Oral anticoagulation Oral anticoagulation § 950,000 patients on Warfarin in the UK § Vitamin K dependant factors § Factor VII – half life of 4-6 hours § Factor IX – half life of 24 hours § Factor X – half life of 48 hours § Factor II – half life of 60 hours, therefore warfarin and heparin have to overlap for approx 4-5 days when starting treatment
Warfarin § Works by blocking the ability of vitamin K to carboxylate the factors, ie. stops glu to gla, thus leaving them in inactive form (unable to bind calcium).
Indications § Venous thromboembolism § LMWH may be advantageous in VTE complicating cancer § Target INR of 2.5 § Recurrent VTE INR 2.5 v 1.5 v Placebo – recurrence rate 2.5% v 7.5% v 20% § INR 2.5 - lower recurrence rate and no increase in bleeding § Target INR of 1.75 in patients with a very high bleeding risk § If temporary risk factor § At least 6 weeks for calf vein thrombosis § At lest 3 months after proximal DVT § Idiopathic or permenant risk factors § 6 months anticoagulation § Risk of recurrence § Elevated D-dimer 1 month after treatment may predict recurrence § Male gender § Unprovoked § Most likely to occur within the first 2 years (10%) after stopping treatment
§ Heritable thrombophilia § Recurrence rates whilst on anticoagulation with INR of 2.5 are similar to those without heritable thrombophilia
§ APLS § Target INR of 2.5 is recommended for venous thrombosis § Arterial thrombosis, insufficient evidence, but a target of 3.5 is often used
§ IVDU § treatment with LMWH is a safe alternative
§ Cardioversion § INR of 2.5 for 3 weeks before and 4 weeks after cardioversion § To minimise cancellations, a target of 3 can be used to prior to the procedure
§ Heart valve prosthesis § For patients in whom valve type and location are known § Bileaflet – aortic 2.5 § Tilting disk – aortic 3.0 § Bileaflet – mitral 3.0 § Tilting disk – mitral 3.0 § Caged ball/ caged disk – aortic or mitral 3.5 § Not known § INR of 3.0 for aortic § INR of 3.5 for mitral
§ Peripheral arterial thrombosis and grafts § First line is antiplatelets § If long term AC given to patients at high risk of femoral graft failure – INR of 2.5
§ Coronary artery thrombosis § Meta analysis found that aspirin and warfarin reduced incidence of MI and stroke, but was associated with higher bleeding risk § Included several studies performed before widespread coronary stenting § Target INR of 2.5 is recommended
§ PNH § 10 year risk of thrombosis in those with large clones (PNH granulocytes >50%) = 44% v. 5.8% in those with smaller clones § Long-term AC with target INR of 2.5 is recommended for patients with large clones and plts >100 § Can also be considered for others if additional thrombotic risk factors
§ Cancer § LMWH superior to warfarin § CLOT study
§ Anticoagulation in the preoperative period § Unless very high risk of thromboembolism, AC should be temporarily discontinued § Does not need to be stopped for dental extraction if INR <3
§ Reversal for bleeding § IV Vit K 5-10mg (works quicker than oral) § Factor concentrate rather than FFP
Haemorrhage § Risk is variable according to the study § 2.4 – 8% per patient year § Risk factors § Intensity of anticoagulation § Co-morbidity § Other medications § Quality of management § Age § Risk doubles for each point increase in the INR above 3
Loading § Rapid fall in Factor VII (short half-life), but also protein C (Vit K dependant with short half life also) § This may result in a hypercoagulable state rather than hypocaogulable and explains why some patients with protein C deficiency get skin necrosis when starting therapy
INR § Corrects the PT ratio for differences in the sensitivity of thromboplastin reagents § Allows for comparison of results between labs § Patients PT/ Mean normal PT x International sensitivity index (ISI) § ISI is specific to each thromboplastin reagent
Genetics § Polymorphisms in either CYP2C9 or Vitamin K epoxide reductase (VKORC1) affect warfarin sensitivity § Warfarin clearance is by hepatic metabolism largely mediated by CYP2C9 (part of the cytochrome P450 system) § Most important polymorphisms are CYP2C9*2 and *3 which result in a 30 and 80% reduction in enzymatic activity respectively, resulting in increased anticoagulant effect. § VKORC1 is the enzyme inhibited by warfarin § Polymorphisms result in either low or high level haplotypes; high level haplotypes require higher doses. § Factor IX propeptide mutations § Highly sensitive to warfarin; APTT >> PT § Can treat with warfarin, but monitor FIX (10-15%)
Alternatives § Controversial, but could consider long term secondary prophylaxis with a reduced INR after an initial period of normal anticoagulation – may be appropriate for those in whom frequent INR monitoring is difficult. § New drugs – direct Xa and thrombin inhibitors which don’t require monitoring
Oral anticoagulation and patient self-testing § Near patient testing § Patient self management
1. Consider only in patients on long-term warfarin § Exceptional circumstances can be considered for patients with short term indications § 2-3 months before a patient becomes fully accustomed 2. Contraindications § Previous non-compliance 3. Previous stability of INR is not a prerequisite § unstable patients may benefit from autonomy and increased frequency of testing 4. Target INR must be documented 5. Must retain contact with a named clinican 6. GP and clinician initiating warfarin must be informed 7. Informed consent § Includes agreement to attend clinic regularly and record results accurately 8. Training § Ideally national training programme as in Germany where 400,000 patients self dose § competence to perform an INR must be assessed § competence to interpret an INR must be assessed § based on an individual algorithm 9. European-marked devices that have undergone evaluation by an expert independent body eg. MHRA 10. Internal quality control § Electronic QC should be used every time monitor is used § IQC material should be used when new batch of test strips § IQC material should be used if unexpected result § IQC should be tested every 3 months 11. External quality assessment § Formal EQA program eg. NEQAS § Assessed in a centre that is formally EQA accredited § Venous sample at same time as POC sample – every 6 months 12. Abnormally high values § Repeat test if result between 4-8. The repeat analysis should be within 0.5 § INR >8, venous sample is required
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