Ideal Anticoagulant1. High efficacy-to-safety index2. Fixed dosing3. No need for laboratory monitoring4. Orally available5. Rapid onset of action6. Availability of a safe antidote7. Freedom from non-anticoagulant side effects8. Minimal interaction with other drugs / foods9. No accumulation in renal (+/- hepatic) failure

WarfarinMechanismInhibit vitamin K reductaseExtrinsic pathy of cogulation cascadeHalf life is40 hours ( 2-5 days)Warfarin takes 72 hours to be effective

Pharmakineticsa) absorbed readily by GIb) metabolised in liverc) excreted in kidney

Side Effects of WarfarinAlopeciaRashNauseaDiarrheaEffect in uterus ( week 8-12)

Interaction with Fooda) Alcoholb) Vitamin due to Vit K containingc) Diet due to vit K containin

AntidoteAlways given more than 1. Never monotherapy durign urgent reversal

a) vit K ( oral – 24 hr, IV 6-8 hr)b) FFP

a. Typical dose 10-15 ml/kgb. Problems if cardiac / renal failure with volume overloadc. Need to know blood groupd. Needs to be thawed (half hour) and takes a couple of hours to

administere. Useful if serious bleeding but not life/limb or eyesight threatening

bleedingf. Give with vitamin K

c) PCC ( octaplex)a. Use in lifethreatening or limb thretening hemorrhage ( intracranial

hemorrhage)b. Octaplex = plasma derived PCC containing clotting factors 10, 9, 7, 2c. Given with vitamin K + stop warfarind. Effective in 10-20 mins

Prior to reversing must considera) bleeding severityb) indicatio or anticoagc) degree and speed of reversal

Contraindication for Warfarin

Indication for warfarin

( tissue factor)

Factors associated with increased bleeding risk– Poor INR control– Hepatic or renal disease– EtOH abuse– Malignancy– Anaemia– Prior bleeding history– Age– Excessive fall risk– Prior history of stroke

CHADS2-VAS Score to Estimate need for Warfarin in Patient with AF

Managementa) Surgery

a. Stop warfarin 7 days preop ( 4 days if high risk thrombosis patient ie mechniacal mitral valve or recent VTE)

b. Bridge by LMWH 4 days preop at 1 mg/ kg when INR < 2c. Make sure last dose is 24 hours before surgeryd. Eliminate on morning of surgery dosee. NOTE: mitral valve higher risk of thrombosis than aortic

b) Post surgerya. Restart at the evenign with haparin 1 mg/ kg + warfarin until INR > 2b. Else restart at da y1 until INR > 2c. Use IVC filter if anticoagulation is contraindicated postoperatively ( if

recent VTE < 1 month ago)d.

c) Starting INRa. Must overlap using heparinb. During initial start of first 5 days of warfarin, there is increase risk of

thrombosis due to i. Protein C deficiency

ii. Clotting factor 7 deficiency cause thromboticd) Initiating warfarin

a. Baseline testsi. FBC, LFT, INR, citrate filled to top to avoid false data

ii. INR > 1.4, must find causeiii. Platelet < 70 or deranged LFT , contact hematology

iv.

v. Oral anticoagulant pack : yellow book,patient info, patient alert card

b. Regimeni. Fast outpatient induction

1. 5mg for 4 days, INR D5 + 62. Not suitable for elderly3. For young fit patient

ii. Fast outpatient1. 10 mg on D1 + D2, INR D3, d5, d62. suitable for elderly people with PE due to prone to

bleedingiii. Slow induction

1. 3 mg + INR d72. For AF only3. Not for frail patient on amiodarone, impaired LFT

iv. adjustment is normally 0.5- 1.o mgv. At diischarge

1. TTO2. Yellow book3. Counsel4. Refer to anticoag team

HEPARINWeight adjusted dose

No need for routine monitoring (except in pregnancy, infancy, renal failure and morbid obesity)Antidote: protamine sulphate

Recommendations1. LMWH given for at least 6 months is also the preferred approach for long-

term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2 to 3 are acceptable for long-term therapy when LMWH is not available.

2. After 6 months, indefinite anticoagulant therapy should be considered for selected patients with active cancer, such as those with metastatic disease and those receiving chemotherapy. This recommendation is based on Panel consensus in the absence of clinical trials data.

Adverse Effectsa) osteoporosis

Contraindications to heparinSimilar to warfarin except it can be used in pregnancy

Heparin pharmacokinetics• LMWH

– Rapidly and completed absorbed via S/C injection. Peak activity 1-4 hours post dose.

– Renal elimination primarily (half life 4-5 hours) although small degree of hepatic metabolism

• IV heparin– Elimination as above– Half life 30 mins – 2 hours

Non Bleeding Adverse Effects of heparin• Allergic• HITTS (next slide)• Local skin reaction• Hyperkalaemia• Osteoporosis

Heparin induced thrombocytopenia and thrombosis syndrome (HITTS)a. The consequence is skin necrosis due to thrombocytopenia

Dosing enoxaparin• Therapeutic – adjusted according to weight (and renal function)• Depends on indication

1. Treatment of VTE / peripheral vascular surgery2. Treatment of unstable angina and non-Q-wave myocardial infarction

3. Treatment of acute ST-segment elevation myocardial infarction4. Prevention of extracorporeal thrombus formation during

haemodialysisDose adjustments• A dose adjustment is required for patients with severe renal impairment

(creatinine clearance < 30 ml/min), according to the following tables, since enoxaparin exposure is significantly increased in this patient population:

• Dosage adjustments for therapeutic dosage ranges

Standard dosing Severe renal impairment

1 mg/kg SC twice daily 1 mg/kg SC once daily

1.5 mg/kg SC once daily 1 mg/kg SC once daily

30mg-single IV bolus plus a 1mg/kg SC dose followed by 1mg/kg twice daily.

30mg-single IV bolus plus a 1mg/kg SC dose followed by 1mg/kg once daily.

75years of age (for acute STEMI indication only)

0.75mg/kg SC twice daily without initial bolus.

1mg/kg SC once daily without initial bolus.

Dosage adjustments for prophylactic dosage rangesStandard dosing Severe renal impairment40 mg once daily 20 mg once daily

Anti Xa monitoring

Renal Failure• New onset renal failure will lead to accumulation of novel anticoagulants.• Dabigatran dose reduction should be considered if eGFR 30-50 ml/min and is

contraindicated if eGFR <30 ml/min• Rivaroxaban should be dose reduced if eGFR <49 ml/min and is

contraindicated if <15 ml/min.

Novel Anticoagulants and Clotting Tests• NB There is no rapidly available INR equivalent. Prolongation of standard

clotting times do not correlate with level of circulating anticoagulant • Interpretation of coagulation assay results should consider time of

dabigatran administration relative to time of blood sampling – Dabigatran

• The APTT ratio is modestly prolonged by Dabigatran (the PT hardly at all)

– Rivaroxaban• The Prothrombin Time (PT) is the most sensitive routine test

to Rivaroxaban but should be considered qualitative only. • The APTT is more modestly affected. The TT will be normal.

Antidote:a) rivaraxaban – PCCb) dabigatran – reversal agent VIIa and FEIBA