Introduction

Anticoagulation (“blood-thinning”) is a therapeutic mechanism used to reduce the risk of blood clots, or to treat already established blood clots for various indications, including; venous thromboembolism (for prevent and for treatment), atrial fibrillation, after heart valve replacement, and after acute myocardial infarction.

The drugs used for anticoagulation typically target different aspects of the clotting cascade, to alter the process by which clots form. Clots are in a constant state of flux – of being broken down, and new clot forming. By slowing down the rate of new clot formation, but leaving the rate of clot break-down unaltered, anticoagulation can prevent the formation of clots, and speed-up the break-down of larger clots. Anticoagulants do not actively cause breakdown of clots – this can be achieved by another class of drugs through a process called thrombolysis. 

• Thrombolsys is typically reserved for life-sthreating situations – such as a large pulmonary embolism causing harm-dynamic instability, or large ischaemic stroke or myocardial infarction. Thrombolysis carries significant risks of bleeding (which can be fatal). The use of thrombolysis in MI and stroke is in decline, as intervention procedures such as PCI in MI and “clot retrieval” ins stroke have become more widely available.

There are typically three types of medication used for anticoagulation:

• Heparin – of which there are severeal types with different uses – e.g. unfractionated heparin, clexane
• NOACs – novel oral anticoagulants
  • The nomenclature for this can be confusing!
  • Newer guidelines no say that NOAC stands for non-vitamin K oral anticoagulant
  • Some people now refer to them as DOACs – direct oral anticoagulants
• Warfarin

NOACs are largely superseding the use of warfarin for many indications, as they are much more convenient for patients. However, they are not easily reversible in case of massive bleed. Heparins have a narrower range of indications, but are still used in many specific situations.

NOACs

Examples: Apixaban, dabigatran, rivaroxaban

There are two basic mechanisms for NOACS:

• Dabigatran is a thrombin inhibitor (NB Dabiga-T-ran inhibits T-rhombin)
• Apixaban and rivaroxaban are factor Xa inhibitors (Api-Xa-ban, rivaro-Xa-ban)

Indications

• Treatment of newly diagnosed DVT or PE
  • Unlike with warfarin, covering with heparin for first few days is not required
• Atrial fibrillation where CHA₂DS₂-VASc score suggests the need for anticoagulation
• Prevention of VTE after surgery

Particularly for treatment of VTE and AF NOACs have mostly superseded the use of warfarin due to ease of use for the patient.

Monitoring

• Unlike warfarin, there is no defined way of monitoring the effects of NOACs

Contraindications

• Valvular heart disease or mechanical heart valve
• Renal failure (CrCl <30)
• Liver failure
• Active bleeding or history of bleeding disorder
• Pregnancy or breast feeding

Reversal

• Reversal is not straight-forward – unlike for warfarin
• A reversal agent exists for dabigatran – Idracizumab – but its efficacy is not well established
• No reversal agents exists for rivaroxaban or apixaban. Academic studies have shown that prothrombin complex (prothrombinex) can normalise prothrombin time, but it is not routine clinical practice to use it
• Dialysis may help to remove active drug from the blood and normalise clotting
• Guidelines for management of bleeding in patients taking NOACs suggest:
  • Withhold further doses
  • Send coagulation profile
  • If ingested in last two hours – use activated charcoal – especially in cases of overdose
  • Discuss with haematologist on call

Advantages of NOACs vs Warfarin

• Do not require monitoring
• Standardised dosing
• Onset of action within 3 hours – and so concurrent use of heparin as is indicated with warfarin for the first few days – is not required
• Less likely to interact with other drugs and pre-existing conditions than warfarin
• (Unproven) – possibly lower incidence of life-threatening bleeding events

Disadvantages of NOACs vs Warfarin

• Reversal is not possible with some agents, and difficult with others
• Narrower range of indications (not suitable in case of heart valves, or valvular heart disease)
• (Unproven) – possibly higher risk of GI bleeding

Warfarin

Introduction

Warfarin is a vitamin K antagonist. It is very useful, because unlike heparins, it can be taken orally.

• Remember that the extrinsic pathway produces a bit of fibrin quickly whilst the intrinsic pathway produces large amounts but takes a while to get going. Thus the PT, which is a measurement of how quickly a small clot forms, relies on the extrinsic pathway.
• INR – the internal normalised ratio. This is basically a comparison of the patients clotting ability compared to the ‘average’ of the population. It is a ratio of the patient’s PT (prothrombin time)to that of the average PT – and as a result, this test only looks at the extrinsic clotting pathway. You can use it to look at liver function, warfarin dose and vitamin K status.

 

The ISI is a different value for different drugs, but is normally between 1.0 and 2.0.
The normal INR value is between 0.9 and 1.3. When someone is on warfarin therapy, the target is usually between 2-4 but may vary for individuals. i.e. this basically means the target when on warfarin therapy is to have a prothrombin time 2-4x greater than that of the ‘average’ person
Patients on warfarin (and other vit K antagonists) need to have individualised doses, and this means the treatment in both inconvenient and has a low margin of safety. 

Mechanism

By preventing the activation of vitamin K, warfarin reduces the production of factors II, VII, IX and X.

Pharmacokinetics

• Absorbed rapidly and completely from the gut
• Binds well to albumin
• Peak time of action is about 48 hours after administration, but peak concentration in the blood is about an hour after administration
  • For immediate effect anti-coagulation, you have to give HEPARIN for the first few days of warfarin therapy
• The effect on prothrombin time is initially seen after 12-16 hours, and lasts approximately 4-5 days.
• Half life is very variable, but is on average about 40 hours
• It crosses the placenta, and is teratogenic – thus it should not be given in pregnancy at all! In the early stages it can causes defects, and in the later stages it can cause haemorrhages in the foetus itself – usually intracranial haemorrhage.
• It is metabolised by the cytochrome P450 system – thus it interacts with many drugs – making administration and monitoring of dosage more difficult.
  • Warfarin is monitored by using the prothrombin time (PT), which is expressed as the INR. The dose of warfarin is adjusted to give an INR of 2-4

Unwanted effects

• Haemorrhage – this is especially common to the bowel and brain. This can be counteracted by the administration of vitamin K, or giving fresh plasma containing clotting factors.
• Teratogenicity (meaning it causes birth defects)
• Necrosis of soft tissues – this occurs mainly to tissues in the buttock and breast and is a result of thrombosis in venules. It generally occurs shortly after administration, and is a result of inhibition of synthesis of protein C – which is another effect of warfarin, and which happens more quickly than the inhibition of activation of vit K. thus for a short time after the initial administration, patients are in a hypercoagulant state. This is rare, but serious. To combat this issue, treatment is usually started with heparin, before treatment with warfarin begins.

Interactions with warfarin

Things that potentiate the effects of warfarin

• Liver disease – this reduces the number of clotting factors produced (2,7,9,10 are affected)
• High metabolic rate; e.g. thyrotoxicosis and fever – as these increase the rate at which clotting factors are degraded

• Agents that inhibit hepatic metabolism – such as many antifungals, and other specific drugs, including cimetidine, ciprofloxacin, chloramphenicol, co-trimoxazole, imipramine, metronidazole and amiodarone.
• Drugs that inhibit platelet function – Aspirin and other NSAIDs – as these inhibit platelet thromboxane synthesis. Also some antibiotics, including moxalactam and carbenicillin
• Drugs that displace warfarin from its binding site on albumin – e.g. NSAIDs and chloral hydrate – as this will increase the concentration of warfarin in plasma
• Drugs that inhibits synthesis of vitamin K – such as the cephalosporins

Things that decrease the effects of warfarin

• Pregnancy
• Hypothyroidism – where there is reduced metabolic rate, and thus reduced breakdown of coagulation factors

• Vitamin K – it is found in some vitamin preparations and some form of parenteral feeding
• Drugs that induce hepatic cytochrome P450 enzymes – this increases the degredation of warfarin. Examples include rifampicin, carbamazepine, barbiturates and griseofulvin

Therapy regimens

• The initial PT will be measured and an individual dose will be calculated. In an emergency situation, this step may be skipped.
• Patients will usually take an initial dose of 5-10mg. Then they will have subsequent doses of 5mg. Often at day * in the INR is measured, but it is unlikely the dose will be altered at this stage as the INR is likely to be too low.
• in patients requiring rapid anticoagulation, you can give 10mg/day for 2 days
• The maintenance dose is usually between 3-9mg. This needs to be taken at the same time every day.
• Monitoring – the INR has to be monitored regularly:
• Until the target INR is reached, it needs to be monitored EVERY DAY.
• The target INR is reached when you have consistent INR values on 2 consecutive days
• Then you monitor 1-2 per week, until the week INR is stable.
• Now you can monitor every 6-12 weeks
• A change in the patient’s status, e.g. diagnosis of a new condition, requires more frequent monitoring.
• Monitoring is usually carried out at Anti-coagulant clinics. These may be available in primary or secondary centres
• Some patients may be able to self-monitor – this involves some training, but is accurate, and more convenient for patients. This basically involves an electronic portable coagulation monitoring device e.g. coagucheckS®. This looks a little bit like a glucose monitoring kit. Patients using such devices will still need regular checks at hospital to check they are using the device correctly, and managing their INR

General advice

• Take the prescribed dose at the same time every day
• Report and bruising or bleeding immediately
• Avoid pregnancy
• Avoid aspirin and other NSAID’s– use alternative painkillers / drugs. Paracetomol also interferes with the metabolism of warfarin, and vice/versa.
• Advise patients they can take up to 6 paracetomol/day when on warfarin – if they need further pain relief – seek medical advice.
• Avoid contact sports and other activities with a high risk of (head) injury
• Alcohol – can interfere with warfarin therapy, but general social/light drinking is ok. Patient’s should avoid bingeing. As long as they drink roughly the same amount from week to week, the impact on warfarin will be minimised
• Cranberry juicecan alter the metabolism of warfarin
• Drug interactions – warfarin interacts with lots of drugs. Check with a pharmacist (or BNF) before prescribing to check conflicts with patients current medications. Tell the patient to speak to their doctor or pharmacist before taking any (including herbal) medications. Also ask the patient to inform every medical practicioner that they come into contact with that they are on warfarin.
• Macrolide antibiotics – e.g. clarithromycin, erythromycin are a particularly common group of drugs that should be avoided whilst on warfarin.

Complications

• Severe haemorrhage – e.g. GI bleed – stop therapy immediately and admit to hospital
• Mild bleeding – e.g. haematuria, epistaxis (nose bleed) – stop warfarin and give IV vit K 5-10mg.

• If there are additional RF’s for bleeding, then you can give 5mg vit K IV. If the INR is still high after 24 hours, you can give another 5mg.
• If the INR is 6-8, then stop warfarin, and restart when it is in the therapeutic range
• A high INR is often due to a drug interaction. Check. Interaction include:
  • Alcohol
  • Paracetomol
  • SSRI’s
  • Lipid regulating drugs
  • Cranberry juice
  • Flu vaccine
  • St. John’s Wort
  • Allopurinol (treatment for gout)
  • Advise patients to check with pharmacists / alternative therapists when they start any new medications for interactions with warfarin
  • Changes in diet can also affect therapy – particularly big changes involving salads and vegetables.

Stopping therapy

Special instances

• Surgery – anticoagulants should be stopped before surgery. In those at particularly high risk, Heparin can be used short term. For dental surgery, as long as the INR is in the therapeutic range, then no special measures need to be taken
• Cancer patients – LWMH is better at reducing risk of embolism in these patients
• IV drug user – LMWH is preferred due to difficulties in monitoring INR due to the lifestyle of these patients.

• Warfarin is named after the Wisconsin Alumni Research Foundation – who discovered the drug after cows feed was changed in the USA, to contain sweet clover, and loads of cows died from haemorrhagic stroke.

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