Warfarin History Oral anticoagulants were discovered after a change in agricultural policy in North America in the 1920’s, which resulted in sweet clover being fed to cattle in place of corn. However, an epidemic of haemorrhagic cattle deaths followed. This was identified to be due to a coumarin compound in spoilt sweet clover. The first use of this newly discovered coumarin, as many patients will tell you, was of course as a rat poison. Later it was developed for clinical use. International Normalised Ratio (INR) Oral anticoagulation is monitored via the prothrombin time (PT), which is the time taken for citrated plasma to clot with the addition of Tissue Factor. For reasons of standardisation between different laboratories an INR is used: INR

=

PT of the patient PT of normal plasma

x

k (constant of reagents used)

Mechanism Warfarin only exerts its effect in vivo, interfering with the post-transcriptional γ-carboxylation of glutamic acid residues on clotting factors II, VII, IX and X. This renders the clotting factors functionless, which are called proteins induced by vitamin K absence (PIVKA). However, an important point to recognise is the half-life of each factor, VII = 6 hours, to II = 60 hours. Hence, it is impossible to achieve anticoagulation in less than 48hrs, and the INR during the first 2-3 days does NOT reflect the degree of anticoagulation. During this time the patient is given heparin, acting immediately, in order to achieve anticoagulation. The most helpful time for judging the effect of administered warfain is 3-4 days after initiation.

Extrinsic System

Intrinsic System

Substances released from damaged tissue

Vascular endothelial damage

Factor VII

Inhibition

Factors IX and X

Warfarin

Prothrombin IIA Thrombin II Fibrinogen

Fibrin

Simplified View of Coagulation Cascade

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“Brain SWEPT” • Brain- extract used as the tissue factor stimulus for extrinsic system activation in prothrombin time test • S Seven: main factor inhibited by warfarin • W Warfarin • E Extrinsic system • P Promthombin • T Time

Indications, Targets and Typical Durations Condition Atrial fibrillation (AF) Post-op Deep Vein Thrombosis (DVT) DVT- non surgical patient – no risk factors DVT +/or Pulmonary Embolus (PE) with persistent risk factors

INR range 2–3 2–3 2–3 2–3

Typical Duration Long-term 6 weeks 3 months Varies according to risk – discuss with haematologist Long-term Long-term Long-term 3-6 weeks Not required long-term in the absence of AF

Recurrent DVT and / or PE. Recurrent DVT and /or PE whilst on Warfarin Mechanical, prosthetic heart valves Bioprosthetic valves

2–3 3–4 3–4 2–3

Arterial grafts

Not recommended Table 1: Indications for anticoagulation

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Administration Warfarin is given orally and is absorbed rapidly and completely from the gastrointestinal tract, taking only one hour to reach maximum plasma concentration. In addition it is heavily protein bound (99%), and is metabolised by the liver (See figure 1).

Pharmacology Mouth Gut Blood attached to albumin Liver-reduces activation of vitamin K-dependent clotting factors 10, 9, 7, 2 (“1972”) Metabolised by cytochrome p450 enzyme complex Figure 1 Before starting warfarin Before loading, it is advisable to carry out some baseline tests: PT, APTT, platelets, LFT’s and FBC. This will dictate whether a full or reduced loading dose will be used. Important Note There are several different loading regimes, Fennerty’s being the most common one used in hospital practice (Table 2). This is shown for illustration only; please make sure you check and use the regime recommended within your Trust. The most important INR to be measured is day 4 (i.e. when warfarin is acting to its full effect), as this predicts the maintenance dose (Table 2).

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DAY 1st 2nd 3rd

4th

INR < 1.4 < 1.8 1.8 > 1.8 < 2.0 2.0-2.1 2.2-2.3 2.4-2.5 2.6-2.7 2.8-2.9 3.0-3.1 3.2-3.3 3.4 3.5 3.6-4.0 > 4.0 < 1.4 1.4 1.5 1.6-1.7 1.8 1.9 2.0-2.1 2.2-2.3 2.4-2.6 2.7-3.0 3.1-3.5 3.6-4.0 4.1-4.5 > 4.5

WARFARIN dose (mg) 10 10 1 0.5 10 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 >8 8 7.5 7 6.5 6 5.5 Predicted maintenance dose 5 4.5 4 3.5 3 Miss out 1 day’s dose then give 2mg Miss out 2 days’ doses then give 1mg Table 2.1

Interactions Many, many different drugs interact with warfarin and it is always worth checking in the BNF. A few are so important that they are should be remembered, as they seem to occur commonly in clinical practice and hence are avoidable (Table 2). POTENTIATING DRUGS INHIBITING DRUGS Barbiturates Allopurinol Dipyridamole Amiodarone Carbamazepine Erythromycin Cholestyramine Fluconazole Antibiotics Griseofulvin Aspirin Metronidazole Miconazole Bezafibrate Oral Contraceptives NSAIDs* Rifampicin Cimetidine St John’s Wort Phenytoin Ciprofloxacin Sucralfate Simvastatin Clopidogrel Vitamin K Tamoxifen Co-proxamol Thyroxine. Danazol This is not an exhaustive list, please consultant Appendix 1 of the British National Formulary for a more comprehensive list. Those in bold seem to be the commonest. Table 3.

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Some of these interactions may be related to the pharmadynamics of warfarin- see Figure 2.

Interactions with Warfarin Pharmacology

Clot

Antibiotics destroy vit K producing bacteria; avoid co-trimoxazole; Care with metronidazole erythromycin, amoxycillin & trimethoprim; check INR

Mouth Cholestyramine can bind warfarin in gut reducing its absorption

Gut Blood attached to albumin

OCP slightly increases clotting factors Enzyme inducers: Anti-epileptic drugs eg Phenytoin, Carbamazepine Rifampicin Griseofulvin Chronic alcohol

Bleed

Aspirin and NSAID’s damage gut mucosa and displace warfarin

Liver-reduces activation of vitamin K-dependent clotting factors 10, 9, 7, 2 (“1972”) Metabolised by cytochrome p450 enzyme complex

Steroids Liver disease also reduces “1972” Enzyme inhibitors Cimetidine Omeprazole Acute binge OR Stopping chronic alcohol

Figure 2: Interactions with warfarin Adverse Effects Haemorrhage: bruising, nosebleeds, gum bleeds and haematuria are the most common (especially in the elderly). The risk is markedly increased when the INR is >5.0, and reversal protocol needs to be observed (see Figure 4). However, the use of vitamin K to reverse the effect of warfarin must be done with the knowledge that the control of INR will probably be erratic over the following few weeks. Hence, try to avoid using it and if it is needed try small doses to begin with. The 10mg ampoule of vitamin K is for alcoholics and should not normally be given in its entirety; try 2mg to begin with and titrate from there. Other reactions include: skin rashes, alopecia and purple toes! Phenindione is an alternative if sensitivity is a problem.

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Figure 4: Guidelines for managing bleeding On The Ward Warfarin management is an important task for most house officers. This is usually straightforward, but can be tough, as some patients are very ill, which alone can affect the INR and many are prescribed a list of drugs with the potential to interact. It should always be remembered that today’s INR relates to the dose given 48 hours ago and local guidelines will help in prescribing an appropriate dose. The guide in figure 5 is approximate, and it may not be possible to change to a constant dose e.g. if a patient is on 5mg each day and has an INR of 3.4 (aiming for an INR of 2-3), they may need altering doses of 4mg one day then 5mg the next. One question to know the answer to is the colour code of warfarin tablets (Brown = 1g, Blue = 3g, Pink = 5g), which is important if the patient is to comply with dose prescription. As always, if in any doubt, consult your senior colleagues and seek advice from the haematology department.

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Altering the Warfarin dose to achieve an INR 2-3

Figure 5 Surgical Patients Surgical patients may present a further challenge: the pre-operative reversal of anticoagulation. Remembering that it takes 2-3 days before the effect of warfarin has ceased, this may leave the patient at risk of thrombosis during this reversal time. So, patients are usually covered using a heparin infusion, which acts immediately and can quickly be reversed quickly for the operation. Assessing both heparin and warfarin How can we clinically measure the efficacy of both warfarin and heparin? The former mainly affects the extrinsic pathway (INR) and the latter mainly affects the intrinsic pathway (Activated Partial Thromboplastin Time (APTT, the time taken to formation of a clot on incubating citrated plasma with kaolin). The anticoagulation target for heparin is 1.5 to 2.5 times the normal APPT. This can be maintained, and monitored, whilst simultaneously monitoring the reversal of warfarin via the INR. Once the INR is normalised, the clinician can be assured that the anticoagulation can be QUICKLY reversed, as only heparin is acting to anticoagulate the patient. Once the operation is complete, it is dependent upon the operation how soon the warfarin is recommenced (risk of haemorrhage, which can’t be reversed quickly). The patient will still need heparin cover until the INR is within therapeutic range, using the same principles as described above, monitoring the INR and APTT separately. Pregnancy Oral anticoagulants are best avoided during pregnancy and by women attempting to conceive, as warfarin is teratogenic in early pregnancy and towards the end of pregnancy may cause neonatal hemorrhage. However, heparin can be given throughout pregnancy; full therapeutic doses can be given subcutaneously if necessary. Specialist advice is desirable. Remember, heparin over such a long period of time will cause osteoporosis, so the patient must have bone protection.

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Case History A 47yr old woman suffers a DVT after undergoing a cholecystectomy 2 weeks ago, being discharged after an uneventful recovery 1 week ago. Q1. Do you admit this patient to hospital? Q2. What drug(s) would you prescribe, provided there are no contraindications? Q3. What is the long-term treatment? Q4. How would you determine the dose(s)? Q5. What advise would you give this patient? A1. This patient must be admitted: life-threatening risk of PE. A2. Heparin should be given immediately, infusion can be used as discussed above, but low molecular weight heparin (LMWH) is now preferred. This is due to the fact that LMWH does not need to be constantly monitored (like an infusion), but the dose varies depending on brand. The commonest one use is enoxaparin: treatment dose being 1.5mg/kg/24hrs. Don’t get confused with the prophylactic dose, which is a standard 40mg (20mg if low risk). Warfarin should be commenced at the same time, according to a standard loading regime (as above). A3. Warfarin treatment should be continued for 6 weeks and the target range should be an INR of 2-3. A4. The warfarin dose is determined by the INR. Subcutaneous heparin is determined by the patient’s weight and is 1.5mg/kg for treatment of established deep vein thrombosis or pulmonary embolus e.g. if her weight were 70kg, the calculated dose of enoxaparin would be 105mg once daily: a single 100mg subcutaneous injection would probably be used every day for 5 days. Remember to refer to local guidelines on duration of treatment and if in any doubt, consult your senior colleagues. A5. Discuss: • • • • • • •

ND Clement

What it is for, and potential benefits Constant monitoring of INR, daily then weekly then monthly INR’s Drug interactions Need for compliance Need for anticoagulation booklet Side-effects e.g. bruising, haemorrhage Alcohol avoidance

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Short Notes On Heparin Unfractionated heparin is a glycosaminoglycan that binds antithrombin, which enhances its action of inhibiting thrombin, factors IX and X. However, due to its short half-life (about 1.5 hours) it needs to be given by continuous intravenous infusion. A standard regime would be: loading dose: 5,000 units IV followed by a maintenance dose: 24,000-48,000 units/day by continuous infusion. The drawback is the need for frequent measurement of the APTT (approx every 12hrs), which is used to change / titrate the rate of the infusion. Also, the patient has the inconvenience of being attached to a syringe driver. Long term, apart from the risk of bleeding, there is a significant risk of osteoporosis. Newer fractionated heparins In contrast, the clinical advantages of low-molecular-weight heparin (LMWH) include: predictability, dose-dependent plasma levels, a long half-life and less bleeding for a given antithrombotic effect. This means that it is possible to use LMWHs without a syringe driver and without the need for frequent monitoring, using regular subcutaneously injections. It also makes life easier for the prescriber as doses can be calculated easily depending on the indication (e.g. enoxaparin: 40mg for prophylaxis or 1.5mg/kg for DVT/PE). There is a further small advantage: a risk that occurs with unfractionated heparin, but is seldom mentioned as it is rare, is immune-mediated thrombocytopenia. This risk appears not to be associated with short-term use of LMWH.

Reference 1

Suggested warfarin schedule based on INR – modified from Fennerty et al. Reproduced with permission from Drugs and Therapeutics Bulletin, Vol 30, No 20, 28 September 1992

Dr ND Clement October 2005

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