Antithrombotics

(Ref. include BSH2024)

intro

Warfarin

Half-Life:

• Warfarin: 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%

Genetic effects on Warfarin

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

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

Target INR

 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

 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 —> foetus more anticoagulated than the mother due to immature foetal liver enzymes

Discontinuing warfarin for pregnancy

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

First Trimester - Foetal Warfarin Syndrome (FWS)

• Occurs following warfarin exposure during gestational weeks 6-12

• Affects ~10% of foetuses exposed. Possible dose-response relationship.

• 6% congenital abnormalities

• Nasal hypoplasia —> neonatal respiratory distress

• Stipling of vertebrae & epiphyses —> hypoplasia of extremities

Second and third trimester risks

• Risk of foetal, placental and neonatal haemorrhage

• Other reported adverse outcomes from warfarin use in pregnancy

  • CNS – microcephaly, hydrocephalus, Dandy-Walker malformation

  • Eyes – blindness

  • Still birth, neonatal death, premature delivery

  • Others – scoliosis, developmental delay, deafness, CHD, seizures

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.

Unfractionated Heparin (UFH)

Note: Heparins are derived from porcine or bovine intestine.

Mechanism of Action:

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: 1-2 hours (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: 

• Anti-FXa - 0.3-.07iu/ml is typical therapeutic range - overall preferable to APTT ratio but not often not available 24/7 outside tertiary centres.

• APTT Ratio - Only use if pre-treatment APTT is normal. Many significant analytical variables such as reagents used, acquired AT deficiency, acquired elevated FVIII and fibrinogen.

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 increases with repeat exposure, rapid admin, and vasectomy

When to consider monitoring levels of fixed dose, non-vka anticoagulants

Renal impairment

When take interacting drug

Extremes of weight (<50 or >120 kg)

Spontaneous or traumatic haemorrhage

Following overdose or to assess compliance

Prior to emergency surgery, neuroaxial anaesthesia and elective surgery

GI disorders that may affect drug absorption

Use of non-standard doses

High risk pregnancy, such as presence of mechanical heart valve

Bridging from one AC to another

Trough levels for accumulation in the very elderly

Low Molecular Weight Heparin & Heparinoids

low molecular weight heparin (LMWH)

Half-life: 3-5 hours

Peak effect: 3-4 hours after administration

Excretion: Renal

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

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

Mechanism of Action:

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

Drug Monitoring

Anti-FXa activity correlates poorly with risk of bleeding/thrombosis and not shown to improve clinical outcomes

Consider monitoring for scenarios listed above

If performed, expected therapeutic Anti-FXa levels: 

• 4-6 hour peak = 0.5-1.0 iu/ml.

• Pre-dose trough = <0.3 iu/ml

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

Mechanism of action: Synthetic pentasaccharide, Xa inhibitor

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

Drug Monitoring:

Coag assay: Fondaparinux Anti-FXa

Therapeutic ranges not established but mean levels as follows:

• 2.5mg daily —> 3hr post dose peak = 0.4-0.5mg/l

• 7.5mg daily —> 3hr post dose peak = 1.2 - 1.26mg/l

Danaparoid

Mechanism of action: IV/SC Heparinoid, derived from a different fraction of porcine bioproducts

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

Excretion: Renal

Xa:IIa activity ratio: 20

Reversal: Plasmapheresis will remove danaparoid from circulation.

doac vs vka

DOAC Limitations

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

Limited lab assessment in emergencies

Limited used in chronic renal impairment

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

direct thrombin inhibitors

dabigatran

Half-life: 12-17 hours

Excretion: 80% Renal, 20% Hepatobiliary

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

Mechanism of action:

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

Effect on Routine Coagulation 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.

• FGN - may show spurious marked underestimation if reagents contain low levels of thrombin.

• Factor assays underestimated in presence of dabigatran if clot-based assays used.

• DRVVT false positives occur

Drug monitoring:

• Dilute TT (e.g.Haemclot) – a modified TT assay designed for dabigatran monitoring

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

• Chromogenic Anti-IIa assay also available

Expected Drug levels:

• For 150mg BD, expected peak = 0.184mg/l and trough = 0.09mg/l

Perioperative table

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

Drug levels to guide need for emergency drug reversal

• >50ng/ml may justify use of reversal agent

• <30ng/ml is considered safe for patients requiring urgent surgery or thrombolysis for stroke

Or if not available, a normal thrombin time excludes the presence of dabigatran.

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 prophylaxis: RE-NOVATE

Argatroban

Half-life: 50 minutes

Excretion: Rapid hepatic clearance via CYP450 3A4 enzyme

IV infusion, licensed for treatment of HIT

Drug Monitoring

• Monitor with dilute TT, ECT, ECA or Anti-FIIa

• If above not available, use APTT ratio (aim 1.5 – 3.0), 2 hrs after initiation.

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

Effect of Routine Coagulation 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 (PCC)

• Octaplex 30 units/kg (max 3000 units) / Beriplex 50 units/kg (max 5000 units)

• This is a supportive measure rather than a reversal / antidote to the DOAC effect

Andexanet alfa

• Recombinant modified human factor Xa decoy protein. ~£15,000 per treatment.

• ANNEXA-4 2019. Single arm trial. 1o outcomes were change in anti-Xa activity and physician-assessed haemostatic efficiency.

• Given as a bolus followed by infusion.

• Approved by NICE in 2021 solely for use in the setting of life-threatening GI bleeding (and only for rivaroxaban or apixaban. Edoxaban is not included in the NICE recommendation)

• ANNEXA-I. 530 adults with intracranial haemorrhage on rivaroxaban or apixaban. Andexanet vs Standard Care (87% of which got PCC). Study stopped early at interim analysis, due to superiority in primary outcome (‘effective haemostasis at one month’) vs usual care. No diff. in functional outcome or 30-day mortality. higher rate of thrombosis in andexanet arm. Written publication awaited (as of Oct 2023)

• As of 2023, there has been no direct comparison of andexanet vs PCC

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: 5-9 hours

Excretion: 66% Hepatobiliary, 33% Renal

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

Drug Monitoring:

• Rivaroxaban Anti-Xa

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

Pre-Op Table

Trials: ROCKET-AF, EINSTEIN, RECORD, SELECT-D

Apixaban

Appears to have lower rate of bleeding complications compared to other DOACs (e.g. this and this) with the important caveat that there are no head to head trials to draw this conclusion from.

Half-life: 8-15 hours

Excretion: 75% Hepatobiliary, 25% Renal

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

Drug Monitoring

• Apixaban Anti-FXa

• Plasma drug levels assays: For 5mg BD, expected peak = 0.128mg/l and trough = 0.05mg/l

Pre-Op Table

Trials: ARISTOTLE, Caravaggio, ADAM

Edoxaban

Lactose free (unlike other Xa inhibitors)

Half-life: 10-14 hours

Excretion: 50/50 Hepatobiliary/Renal

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

Drug monitoring: Edoxaban Anti-Xa

Pre-Op Table

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

Direct Factor XIa Inhibitors

Watch this space. Drugs in development

Direct Factor XIIa Inhibitors

Watch this space. Drugs in development

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