days pre-op)

Answer 5

no difference in death/nonfatal MI/stroke/PE/renal failure or bowel infarct, major haemorrhage & no difference in cardiac tamponade. No sig difference in death or severe disability at 1 year.

Issues included short follow-up (phone call 30 days), half the pts receiving aspirin also had TxA, a large number of pts were eligible but not enrolled, stopped early due to higher event rates than anticipated but the composite end-point included biomarker elevation only- not equivalent in weight against other outcomes

ACC/AHA 2021: further trial showed that if aspirin initiated the night before surgery, incr major bleeding & transfusion rates but no difference in early or late MACE cf placebo.

Therefore, DON’T initiate aspirin for the first time <24hrs prior to CABG.

Question 6

:) What are the benefits of aspirin after CABG?

Answer 6

mortality benefit

Question 7

:) How should aspirin be managed perioperatively for CABG?

Answer 7

if already on it, continue pre-op including day of surgery unless v high bleeding risk. Recommence it 6hrs after surg or extubation (whichever first). The deleterious effects of aspirin on post-op bleeding & transfusion requirement can be attenuated by antifibrinolytic therapy.

Question 8

:) How should aspirin be managed preoperatively for CEA patients? why? does dose matter?

Answer 8

should be started prior to CEA & continued indefinitely, unless contraindications, in both symptomatic & asymptomatic CEA due to reduced stroke risk. Low-dose (81-325mg) aspirin is more effective than high-dose

Question 9

:) How should aspirin be managed for pts undergoing peripheral artery surgery (including large artery aneurysms)? What is the timing & dosing pre- & postoperative for popliteal artery aneurysms?

Answer 9

All pts should have it (commence if not already on it) as it reduces risk of early stent-graft thrombosis following endovascular repair of popliteal artery aneurysms. For repair popliteal artery aneurysms, should start at least 48hrs before the procedure (325-650mg), if within 48hrs give 650mg loading (unless contraindication). Should have postop DAPT for at least 4/52 if bleeding risk low.

Question 10

:) How long should pts be on DAPT after DES or BMS?

Answer 10

for ACS, at least 12/12 but may consider discontinuation of aspirin after 1-3 months & discontinuation of P2Y12 @ 6/12 could be considered if high risk bleeding. For SIHD: BMS at least 1/12 DAPT. DES at least 6/12 DAPT but 1-3 months could discontinue aspirin & at 3/12 if high bleeding risk may discontinue P2Y12.

Question 11

:) What are some surgeries where the risk of major bleeding may outweigh risk of stent thrombosis if urgent surg required within 4-6/52 of BMS or DES placement?

Answer 11

neurosurgery, posterior eye or prostatic

Question 12

:) For how many days is clopidogrel generally stopped before surgery?

Answer 12

5

Question 13

:) For how many days is prasugrel generally stopped before surgery?

Answer 13

7

Question 14

:) For how many days is ticagrelor stopped before surgery?

Answer 14

3-5

Question 15

:) What is a systems consideration for pts within 6/12 of BMS or DES insertion requiring an antiplatelet to be ceased for non-cardiac surgery?

Answer 15

Perform the surgery @ a centre with 24-hour interventional cardiology coverage

Question 16

:) For how many days do pts require DAPT after balloon angioplasty without stenting? How common is this?

Answer 16

14 days. <5% of PCIs are performed in this manner.

Question 17

:) For how many days after balloon angioplasty should urgent surgery ideally be deferred (if can’t wait 14 days)?

Answer 17

48hrs, to confirm stable PCI result

Question 18

:) Does using aspirin impact on the placement of neuraxial block?

Answer 18

No, but consider impact if combined with other meds impacting coagulation eg. NSAIDs

Question 19

:) How long should clopidogrel be withheld prior to placing a neuraxial block?

Answer 19

5-7 days

Question 20

:) What are the 3 types of acute coronary syndromes?

Answer 20

STEMI, NSTEMI & unstable or crescendo angina

Question 21

:) What is the approach to a patient who requires urgent or emergency surgery but who has known or suspected coronary artery disease (or ACS!), heart failure or severe valvular heart disease?

Answer 21

urgent cardiology consult for suggestions re: monitoring & medication management (& rarely additional cardiovascular testing)

Question 22

+2021 ACC/AHA coronary revascularisation guidelines:
What are some situations where myocardial revascularisation BEFORE non cardiac surgery may improve perioperative outcomes?

What is the cornerstone of therapy for prevention of thrombotic complications with PCI?

What is clopidogrel?

For pts undergiong urgent CABG, for how long should clopidogrel & ticagrelor be discontinued? and elective?

and CABG?

For how long should DAPT be continued after PCI?

If a pt has AF & undergoas PCI, what should happen with their anticoagulants?

Answer 22

-pts with significant CAD undergiong high-risk surgery have incr incidence periop CV events but routine prophylactic revascularisation does not reduce risk of death or CV events. Studies excluded pts with high-risk anatomy (unprotected L) main, multivessel CAD, solid organ transplant); for such pts, heart team approach for risk:benefit analysis.

If pts are symptomatic with other clinical indications for revascularisation, consider in accordance with recommendations but not solely to reduce periop complications.

-consider if: unstable CAD (ACS) who are candidates for emerg or urgent revasc, significant L) main disease, pts with high-risk features on noninvasive testing (eg. reversible large anterior wall defect, extensive stress-induced wall motion abnormalities).
Downsides to re-vascularisation are the durations of recovery from CABG or duration of DAPT required prior to proceeding with non-cardiac surgery.
Evidence not robust & suggests pts w stable CAD don’t benefit from prophylactic revascularisation before non-cardiac surgery.

DAPT with aspirin & an oral P2Y12 inhibitor (clopidogrel, ticagrelor or prasugrel)

a prodrug with an active thiol metabolite (CYP2C19>CYP2C9) which irreversibly blocks P2Y12 platelet ADP receptor, reducing platelet aggregation

Genetic polymorphisms may –> poor metabolism of prodrug & inadequate effect, increasing CV risk

The half-life of the parent drug is 6 hours, half-life of active thiol metabolite 30mins

The effect on platelets is irreversible, lasting the lifetime of the platelet (7-10 days); platelet aggregation/bleeding time returns to baseline after 5 days.

Compared to the other P2Y12 inhibitors, clopidogrel is the least potent, requiring longer time to plt (-) after a loading dose. Therefore, the more potent ticagrelor or prasugrel (or clopidogrel) should be used for PCI in ACS. For pts with SIHD undergoing PCI, prasugrel & ticagrelor haven’t been studied for long-term clinical outcomes so use aspirin & clopidogrel. Also, for pts who are undergoing PCI immediately after anti-fibrinolytics, use clopidogrel (others not studied). ?older pts having ACS w PCI clopidogrel may be better than potent ones (lower bleeding risk). Prasugrel is contraindicated in pts w previous TIA or CVA, caution advised in pts <60kg or age >=75kg.

24hrs to reduce major bleeding complications (ACC/AHA 2021) (CABG <5 days after discontinuation of clopidogrel ass’d w major bleeding risks- tamponade or re-operation)
Elective: clopidogrel 5 days, ticagrelor 3 days, prasugrel 7 days (reduce major bleed, product transfusion).

For SELECT patients undergoing PCI, shorter-duration DAPT (1-3 months) is reasonable, with subsequent transition to P2Y12 inhibitor monotherapy to reduce risk of bleeding events, without significant difference in MACE (but these trials were not powered to assess differences in stent thrombosis).

After DES for stable IHD, should have at least 6/12 aspirin + clopidogrel BUT may discontinue aspirin & continue clopidogrel monotherapy after 1-3 months. After 3 months if the patient has high risk of bleeding on DAPT, may discontinue P2Y12 (-).
After 6/12 if no high risk bleeding, may continue DAPT up to max 12/12.

After BMS for stable IHD, should have at least 1 month of aspirin + clopidogrel. if no high risk bleeding, may continue DAPT >1 month, up to max 12/12.

After PCI for ACS, @ least 12/12 aspirin + a P2Y12 (-); it may be reasonable to continue for >1yr if no significant bleeding risk, but may consider discontinuation of aspirin @ 1-3 months & proceed with P2Y12(-) monotherapy. If high risk of overt bleeding, discontinuation of P2Y12(-) @ 6/12 may be reasonable.

After CABG, lifelong aspirin. in selected pts, DAPT w aspirin & ticagrelor or clopidogrel for 1 year may be reasonable (different pathophys; to prevent vein graft occlusion).

If a pt with AF on an oral anticoagulant undergoes PCI, discontinue aspirin after 1-4 weeks & maintain P2Y12 inhibitor along with NOAC or warfarin. NOAC may have lowerste bleeding risk than warfarin.

Rates of stent thrombosis with modern DES is similar or lower than BMS; BMS are rarely used, may be considered if: the patient won’t be able to take DAPT for at least 30 days or high risk of bleeding.

Question 23

:) Should pts undergoing cataract surgery have aspirin withheld?

Answer 23

no since the risks associated with either continuing or discontinuing aspirin are very small

Question 24

:) What’s dipyridamole & what’s the half-life of it’s MR preparation? Evidence for periop cessation? if decide to, how long?

Answer 24

Has vasodilator (phosphodiesterase and adenosine deaminase inhibitor) & anti-platelet activity, usually used after CVA or TIA, 10 hrs.
No data on safety of continuing dipyridamole perioperatively, consider balance of bleeding & ischemic events, withheld 2 days if decide to- if combo aspirin & dipyridamole, withheld 7-10 days prep.

Question 25

:) What's cilostazol & what's it's half-life? How long stop preop?

Answer 25

Selective PDE-3 enzyme inhibitor, weaker reversible anti platelet activity than P2Y12 receptor blockers. Used for claudication symptoms. 21hrs. Should stop for at least 3 days (manufacturer says at least 5 days). Claudication symptoms may recur then cease again once the medication recommenced.

Question 26

:) How do COX-1 (nonselective) & COX-2 selective NSAIDs impact platelets? How long should they be held prior to surgery?

Answer 26

COX-1 inhibitors reduce levels of TxA2 hence reduce platelet aggregation. COX-2 inhibitors don't impact platelets but have negative cardiovascular effects. Should withhold NSAIDs at least 3/7 before surgery (platelet function does normalise within 24hrs of ibuprofen, after holding most other NSAIDs platelet function normalises within 3 days).

Question 27

:) What is bridging anticoagulation & it's purpose?

Answer 27

The administration of a short-acting anticoagulant, typically LMWH, during the interruption of a longer-acting agent, to minimise the time the patient isn't anticoagulant, minimising their risk of peri-operative thromboembolism.

Question 28

:) In which patients is bridging required?

Answer 28

1. Those taking warfarin with a mechanical mitral valve or a mechanical aortic valve with additional stroke risk factors. 2. Embolic stroke within the previous 3/12 or very high stroke risk (CHADS2-vasc score 7-9) 3. VTE within the previous 3/12 (since diagnosis- except if calf DVT with no evidence of calf DVT on repeat US) 4. Selected pts who have had recent coronary stenting 5. Previous thromboembolism during interruption of chronic anticoagulation

Question 29

:) What are the elements of the CHA2DS2-Vasc score?

Answer 29

CHF (1) HTN (1) Age >=75 (2) DM (1) prior TIA/CVA/thromboembolism (2) Vascular disease (peripheral artery disease, MI, aortic plaque) (1) female sex (1) age 65-74 (1)

Question 30

:) What are the 3 major risk factors for thromboembolism?

Answer 30

1. AF (if CHA2DS2-Vasc 7-9 or if TIA/stroke within 3/12 or if rheumatic valvular heart disease) 2. Prosthetic heart valves (mechanical MVR or AVR with additional risk factors (LVEF <=30%, hypercoaguable (infection or cancer surgery), AF, previous thromboembolism) or if stroke or TIA within 6/12) 3. recent (within 3/12) venous or arterial thromboembolism or VTE with severe thrombophilia

Question 31

:) Has the CHA2DS2-Vasc score been prospectively validated in the perioperative setting?

Answer 31

No

Question 32

:) What dose of vitamin K, given the day before surgery if the INR is >1.5, should reduce the INR to 1.4 on day of surgery? how long via K take (orally vs IV) to work?

Answer 32

1-2.5mg PO oral 6-10hrs, IV 1-2hrs

Question 33

:) Why should patients with mechanical valves NOT routinely have high-dose vitamin K given before invasive procedures?

Answer 33

those with mechanical valves since this will delay & reduce the effects of re-anticoagulation with a vitamin K antagonist after the procedure

Question 34

:) For how long after mitral valve replacement or repair should elective non-cardiac surgery be delayed, where possible?

Answer 34

3 months, since the risk of thromboembolism is highest within that timeframe

Question 35

:) For how long is VKA therapy generally recommended after placement of bioprostetic MVR or AVR?

Answer 35

3/12 (INR goal 2.5)

Question 36

:) How to approach a patient with mechanical valve on a VKA having dental extraction, minor derm surgery or anterior eye surgery (minor procedures in which bleeding easily controlled) or PPM/ICD insertion?

Answer 36

can generally continue the VKA for procedure as long as INR not supra therapeutic (based on 2014 AHA/ACC valve guidelines)

Question 37

:) How to approach a pt at low thromboembolic risk who's on a VKA?

Answer 37

withhold warfarin 3-5 days

Question 38

:) What is the anticoagulant regimen for pts with TAVR (bioprosthetic)?

Answer 38

aspirin & clopidogrel for 6/12

Question 39

:) Which patients with mechanical valves require bridging with UFH or SC LMWH?

Answer 39

Those with mechanical MVR or TVR, mechanical AVR with risk factors or an older generation mechanical AV (such pts will be on warfarin with INR goal 3 & long-term daily aspirin)

Question 40

:) What are some additional thromboembolic risk factors which would prompt requirement for bridging in a pt with mechanical AVR requiring surgery where INR must be <1.5?

Answer 40

>1 valve, LVEF <30, AF, previous thromboembolism, hypercoaguable condition (eg. cancer surgery or infection), older generation mechanical valve

Question 41

:) How to bridge?

Answer 41

Admit the pt (safety of bridging at home hasn't been established). Cease warfarin 5 days before procedure & commence IV UFH or LMWH, generally 3 days before procedure, when the INR falls below therapeutic range (aim <1.5 for OT). discontinue LMWH 24hrs before procedure; if BD LMWH is given, omit the evening dose night before. if once-daily, give half the dose the morning of the day before. This is based on biologic half-life of LMWHs of 3-5hrs, the fact that some residual anticoagulant effect of therapeutic LMWH may be present at 24hrs. discontinue UFH 4-5hrs before procedure (biologic half-life 45mins) Recommence heparin asap after surgery & continue it until INR in goal therapeutic range for 2 consecutive days.

Question 42

:) Pros & cons of LMWH vs UFH?

Answer 42

more convenient, may result in more predictable anticoagulation but cannot reverse as rapidly/reliable if severe bleeding occurs

Question 43

:) Should aspirin be continued during bridging?

Answer 43

Yes, unless risk major bleeding (neurosurgeon, prostate, posterior eye) in which case withhold aspirin 5/7 prep

Question 44

:) What doses of LMWH given during bridging? or UFH?

Answer 44

1mg/kg LMWH 12-hourly, 18 units/kg/hr UFH adjusted to APTT 1.5-2x control

Question 45

:) How long stop bridging LMWH or UFH prior to surg?

Answer 45

LMWH 24hrs pre procedure, UFH 4-6 hrs

Question 46

:) What agent should be used to emergently reverse VKA in pt w mechanical valve?

Answer 46

4-factor PCC or FFP with low-dose oral vitamin K- vit K has slower onset but longer half-life than PCC or FFP so slower to get therapeutic VKA postop if use high-dose vit K

Question 47

:) How to manage a pt within 3/12 of a VTE?

Answer 47

delay surgery if possible until 3/12 have passed- no clear evidence for when thromboembolic risk declined to baseline. If Emerg surgery, bridging anticoagulation may be used.

Question 48

:) What's the risk of recurrent early VTE if not anticoagulated? how about if receive warfarin therapy

Answer 48

50%, declines to 5% after 3/12 warfarin therapy

Question 49

:) What's the risk of recurrent arterial embolism from any cardiac source in the first month after an event?

Answer 49

0.5% per day

Question 50

:) Definition of & examples of high bleeding risk surgery?

Answer 50

2-4% 2-day risk of major bleed (major bleed= fatal, involves critical anatomic site (intracranial, pericardial), requires surgery to correct, Hb drop >=20, transfusion >= 2 units rbc) procedure >45 mins, AAA repair, CABG, foot/hand/shoulder, laminectomy, neurosurgery, breast Ca, polypectomy, TURP, vascular & gen surg

Question 51

:) Definition of & examples of low bleeding risk?

Answer 51

0-2% 2-day risk major bleed abdo hernia repair, abdo hysterectomy, arthroscopic surgery lasting <45 mins, axillary node dissection, bronchoscopy with or without biopsy, cholecystectomy, GI endoscopy +/- biopsy, thoracocentesis, tooth extraction

Question 52

:) What are the fasting guidelines?

Answer 52

adults can have limited solid food up to 6hrs & clear fluids up to 2hrs preop. infants <6/12 can have formula up to 4hrs, breastmilk up to 3hrs & clear fluid (no >3mL/kg/hr) up to 1hr before OT. Children >6/12 can have breastmilk or formula up to 6hrs & clear fluids (no >3mL/kg/hr) up to 1hr before anaesthesia.

Question 53

:) What's the glucocorticoid:mineralocorticoid potency of dexamethasone? pred? hydrocortisone? dex's anti-inflammatory potency compared with prednisolone or hydrocortisone?

Answer 53

25:0 4:0.8 1:1 dexamethasone is 25x more potent than hydrocortisone & 6x more potent than pred, so 0.75mg dex is equivalent to 20mg hydrocortisone equivalent to 5mg pred 6x pred, 25x hydrocortisone

Question 54

:) what's the dose of rivaroxaban for nonvalvular AF (to prevent stroke & systemic embolism)? peripheral artery disease (stable) or CAD for prevention of MACE? venous thromboembolism?

Answer 54

-20mg once daily with the evening meal (15mg if CrCl 30-40L/min) -2.5mg BD (in combination with daily low dose aspirin) for prevent major CV events in CAD or PAD -10mg BD for VTE prophylaxis hip or knee OT -15mg BD for 21 days followed by 20mg once daily- if provoked VTE, duration of therapy is 3/12 (providing provoking factor no longer present), if unprovoked, >=3/12 depending on risk of VTE recurrence and bleeding risks. For prophylaxis against VTE recurrence for pts at elevated risk of recurrent VTE following >=6/12 therapeutic anticoagulation, a reduced-intensity regimen of 10mg daily. -reduce dose in renal impairment, avoid if CrCl <30mL/min

Question 55

:) For how long should rivaroxaban be withheld prior to neuraxial?

Answer 55

72hrs

Question 56

:) When can emergency surgery be performed when a patient is on dabigatran?

Answer 56

whenever needed if life-threatening, however ideally 1-2 elimination half-lives 13-24hrs

Question 57

:) Which DOAC can be removed by haemodialysis? what's this handy for?

Answer 57

dabigatran if pt on haemodialysis, they can have it prior to transplant to remove approx 60% plasma [] dabigatran in 2-3hrs, rebound effect can occur as dabigatran highly lipophilic, can redistribute from esxtravasc to intravasc space a few hours after hemodialysis so repeat haemodialysis sessions may be useful in the immediate post-transplant setting.

Question 58

:) What's a risk stratification tool for VTE?

Answer 58

Caprini score (considers pt & surgical factors)

Question 59

:) Whats the dosage for VTE prophylaxis?

Answer 59

enoxaparin 0.5mg/kg BD or UFH 5000IU BD, subcut

Question 60

:) What are particular high risk factors (pt) for VTE?

Answer 60

stroke <1 month, acute spinal cord injury <1 month, multi-trauma, hip/pelvis/limb fracture

Question 61

:) What are moderate risk factors for VTE?

Answer 61

past Hx of VTE FHx of VTE coagulopathy (FVL, PT20210A mutation, lupus anticoagulant, anticardiolipin ab, homocystienaemia, HIT (left untreated, heparin-induced thrombocytopaenia= 5-10% daily risk VTE), other congenital or acquired thrombophilia)

Question 62

:) What are some low risk factors for VTE?

Answer 62

malignancy confined to bed immobile in plaster cast preg/postpartum obesity Hx recurrent/unexplained miscarriage AMI heart failure serious lung disease

Question 63

:) What's dabigatran?

Answer 63

An oral anticoagulant, a prodrug, potent, competitive & reversible direct thrombin (IIa) inhibitor

Question 64

:) What are some advantages/disadvantages of dabigatran vs warfarin?

Answer 64

-No need for monitoring (eg. INR with warfarin) BUT since can't monitor (dilute thrombin clotting time not widely available), difficult to know if therapeutic level achieved -Like warfarin it can be reversed- but idarucizumab expensive, relatively difficult to access, coagulation risks. CAN be removed by haemodialysis but since so lipophilic, may get a rebound dabigatran effect as moves from fat. -Relatively predictable pharmacokinetics provided renal function normal (cf warfarin which is influenced by vit K levels, liver function (dabigatran doesn't use the CYP450 enzyme pathway for elimination), warfarin has variable time to full effect & highly variable elimination half-time of 20-60hrs (mean 40) with clearance of warfarin & synthesis of new CFs required for offset)- dabigatran kinetics heavily influenced by renal clearance, it has prolonged duration of action in renal dysfunction (T1/2B delayed to 28hrs in severe renal impairment vs 12-17hrs with normal renal function) -rapid onset after PO administration so can get full anticoagulation in short time- bridging usually not required (easier to manage postop anticoagulation cf warfarin for minor/low bleeding risk surgery). -No risk thrombosis on commencement (unlike warfarin which has initial hyper coagulability due to inhibition of anticoagulant proteins C & S initially as the half-lives of the pro-coagulant factors in circulation pass- in high-risk pts require cross-bridging with enoxaparin while INR becoming therapeutic) & has relatively rapid onset (useful for postop re-establishment of anticoagulation) -warfarin only once daily dosing (dabigatran BD therapeutic, daily prophylactic for Rx of VTE/PE)- despite warfarin having the disadvantage of INR monitoring -evidence: dabigatran superior to warfarin for stroke prevention in non-valvular AF, lower overall bleeding but dabigatran higher rates GI bleeding.

Question 65

:) What CHA2DS2-Vasc score moves from high to moderate risk?

Answer 65

<7

Question 66

:) For how long should dabigatran be held prior to high bleeding risk surgery? Neuraxial?

Answer 66

at least 48hrs if normal renal function (48-72hrs if CrCl >50mL/min), 96hrs if CrCl 30-49mL/min Neuraxial: 72hrs if CrCl >80mL/min & no additional risk factors (eg. age >65yo, HTN, concomitant antiplatelets) 96hrs if CrCl 50-79mL/min 120hrs if CrCl 30-49mL/min no neuraxial if CrCl <30mL/min

Question 67

:) How long before high bleeding risk surgery is heparin infusion ceased?

Answer 67

4hrs

Question 68

:) Why are DOACS often preferred to warfarin?

Answer 68

lower risk of bleeding stable pharmacokinetics ease of use for pts & prescribers

Question 69

:) How is thrombin produced & how does it act?

Answer 69

From cleaving prothrombin Promotes clot formation through activating factors V, VII, XI & catalysing the conversion of fibrinogen to fibrin & by stimulating platelet activation Insufficient thrombin activity promotes bleeding, excess thrombin activity promotes thrombosis

Question 70

:) While dabigatran has relatively few drug reactions unlike warfarin & doesn't use the CYP450 enzyme pathway for elimination, what are some potential interactions?

Answer 70

Dabigatran levels may be increased by P-gp inhibitors (amiodarone, clarithromycin, verapamil)

Question 71

:) why is dabigatran formulated as a prodrug in a non-crushable capsule?

Answer 71

poor POBA (3-7%)

Question 72

:) Does dabigatran have active metabolites?

Answer 72

Yes, 4

Question 73

:) How is dabigatran cleared?

Answer 73

predominantly renal

Question 74

:) For which patients does dabigatran require dose adjustment?

Answer 74

elderly, renal impairment, not hepatic impairment

Question 75

:) What's factor Xa essential for?

Answer 75

generating thrombin from prothrombin (via prothrombinase)

Question 76

:) How do apixaban & rivaroxaban work?

Answer 76

direct inhibitors of free & clot-bound factor Xa

Question 77

:) What does thrombin do?

Answer 77

Converts fibrinogen to fibrin

Question 78

:) What's the PO bioavailability of apixaban & rivaroxaban like? and their PPB?

Answer 78

Good! Apix 50-60, riva 60% sans food 100% with food And high PPB Given as active drug

Question 79

:) How are apixaban & rivaroxaban excreted?

Answer 79

renal & faecal, so less likely to accumulate in renal failure cf dabigatran

Question 80

:) What's the time to peak plasma level for dabigatran, rivaroxaban & apixaban?

Answer 80

2hrs, 2-4hrs, 1-4hrs

Question 81

:) what's dabigatran's half life? rivaroxaban? apixaban?

Answer 81

12-14hrs rivaroxaban young 5-9hrs, elderly 11-13hrs apixaban 8-15hrs

Question 82

:) What's the relative renal excretion of dabigatran cf rivaroxaban & apixaban?

Answer 82

80% vs 35% & 27%

Question 83

:) relative PB of the DOACs?

Answer 83

dabi 35% riva >90% apix 87%

Question 84

:) What are the 3 main indications for DOACs? And the 4th TGA approved indication for which a DOAC doesn't currently have PBS approval?

Answer 84

1. prevention of stroke in non-valvular AF 2. VTE prophylaxis after ortho surgery 3. Rx or prevention of recurrence of VTE/PE (all 3 DOACs useful for VTE Rx & lowering risk of VTE-related death) 4. Rivaroxaban for prevention of MACE (stroke, MI, CV death) in pts with CAD or PVD

Question 85

:) How does evidence for rivaroxaban compare with warfarin?

Answer 85

Rivaroxaban is non-inferior to warfarin in stroke prevention & has lower rates of intracranial & fatal haemorrhage higher rate of GI bleeding cf warfarin

Question 86

:) How does evidence for apixaban compare with warfarin?

Answer 86

Superior to warfarin in stroke prevention reduced bleeding complications cf other DOACs

Question 87

:) How do DOACs compare with enoxaparin (40mg/day) in VTE prevention after ortho surgery?

Answer 87

All 3 DOACs are superior for VTE prevention without incr bleeding complications- rivaroxaban may have slightly higher bleeding rates than the other DOACs higher pt satisfaction

Question 88

:) What's the dose of apixaban for prevention of non-valvular AF? For VTE prophylaxis after hip/knee surg? Rx/prevention VTE or PE?

Answer 88

5mg BD, halve dose if age >=80, wt <=60kg, Cr >=133micromol/L 2.5mg BD 10mg BD for 1 week then 5mg BD (prevention 2.5mg BD after Rx for >=6/12)

Question 89

:) After biprosthetic tricuspid or mitral valves, following initial 3/12 warfarin, what is adequate to use for thromboprophylaxis?

Answer 89

low-dose aspirin

Question 90

:) Which standard laboratory test is highly sensitive to dabigatran? Can it be used for dabigatran monitoring?

Answer 90

thrombin time a normal TT (<20s) excludes presence of dabigatran can't be used for dabigatran monitoring as very low/clinically insignificant plasma dabigatran produces a very long/unmeasurable TT & aPTT

Question 91

:) Which standard lab test is useful for monitoring rivaroxaban?

Answer 91

prothrombin time- normal PT indicates that a clinically significant rivaroxaban effect isn't likely

Question 92

:) Is anti-Xa activity useful for monitoring apixaban or rivaroxaban?

Answer 92

Not recommended for routine monitoring, however anti-Xa activity of <0.1IU/mL calibrated for LMWH excludes an increased risk of bleeding in pts taking these drugs

Question 93

:) Are specific plasma drug assays available for rivaroxaban & apixaban? and can dabigatran levels be monitored? How may this be useful?

Answer 93

Yes- although routine monitoring isn't needed for dose adjustment due to their predictable pharmacokinetics. Generally, plasma level of 50ng/mL or more is considered therapeutic. Dabigatran levels can be monitored using the Hemoclot assay May be useful to monitor during the perioperative period, if the pt has had a major haemorrhage or if there's been a significant change in renal or hepatic function. No studies correlate specific plasma drug levels with clinical outcome.

Question 94

:) How do DOACs effect bedside viscoelastic tests?

Answer 94

Prolong the CT for EXTEM & INTEM on ROTEM, dose-dependent

Question 94

:) What may be a useful test, albeit qualitative only & not validated for use for clinical outcomes in periop period, that correlates with plasma DOAC presence & may be useful in the emergency setting where rapid detection of the presence of a drug would alter management?

Answer 94

urine dipstick (DOASENSE)

Question 95

:) For how long before surgery should a DOAC be withheld?

Answer 95

depends on the: -DOAC -dose (prophylactic or therapeutic) -type of surgery (bleeding risk), neuraxial longer withholding -renal function -pt age a minimum of 2-3 half-lives are required for low bleeding risk procedures, 4-5 half-lives if high bleeding risk (longer for dabigatran if renal impairment)

Question 96

:) Is there a role for bridging with DOACS?

Answer 96

Yes- if surgery is delayed & a DOAC has been held for >4 days, bridge with LMWH or heparin infusion. Otherwise, no role for pre-op bridging since the half-life of the drugs & time off Rx is so short.

Question 97

:) What plasma levels are reasonable for safe performance of many types of surgery? how about for high bleeding risk procedures? neuraxial?

Answer 97

<50ng/mL high bleeding risk procedures it's <30ngm/L for apixaban or rivaroxaban neuraxial or dabigatran <20ng/mL ie. if the plasma level is 20-50ng/mL for dabigatran or 30-50ng/mL for rivaroxaban or apixaban, minimal residual effect & can proceed with caution if surgery can't be delayed 8hrs

Question 98

:) What's the risk of recurrence of thromboembolic events among patients receiving a DOAC for management of VTE or PE? why is this a concern perioperatively?

Answer 98

up to 3% such pts may require longer time off high-dose DOAC, they should have a bridging plan or consideration of IVC filters or LAA devices if need to stop anticoagulation & bridging difficult

Question 99

:) For how long after the last dose of a DOAC, for Rx of VTE, should neuraxial be avoided? how about after the last dose of a DOAC, with lower doses for prevention of VTE, should neuraxial be avoided? how about for pts on dabigatran with CrCl <30mL/min

Answer 99

Minimum 72hrs (plasma level <20ng/mL- ie. almost undetectable) even longer with dabigatran in renal impairment (96hrs if CrCl 50-79mL/min, 120hrs if CrCl 30-49mL/min) Pts on dabigatran with CrCl <30mL/min shouldn't undergo neuraxial blockade

Question 100

:) When should a DOAC be recommenced after a neuraxial or after catheter removal?

Answer 100

6hrs

Question 101

:) Should DOACs be given with a regional catheter in situ? what if it's accidentally given?

Answer 101

NO if inadvertent dosing, wait @ least 34hrs for dabigatran, 22 for rivaroxaban & 26hrs for apixaban

Question 102

:) What's a nonspecific reversal agent for the DOACs? and specific?

Answer 102

PCC (prothrombinex) 25-50IU/kg specific = idarucizumab for dabigatran (available), adnexanet alfa (n/a in Ax)

Question 102

:) For which pts presenting for emergency surgery may the use of activated charcoal be useful to limit DOAC effect?

Answer 102

those where the DOAC was ingested within 3 hrs

Question 103

:) What plasma levels of DOAC are considered high enough to warrant reversal?

Answer 103

>50ng/mL

Question 104

:) is haemodialysis useful for rivaroxaban or apixaban?

Answer 104

no- only dabigatran

Question 105

:) For urgent surgery where reversal being considered prior to obtaining plasma DOAC levels (and urine dipstick +ve, suggesting likely significant DOAC in the plasma), what factors may be considered when deciding whether to give empirical reversal?

Answer 105

time since ingestion (delay of 12-24hrs often reduced plasma levels significantly if normal renal/hepatic function & on low doses) type of surgery (eg. high bleeding risk/critical site) renal function

Question 106

:) what's idarucizumab? what dose for undetectable dabigatran levels? what's a risk of taking idarucizumab?

Answer 106

monoclonal antibody binding to dabigatran with very high affinity (300x > affinity to thrombin) dose of 5g reduces dabigatran to <20ng/mL within minutes, for 24hrs in most pts a 2nd dose may be required after 24hrs if postop bleed in the RE-VERSE-AD trial, 7% of pts had thrombotic complications within the 1st 90 days

Question 107

:) What's adexanet alfa?

Answer 107

specific reversal agent for apixaban & rivaroxaban recombinant form of modified human factor Xa that binds to the drug but has no active site hence no effect on coagulation given as a bolus then infusion as short half life (5hrs). Thrombin generation levels return to 96% normal after administration.

Question 107

:) In what proportion of pts, taking DOACS, can major bleeding be controlled with the off-label use of PCC 25-50IU/kg? risks?

Answer 107

2/3 thrombotic complications

Question 108

:) Can FFP be given to reverse DOACs?

Answer 108

no [] of clotting factors too low to be effective

Question 109

:) what's a possible approach to emergency surgery with a pt on DOACs?

Answer 109

proceed to OT with caution, Rx with reversal agent if major bleeding occurs (given thrombotic risks). Consider mechanical compression, blood transfusion, temp Mx, antifibrinolytic & BP control as supportive measures.

Question 110

:) after high bleeding risk surgery, when should DOACs be recommenced?

Answer 110

48-72hrs, even longer if haemostasis has been difficult to achieve. Bridging may be considered in these cases, particularly if high risk of thromboembolism. when recommencing postop, always consider if there have been acute changes in pts renal function- consider dose reduction until renal function improves.

Question 111

:) When can a DOAC be resumed after removal of a regional catheter?

Answer 111

at least 6hrs

Question 112

What does fondaparinaux inhibit?

Answer 112

Factor Xa

Question 113

Why may selective COX-2 inhibitors incr risk of MI & stroke?

Answer 113

They inhibit endothelial COX-2 derived prostacyclin but not plt COX-1 derived TxA2

Question 114

Why COX-1 inhibition may trigger asthma?

Answer 114

Inhibit the COX-pathway allowing activation of leukotriene pathway & release of leukotrienes that induce bronchospasm & nasal obstruction

Question 115

After ceasing aspirin, how long does it take for platelet activity to be restored?

Answer 115

Aspirin’s plasma half-life is 20 mins. Once discontinued it doesn’t impact new plts once formed. The lifetime of a plt can be up to 10 days but plt activity restored by 10%/day due to turnover Can have normal haemoostasis with as little as 20% normal plt COX activity

Question 116

What’s heparin-induced thrombocytopenia? Mortality of HIT?

Answer 116

Life-threatening complication from exposure to heparin, an autoantibody directed against endogenous platelet factor 4 in complex with heparin. Type 1 is mild, nadir usually around 100 & plts typically normalise with continued heparin & there’s no thrombosis, heparin can continue Type II is clinically significant- the autoantibodies to platelet 4 complex to heparin (PF4/heparin antibodies), it activates platelets causing catastrophic arterial & venous thrombosis and thrombocytopenia (HITT). Can get thrombosis, life-threatening limb gangrene, continue until heparin ceased AND a non-heparin anticoagulant initiated. Untreated, mortality 20%

Question 117

+for CABG LO: what are elements of fast-track/ERAS anaesthesia for CABG?

Answer 117

Prevent early postop complications, minimise exposure to opioid-based analgesia, reduce time to extubation, time in ICU & hospital LoS. -early PO intake -bundled SSI prevention (IV insulin infusion to maintain BGL <18 but avoid hypoglycaemia, measure periop HbA1c, redose prophylactic antimicrobials if >2 half-lives of the antibioitc or excessive blood loss. advise smoking cessation) -multimodal nonopioid analgesia (paracetamol, ketamine, dexmed +/- truncal nerve blocks) -protocolised short-acting anaesthetics (volatile vs sevo maintenance doesn't impact mortality rate after cardiac surgery -lung-protective ventilation strategy (TV 6mL/kg predicted body weight) -targeted-organ perfusion strategies (goal-directed fluid & vasopressor therapy- inconsistent evidence) -early postop ambulation

Question 118

+ 2021 ACC/AHA recommendations regarding B blockers & amiodarone in CAGBG:

Answer 118

if no contraindications, B-blockers or amiodarone pre-CABG reduce incidence of postop AF. Amiodarone also decr incidence of stroke & reduces hospital LoS, only complication occ bradycardia (individualised, risk toxicity & systemic hypoT). Periop B-blockers may also reduce in-hospital & 30-day mortality rates but their role in preventing acute post-op MI, stroke, AKI or ventricular arrhythmia is unknown. Pharmacogenetic variation may play a role; non-CYP2D6 metabolised agents (atenolol & sotalol) lower incidence of operative death vs CYP2D6-metabolised agents (metoprolol, propranolol, carvedilol, labetalol). Also, impact on pts w reduced LVEF not established.

Question 119

A patient presents for a trans-urethral resection of the prostate (TURP). He had a single drug- eluting coronary stent for angina pectoris inserted six months ago and is taking clopidogrel and aspirin. The most appropriate preoperative management of his medications is to

Answer 119

stop both