BLOOD COAGULATION

Point of Care Testing for Monitoring Oral Anticoagulant Control

Wednesday 15^th June 2011

Royal College of Physicians
Edinburgh

ABSTRACTS

The which, what and how of POC testing and quality control

 Dianne P Kitchen, UK NEQAS Blood Coagulation, Sheffield, UK

The introduction of Point of Care (POC) testing has allowed users that have not been trained in laboratory procedures to perform tests. For this approach to be successful a robust testing device is required together with the implementation of quality control procedures that ensures reliable and precise results. There are a number of POC INR monitoring devices in use in the UK at present which fulfil these criteria but the onus for undertaking quality control is upon the users as there is at present no accreditation or legal requirement to perform this essential component of the testing process.

The International Normalised Ratio (INR) system was introduced so that results could be compared when using different measuring systems such that a patient’s INR should be the same wherever and by whatever method in the world it was measured. This however may only apply when the patient is within the range for which the reagents are calibrated (1.5-4.5) and when they are stable (not moving into or out of an under or over anticoagulated state). It must be remembered that the INR is calculated value derived from the following equation:-

INR = (Patient’s Prothrombin Time /Mean Normal Prothrombin Time)^{International Sensitivity Index}

For the POC INR devices the manufacturers have already determined the Mean Normal Prothrombin Time (MNPT) and International Sensitivity Index (ISI) and the calculations are automatically performed by the device.

Quality control can be considered as a two part process made up of both Internal Quality Control (IQC) and External Quality Assessment (EQA) that link together to ensure precision and accuracy. The IQC is purchased from the manufacturer of the testing device and tested when deemed suitable by the user. The EQA is provided by an external body such as UK NEQAS for Blood Coagulation and is tested at set times (4 surveys per year with two samples per survey). Having the correct QC procedures in place can identify any problems with the test strips, testing device or the pre determined INR calibration.

In Conclusion IQC and EQA are required for INR testing, whether those tests are undertaken in the laboratory or using a POC device the QC should be of the same standard and recorded in a thorough organised manner. It is the responsibility of each user of these devices to know if the QC has been performed in the appropriate timeframe and giving suitable results before testing any patients samples.

Laboratory and POC INR results: Which to believe?

Steve Kitchen, Sheffield Haemophilia and Thrombosis Centre

and UK NEQAS for Blood Coagulation, Sheffield, UK

The INR system involves a calibration carried out by  determination of paired Prothrombin times (PTs) on a  series of plasma samples from healthy normal subjects and from patients stabilized on vitamin K antagonist (VKA)  therapy using a reference and test thromboplastin. The WHO hold a series of reference thromboplastins as International Standards (IS) for this purpose. The paired PT’s are plotted on a scatter plot with logarithmic scale and a regression line fitted though the data. The slope of the line indicates the responsiveness of the test thromboplastin relative to the WHO International Standard used to derive the International sensitivity Index (ISI) , which in turn is used to calculate INR  ( see figure below).

When using the INR system the same result should be obtained irrespective of the method that has been used to derive the value, but there are occasions when this does not occur. The patient samples used for performing the calibrations are from stabilized out patients who have INRs between 1.5 and 4.5 at the time of analysis (WHO 1999). The system is therefore only validated for these levels of INR result. Agreement between INRs obtained using different methods may be poor in other circumstances. This is a particular problem where INRs are markedly elevated above the therapeutic range.  In one UK NEQAS survey the median result obtained using different lab methods ranged from 5.7 to 6.7 depending on technique.  More extreme differences frequently occur in over anticoagulated patients if 2 methods are used for measurement, irrespective of whether one or both methods is a POC test. Sometime results are higher with the one method compared to a second and sometimes the reverse occurs, so the relationship is not consistent

 Differences may also occur when patients have lupus anticoagulant (LA) where the prolongation of PT/INR is a combination of VKA therapy and interference in the test by LA. Some reagents and certain patients are particularly prone to this problem. In one published case (Carrasco et al, 2004) the POC INR was consistently higher than the laboratory INR as follows (4 different days)

Similar issues can occur between 2 lab methods. An example from our lab is shown below (5 different days)

POC INR results may not agree with those generated in the local hospital laboratory so one approach as part of the quality control process is to collect a venous sample at the same time as the POC test and despatch this for analysis in an appropriate hospital laboratory. There are reports that INR results in hospital laboratories are not always in agreement (more than 0.5 INR units different) with each other, or with POC INR results. Some patients always show discrepancies between INRs determined with 2 different techniques despite being stabilised on oral anticoagulant therapy.

In a questionnaire completed in 2007 by 810 centers who participated in the UK NEQAS programme 74% sent comparison samples to the laboratory, half of whom did so if the POC device gave a high INR reading. 

Where possible it is advisable to establish the average difference between the 2 methods by testing approximately 20 stable patients with both methods.  Once this data is available , if any change then occurs in this relationship between the methods , a thorough investigation can be performed to look for things such as changes in batches of POC test strips or laboratory reagent/instrumentation.  It is important to establish whether there is a consistent bias between results rather than an occasional discrepancy and for this thorough record keeping is important.

References

WHO Expert Committee on Biological Standardization. Forty-eighth report. Guidelines for thromboplastins and plasma used to control oral anticoagulant therapy. Van den Besselaar AMHP, Poller L, Tripodi A.  WHO Technical Report Series 1999; 889: 64-93.

Carrasco C, Campbell B, Shiach C. B J Haem 2004:124:562-563. Effects of the lupus anticoagulant on the control of oral anticoagulant treatment.

Training issues for POCT in the secondary care setting

Caroline Baglin, Addenbrooke’s Hospital, Cambridge, UK

Patients on warfarin need regular blood testing of their prothrombin time (PT), with the result of the test called the INR - International Normalized Ratio. Monitoring of the INR is essential because too high an INR puts an individual at risk for bleeding, and too low an INR at risk for clotting. There are different ways to get an INR tested and warfarin adjusted. This can be by either venous or capillary sampling.

Since the early 1990’s capillary sampling can be performed using a “point of care” instrument either by healthcare professionals or patients. If performed by a patient they may then contact their anticoagulation service and receive dosing instructions, or they may be taught to adjust their own warfarin dose. The point of care devices available can be sold directly to patients without healthcare professional support. The issue of appropriate training and consistent quality control of the instrument are key for this form of care to be safe and effective.

There are no nationally set formal training requirements for either healthcare professional, in both primary and secondary care, or patients to use these devices and so the issue is open to local interpretation. Using published articles and national standards set relating to anticoagulant therapy safety I will demonstrate how training issues are addressed by Addenbrooke’s Hospital Outpatient Anticoagulant Service.

New Anticoagulant Drugs

Henry G Watson, Aberdeen Royal Infirmary, Aberdeen, UK

For many years, coumarins have been the only drugs available for long-term anticoagulation.  The problems of initiation and control of warfarin therapy are well versed.   Every practitioner dealing with anticoagulated patients and indeed the patients themselves, are all too aware of the fluctuations in anticoagulant control associated with changes in diet and concurrent medications amongst other things.   In summary,  warfarin has a delayed onset of action, a steep dose response curve, and huge variation in recipient sensitivity determined by genetic polymorphisms and dietary vitamin K content, and enough drug interactions to fill two pages of the British National Formulary.  As a result, alternative oral anticoagulants have long been sought.   The ideal characteristics of these drugs include administration by the oral route, once or twice daily dosing, predictable anticoagulant effect, efficacy, relative safety, no need for monitoring of anticoagulant effect and a low rate of drug interactions.   In addition, rapid reversal by a specific antidote would be a desirable.

Rivaroxaban, a specific inhibitor of Xa and Dabigatran, a direct antithrombin,  have both been licensed for the prevention of venous thromboembolism in patients undergoing major lower limb orthopaedic surgery and have both been assessed in clinical trials of prevention of cardio-embolic stroke in patients with atrial fibrillation and in the treatment of acute deep vein thrombosis and pulmonary embolism with encouraging results.  The Scottish Medicines Consortium (SMC) will probably have made a recommendation on the use of Dabigatran in patients with AF in NHS Scotland before this meeting takes place.   After 60 years of almost exclusive use of warfarin, the use of these new agents in patients with AF and VTE will result in changes in practice and a need for knowledge of the pharmacology and clinical use of these drugs.

In the context of a meeting to discuss POCT, it is relevant to consider the fate of the huge infrastructure which has been built up around the monitoring of the anticoagulant effect of warfarin in hospitals and GP surgeries throughout the country.   There has been debate about the need for measurement of the anticoagulant effect of these drugs and the assays best suited for this purpose which will be considered further.

Warfarin Induction: In Hospital or in the Community?

R Campell Tait, Royal Infirmary, Glasgow, UK

The principle aim of warfarin induction is to achieve therapeutic anticoagulation in a safe, timely and cost-effective manner, convenient for both the patient and the healthcare team and it is these inter-dependent factors, assessed on an individual patient basis which should determine whether induction therapy is undertaken in the community or in a hospital setting.

Key considerations in determining the optimal location for induction therapy include:

The role of warfarin sensitivity genotyping (assessment of VKORC1 and CYP2C9 polymorphisms) in guiding warfarin induction dosing remains uncertain.  Indeed, recent data suggest that early INR responses are equally informative as to future warfarin requirements.   Therefore, at present there is no place for such routine genotyping to determine the optimal induction location or algorithm.

In many cases, the urgency of anticoagulation will determine the most appropriate induction regimen which in turn will determine whether this can be delivered in the community.  Higher dose induction regimens (involving initial doses of 6-10 mg warfarin) which, in general, achieve more rapid therapeutic INR levels (but with greater risk of supra-therapeutic INRs) require more frequent (ie daily) initial INR monitoring and are therefore more easily delivered in the hospital in-patient setting.  However, if patients are mobile and daily (including weekends) community INR monitoring can be provided, such induction could be delivered in the community, or at least as a hospital out-patient.  Patients requiring less urgent anticoagulation (e.g. asymptomatic atrial fibrillation), particularly if elderly, are better suited to a low dose slow induction regimen (2-5 mg initial dose) which should achieve stable anticoagulation with 3-4 weeks with a lower risk of high INRs and can be delivered in the community more easily.

Managing unstable or over-anticoagulated patients

Michael Makris, Sheffield Haemophilia and Thrombosis Centre, Sheffield, UK

Approximately 1-2% of the population is being treated with warfarin at any one time.  Anticoagulation has to be closely monitored using the INR system because high levels are associated with bleeding whilst low levels predispose to thrombosis.   Individuals with unstable anticoagulation are more likely to experience serious bleeding or thrombosis.   Unstable patients are a feature of all anticoagulation services and pose a significant problem.  Options for their management include better anticoagulation education, widening the target range, using a regular low dose of vitamin K and reviewing the need for ongoing anticoagulation.   Alternatives to warfarin which do not require monitor5ing are particularly attractive for this group of patients and at present the only option is low molecular weight heparin, whilst shortly it will be possible to use the two new oral anticoagulants, Rivaroxaban and Dabigatran.

The major adverse event associated with warfarin use is bleeding which occurs in a major form at 1% per year and is fatal in 0.3% per year.   Risk factors for bleeding include elevated INR, older age, uncontrolled hypertension, trauma and use of anti-platelet drugs.   Although the bleeding risk increases with a rising INR, partial reversal is only required for patients with INR of >8.0%, or those with INR of 6.0-8.0 and with additional risk factors for bleeding.   When reversal within 24 hours is required, the vitamin K should be given intravenously, in which case significant correction is seen within 6-8 hours.  For life-threatening bleeding, the best reversal agent is for factor prothrombin complex concentrate (PCC) which can completely correct the INR within 5-10 minutes.  Despite the clear evidence for the rapid efficacy of PCC, many clinicians continue to use fresh frozen plasma (FFP).   FFP only partially corrects the INR and large volumes need to be administered.  All facilities managing patients on warfarin should have a protocol for the management of patients with elevated INR or bleeding and ideally this should be consistent with the British Committee for Standards in Haematology guideline on Warfarin.  A new update is due to be published in the next six months.

Oral Anticoagulation in Children: Management Issues and Dilemmas

Elizabeth A Chalmers, Royal Hospital for Sick Children, Glasgow, UK

In the UK, the number of children receiving long-term anticoagulation with warfarin continues to increase.   The indications for long-term anticoagulation in children differ from adult practice and most children are prescribed warfarin for the prevention of thrombo-embolic events in the context of surgically corrected congenital heart disease.  The increasing number of children on warfarin reflects overall improvements in survival from these often complex procedures.

Age has a significant effect on the use of anticoagulant therapy.   Not only are the indications for treatment likely to be different, differences in the haemostatic system can affect the response to anticoagulation and pharmacokinetic differences in drug handling are also observed.   These features are particularly marked in very young children where warfarin therapy can be particularly challenging.

Despite these differences, much of the evidence base for the use of warfarin in children is limited or extrapolated from adult practice and there are many uncertainties with regard to optimal practice.

Recent advances with regard to new formulations and the development of point-of-care monitoring have facilitated improvements in the practical management of children receiving long-term warfarin therapy.

Point-of-Care (POC) monitoring using capillary whole blood has facilitated the development of home monitoring for children on long-term warfarin therapy.  Several POC systems have been validated for use in paediatric practice and are increasingly utilised.   Important aspects of this service are the requirement for adequate training for parents,   a support service for dosing and the management of complications and the need for a robust QC system.

The introduction of new anticoagulant agents in adult practice offers the potential for improvements in the management of children requiring long-term anticoagulation.   It will however, be crucial that these agents are developed in the context of well designed paediatric clinical trials in order to improve the evidence base in this area.

Anticoagulant Dosing – do we all agree?

Ian Jennings, UK NEQAS Blood Coagulation, Sheffield, UK

Whilst the accuracy and precision of INR measurement can be monitored with internal and external quality assessment, the quality of anticoagulation management is not readily or frequently assessed, particularly between different centres.  We therefore attempted to evaluate agreement in oral anticoagulant management decisions between participating centres in UK NEQAS programmes.  To do this, participants were asked to indicate whether they used Computerised Dosing Support software (CDSS), and to complete a series of questions with respect to anticoagulant management provision.  Four clinical scenarios were provided, together with past and current INR results.  Participants were asked to provide recommendations on the target INR they would assign to the patient, the dose of warfarin, and a recall interval. 

759 centres returned results; 72% of these were participants in the Point of Care testing programme.  79% reported use of CDSS.  For the first case, a straightforward scenario, there was 99% agreement in dose recommendation.  However, for 3 more complex scenarios, there were differences in target INRs, dosing, and recall recommendations. In some cases, differences related to the software system employed.  The study emphasised a large variation in the approach to managing oral anticoagulation.