Drug

Question 1

Antiplatelet

Answer 1

Aspirin
• Mechanism: non-selective COX1 and COX2 inhibitors —> reduce TXA2 production by platelets

P2Y12 inhibitors
• P2Y12 is component of ADP receptor: ADP is stored in platelet dense granules and released upon activation
- Clopidogrel —> preferred if thrombolysis
- Prasugrel —> preferred if PCI
- Ticagrelor (best choice) —> preferred if PCI

GPIIb/IIIa receptor antagonist
• Drug choices: abciximab, eptifibatide, tirofiban
• Require renal adjustment dose

Question 2

Anticoagulants

Answer 2

Indications
• VTE prophylaxis (e.g. post TKR / THR)
• VTE treatment (DVT / PE)
• Systemic thromboembolism
o Stroke prevention in AF (valvular/ non-valvular)
o Mechanical heart valves
o ACS

Contraindications
• Recent major surgery
• Uncontrolled HT/ haemorrhagic stroke
• Major bleeding diathesis

1. Heparin (IV/SC)
   - inhibit Fxa and thrombin
   - S/E: heparin-induced thrombocytopenia and thrombosis, osteoporosis, hyperkalemia, aldosterone suppression
   - monitoring: APTT Q6h (target 1.5-2.5x baseline)
   - preferred if ESRD
   - Rapidly reversible by protamine sulphate
2. LMWH (SC)
   - Inhibit FXa only
   - reduce dose if CrCL <30
   - partially reversible by protamine sulphate
3. Warfarin
   - vitamin K epoxide reductase competitive inhibitor —> reduce factor 2, 7, 9, 10 activation
   - S/E: skin necrosis, local thrombosis, purple toes syndrome, osteoporosis, teratogenicity, DDI with CTP2C9
   - monitor INR (2-3 for most, 2.5-3.5 for metallic MV)
   - usual: 5mg starting, once daily
   - avoid if ESRD
4. Dabigatran
   - direct thrombin inhibitor
   - lowest risk of ICH among DOAC
   - check RFT before initiation, no need monitor
   - 150mg
   - avoid if CrCL<30
5. Apixaban
   - lowest GI bleeding risk among DOAC
   - 5mg BD, 2.5mg BD if fulfil “ABC rule” for apixaban titration: any two of Age ≥ 80, BW ≤ 60kg, Cr ≥ 133
6. Edoxaban
7. Rivaroxaban

Question 4

Warfarin vs DOAC

Answer 4

Advantages of DOAC
• Faster onset: no need for bridging
• No need dietary restriction (菠菜 通菜 芥蘭 ⾖苗)
• No need INR monitoring
• Similar efficacy in preventing embolic events
• Lower risk of major ICH with lower overall mortality

Disadvantages of DOAC
• More frequent dosing (usually BD)
• No way of monitoring and checking compliance
• Higher risk of GI bleed
• Specific antidotes may not be available
• Higher risk of breakthrough thromboembolic events due to short half-life mortality
• Indications that DOAC cannot be used (below)

Question 5

Conditions where only warfarin (but not DOAC) can be used

Answer 5

Conditions where only warfarin (but not DOAC) can be used – MARS
• Mechanical heart valve
• APLS
• Renal/Liver impairment
• Severe MS (for non-valvular AF, may consider DOAC)

Question 6

Titration of warfarin

Answer 6

• Monitoring of INR: daily until in range for 2 days —> 2-3x/week for 1-2 weeks —> Q6-12week if stable

• Factors affecting INR (SAQ!!)
o ↑INR by CYP2C9 inhibitors: metronidazole, amiodarone, co-trimoxazole, azoles
o ↑INR by altered intestinal flora: FQ (levofloxacin), macrolides (clarithromycin), septrin, metronidazole
o ↓INR by CYP2C9 inducers: rifampicin, carbamazepine, phenytoin
o ↓INR by high vitamin K diet (e.g. green-leaf vegetables)

• Management of abnormal INR
o Too low: consider admission and bridging with LMWH (esp high risk)
o Too high / bleeding: refer below

Question 7

Guideline for overwardarinization

Answer 7

INR <4.5 + no bleeding —> reduce dose / omit next few doses

INR 4.5-10 + no bleeding —> omit next few doses +/- oral vit K 1-2mg

INR>10 + no bleeding –> Oral vit K 3-5mg +/- PCC 15-30 IU/kg (if high risk)

INR>2.0 + significant bleeding —> IV vit K 5-10mg + PCC 35-50 IU/kg

Any INR + life threatening bleeding —> IV vit K 5-10mg + PCC 50 IU/kg + FFP 150-300mL

Question 8

Reversal of anticoagulant

Answer 8

General management
• ABC, stop anticoagulant
• Ix: CBC, clotting, T&S
• Oral activated charcoal if within 4h

Antiplatelet
- platelet transfusion not recommended

Warfarin
Vitamin K1 5mg IV: take 6h to normalise INR —> to be administered with either/ both
• Prothrombin complex concentrate (PCC):
o Content: 4-factor (e.g. Beriplex: 2, 7, 9, 10) or 3-factor (e.g. Prothrombinex:
2, 9, 10 only)
o Pros: not require cross-match, faster action, no fluid overload
o Cons: 1% risk of thrombosis, C/I in active thrombosis / DIC
• FFP: higher risk of fluid overload
• PWH practice: Prothromobinex (2, 9, 10) 50 units/kg + FFP (7)

DOAC
Dabigatran: idarucizumab 5g IV bolus, haemodialysis
Factor Xa inhibitors: PCC 50 units/kg, NovoSeven (rFVIIa), andexanet alpha (decoy receptor to Fxa inhibitors), haemodialysis NOT possible (protein-bound)

Thrombolytics e.g. tPA
- Cryoprecipitate infusion + tranexamic acid 1g IV infusion

Question 9

Peri-procedural Mx of anticoagulant

Answer 9

Principles: Balance risk of bleeding (from procedure) vs risk of thrombosis (from underlying condition)
• Need of interruption of anticoagulation depends on procedural bleeding risk

Low risk: NO need interruption
- Minor dental, dermatological, eye surgery, endoscopy without biopsy

Moderate risk
- SVT ablation, ICD implantation, endoscopy with biopsy
- Prostate biopsy, cardiac catheterization (radial a.)

High risk: MUST interrupt
- CTS surgery, abdomen/pelvic surgery, major O&T surgery
- Neurosurgery, cardiac catheterization (femoral a.)

• Bridging with LMWH (if on warfarin): only if high thrombotic risk
o VTE within last 3 months
o High risk AF (valvular / non-valvular with CHA2DS2-VASc > 6)
o Mechanical heart valves
o Severe thrombophilia

1. Antithrombotic
   • Emergency
   - Withhold P2Y12i ± aspirin
   - Resume aspirin and P2Y12i at Day 3 (after completion of IV PPI)
   • Elective
   Depend on thrombotic risk:
   • PCI < 6 weeks: defer
   • PCI within 6w to 6m: defer if possible, otherwise as follows
   • PCI > 6m: withhold P2Y12 inhibitor 5 days before, resume after haemostasis, continue aspirin throughout
2. Anticoagulant
   • Emergency
   Resume warfarin / DOAC at Day 3 (after completion
   ± LMWH bridging only if high thrombotic risk
   - Elective
   Warfarin:
   • Withhold 5 days before OT of IV PPI)
   • ± Start LMWH bridging when INR subtherapeutic —> until
   12h before OT
   • Check INR 1 day before OT
   • Resume warfarin within 24h post-op ± LMWH bridging
   DOAC: bridging is NOT required
   • Withhold for 2 days generally (exception: 4 days if
   dabigatran + CrCl < 50)
   • Resume within 24h post-op

Question 10

Drug for hyperlipidaemia

Answer 10

Calculation of CVS risk: Framingham risk score, QRISK / QRISK2
Lipid lowering agents indicated if 10-year CVS risk >20%
Drugs for decrease cholesterol

1. Statins (HMG-CoA reductase inhibitors)
   - check LFT and TSH before initiating
   - decrease LDL+TG, increase HDL, decrease CVS risk
   - Efficacy: rule of 6 (2x dose results in 6% decrease LDL, but increased LFT)
   - Administered at night time, and avoid grapefruit juice within 4h
   S/E:
   • Myopathy*: stop if CK > 10xULN / CK >3x ULN + symptomatic
   • Deranged LFT (dose-related): stop if ALT > 3xULN
   • Headache, dyspepsia
   C/I: liver disease, pregnancy/ breastfeeding, hypothyroidism (­increased myopathy)
   Individual statins: in order of ascending potency
   • Simvastatin (Zocor): CYP3A4 metabolite, SLCO1B1 variant a/w ­risk
   of myopathy
   • Atorvastatin (Lipitor): CYP3A4 metabolite, long half-life, no renal
   adjustment
   • Rosuvastatin (Crestor): CYP2C9 metabolite, long half-life, renal adjustment if GFR < 60
2. Ezetimibe
   - decrease LDL
   - Add-on to statin on max dose (not used alone)
   Mechanism: NPC1L1 inhibitor —> decrease cholesterol absorption in small intestine
   S/E: elevated LFT, muscle pain
3. PCSK9 inhibitors (SC)
   - decrease LDL, decrease CVS risk
   - Proprotein convertase subtilisin/kexin type 9: degrade LDL-R in liver —> higher plasma LDL-C levels
   Examples: alirocumab (Praluent), evolocumab (Repatha)
   New drug: inclisiran (siRNA: decrease synthesis of PCSK9)
4. Bile acid sequestrant
   - Decrease LDL
   - Mechanism: form non-absorbable complex with bile acids in intestine —>
   sequestrant decrease enterohepatic circulation —> ­fecal loss of LDL bound to bile salt
   Example: cholestyramine (Questran), colestipol (Colestid)
5. Fibrates
   - decrease TG
   - Pharmacokinetic DDI with most statins
   • Gemfibrozil: cannot be used with statin (decrease statin metabolism —> increase risk of myopathy / rhabdomyolysis), C/I in CKD
   • Fenofibrate: relatively safe with statin, require renal adjustment
   S/E: elevated LFT, muscle pain
6. Bempedoic acid
   - decrease LDL
   - similar to statin
   - les MSK S/E
   - for statin intoleratable patient
7. Omega 3 Eicosapentaenoic acid
   - decrease TG