Antithrombotics

 

Warfarin

warfarin.png

Half-Life: 35-45 hours (Acenocoumarol 10 hours, Phenindione 8 hours)

 

Bleeding requiring hospital admission (% per year):

  • Aspirin 2.6%  

  • Warfarin 4.3% 

  • Clopidogrel 4.6% 

  • Warfarin + Aspirin 5.1%

  • Warfarin + Clopidogrel 12.3%

  • All 3 taken together 12%

CYP2C9 mutation: Increases warfarin half-life and leads to over-anticoagulation

 

VKORC1 gene: Decreases warfarin requirements and leads to over-anticoagulation

 

Target INR

inr.png

 

Management of High INR

 

Major Bleeding                                     PCC + 5mg Vit K IV

Non-Major Bleeding                             1-3mg Vit K IV & investigate source of bleeding

INR >8 not bleeding                             1-5mg Vit K PO

INR 5-8, not bleeding                           Withold 2 doses and reduce maintenance dose

 

What constitutes poor INR Control?

 

Any one of:

  • Two INR values <1.5 in last 6 months

  • Two INR values >5, or One INR Value >8 in the last 6 months

  • Time in Therapeutic Range (TTR) less than 65%

 

CYP450 Drugs

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 Warfarin Teratogenicity (FWS)

 

Pathophysiology

  • Osteocalcin carboxylation for bone formation is a vitamin K dependent process

  • Warfarin has low molecular weight —> easy transfer across the placenta —> AC effect in fetus

Discontinuing warfarin for pregnancy

  • Take pregnancy test at first day of missed period, with goal of stopping warfarin prior to 6 weeks.

 

Risks of First trimester warfarin use

  • 6% congenital abnormalities

  • Nasal hypoplasia —> neonatal respiratory distress

  • Stipling of vertebrae & epiphyses à hypoplasia of extremities

 

Second and third trimesters

  • Overall, 50% of babies have a severe disability

  • CNS – microcephaly, hydrocephalus, Dandy-Walker malformation

  • Eyes – blindness

  • Still birth, neonatal death, premature delivery

  • Others – scoliosis 17%, developmental delay 30%, deafness 12%, CHD 8%, seziures

Breastfeeding

  • Warfarin is safe in breast feeding

 

Warfarin & Anti-platelets

 

Already on anti-platelet and need to start warfarin

  • If on single anti-platelet <12 months after ACS should continue (consider using aspirin >clopidogrel)

  • If on DAPT, discuss with cardiology ?shorter duration

  • If on anti-platelet for 1o prophylaxis, PVD, prev stroke or stable IHD then stop the anti-platelet

 

Already on warfarin and need to start anti-platelets

  • If requires coronary stent, consider using bare metal stent

  • If PCI not required, give DAPT for 4 weeks then stop cloidogrel

  • Review the indication for warfarin and assess risk/benefit

 

Perioperative Management

 

Elective surgery

  • Stop 5 days prior to surgery, check INR day -1, give vit k if INR >1.5, check INR day of surgery

  • Restart at normal dose, or 2 days of double dose, on the evening of surgery

 

Bridging

Meta-analysis found increased bleeding rate with no reduction in thrombotic risk.

However, consider if:

  • <3 months since VTE and surgery cannot be delayed

  • High risk VTE patient – e.g. prev VTE whilst on anticoagulation

  • Mechanical heart valves except bileaflet aortic

  • <3 months since stroke/TIA

  • History of stroke/TIA plus 3 of: CCF, uncontrolled HTN, >75yo, Diabetes

Post-op - Use prophylactic dose, restart bridging at 48 hours.

 

Patient Self-Test and Self-Management

 

Available devices – CoaguCheck, Protime, INRatio

Quality Assurance

  • Internal QA – electronic, on-board (control integrated onto test strip), liquid control with INR of 2-4

  • External QA – every 6 months, test same sample on patient device and anticoag clinic equipment

 

Clinical outcomes – Reduced mortality and VTE. Unchanged bleeding rate. Trial included 99 patients >85 y.o.

Patient selection – Motivated patient expected to need AC for >1 year and successfully competes training.

Training consists of Theory and Practical aspects.

 

Wells Score for PE

 

Clinical signs and symptoms of DVT                                                                  +3

PE is No. 1 diagnosis or equally likely                                                                +3

HR >100                                                                                                              +1.5

3 days immobile or surgery in last 4 weeks                                                         +1.5

Prev PE or DVT                                                                                                   +1.5

Haemoptysis                                                                                                        +1

Active Malignancy or treatment for malignancy in last 6 months                         +1

 

0-4 (12% incidence of PE) = Unlikely. Check D-dimer. If negative no further action.

5+                                       = Likely. Perform CTPA

 

Duration of Treatment for VTE

 

Initial

  • 3 months for PE and proximal DVT

  • 6 weeks for calf-vein DVT (or no treatment)

  • 6 months LMWH (?or edoxaban) for cancer-associated VTE

 

Continued beyond 3 months:

  • Not required for VTE: provoked by surgery, non-surgical transient risks or confined to the calf

  • Consider long-term treatment:

    • Unprovoked VTE taking into account individual patient risks

    • See DASH Score

  • PE 3-4x more likely to recur than DVT and 2-4x more likely to be fatal if symptomatic compared to a symptomatic DVT

 

DASH Score

 

D-dimer abnormal 1 months after stopping anticoagulation                  +2

Age under 50 years old                                                                          +1

Male Sex                                                                                                +1

Hormone use at time of VTE                                                                  -2

 

0 = 2.4% annual risk of recurrence

1 = 3.9%                                                            1 or less: consider discontinuing

2 = 6.3%                                                            2 or more: consider LT anticoagulation

3 = 10.8%

4 = 20%

 

N.B. Score is based on meta-analysis of prev studies (warfarin only). It is not externally validated. Designed for use in stable patients with a first unprovoked VTE. Five-year recurrence of unprovoked VTE for all comers is 25-30%.

 

HAS-BLED (2010)

Predicts 1 year risk of major bleeding after starting anticoagulation. One point each for:

  • Hypertension

  • Abnormal liver

  • (& Abnormal renal function)

  • Stroke history

  • Bleeding predisposition

  • Labile INR

  • Elderly

  • Drugs that also risk bleeding (aspirin etc)

  • (& Alcohol)

 

Score 0-1 = Low risk (1-3%)

Score 2 = Moderate risk (4%)

Score 3+ = High risk (>5%), consider alternatives to anticoagulation.

 

Unfractionated Heparin

 

heparin.png

Derived from pig intestine.

 

Approx 1/3 of heparin molecules carry a high affinity polysaccharide that binds to Antithrombin (AT).

High Molecular Weight (HMW) Heparin-AT complexes then bind to thrombin (Why only the HMW chains? Because the heparin chain must be of sufficient length (molecular weight) to bridge between AT and thrombin).

Heparin-AT-Thrombin complex inactivates thrombin, preventing fibrin formation and inhibiting thrombin-induced activation of platelets, FV and FVIII.

Non-complexed heparin molecules and Heparin-AT complexes of any molecular weight can inhibit free FXa.

 

Half-life: 45-90 min (Variable due to binding to other positively charged plasma proteins & surfaces)

Molecular weight: 3,000 – 30,000 Da

Xa:IIa activity ratio: 1

Drug monitoring:  Only use APTT ratio if pre-treatment APTT is normal. Reagents highly variable. Alternatives include: Anti-Xa, ACT and TEG

 

Emergency reversal:

  • Protamine sulphate

  • Dose: 1mg neutralizes 80-100 units of heparin, given IV over 5 minutes. Max dose 50mg.

  • Calculate dose based on previous 2 hours exposure. E.g. IV UFH 1250u/hour —> Give 25mg protamine

  • Short half-life, repeat doses may be required

  • Forms a stable, inactive salt with the heparin

  • Derived from fish sperm --> SE: Anaphylaxis. Risk increase with repeat exposure, rapid admin, and vasectomy

 

Low Molecular Weight Heparin & Heparinoids

 

Half-life: Approx 4 hours

Molecular weight: 1,000 – 10,000 Da (Mean: 5000)

Xa:IIa activity ratio: 2.5 – 4 (depending on preparation)

Target therapeutic Anti-Xa level: 

  • 4-6 hour peak = 0.5-1.0 iu/ml.

  • Pre-dose trough = <0.3 iu/ml

 

Produced from heparin by chemical or enzyme depolymerisation --> fragments approx. 1/3 the size of heparin

Results in reduced ability to bind thrombin for reasons given above

Reduced binding to other plasma proteins

 

Benefits Vs UFH:

  • More predictable dose-response relationship

  • Longer half-life

  • Reduced risk of HIT

 

Emergency reversal

  • Protamine reverse 60% of LMWH in healthy vounteers

  • Give only if last LMWH dose within 8 hours of bleeding event

  • Dose: 1mg per 100 Anti-Xa units of LMWH. Repeat dose with 0.5mg per 100 units if required.

  • Consider rFVIIa if life-threatening bleeding despite the above and timeframe consistent with ongoing LMWH effect

 

Fondaparinux

Half-life: 17-21 hours

Synthetic pentasaccharide, Xa inhibitor

rFVIIa in life-threatening bleeding (causes partial correction in healthy volunteers

 

Danaparoid

Half-life: 25 hours (Xa), 7 hours (Thrombin)

Xa:IIa activity ratio: 20

Plasmapheresis will remove danaparoid from circulation.

 

DOAC vs VKA Overview

ideal AC.png

DOAC Limitations

Short half-life and lack of monitoring —> potential compliance issues

Limited lab assessment in emergencies

Cost

Limited used in chronic renal impairment

No antidote yet available for Anti-Xa inhibitors

 

When to measure DOAC levels

Spontaneous or traumatic haemorrhage

Following overdose or to assess compliance

When take interacting drug

Emergency surgery, neuroaxial anaesthesia and elective surgery

Renal impairment

Bridging from one AC to another

Extremes of weight

Trough levels for accumulation in the very elderly

 

Warfarin still best for:

Mechanical Heart valves

Mitral Stenosis

Antiphospholipid syndrome

Long-term stable INR and patient choice

Poor renal function

History of GI bleed

Questionable compliance

Drug interactions that prevent use of DOAC

 

AC in ‘Non-Valvular’ AF (2017, 2016)

DOAC trials varied in how broad their definition of NVAF was in the exclusion criteria

Native valve disease

  • CHA2DS2VASc score 2 or more, plus aortic valve disease, tricuspid disease or MR

    • Can be considered for a DOAC

  • Moderate to severe mitral stenosis

    • Continue to use VKA only

Bioprostheses

  • Can be considered for DOAC after the third month since implantation (ESC)

  • (N.B. for TAVI patients without AF, dual antiplatelets are used, not AC. Trials underway for DOACs)

Mechanical prostheses

  • Continue to use VKA only

 

Dabigatran Etexilate

 

Half-life: 13-18 hours (see below)

Dose: 150mg BD (110mg BD if age >80 or >75 plus high bleeding risk)

 

Mechanism:

Pro-drug --> absorption is pH sensitive --> reduced absorption with use of PPI

Reversible, high affinity binding to thrombin

Direct Thrombin Inhibitor is a reference to heparin, i.e. anticoagulant effect is independent of antithrombin

 

Coag Assays:

  • PT normal in 30% of patients

  • APTT usually prolonged – rate of prolongation flattens out as drug concentration increases —> insensitive

  • TT very sensitive – at high concentration will be prolonged beyond a detectable time. If the TT is normal, patient is not taking dabigatran.

  • Haemclot Assay – a modified TT assay designed for dabigatran monitoring

  • Chromogenic Anti-IIa assay also available

  • ECT – directly assays thrombin activity in plasma —> linear dose-response to therapeutic doses of dabigatran

 

Drug levels: For 150mg BD, expected peak = 0.184mg/l and trough = 0.09mg/l

 

Factor assays and FGN all underestimated in presence of dabigatran if clot-based assays used.

DRVVT false positives occur

 

Perioperative table

dabigatran.png

80% renally excreted, independent of CYP450 enzymes

Re-start at full dose 6-12 hours after minor procedure, or 48-72 hours after major surgery.

 

Drug Interactions

 

P-gp pathway affects absorption of the exetilate pro-drug

 

Inhibitors increase plasma drug concentrations

  • Azoles, amiodarone, diltiazem, tacrolimus

Inducers reduce plasma drug concentrations

  • Rifampicin, St Johns Wort, Carbamazepine

 

Reversal

 

Activated charcoal if last dose within 2 hours prevents further absorption

Idarucizumab

  • Monoclonal antibody fragment. Rapid clearance. Licensed 2016.

  • Dose: 5g, given as 2x 2.5g bolus infusions within 15 minutes of each other.

 

Trials (“RE-“ studies)

 

AF: RE-LY

VTE Treatment: RE-COVER & RE-COVER2

VTE 2o prevention: RE-SOLVE & RE-MEDY

VTE LT 2o prevention: RE-SONATE

ACS: RE-DEEM

TKR prophylaxis: RE-MODEL & RE-MOBILISE

THR propjhylaxis: RE-NOVATE

 

Other Direct Thrombin Inhibitors

 

Argatroban

Half-life: 50 minutes

IV infusion, licensed for treatment of HIT

Monitor with APTT ratio (aim 1.5 – 3.0)

Rapid hepatic clearance via CYP450 3A4 enzyme

 

Hirudin

Natural peptide from Hirudo medicinalis (medical leech)

10% of patients develop anti-hirudin antibodies à actually increases half-life

Therapeutic drug concentration: 0.5-2.5 microg/ml

Monitoring: APTT, ECT, TT, ELISA, Chromogenic, Haemolclot

 

Lepirudin

Half-life: 1.3 hours

Continuous IV/SC infusion

Recombinant hirudin

 

Bivalirudin

Half-life: 25 minutes

Short, synthetic peptide. Binds to circulating and clot-bound thrombin

Reversible as thrombin slowly cleaves the drug (accounts for 80% of drug clearance. 20% renal)

Monitor with ACT during cardiac surgery

 

Factor Xa Inhibitors

 

Coag Assays:

  • PT usually more prolonged than APTT (Rivarox > Apix) but both may be normal

  • Monitor with product-specific Anti-Xa chromogenic assay

  • TT, FGN and D-dimer unaffected

  • DRVVT false positives

 

Drug Interactions:

  • CYP3A4 and P-gp inhibitors both increase rivaroxaban concentrations

    • Ketaconazole, Ritonavir

 

Reversal:

Prothrombin complex concentrate – Octaplex 30 units/kg (max 3000 units)

Andexanet alfa – Recombinant modified human factor Xa decoy protein. Bolus followed by infusion. Not yet available (as of April 2019)

 

Perioperative:

Pre-op: See table for each drug

Post-op: Re-start at full dose 6-12 hours after minor procedure, or 48-72 hours after major surgery.

 

Rivaroxaban

 

Half-life: 7-11 hours

Dose: For treatment of VTE = 15mg BD for 21 days, then 20mg OD

Expected peak PT ratio = 1.3-16 and trough = normal

rivarox.png

Trials: ROCKET-AF, EINSTEIN & RECORD

 

Apixaban

 

Half-life: 9-14 hours

Dose for treatment of VTE: 10mg BD for 7 days, then 5mg BD, then 2.5mg BD after 6 months if ongoing AC

For 5mg BD, expected peak = 0.128mg/l and trough = 0.05mg/l

apix.png

Trials: ARISTOTLE

 

Edoxaban

 

Half-life: 10-14 hours

Dose for treatment of VTE: 5 days LMWH, followed by 60mg OD (30mg for CrCl 15-50, wt <60kg, interacting meds)

edox.png

Trials: Hokusai-VTE (Non-inferiority to dalteparin for treatment of VTE in cancer)

 

Antiplatelet Agents

 

Aspirin

Half-life: 3 hours

Mechanism:

  • Irreversible binding to cyclooxygenase (COX1)

  • --> prevents thromboxane A2 generation and so prevents plt aggregation

  • As platelets are non-nucleated they cannot produce new COX1

  • --> drug effect 7-10 days (lifespan of platelets)

Perioperative

  • Associated with 1.5-fold increase in post-op bleeding but not in the severity of the bleed

  • Continue through most surgery – exceptions: neuro and prostate surgeries

  • Management of Emergency surgery with high bleed risk:

    • Consider 2 units platelets >2 hours since last dose (4-5 hours if enteric coated)

    • (aspirin-inactivated platelets can still be recruited by thromboxane generated in the transfused platelets)

 

Clopidogrel

Half-life: 7-8 hours

Mechanism:

  • Binds to P2Y12 --> preventing ADP-induced plt aggregation

  • (Normal action of ADP is to bind to P2Y12 and P2Y1, in turn activating Gp IIb/IIIa)

Metabolised by CYP2C19

  • Defective genotypes vary by ethnicity and can cause clopidogrel refractoriness

Perioperative

  • Emergency surgery with high bleed risk

  • Consider 2 unit platelets >12-24 hours since last dose (even less evidence for benefit here)

Stop day -7 prior to neuroaxial procedures

 

Dual Antiplatelet Therapy

Duration

  • Minimum 4 weeks post bare metal

  • Minimum 12 months post drug-eluting

  • <12 months for newer bioabsorbable drug-eluting

Perioperative:

  • 4-8% of patients need surgery within 12 months of starting DAPT

  • Hold clopidogrel, continue aspirin for most low risk procedures, inc neuroaxial ones

  • High bleeding risk, also omit aspirin day -3 to day +7

  • If high risk surgery cannot be deferred in a patient with recent ACS

    • Continue aspirin, stop clopidogrel/ticagrelor day -5 or prasugrel day -7

  • For high thrombotic + high bleed risk CABG patients

    • Stop antiplatelets, consider parenteral GpIIb/IIIa inhibitor day -3 to 4-6 hours post op

 

Prasugrel

Thienopyridine drug class (same as clopidogrel)

Mechanism:

  • Binds to P2Y12 preventing ADP-induced platelet aggregation

Prodrug

  • Converted to active drug by CYP450. Metabolised more efficiently than clopidogrel resulting in a greater antiplatelet effect.

 

Dipyridamole

Alpha half-life: 40 min, Beta half-life: 10 hours

Mechanism:

  • Inhibits phosphodiesterase --> accumulation of cAMP --> Intracellular Ca2+ falls --> blocks response to ADP --> reduced thromboxane A2 production preventing plt aggregation.

  • Also prevents cellular uptake of adenosine

 

GPIIb/IIIa Inhibitors

 

Abciximab

Human-murine antibody to GpIIb/IIIa, close to FGN binding site

Short half-life but effect lasts 90-120 hours

SE: Thrombocytopenia in 0.5%. Onset in hours to days. Risk increases with repeated exposure

 

Tirofibran

Half-life 2 hours

Thrombocytopenia in 0.5%

 

Eptifibatide

Half-life 2.5 hours

 

Significant Others

 

Ticagrelor

Reversible binding of ADP receptors

50-60% inhibition of ADP-induced plt aggregation (>clopidogrel)

Half-life: 6-13 hours

 

Cangrelor

IV reversible ADP P2Y12 inhibitor

Continuous infusion

Half-life 90 min

Plt return to normal after 60 minutes

 

Vorapaxar & Atopaxar

Reversible PAR-1 inhibitors

PAR1 and PAR4 receptors are activated by thrombin leading to plt aggregation.

 

Fibrinolytics

 

Streptokinase

IV infusion

Enzyme produced by Group C haemolytic streptococcus

Binds to plasminogen activating it to plasmin independently of fibrin

Hyperfibrinolytic effect lasts a few hours after stopping infusion, but TT remains prolonged for 24 hours.

 

Tissue Plasminogen Activator (t-PA)

Human recombinant protein

Causes fibrinolysis only at the site of vascular injury

 

Reteplase

Non-glycosylated t-PA —> longer half-life

 

Tenecteplase

Modified t-PA —> longer half-life

 

Urokinase

Half-life: 12 minutes

IV infusion

Obtained from human neonatal kidney cells

 

Emergency reversal of Fibrinolytics

For cerebral bleeding within 48 hours of administration

FFP + TXA +/- FGN replacement

 

N.B. Tranexamic Acid (not an anticoagulant obviously)

Synthetic lysine analogue

Half-life: 3 hours

Urinary excretion

Mechanism

  • Competitively binds to the high affinity lysine binding site of plasminogen --> preventing its conversion to active plasmin

  • Also binds to free plasmin

  • --> prevents binding of plasmin/plasminogen to fibrin clot or fibrin monomers.