Editors

RiittaLassila

Warfarin Therapy

Essentials

Warfarin reduces the activity of both vitamin K dependent clotting factors and the natural anticoagulant proteins C and S.
The anticoagulant response is usually obtained after 5 to 7 days of treatment.
When treating an acute thrombosis or when starting the treatment in a patient particularly susceptible to thrombosis, low molecular weight heparin (LMWH) in therapeutic doses is used concomitantly with warfarin in the initial phase, since the susceptibility to thrombosis is temporarily increased during the first days of warfarin therapy.
- LMWH is not stopped until the INR (international normalized ratio) has been within the therapeutic range for at least 24 hours. If the therapeutic range is not achieved within 5-7 days, the warfarin dose should be gradually increased and the patient's INR value monitored at intervals of 1-2 days in order to avoid risk of bleeding due to the double anticoagulation.
- If fondaparinux is used alongside with warfarin, it is discontinued immediately when INR is within the therapeutic target range (the half-life of fondaparinux is long, 17 hours).
The possibility of bleeding must be borne in mind after trauma, particularly when the head, neck, back or torso have been injured, and monitoring of the clinical condition, INR and blood picture must be arranged.
The frequency of INR monitoring should be increased when a new medication is started, an old one is stopped or its dosing changed (INR after 3-5 days), as well as when there is a sudden change in the patient's condition.
In exacerbating heart failure INR has the tendency of rising, and thus the need for warfarin is reduced.
In hypertension, warfarin must only be used when normotension has been achieved (the risk of bleeding is markedly increased if systolic blood pressure is over 160 mmHg).
General factors increasing the risk of bleeding (anaemia, thrombocytopenia, kidney or liver failure) should be reviewed, treated and regularly followed up.
A patient who manages warfarin treatment and its monitoring well may go over to self-monitoring; after sufficient guidance he/she can adjust the warfarin dose him-/herself within defined limits.
After introduction, self-care provides suitable patients with a possibility of managing warfarin therapy with the help of point-of-care (POC) testing in routine situations.
- The training on how to use a POC device, how to control its reliability and how to take care of its service need to be organized in cooperation with a laboratory. An anticoagulation nurse trained in the topic will take care of patient education, with the support of a doctor in anticoagulation-related clinical questions.

Indications for warfarin therapy Anticoagulants Versus Nsaids or Placebo for Venous Thromboembolism, Warfarin or Antiplatelet Therapy for Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation, Warfarin for Preventing Stroke in Patients with Non-Valvular Atrial Fibrillation and No History of Cerebral Ischaemia, Anticoagulants for Non-Rheumatic Atrial Fibrillation and a History of Stroke or Transient Ischaemic Attacks, Anticoagulants for Preventing Recurrence after Acute Ischaemic Stroke

Prophylaxis Deep Vein Thrombosis and treatment Prevention of Venous Thromboembolism of deep venous thrombosis
Pulmonary embolism Pulmonary Embolism
AF in selected cases (CHA₂DS₂-VASc score Indications for and Implementation of Anticoagulant Therapy in Atrial Fibrillation)
In cardioversion of AF
Valvular prostheses of the heart Heart Valve Operation: Patient Follow-Up and Complications
Mitral stenosis, if atrial fibrillation, a thromboembolic event or a thrombus in the left atrium
In association with a large anterior myocardial infarction, if an intraventricular thrombus or a thromboembolic event
Heart failure, if a thromboembolic event or a fresh thrombus in the left ventricle
TIA in selected cases, if aspirin (+ dipyridamole) and/or clopidogrel have failed Transient Ischaemic Attack (TIA)
- Prophylaxis against recurrent stroke is not an absolute indication for warfarin therapy in the absence of AF.
Carotid artery dissection (usually 6 months)
Hereditary or acquired thrombophilia and previous (idiopathic) thrombosis Evaluation of Thrombophilia
LMWH is used in progressive stroke Transient Ischaemic Attack (TIA) and unstable angina Acute Coronary Syndrome and Myocardial Infarction as well as for the prevention of venous thrombosis Prevention of Venous Thromboembolism.
If the need for venous thrombosis prophylaxis in association with orthopaedic joint replacement surgery (knee or hip) is prolonged, warfarin therapy may replace heparin, fondaparinux, dabigatran, rivaroxaban or apixaban.
- There is evidence on the efficacy and safety of direct anticoagulants for 30 days' use with this indication.
Decisions regarding a patient's warfarin therapy and its monitoring must not be undertaken until both the indications for the treatment and its duration, as well as patient's other medication have been clarified.
Direct oral anticoagulants (DOACs) are nowadays the first line therapy (provided that there are no contraindications to them and no drug interactions complicating the treatment appear, and that the patient has no severe primary diseases, such as renal failure or severe trombophilia)
- in the treatment of uncomplicated venous thrombosis in lower extremities and pulmonary embolism
- prevention of stroke in atrial fibrillation.
In an unstable situation (e.g. oncological treatments) anticoagulation can in most cases be carried out using LMWH (either therapeutic dose or higher prophylactic dose).

Contraindications to warfarin therapy

Check contraindications in the pharmacopoeia.
Active bleeding
Severe bleeding previously or during treatment: cerebral bleeding, retroperitoneal bleeding
Recent cerebral infarction (unless it is an indication for the treatment! See Cerebral Infarction (Ischaemic Stroke))
Safety period from 48 hours to 10 days after fibrinolytic therapy depending on the patient's bleeding risks
Severe cerebral microangiopathy, brain metastases
Uncontrolled hypertension
Liver cirrhosis, oesophageal varices, severe hepatic failure and impaired synthesis of coagulation factors
Recent peptic ulcer, colitis, cancer in the gastrointestinal tract
Pregnancy is not recommended during warfarin therapy.
- The most susceptible time for warfarin-induced foetal damage is during weeks 6-12 of pregnancy.
- When pregnancy is confirmed warfarin should be changed to LMWH according to specialist guidance.
Bleeding tendency
Thrombocytopenia (count under 100 × 10⁹ /l), untreated anaemia (haematocrit under 30%)
Amyloidosis, inherited impairment of collagen synthesis or other disorder of the connective tissue, severe vascular malformation
Allergy to warfarin or DOAC
Severe drug interactions
Poor patient compliance (e.g. alcoholism, dementia)
Recurrent accidental falls

Initiation and intensity of warfarin therapy Warfarin Initiation Nomograms for Venous Thromboembolism, Optimal Loading Dose of Warfarin for the Initiation of Oral Anticoagulation

See table T1.
It is recommended that warfarin is started with the estimated maintenance dose (3-5 mg/day according to, for example, the patient's age, hepatic and renal function, diet and other medication).
In addition to INR, check basic blood count including platelet count as well as plasma ALT and creatinine concentrations before the onset of warfarin therapy and then at least once or twice per year during the treatment.
If the patient has anaemia, its cause should be identified and actively corrected if possible.
Pharmacogenetic screening (VKORC-1 and CYP2C9) may help to establish the correct dose and reduce the risk of bleeding at the beginning of treatment (see http://www.warfarindosing.org).
- E.g. a patient who is preparing for prosthetic valve surgery and has earlier had severe bleeding
A higher INR level (2.5-3.5) is needed in patients with a prosthetic mitral valve, a cardiac right-side valvular prosthesis or an old type aortic valve prosthesis. If necessary, aspirin 100 mg/day can be added to the regime unless the risk of bleeding is considered to be high. In such a case, the INR must be checked at least every 3-4 weeks, and the basic blood count with platelets must be measured at regular intervals (e.g. 4 times a year).
- Self-care with monitoring by an INR POC device is a recommended way of managing warfarin therapy in these patients.
In patients with a prosthetic heart valve or otherwise very high risk of thrombosis (e.g. pulmonary embolism and extensive venous thrombosis first 3 months, thrombophilia, antiphospholipid syndrome, active cancer), a good therapeutic level is required. If the INR falls below the therapeutic range, LMWH is recommended in either therapeutic doses or increased prophylactic doses, until the INR has again been within the target range for a couple of days (48 hours).
In venous thrombosis recurring during warfarin therapy, a higher target range (INR 2.5-3.5) is indicated, or warfarin should be changed to subcutaneous LMWH.
- The treatment regimen may in some cases include aspirin, at least temporarily.
- The possibility of malignancy must be excluded by clinical examinations.
In AF, the normal therapeutic range (2.0-3.0) is sufficient. In patients whose risk of thrombosis is low (no heart failure, valvular disease, hypertension, diabetes or previous embolism) but who are at an increased risk of bleeding, less intensive warfarin therapy (INR 2.0 2.5) has been used, but clear evidence of its efficacy is lacking. Anticoagulant therapy is not indicated in AF if the patient's risk of stroke is low. CHA2DS2-Vasc score: see Indications for and Implementation of Anticoagulant Therapy in Atrial Fibrillation.
The risk of bleeding increases in patients aged over 70 years.

Warfarin therapy. Starting, maintaining and adjusting the dose according to INR values (target INR 2.0-3.0) in average-sized adults without comorbidities or medication affecting the treatment efficacy. The table is meant only as approximate guidance because response to anticoagulant therapy varies individually.

Day	INR	Dose when starting with 5 mg tablet	Dose when starting with 3 mg tablet*
1	-	5 mg	3 mg
2	-	5 mg	3 mg
3	<2.0	5 mg	3 mg
	2.0-2.4	5 mg	3 mg
	2.5-2.9	2.5 mg	1.5 mg
	3.0-3.4	2.5 mg	Omit the next dose or 1.5 mg
	3.5-4.0	1.5 mg (Note! Different tablet strength)	Omit the next dose
	>4.0	Omit the next dose	Omit the next dose
4-6	<1.4	10 mg	6 mg
	1.4-1.9	7.5 mg	6 mg
	2.0-2.4	5 mg	3 mg
	2.5-2.9	5 mg	3 mg
	3.0-3.9	2.5 mg	1.5 mg
	4.0-4.5	Omit the next dose, then 1.5 mg (Note! Change to 3 mg tablet)	Omit the next dose, then 1.5 mg
	>4.5	Omit the next 2 doses, then 1.5 mg (Note! Change to 3 mg tablet)	Omit the next 2 doses, then 1.5 mg
Weekly dose based on INR value
7-	1.1-1.4	Increase the weekly dose by 20%
	1.5-1.9	Increase the weekly dose by 10%
	2.0-3.0	Same weekly dose
	3.1-4.5	Decrease the weekly dose by 10%
	>4.5	Stop until INR < 4.5, restart with a 20% smaller weekly dose

Usually INR stabilizes within 5-6 days in a stable clinical condition. Always aim at as even daily dosage as possible. Make dosage changes in small steps bearing in mind the slow pharmacokinetics of warfarin.
If the dosage is difficult using either the 3 mg or 5 mg tablet strength, consider changing the tablet strength based on the weekly dose calculation.
The need for a small dose is suggestive of slow metabolism. If the patient is at risk of bleeding, but the indication for warfarin is strong, a pharmacogenetic dosage prediction may be performed (see http://www.warfarindosing.org/).
INR usually decreases by about one unit per day without a warfarin dose, except in slow metabolizers (small warfarin dose, e.g. < 1.5 mg per day).

* In primary health care, the starting dose should be 3 mg in small-sized and elderly patients, after thrombolytic therapy and in patients whose INR is spontaneously > 1.2, and the INR should be checked as early as on day 3

When adjusting anticoagulant therapy, notice that thrombotic complications occur more often when INR falls under the lower limit of therapeutic range (2.0 or 2.5) than bleeding complications occur when INR exceeds the therapeutic range, when the degree of being under or over the therapeutic range (in absolute numbers) is equal in size. The curve describing frequency of complications is exponential when INR is under 2.0 or over 4.5.

INR determinations Vitamin K for Improved Anticoagulation Control in Patients Receiving Warfarin, Computer-Assisted Management of Anticoagulant Therapy, Self-Monitoring and Self-Management of Oral Anticoagulation

For starting treatment, its maintenance and adjustment, see table T1.
INR determinations should initially be carried out every 2-3 days, then weekly until adequately stable INR values have been achieved. Adjustments are made to the total weekly doses. All changes should be as small as possible, and the aim should be to keep the daily doses constant and to use only one tablet strength (e.g. not 5-7.5-5 mg but 6-6-6 mg).
Once warfarin therapy stabilises, the frequency of the INR checks can be reduced to approximately once every one or two months.
More frequent monitoring must be resumed if new medication is added or there are significant changes in the patient's health status.
More frequent checks are warranted without hesitation in the following situations:
- gastrointestinal disorders (vomiting, diarrhoea),
- hepatic function changes,
- function of the kidneys changes
- worsening heart failure,
- introduction of a new medicine (e.g. a course of antibiotics),
- discontinuation of a previous medicine, stopping smoking, or making definite and rapid changes in diet,
- acute trauma, e.g. falling, and
- suspected anaemia.
The amount of dietary vitamin K should stay fairly constant. Low-dose (100-200 µg) vitamin K may help augment anticoagulation control in patients with fluctuating INRs.
- Dietary supplements containing 100 µg of vitamin K are available on the market.
- Pharmacies may extemporaneously prepare capsules or dosed powder containing e.g. 150 µg of phytomenadione to be taken once daily. The local pharmacist should be consulted concerning the formulation of the prescription.
- The simplest way to promote low-dose vitamin K intake is to recommend regular use of vitamin-K containing green vegetables.
- INR should be determined after dietary changes or after initiation of vitamin K supplement intake.
Self-monitoring of INR values with point-of-care equipment is a good choice for suitable patients and reduces the emergence of complications. However, self-monitoring requires commitment, patient selection and quality control of the INR device.
If INR readings fall below the target range, therapeutic-dose LMWH should be added temporarily to the treatment regime in cases where the indication for anticoagulation is particularly important, e.g. acute PE and prosthetic mitral valve, or the patient has a particular risk of thrombosis. LMWH is an applicable alternative to warfarin as anticoagulation therapy, if repetitive medical procedures are required or if the patient has long-term courses of antimicrobial drugs or is undergoing active therapy for a malignancy.

Interactions

The risk of bleeding is increased by agents that interfere with platelet function, including aspirin, NSAIDs, dipyridamole, clopidogrel, ticagrelor and prasugrel, which may, however, be used short-term if necessary (arterial stent), provided that a good INR balance is maintained (INR at target range more than 70% of the treatment time [TTR = time at therapeutic range]) and the patient is not anaemic.
Paracetamol does not increase the bleeding risk, unless the dose is very high (continuous daily dose of > 2 g increases risk of bleeding).
Aspirin is usually not used concomitantly with warfarin, but in certain situations where the patient's risk of thrombosis is increased the combination can be used to intensify the anticoagulant effect (prosthetic mitral valve + AF, pulmonary embolism that recurs during warfarin therapy, or myocardial infarction, stroke or other arterial occlusion that occurs during either aspirin or warfarin therapy).
Other drugs increasing the risk of bleeding include selective serotonin reuptake inhibitors (SSRIs) and analgesics that affect noradrenaline metabolism (SNRIs, e.g. tramadol).
Enzyme induction or inhibition (CYP-450) of various agents, and their binding to plasma proteins, cause interactions that warrant the regular monitoring of the therapeutic effect of warfarin.
Acute illness, injuries, changes in medication (starting or discontinuing), changes in diet and smoking cessation or restarting smoking also necessitate more frequent monitoring.
INR does not reliably indicate bleeding risk when using drugs that influence it through other mechanisms than the vitamin K dependent clotting factors (e.g. by inhibiting thrombocyte function).
The efficacy of warfarin therapy is affected by a variety of medicines and and natural health products. Check this always from the package insert and relevant databases.

Potentiating the effect

Antifungal drugs (e.g. ketoconazole, fluconazole and miconazole), even when used topically (gels, creams, suppositories and solutions)
- Avoid use of azole group drugs altogether (terbinafine is safer).
Metronidazole, broad spectrum antimicrobial drugs, azithromycin, sulfa-trimethoprim and several other antimicrobials, e.g. fluoroquinolones, together with conditions associated with their use.
- Metronidazole in systemic use strongly increases the effect of warfarin; in topical usage the effect is smaller. If its use cannot be avoided, temporarily decrease the weekly dose of warfarin immediately by an average of 20-50% and monitor INR frequently.
Amiodarone: reduce warfarin dosage by an average of 30-50% when starting amiodarone and monitor INR frequently. Dronedarone does not have significant interactions with warfarin.
- When using metronidazole and amiodarone, the dose reduction is individual and its effect is more sensitive in patients with a low dose of warfarin; monitoring INR more frequently is of help in estimating the dose.
Clofibrate, gemfibrozil and statins (not pravastatin)
Allopurinol, quinidine, tamoxifen, toremifen
Aspirin, NSAIDs, clopidogrel, prasugrel, ticagrelor, dipyridamole (platelet inhibition)
SSRIs and SNRIs, tramadol
Melatonin, which cannot be recommended if there are risks of bleeding.
Omega-3 fatty acids reduce platelet function and thus increase the anticoagulant activity of warfarin.
Infections, trauma, liver disease, severe renal failure, heart failure (hepatic congestion), malabsorption, catabolism
Advanced age and small body frame
Ginger, cinnamon, grape juice, cranberry juice in large doses
Temporary heavy alcohol consumption

Decreased anticoagulation

Cholestyramine, colestipol
Carbamazepine, phenytoin
Rifampicin
Vitamin K and a vegetarian diet
Heavy smoking (should be taken into account when stopping smoking)

Duration of the treatment Duration of Anticoagulant Therapy in Venous Thromboembolism, Anticoagulation for the Long Term Treatment of Venous Thromboembolism in Patients with Cancer

See article Deep vein thrombosis, table 2 Deep Vein Thrombosis.
The duration of the treatment of recurring thromboembolism may be shorter than the one indicated in the table, if a clear predisposing factor is present: surgery, trauma, labour, immobilization etc.
The duration of the treatment of recurring spontaneous thromboembolism is, in principle, long or permanent, but the treatment is beneficial only when managed carefully.
The safety and efficacy of the therapy mush be evaluated regularly, and potential complications affect the duration of the treatment.
When considering the discontinuation of anticoagulation 6 months after a spontaneous thromboembolism, investigations aimed at excluding potential malignancy should be directed according to clinical examination and relevant laboratory tests.
ASA should be considered as secondary prevention after anticoagulation therapy of deep vein thrombosis or pulmonary embolism, provided that there are no contraindications, at least if there are concurrent risk factors of arterial occlusion and if risk of bleeding is not increased.

Pregnancy and breastfeeding

Monitoring and treatment of pregnancy of persons with artificial heart valves should take place in hospitals with adequate expertise in the matter.
Warfarin should be substituted with LMWH during early pregnancy.
Warfarin may be resumed during mid and late pregnancy if necessary in patients with artificial heart valves. However, as warfarin is teratogenic the aim should be to principally use LMWH, usually in therapeutic doses. In late pregnancy LMWH is usually used instead of warfarin, in order to prevent uncontrollable bleeding during labour.
Warfarin is not contraindicated during breast feeding.

Temporary reduction of warfarin dose; bridging therapy

Any interruption in the anticoagulant therapy (refers both to warfarin and LMWH), imposed by a surgical procedure, must be kept as short as possible.
In minor procedures and/or when the bleeding risk is deemed manageable, warfarin therapy does not need to be paused.
A pause is required when the patient is to undergo major surgery or another procedure that is associated with an obvious risk of bleeding, and in cases where any bleeding would have serious consequences.
Minor surgery (e.g. cataract surgery), endoscopic operations, as well as. single biopsies taken out under direct vision and punctures performed under ultrasound guidance (e.g. ascites puncture) will only require reduction of the warfarin therapy down to the lower limit of the target range (INR about 1.8-2.5), in accordance with the nature of the procedure and the indication for anticoagulation. Cataract surgery or an extraction of a single tooth does not usually require more than an INR reading preferably taken the day before the procedure.
There is no need to reduce the intensity of anticoagulation if haemostasis can easily be achieved and when bleeding can be managed locally, for example with fibrin glue.
- In a single tooth extraction or gingival treatments a tranexamic acid tablet may be chewed and swished around the mouth with a small amount of water for a few minutes. The solution is then spat out. The treatment can be repeated a few times a day.
Any referral letter must include information regarding the indication for anticoagulation, the possibility of reducing the warfarin dose and any experience from a possible prior dose reduction.
The periprocedural management must be planned beforehand; the planning is the responsibility of the unit carrying out the procedure.
Hospitals and other specialized care units may provide advice on different procedures. Find out about local information available for such purposes.
The risk of thrombosis and the implications of possible bleeding (e.g. appendectomy vs. neurosurgery) must always be assessed when reducing or stopping warfarin therapy before a surgical procedure or due to bleeding.
- The risk of thromboembolism in AF varies according to the CHA₂DS₂-Vasc score (see Indications for and Implementation of Anticoagulant Therapy in Atrial Fibrillation).
Bridging therapy refers to the replacement of warfarin with individually dosed heparin pre- and postoperatively during major surgery with high risk of bleeding.
- Warfarin is withdrawn 3-5 days before the planned surgery and the INR is checked.
- If the INR is 5, the patient will usually need 5 days off warfarin (likewise an INR of 3 will need 3 days) to allow the INR to return to below 1.5 by the day of surgery.
- Surgery can be carried out provided that the INR is < 1.5 (1.0 in high risk of bleeding), both during surgery as well as postoperatively until haemostasis has been secured.
- If the patient is at a risk of thrombosis, LMWH is administered either in therapeutic (e.g. prosthetic mitral valve, severe predisposition to venous thrombosis, acute thrombosis) or prophylactic doses, according to the degree of risk of thrombosis and bleeding.
See also local guidance on pausing anticoagulant therapy and on bridging therapy.

Amending warfarin therapy for planned surgery and invasive procedures

If the planned procedure is minor and the risk of bleeding is low, anticoagulant therapy may continue without interruption in cases where it is clearly indicated (target INR 2.0-2.5).
Warfarin can be withdrawn before surgery if the risk of bleeding is high and the need for anticoagulation relative (AF in a patient at a low risk of thrombosis), and the risk of thrombosis during and after the withdrawal is considered to be low. Depending on the need, prophylactic doses of LMWH can be started postoperatively (12-48 hours after surgery).
If the indication for anticoagulation is very strong (e.g. two prosthetic valves, prosthetic mitral valve + AF or a history of stroke, a history of severe venous thrombosis, or thrombosis in the previous 3 to 6 months), heparin is used prior to surgery in therapeutic doses and after surgery it is started at prophylactic dose, increasing the dose gradually (in 48-72 hours) according to haemostasis, when haemostasis is stable.
- Warfarin therapy in patients with an artificial heart valve and in the aforementioned patients with high risk of thromboembolism must usually not be interrupted or even reduced, unless warfarin is replaced by another anticoagulant, in practice by LMWH in (almost) therapeutic doses until primary haemostasis is secured.
After a minor procedure, warfarin may be resumed on the evening of surgery.
After major surgery, warfarin must not be resumed until it has been ascertained that
- there is no need for repeat surgery
- postprocedural haemostasis is adequate
- the patient is not receiving medicines likely to interact with warfarin, such as broad spectrum antimicrobials.
- LMWH therapy is recommended in severe infections.
If the reintroduction of warfarin is not feasible due to the above reasons, LMWH is continued until the situation has stabilised.
Warfarin therapy after a surgical procedure is resumed with a dose that is no higher than the patient's usual maintenance dose and not before the patient is able to tolerate oral intake.
LMWH must be continued in patients at a high risk of thrombosis until the INR is within the therapeutic range (for 2 days).

Thrombosis despite warfarin therapy

The most common cause is a too low dose (INR below the therapeutic range).
Idiopathic thrombosis (no identified cause) is more likely to recur (15-20%/year). The underlying cause may prove to be cancer or antiphospholipid antibody syndrome.
Cancer is associated with a high risk of thrombosis, and warfarin is not always effective. In these cases LMWH, which is the first-line choice for the treatment of venous thrombosis and pulmonary embolism, is indicated for the duration of at least 6 months.
Thrombophilia associated with antiphospholipid syndrome does not always respond to warfarin. LMWH may be used instead of warfarin.

Complications

Warfarin therapy is associated with at least a 5-fold higher risk of bleeding when compared with patients not taking warfarin. The risk is greatest at the beginning of therapy, and 1-2% of patients will experience a serious bleeding episode during the first year and 6% a significant episode.
- Compared to warfarin, the new anticoagulants have in clinical trials been associated with a lower risk of cerebral bleeding, but the risk of gastrointestinal bleeding has been similar or higher.
The risk of bleeding is increased by the following: intensive anticoagulation, advanced age, frequent falls, uncontrolled hypertension, alcoholism, previous history of gastrointestinal bleeds, medication predisposing the patient to bleeding (anti-inflammatory drugs, antiplatelet drugs, SSRIs, SNRIs), hepatic and heart failure, renal failure, brain metastases anaemia and thrombocytopenia.
If the therapeutic indication is relative (e.g. AF with no emboli) the target INR may be reduced to the lower limit of the therapeutic range (2.0-2.5).
A single intravenous dose of tranexamic acid may be considered, but repeated doses increase the risk of thrombosis. Tranexamic acid as topical treatment is recommended at least in bleeding of the skin and oral region.

Treatment of bleeding complications Prothrombin Complex Concentrate for Reversal of Vitamin K Antagonist Treatment, Tranexamic Acid in People on Anticoagulants Undergoing Minor Oral Surgery or Dental Extractions

A clotting factor concentrate is useful when anticoagulation needs to be reversed quickly (e.g. emergency surgery, serious bleed). Plasma products can be used during a bleed to provide volume replacement.
Vitamin K: patients with artificial heart valves, 0.5-2 mg intravenously or orally (taken from the ampoule and diluted in water or other drink) 1. The effect will not begin until after about 8-12 hours, but it is of benefit when the effect of fresh frozen plasma or clotting factor concentrate has passed (the half life of vitamin K dependent clotting factors is relatively short). If the INR is high and the bleeding severe, a 10 mg dose of vitamin K should be administered. When bleeding has stopped, LMWH is introduced gradually and warfarin resumed only when the situation has stabilised.
Usually warfarin should be started with maintenance dose and continue it until INR target level is reached.
If a large dose (> 5 mg) of vitamin K has been administered to reverse the effect of warfarin, and warfarin therapy is then resumed, it may take several days to reach the INR target. During this time, LMWH should be used in patients with a high risk of thrombosis until INR has been within the therapeutic range for 2 days.
Local haemostasis is important; fibrin glue can be used as well as local tranexamic acid (it can also be used for wound care in gauze dressings, and in oral mucosal bleeding a tablet can be chewed and swished around the mouth with a small amount of water for a couple of minutes, after which the chewed tablet mass should be spat out).

High INR without bleeding

Ensure that the patient has no visible bleeding or symptoms or signs suggesting a bleeding (normal blood pressure and pulse, no anaemia or thrombocytopenia, check basic blood count with platelets as necessary)
Advise the patient to seek immediate care at an emergency department if any signs of bleeding (headache, melena, cardiovascular symptoms) or of thromboembolism appear.
Pause warfarin therapy and consider giving vitamin K orally if the patient's bleeding risk is high or his/her INR is considerably high.
- Vitamin K accelerates the decrease of INR level.
- A small dose (1 mg) of vitamin K decreases INR moderately, but enables an earlier restart of warfarin therapy.
- If the dose of vitamin K has been more than 1 mg, its effect usually lasts for several days, which should be taken into account when restarting warfarin.
- Also the risk of thrombosis (the indication of patient's anticoagulant therapy) affects the choice of treatment: for example, in the case of a patient with prosthetic heart valve or of a patient who otherwise has a high risk of thrombosis, only a small dose of vitamin K is given, if the vitamin is considered necessary.
INR > 9
- Pause warfarin for 1-2 days.
- If deemed appropriate, 1-3 mg of vitamin K is given orally (Konakion Novum^® injection solution 10 mg/ml, orally 0.1-0.3 ml; medication is taken from the ampoule and dissolved in water or in another drink). A smaller dose (1-2 mg orally) is used in patients with a prosthetic heart valve.
- INR is monitored daily.
- When INR has decreased to the target level, warfarin is restarted using a smaller weekly dose than previously (taking into account the earlier INR trend), unless there is a clear transient reason for the INR elevation.
- If INR decreases below therapeutic range in a patient with a prosthetic heart valve, an LMWH may be used for a couple of days.
INR 5-9
- Skip 1-2 warfarin doses.
- If deemed appropriate, 1-2 mg of vitamin K may be given orally. A high bleeding risk and low thrombosis risk support vitamin K administration.
- INR is determined the next day and thereafter as required by the situation.
- When INR has returned to target level, warfarin is continued using a lower weekly dose than previously (taking the earlier INR trend into account).

References

Crowther MA, Julian J, McCarty D, Douketis J, Kovacs M, Biagoni L, Schnurr T, McGinnis J, Gent M, Hirsh J, Ginsberg J. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet 2000 Nov 4;356(9241):1551-3. [PubMed]
Brighton TA, Eikelboom JW, Mann K et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012;367(21):1979-87. [PubMed]
Liew A, Douketis J. Initial and long-term treatment of deep venous thrombosis: recent clinical trials and their impact on patient management. Expert Opin Pharmacother 2013;14(4):385-96. [PubMed]

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