MI L Volume 5 No. 6 August 2011 This Medicines Information Leaflet is produced locally to encourage prescribing which is cost effective to the NHS. Information will be given on quality improvement issues and the costs to hospital and community. Guidelines on when to use and how to monitor Unfractionated Heparin in adults H eparin remains the most widely used parenteral antithrombotic. The general adoption of low molecular weight heparin (LMWH) represents a significant therapeutic advance in terms of ease and convenience of administration. There may also be some advantages in terms of efficacy and fewer sideeffects. This leaflet gives guidance on when to use intravenous unfractionated heparin (UFH) for treatment of thrombosis (it does not address prophylaxis where LMWH is preferred). tin Time (APTT) is simpler than using LMWH and relying on anti-Xa levels 3. Very obese patients (more than 120 kg), in whom dose adjustment of LMWH therapy is less predictable. Mode of action Baseline tests (before treatment) Heparin is a glycosaminoglycan, extracted from porcine mucosa and is available as the sodium or calcium salt. Its anticoagulant properties depend on the presence of a specific pentasaccharide sequence which binds with high affinity to antithrombin and potentiates its activity. Metabolism is by a saturable mechanism, involving binding to endothelial cells and clearance by the reticuloendothelial system, and a non-saturable mechanism involving mainly renal clearance. There is no evidence that heparin crosses the placenta. Measure: APTT; Prothrombin Time (PT); platelet count and potassium. When to consider using UFH instead of LMWH LMWHs have replaced UFH as the preferred option in most clinical situations. Use of UFH is only considered in the following situations: 1. Patients who might require their anticoagulation to be stopped rapidly e.g. patients at very high risk of bleeding and those who may require urgent invasive procedures (the half-life of UFH is dosedependant, around 45-60 min unless renal function is severely impaired). 2. Patients in severe renal failure: titration against the Activated Partial Thromboplas- Indications for intravenous UFH If patient’s condition (see above) warrants the use of UFH rather than LMWH this must be clearly documented in the patient’s notes together with the indication for use. Dose Note: Unfractionated heparin dosing is unpredictable and a high percentage of patients will still have APTT results outside the desired range even with careful monitoring. The risks of this must be taken into account when deciding to use UFH rather than LMWH. Loading dose: 5000 units heparin or 75 units/kg (maximum dose of 10,000 units) Omission of loading dose delays effective anticoagulation. Maintenance dose: Initially 1400 units heparin per hr or 18 units/kg per hr (maximum dose of 2500 units per hr), equivalent to infusion rate of 1.4mL per hr using infusion solution of 1000 units of heparin per mL. Cardiology: Reduce initial infusion rate (see below for criteria) to 1000 units per hr (12 units/kg per hr), equivalent to infusion rate of 1mL per hr using infusion solution of 1000 units of heparin per mL : Patients receiving aspirin and clopidogrel, Patients post-alteplase (rt-PA, tissue-type plasminogen activator) Medicines Advisory Committee. Oxford Radcliffe Hospitals August 2011 2 Medicines Information Leaflet Patients on heparin during intra aortic balloon pump support Patients post abciximab (Reopro®) Note: Patients with prosthetic heart valves requiring heparinisation prior to surgery - discuss initial heparin dose with Cardiologist. Table 1: Adjustment of heparin infusion rate based on APTT using infusion solution of 1000 units per mL concentration. Administration Loading dose: Give as slow IV bolus over 35mins. Preparation: Use a standardised ready to administer heparin preparation of 1000 units per mL (ie undiluted). Maintenance dose: Give as continuous IV infusion. Start intravenous infusion at 1400 units per hr =1.4 mL per hr (or 18 units/kg per hr). Adjust dose according to APTT (see monitoring section below and Table 1). A lower initial infusion rate is used for some cardiology patients (see above). The infusion rate must be accurately controlled using a syringe pump. Preparation: Use a standardised ready-to-administer heparin preparation of 1000 units per mL. Standard volume of infusion is 25mL (ie 25,000 units in 25mL undiluted). See heparin injectables monograph for complete preparation and administration details. Once prepared the infusion should only be used for 24 hours and any remaining infusion solution discarded. The infusion must be monitored at hourly intervals using infusion monitoring chart. Monitoring APTT # The target APTT is 60 – 100 seconds. Check APTT 4 hrs after start of infusion, and adjust infusion rate according to Table 1. Recheck APTT 6 hrs after any change of dose (4 hrs if greater than 170 or less than 45) or, if no change required check within 24 h. Target APTT and infusion rate changes must be documented appropriately. In general ward areas all dose and infusion rate changes must be hand written on the in-patient drug chart and signed by a doctor. Patient Monitoring Monitor patient for signs of bleeding. Platelet counts should be measured on alternate days from days 4-14 of therapy (see below). Potassium should also be monitored regularly, especially if therapy exceeds 7 days. APTT (s) Action greater than 170 stop for one hr and reduce infusion rate by 300 units/hr (0.3 mL/hr) 126 - 170 reduce infusion rate by 200 units/hr (0.2 mL/hr) 101 - 125 reduce infusion rate by 100 units/hr (0.1 mL/hr) 60 - 100 no change 45 - 59 increase infusion rate by 200 units/hr (0.2 mL/hr) Less than 45 give a 5000 unit bolus IV and increase infusion rate by 300 units/hr (0.3 mL/hr) # An APTT of 60 – 100 seconds corresponds to 0.35-0.7 anti-Xa units/mL with the current laboratory reagent. It will need to be reviewed when the APTT reagent is changed. ***Before changing the rate of infusion, check that the initial rate was correct *** Compatible infusions: Glucose 5%, Sodium Chloride 0.9% Heparin is incompatible with a number of medicines including many antibacterials. Contact Medicines Information (Ext 21505) for further advice. Heparin and intramuscular injections Intramuscular injections should be avoided in patients receiving anticoagulants, except for adrenaline for severe anaphylaxis. Contra-indications severe liver disease peptic ulcer severe / uncontrolled hypertension known haemorrhagic diathesis thrombocytopenia recent cerebral haemorrhage. injuries to or recent operations to the eyes/ears or central nervous system. spinal or epidural anaesthesia infective endocarditis 3 Medicines Information Leaflet Cautions concomitant medicines that may enhance anticoagulant effect e.g. aspirin, clopidogrel, dipyridamole, iloprost, NSAIDs hepatic impairment renal impairment active tuberculosis Adverse effects haemorrhage thrombocytopenia (see below) hyperkalaemia (see below) osteoporosis alopecia on prolonged use hypersensitivity reactions (including urticaria, angioedema, and anaphylaxis) Hyperkalaemia Inhibition of aldosterone secretion by heparin can result in hyperkalaemia; patients with diabetes mellitus, chronic renal failure, acidosis, raised plasma potassium or those taking potassium-sparing drugs seem to be more susceptible. The risk appears to increase with duration of therapy and the CSM has recommended that the potassium concentration should be measured in patients at risk of hyperkalaemia before starting heparin and monitored regularly thereafter, particularly if heparin is to be continued for longer than 7 days. Heparin and surgery In patients with normal renal function intravenous UFH can be stopped 6 hrs before surgery to allow coagulation to return to normal. Heparin-induced thrombocytopenia(HIT) Clinically important HIT is immune-mediated and does not usually develop until 5–10 days after starting heparin therapy unless the patient has been exposed to heparin before. HIT can be complicated by thrombosis. All patients who are to receive heparin should have a platelet count on the day of starting treatment. For patients previously exposed to heparin in the last 100 days, obtain a platelet count 24 hrs after starting heparin. For all other patients alternate day platelet counts should be performed from days 4 to 14 of therapy. Signs of HIT include a 50% reduction of platelet count, thrombosis, or skin allergy. If HIT is strongly suspected or confirmed, heparin should be stopped and an alternative anticoagulant should be given. Contact the on-call haematology registrar for advice. Overdose/Reversal In an emergency the anticoagulant effect of heparin can be inhibited by protamine sulphate. One mg of protamine sulphate inhibits the effect of 100 units of heparin – usually the maximum dose is 50 mg given by slow IV injection (rate not exceeding 5mg per minute) Switching from UFH to LMWH If patients are to be switched from intravenous UFH to subcutaneous LMWH, the UFH infusion should be stopped approximately 4 hours before the first dose of LMWH is due (providing patient’s renal function is normal and last APTT result is within range i.e. 60-100). Safe Medication Practice for prescribing Heparin Infusions Target APTT should be documented Heparin should always be prescribed with ‘UNITS’ written in full Always use standard heparin infusion concentration of 1000 units per 1mL The prescription must state  Heparin dose in units for bolus dose  Heparin infusion rate in mL per hour  Infusion volume  Route  Time for next APTT Infusion rate changes must be prescribed by doctor. Infusion must be changed every 24 hrs References Baglin, T., Barrowcliffe, T.W., Cohen, A. & Greaves, M. (2006) Guidelines on the use and monitoring of heparin. Br J Haematol, 133, 19-34. Sweetman SC (Ed). Martindale: The Complete th Drug Reference. 35 Ed, Pharmaceutical Press; London 2007. th Trissel L.A. Handbook on injectable Drugs. 10 Edition, American Society of Health-System Pharmacists Inc, Bethesda. Prepared by: David Keeling, Consultant Haematologist; Jo Coleman, Medicines Safety Pharmacist; Scott Harrison, Lead Pharmacist - anticoagulation. With advice from: Colin Forfar, Consultant Cardiologist.