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High international normalised ratio ( INR )- Consider aspects which may have caused INR to be out of range and level of INR
Any medication change ? antibiotic , amiodarone Missed dose or taken too much ? Any intercurrent illness ? gastroenteritis fever , onset of jaundice , weight loss , ? worsening renal function Excessive alcohol consumption ? herbal remedies OTC meds eg cranberry juice , miconazole gel Smoking cessation ( can ↑ the effect of warfarin )
Key drug interactions enhancing the effect of warfarin ( CKS )
alcohol-Advice to avoid binge drinking. Heavy drinkers who cannot abstain should not take warfarin. alcohol acts as both enzyme inhibitor and inducer
amiodarone –Amiodarone and warfarin potentiate the effect of warfarin and prolongs the INR -increased risk of bleeding . Interaction may persist for a month or more after stopping amiodarone
Antibiotics- check INR 4-7 days after any antibiotic use Co-trimoxazole consider if trimethoprim could be used or reduce the warfarin dose Metronidazole – reduce warfarin dose as necessary
antidepressants-avoid SSRI and SNRI if possible ( antiplatelet effect ) consider trazodone instead
Azoles- measure INR 4-7 days after using fluconazole , miconazole and voriconazole (adjust the dose based on INR ) monitoring also recommended for topical or intravaginal miconazole
Cranberry juice – avoid.
Corticosteroids- Check INR 4-7 days ( if high dose prednisolone given ) and adjust the warfarin based on INR
Antiviral medication therapy-Monitor INR closely- possible changes in liver functions during treatment These are boceprevir , daclatasvir , dasabuvir , ombitasvir , paritaprevir , ritonavir , sofosbuvir , ledipasvir with sofosbuvir and simeprevir
fibrates –avoid , if concomitant use then reduce warfarin dose by 1/3rd to 1/2
Glucosamine-Avoid- enhance anticoagulant effect ( mechanism unclear )
Tamoxifen-avoid where possible or reduce dose by one half to two thirds and check INR 1-2 weeks after starting treatment with tamoxifen
thyroxine –reduce warfarin dose as necessary and consider weekly monitoring if thyroxine dose is being adjusted
Situations when Warfarin sensitivity is increased - a dose reduction may be needed-Hepatic dysfunction and/ or jaundice Alcohol abuse particularly binge drinking Congestive heart failure Anorexia Hyperthyroidism Acute pyrexial state Changes in diet resulting in reduced Vit K intake Smoking cessation. Liver enzyme inhibitor drugs increase the INR
Almost any drug can interact with warfarin Pay particular attention to any drug that potentiating GI ulceration and subsequent GI bleeding ( eg alendronic acid or NSAIDs ) Any drug that inhibits platelet function eg NSAID , aspirin, clopidogrel
In addition -these drugs can also enhance the A/C effect-Allopurinol Cimetidine Ciprofloxacin Fluvastatin Omeprazole Simvastatin Testosterone Tetracyclines Tramadol SSRis
These can also effect the INR-chondrotin ginger garlic ginseng ginkgo biloba glucosamine St John’s wart
risk of bleeding is increased-Age > 65 History of stroke ( ever ) History of GI bleed ( ever ) Recent MI ( within previous 1 month ) or severe anaemia ( Hct < 30 % ) or Renal insufficiency ( Scr > 130 µmol/l ) or diabetes mellitus Warfarin started within last 1 month Severe liver dysfunction Renal failure Uncontrolled hypertension Change of > 2.0 INR units from last Malignancy Recent surgery Concomitant antiplatelet/ NSAID therapy
increased risk of clotting –Mechanical prosthetic valve Bioprosthetic valve < 3 months DVT/ PE < 12 weeks of therapy Antiphospholipid syndrome or > hypercoagulable state Atrial fibrillation + valvular heart disease prior stroke or systemic embolism +/- 12 wks of therapy H/O embolization on anticoagulant therapy Acute MI in previous 12 weeks
treatment options –Dose omission Oral Vit K ( Phytomenadione ) Intra Venous Vit K Fresh frozen plasma ( FFP ) Prothrombin complex concentrates ( PCC eg Beriplex )
Low dose oral vitamin K therapy promptly reduces INR Oral administration is more effective than s/c Vit K injection and as effective as IV when INR values are compared 24 hrs post administration a 1 mg Vitamin K dose is an appropriate dose for patients with INR values between 4.5 and 10 ( Sarah E Wislon et al 2004 )
INR 5-8 non bleeding patients-Withhold 1 or 2 doses of warfarin ( or more if appropriate ) and lower the maintenance dose Reinstate warfarin at a lower dose once INR back in range Investigate the cause of ↑ INR Vitamin K can be used 1-2 mg – particularly if any additional risk factors for bleeding Patient can be managed in the community
INR > 8 and no bleeding –Stop warfarin -restart when INR less than 5 Consider giving 1 to 5 mg Vitamin K orally ( eg Konakion MM Paediatric ) particularly if any risk factors for bleeding If anticoagulant therapy is not to continue then administer 5 mg of Vitamin K orally Vitamin K should only be used orally or intravenously IV active within 6-8 hrs Orally active within 12-14 hrs Oral vitamin K can be repeated after 24 hrs if the INR still remains high These patients can be managed in primary care
Minor bleeding –Minor bleeding and INR greater than 5 – stop warfarin and ensure urgent review undertaken at hospital Warfarin can be restarted when INR < 5 Some protocols mention that any patient who is bleeding should be admitted to hospital ( irrespective of what the INR is ) – it would be prudent to discuss such scenarios with med O/C registrar/ consultant
Major bleeding –Major bleeding – stop warfarin Find out where the patient is and dial 999 for immediate hospital transfer Inform A/E about the patient If it does not delay the patients transfer then patient should receive 5 mg Vit K IV ( eg Konakion MM Paediatric ) This should be considered as significant clinical event and reviewed
LINKS AND RESOURCES
PATIENT INFORMATION
Warfarin anticoagulant record booklet from medicine compendium https://www.medicines.org.uk/emc/rmm/1081/Document
NHS on Warfarin https://www.nhs.uk/medicines/warfarin/
American Heart Association on Warfarin https://www.heart.org/en/health-topics/arrhythmia/prevention–treatment-of-arrhythmia/a-patients-guide-to-taking-warfarin
NHS Inform Scot on Warfarin https://www.nhsinform.scot/tests-and-treatments/medicines-and-medical-aids/types-of-medicine/warfarin
A 20 page leaflet – Living with Warfarin from Govt of Western Australia DOH https://ww2.health.wa.gov.au/~/media/Files/Corporate/general%20documents/Quality/PDF/Living-with-Warfarin.pdf
A printable colourful leaflet 8 pages from anticoagulation UK https://www.anticoagulationuk.org/downloads/Living%20with%20Warfarin%20August%202017.pdf
A 3 page printable leaflet on Warfarin from Thrombosis Canada https://thrombosiscanada.ca/websiteResources/EducationalSheets/M159_Warfarin.pdf
INFORMATION FOR HEALTHCARE PROFESSIONALS
An amazing resource from NES Scot on various factors that can affect Warfarin- if you deal with warfarin dosing regularly this is a must-read https://www.nes.scot.nhs.uk/media/2459987/anticoagulation_08_2.pdf
British Society of Haematology Guideline Oral Anticoagulation with warfarin 4 th edition https://b-s-h.org.uk/guidelines/guidelines/oral-anticoagulation-with-warfarin-4th-edition/
Medical Journal of Australia -An update of consensus guidelines for warfarin reversal https://www.mja.com.au/journal/2013/198/4/update-consensus-guidelines-warfarin-reversal
UNC Health Care Pharmacy Services Emergent Anticoagulation Reversal UNC Medical Center https://www.med.unc.edu/emergmed/files/2018/04/Anticoagulation-Emergent-Reversal-Guideline-1.pdf
Warfarin common drug interactions from Worthing and Southlands Hospitals https://www.sps.nhs.uk/wp-content/uploads/2017/09/36_Interactions_NPSA_18_AC_WSussex_Oct09.pdf
Stockleys drug interactions https://www.pharmpress.com/stockleys
References
- Derbyshire Joint Area Prescribing Committee ( JAPC ) Guideline on oral anticoagulation with warfarin November 2017
- Countess of Chester Hospital NHS Foundation Trust Wirral Oral Anticoagulants: Guideline for prescribing, monitoring and management
- Amiodarone and Warfarin Interactions Am Fam Physician 2002
- Anticoagulation- Oral CKS NHS
- HAS BLED Score MD Calc https://www.mdcalc.com/has-bled-score-major-bleeding-risk
- Factors affecting Warfarin – https://www.nes.scot.nhs.uk/media/2459987/anticoagulation_08_2.pdf
- How to treat a patient whose INR is too high Clinical Pharmacist 1 JAN 2009
- Wilson, Sarah E et al. “Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review.” CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne vol. 170,5 (2004): 821-4. doi:10.1503/cmaj.1030478