Antithrombotics

 

Warfarin

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

 

Bleeding requiring hospital admission (% per year):

 

Aspirin 2.6%                                            Warfarin + Aspirin 5.1%

Warfarin 4.3%                                        Warfarin + Clopidogrel 12.3%

Clopidogrel 4.6%                                  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

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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 à easy transfer across the placenta à AC effect in fetus

 

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

 

First trimester warfarin use

-        6% congenital abnormalities

-        Nasal hypoplasia à 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

 

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:

o   <3 months since VTE and surgery cannot be delayed

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

o   Mechanical heart valves except bileaflet aortic

o   <3 months since stroke/TIA

o   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:

o   Unprovoked VTE taking into account individual patient risks

o   See DASH Score

-        PE 3-4x more likely to recure than DVT and 2-4x more likely to be fatal is 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

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

Heparin-AT complexes of any molecular weight inhibit free FXa without the need for binding

 

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 is pre-treatment APTT is normal. Reagents highly variable

                                                      Alternatives: 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 à 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 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

 

DOAC Limitations:

-        Short half-life and lack of monitoring à 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 AHA/ACA and ESC/EACTS guidelines, BMJ editorial)

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

-        Native valve disease

o   CHA2DS2VASc ³2 plus aortic valve disease, tricuspid disease or MR

§  Can be considered for a DOAC

o   Moderate to severe mitral stenosis

§  Continue to use VKA only

-        Bioprostheses

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

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

-        Mechanical prostheses

o   Continue to use VKA only

ideal AC.png

 

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 à 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 à 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.

 

Perioperative:

 

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)

 

Antiplatelets

 

Aspirin

-        Half-life: 3 hours

-        Mechanism:

o   Irreversible binding to cyclooxygenase (COX1)

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

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

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

-        Perioperative

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

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

o   Emergency surgery with high bleed risk

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

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

 

Clopidogrel

-        Half-life: 7-8 hours

-        Mechanism:

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

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

-        Metabolised by CYP2C19

o   Defective genotypes vary by ethnicity and can cause clopidogrel refractoriness

-        Perioperative

o   Emergency surgery with high bleed risk

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

o   Stop day -7 prior to neuroaxial procedures

 

Dual Antiplatelet Therapy

-        Duration

o   Minimum 4 weeks post bare metal

o   Minimum 12 months post drug-eluting

o   <12 months for newer bioabsorbable drug-eluting

-        Perioperative:

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

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

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

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

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

o   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:

o   Binds to P2Y12 preventing ADP-induced plat aggregation

-        Prodrug

o   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

-        Mechanisms:

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

o   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 à longer half-life

 

Tenecteplase

-        Modified t-PA à 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

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

o   Also binds to free plasmin

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