February 2004 MHRA Patient self-testing using the Roche CoaguChek S. best choice best practice nww.medical-devices.nhs.

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1 February 2004 MHRA Patient self-testing using the Roche CoaguChek S best choice best practice nww.medical-devices.nhs.uk

2 WHAT YOU CAN EXPECT FROM MHRA EVALUATION REPORTS The Device Evaluation Service (DES) aims to provide independent and objective evaluations of medical devices available on the UK market. Specialist centres, mainly in NHS Trusts, do the evaluations under long-term contract to, and in accordance with protocols approved by, the MHRA*. The evaluations are usually of a unit supplied by the manufacturer. We would expect this unit to be representative of the product on the market but cannot guarantee this. Prospective purchasers should satisfy themselves with respect to any modifications that might be made to the product type after MHRA s evaluation. The reports are intended to supplement, not replace, information already available to prospective purchasers *Medicines and Healthcare products Regulatory Agency (MHRA) The Medical Devices Agency has merged with the Medical Control Agency to form the Medicines and Healthcare products Regulatory Agency. Details available Crown Copyright 2003 Apart from any fair dealing for the purposes of research or private study, or criticism, or review, as permitted under the Copyright, Designs & Patents Act, 1988, this publication may only be reproduced, stored or transmitted in any form or by any means with the prior permission, in writing, of the Controller of Her Majesty's Stationery Office (HMSO). Enquiries concerning reproduction outside those terms should be sent to HMSO at the undermentioned address: The Copyright Unit Her Majesty s Stationery Office, St Clements House, 2/16 Colgate NORWICH, NR3 1PD

3 MRHA Evaluation Patient Self-testing Using the Roche CoaguChek S Monitor Department of Health Evaluation Centre K Williams C Gardiner IJ Mackie SJ Machin H Cohen Department of Haematology University College Hospital Gower Street. London WC1E 6AU

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5 Contents Summary... 3 Introduction... 5 Description of the instrument... 6 Instrument details and operation... 9 Operational details Quality control Consumables Protocol Technical assessment Statistical analysis Results Quality control results INR Comparability studies Patient acceptability Carryover Microbiological safety Discussion Conclusion References Acknowledgements Appendix Manufacturer's comments How to obtain MHRA evaluation reports MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 1

6 2 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

7 Summary The CoaguChek S has previously been evaluated in a laboratory/outpatient setting (MDA 01026) with testing performed by biomedical scientists. Acceptable levels of imprecision, reliability and comparability with reference laboratory methods was demonstrated. In this study we assessed the performance of the CoaguChek S in a patient self-testing environment. The primary aim of this evaluation was to determine whether patients could obtain safe and accurate INR values through self-testing using the CoaguChek S. Secondary aims were to assess patient: acceptability, compliance in selftesting, ability to record results and perform quality control measurements. The optimum period between quality control measures was also examined. Patients were randomised to either self-testing or a control group. Both groups continued to have their anticoagulation monitored every four weeks in the hospital laboratory. Dosage adjustments were performed by the anticoagulant clinic staff using the laboratory INR. Eighty-four patients were randomised to the study: 44 to self-testing and 40 to the control group. Following training, and subject to satisfactory assessment, the self-testing group performed weekly INR measurements using the CoaguChek S over a six month period. Fifteen patients (18%) failed to complete the study; five were unable to obtain an adequate sample, three had deteriorating health, two moved from the area, one discontinued warfarin and four demonstrated compliance problems. Of 31 self-testing patients who completed a questionnaire, 27 found the CoaguChek S easy to use, 27 were confident in the result they obtained and 24 preferred self-testing to the hospital anticoagulation clinic. When comparative INR data were analysed (n = 234), excellent agreement was obtained between the methods (r = 0.95), median INR and Inter Quartile Range (IQR) CoaguChek S = 2.90 (1.15) laboratory = 2.96 (IQR 1.17), with a mean difference of 0.05 INR units. Overall, 85% of results were within 0.5 INR units of each other. On four occasions, differences of >1.0 INR unit were obtained, but in each case anticoagulation was poorly controlled (INR > 4.5 by both methods) and the INR differences between methods would not have significantly altered patient management. We conclude that self-testing is a safe alternative to attending the hospital clinic and is acceptable to most (94%) patients.. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 3

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9 Introduction In recent years, there has been a large increase in the number of patients placed on long-term anticoagulant therapy. It is estimated that 750,000 people in the United Kingdom currently take warfarin and this number is expected to increase at approximately 10% per year. This is largely due to an ageing population and newer indications for long term anticoagulation, particularly atrial fibrillation (Petersen et al. 1989). Recent studies suggest that low dose oral anticoagulation may be of benefit in the primary prevention of ischaemic heart disease (MacCallum et al. 2000) and long-term, low intensity oral anticoagulation appears to effective in preventing recurrent venous thromboembolism (Ridker et al. 2003). This is expected to lead to a further increase in patient referrals. The traditional model of long-term anticoagulant care involves repeated attendance at a hospital based anticoagulant clinic where the patient s International Normalised Ratio (INR) is estimated from venous citrated blood samples in the Haematology laboratory. The patient's warfarin dose is then calculated by a Haematologist (at varying grades), Physician, a Haematology nurse specialist or other health care professional. This is now increasingly performed with the aid of computerised decision support software (CDSS) eg, Dawn AC or PC-BAP. The patient s result and warfarin dosage is recorded in their yellow Department of Health anticoagulant booklets. The patients may then wait to see a Haematologist or a nurse specialist, who returns their books and answers any queries or alternatively the book may be returned by post. Typically, patients are seen in clinic every 4-12 weeks depending on the stability of their INR response. When a patient s INR is outside the therapeutic range the patient attends clinic at shorter intervals especially if a change in dosage is required. Patients in the UK should expect to be within 0.5 INR units of their own target INR for at least 50% of the time (BCSH guidelines 1998). Several new models of patient care, involving various degrees of decentralisation, have been suggested. Many of these rely on near patient testing (NPT), also known as point-of-care testing (POC), which may be defined as testing performed in close proximity to patients. There has been much recent interest in the concept of patient self-testing for patients receiving oral anticoagulation as an alternative to the current model of hospital based anticoagulant clinics, providing that it can be proved to be safe and practical. This involves the measurement of the INR by the patients themselves using capillary blood (fingerprick) samples on small hand-held coagulation monitors. The CoaguChek S is a small portable coagulation monitor that measures PT/INR on native venous or capillary whole blood. It is designed for use in oral anticoagulant control by non-laboratory healthcare staff and patients. It has previously been evaluated by the MHRA (MDA 01026) in a laboratory/hospital out-patient department setting, by experienced laboratory staff, using our standard near-patient protocol, modified from Giddings et al (1989). Acceptable levels of imprecision, reliability and comparability with conventional laboratory techniques were demonstrated. However, as the MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 5

10 Introduction CoaguChek S is aimed at the patient self-testing market, it is now important to assess its performance in a patient self-testing environment. Description of the instrument The CoaguChek S is a portable coagulometer, which will store up to 60 test results as well as time and date. Data storage includes test cartridge code information and QC results (available by time and date). It is possible to download batch reports to a printer or personal computer via an RS232 interface. The system is powered by a battery or AC adapter. It performs PT/INR only, using a test strip containing dry rabbit brain thromboplastin (ISI = 1.6). It is designed for use in oral anticoagulant control by non-laboratory healthcare staff and patients. It has previously been evaluated by the MDA (MDA 01026) in a laboratory/hospital out-patient department setting, by experienced laboratory staff. Acceptable levels of imprecision, reliability and comparability with conventional laboratory techniques were demonstrated. The instrument is supplied in a carry case containing the SOFTCLIX lancing device, lancets, AC adapter and the user manual. It has the following major components. Principal components Figure 1: CoaguChek S monitor 6 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

11 Introduction a) Display screen: The display screen contains twenty eight icons. It displays results, menu options, data entry prompts, icons relating to the function key and status messages. b) On/off key: The on/off key turns the monitor on and off. c) Mem button: Pressing the memory button recalls the memory d) Test chamber flap: Lift to clean measurement chamber. e) Sample application area: Blood is applied here when the test strip is in place. A yellow LED flashes when the monitor is ready to receive a sample. f) Test strip guide: Test strips for patient and quality control testing are inserted here. g) Power input: The power port accommodates the 10V AC adapter, which provides power to the monitor. If the AC adapter is not used alkaline batteries (1.5V,AA LR6) should be used (a set of four batteries, lasts for about 30 tests). h) Set button: This button is used to set various monitor parameters i) Communications port: The RS232 port is provided to transfer data from the CoaguChek S instrument to a printer. j) Code key slot: This accommodates the code key when the instrument requests it. The code key contains test strip calibration data. Figure 2: CoaguChek S system Identification of samples and results Results are displayed on the screen and may be printed via the communications port. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 7

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13 Instrument details and operation Name Manufacturer Distributor Dimensions Roche CoaguChek S Roche Diagnostics GmbH Sandhofer Straße 116 D Mannheim Roche Diagnostics Limited Bell Lane Lewes East Sussex BN7 1LG. Width Depth Height Weight mm mm 44.5 mm 454 g (including batteries) Power Input 100 to 240VAC ± 10% 50 to 60 Hz Back-up battery Four 1.5V AA (LR 6) batteries Operating environment Operating temperature C Storage temperature 2-8 C Operating relative humidity (without condensation) % Operate the monitor on a level surface, free of vibrations Sample size 10 µl (at least) of whole capillary blood Instruction manual The CoaguChek S instruction manual was presented in A4 format. All the necessary information required for instrument operation was provided. Training Both of the evaluators attended a one day training course held by Roche Diagnostics. Patients were trained by the Nurse Researcher/Practitioner. Patients in the self-testing group attended two training sessions lasting approximately one hour each. At the first session they were trained in the selftesting and quality control procedures. The second session was held one week later. Patients were asked to practice their self-testing and quality control procedures at home. At the second session they were observed by the nurse researcher when performing these procedures, in order to assess their ability to MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 9

14 Instrument details and operation self test. Patients who were assessed as being unable to self test were withdrawn from the study. Operational details Analytical procedure The instrument is switched on using the on/off switch on the front of the monitor, after which the date, time and code numbers will be displayed. The code numbers of the inserted code chip will be displayed, and they can be compared with the last three digits on the test strip foil pouch. If any of these tests fail, a message will be shown on the screen, otherwise a new test strip will be requested. The appropriate test strip is inserted into the strip slot (Figure 3) and the memory is searched for information (calibration data etc.) on the relevant strip batch. Once the strip has reached operating temperature, the apply sample sign (a flashing drop of blood), will appear on the screen. Blood is collected by pricking the finger using the SOFTCLIX lancing device and gently squeezing to obtain a hanging drop of blood. The first drop of blood (minimum 10µl) is applied within 15 seconds of pricking a fingertip to the centre of the application well, a flashing yellow area. The blood is drawn into the reagent chamber of the cuvette by capillary action, where it mixes with the test strip reagent (rabbit brain thromboplastin) and magnetic iron (ferric oxide) particles. The blood sample moves along the reaction path until a clot forms. The CoaguChek S system operates on magnetic principles; it detects the clot due to the immobilisation of magnetic iron particles within a magnetic field (Figure 4). The movement of these magnetic particles is detected by reflectance photometry. Movement starts as soon as a drop of blood is introduced to the test strip and is immobilised by clot formation (Figure 5). The result, said by the manufacturer to be equivalent to the laboratory plasma PT/INR, is displayed on the LCD display. Each newly manufactured batch of test strips is calibrated against an internal Reference preparation and any lot-to-lot variability is corrected electronically using information coded on the specific code key. It is important to note that because of the magnetic principles of this instrument, operators should keep the monitor and test strips away from magnetic materials and fields eg cellular phones or microwave ovens. The PT is displayed in plasma equivalent seconds, PT ratio or INR. Plasma equivalent seconds is the time that would have been achieved using a plasma prothrombin time and is interpolated from comparative data generated with the reference preparation. Although the raw ISI of the thromboplastin is 1.6, the INR result displayed is calculated with reference to HepatoQuick (which has an ISI of 1.0), which is used in the primary calibration. 10 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

15 Instrument details and operation Figure 3: Test procedure Insert test strip Prick finger Add drop of blood to application area Read result from display MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 11

16 + Instrument details and operation Figure 4: CoaguChek S Principle Photodetector LED Reaction Zone Application Zone Heater Test Carrier Bias Magnet Electromagnet Figure 5: CoaguChek S principle + + Time Immobilization of magnetic particles due to clotting (Fibrin network ) Magnetic Particles: Bias Magnet: Electromagnet: vertically oriented on on horizontally oriented on off Quality control The CoaguChek S quality control (QC) material consists of a single use vial with a stated target INR range, typically between 2.0 and 5.0. Each vial contains activator solution (calcium chloride) and a breakable glass capsule containing citrated rabbit plasma (powder). This control is reconstituted by squeezing on the vial firmly, allowing the surrounding solution to mix with 12 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

17 Instrument details and operation powder from inside the capsule. Once the control is reconstituted it should be used within five minutes. QC data is stored by the CoaguChek S and may be down-loaded to a PC or an external printer. Operational time and throughput rate As the CoaguChek S is a semi-manual instrument, the rate of throughput is dependent on the operator and the nature of the samples tested. It was therefore inappropriate to perform throughput rate studies on this instrument. Consumables During the evaluation, most orders for reagents and consumables were processed within 2-3 days. Consumables utilised on the CoaguChek S are: PT test strips lancing device (SOFTCLIX II or SOFTCLIX Pro) and lancets. SOFTCLIX II was designed for self-monitoring by the patient. SOFTCLIX Pro was designed for use by healthcare professionals for blood collection from different patients. PT/INR quality control (QC) The list price of the CoaguChek S Care Kit (includes monitor, manual, quick Reference card, SOFTCLIX II, lancets, power supply, batteries, timer, carry case 4 controls and 12 test strips)is Ex. VAT The CoaguChek may also be purchased on interest free credit (Initial payment of 49 followed by 10 monthly payments of 35.) CoaguChek S PT mini test strips (x 48) CoaguChek S PT mini test strips (x 12) CoaguChek S PT quality control (x 4) The test strips are now available for NHS patients on the drug tariff (May 2002), which means that they can be obtained on prescription from general practitioners. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 13

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19 Protocol Protocol Ethical approval was granted by the Joint UCL/UCLH Committees on the Ethics of Human Research. Aims of the study The primary aim of the study was to determine whether patients can obtain safe accurate INR values through self-testing using the CoaguChek S. Other aims were: To ascertain whether self-testing has an effect on the proportion of time spent within the therapeutic range for each patient. To determine the optimum period between quality control measurements To assess the patient compliance in self-testing, recording results and performing quality control measurements. To assess user acceptability. Selection and exclusion criteria Patients receiving oral anticoagulation therapy with warfarin for a period of at least six months were recruited to the study. Following a training course in the use of the CoaguChek S, patients were assessed for competency. Those who were not deemed fully competent were excluded from the study. Patients who considered physically incapable of using the CoaguChek S due to severely impaired dexterity were included only if there was a stable personal carer. Previous poor compliance was defined as non-attendance at clinic on three or more occasions in the previous year (without good reason), or known alcohol or substance abuse. Study design This was planned as a case controlled non-crossover study with 60 patients in each limb. It was not possible to recruit the full number of patients in the time allocated, however eighty-four patients were recruited over a period of six months. The intervention group (self-testing) patients were trained in the use of the CoaguChek S by nursing staff and, subject to a satisfactory assessment, proceeded with the trial. These patients were asked to test themselves at home once a week and record the result for a six-month period. They were also asked to perform a weekly quality control test, the result of which was also recorded. The result obtained on the CoaguChek S was not to be used in the management of the patient during this study. These patients also attended clinic at UCLH every four weeks (or more frequently if deemed clinically necessary), where they were seen and dosed by the nurse in charge. A sample of venous blood was taken into citrate for INR determination in the routine laboratory, using Innovin (Dade-Behring) on a Sysmex CA-1500 (Sysmex UK Ltd.), a method previously evaluated by the MRHA (MDA 00076). A drop of native venous blood was also tested on the CoaguChek S by the nurse in charge. These results were used for all INR comparisons. Lyophilised quality control preparations provided by UK NEQAS were also tested on at least one occasion during the study. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 15

20 Protocol After three months patients using the CoaguChek S were asked to complete a user acceptability questionnaire (see below). This covered; Perceived ease of use Number of fingerpricks required per measurement Number of test strips wasted as a result of failed analysis Patient confidence in using the instrument Patient confidence on the result obtained 16 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

21 Protocol The control group patients continued to have their testing performed in the laboratory at UCLH every four weeks or (or more frequently if deemed clinically necessary). All monitoring of patient anticoagulant therapy and dosing was performed by the Haematology nursing or clinical staff at UCLH, for both groups of patients. All patients were asked to report any unexpected bleeding or bruising, excessive bleeding or bruising (defined as out of proportion to trauma suffered) and hospital admissions. If discrepancies between laboratory and patient self-testing results arose, the patient were asked to test themselves on their CoaguChek S in the presence of a nurse at UCLH. A sample of plasma was then also tested in the laboratory. In the event of suspected non-compliance, a plasma sample was stored so a warfarin assay could be performed. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 17

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23 Technical assessment Methods Patients were randomly allocated to either self-testing or control groups as described in the previous section. Self-testing patients tested themselves at home once a week and recorded the result for a six-month period and also performed a weekly quality control test. The results obtained on the CoaguChek S were not used in the management of the patients during this evaluation. All patients attended clinic every four weeks (or more frequently if deemed clinically necessary). At these visits a sample of venous blood laboratory (reference method). In addition a drop of capillary blood obtained by fingerprick sampling was tested on the CoaguChek S by the patient in presence of the nurse researcher. This result was used for comparative studies. If the weekly internal quality control test was out of range patients were asked to repeat the test. If the second test was also out of range, patients were then asked to attend clinic with their CoaguChek S monitors. A repeat QC test was performed in clinic to check for any technique problems. If their technique appeared satisfactory, an internal quality control test was performed on the both the patient s monitor and the clinic monitor using the sample internal quality control sample. If there was a difference of greater than 0.5 INR units the patient was given a new monitor. The original monitor was returned to Roche Diagnostics for testing. The reference INR method throughout the study was performed using fresh plasma (citrated blood samples were centrifuged at 2000 g for 15 minutes at room temperature) on the CA-1500 using Innovin. CoaguChek S Reagents CoaguChek S PT Test strips, containing rabbit brain thromboplastin with stabilisers and preservatives Procedure Clean a finger by wiping with alcohol swabs and allow to dry; or wash finger with soap and warm water and dry thoroughly. Place the monitor on a level surface that is free of vibrations and switch it on. Ensure that the code number displayed on the screen matches the one on the test strip. Insert a PT test strip into the strip slot. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer 19

24 Technical assessment When the apply sample sign (flashing drop of blood) appears on the screen, apply one drop of capillary blood to the centre of the application well on the strip (where the yellow light is flashing). Record the result displayed. Reference method Reagents Innovin Dade-Behring) lyophilised human recombinant thromboplastin with calcium ions reconstituted with 20 ml of distilled water Instrument CA-1500 (Sysmex) Procedure Place Innovin in the cooled reagent position indicated. Place samples in the reagent rack. Select PT for each sample. Record result. Statistical analysis Unless otherwise stated, the word "mean" in the subsequent section refers to the arithmetic mean. Data were analysed using Statgraphics (STSC Inc, Rockville, Maryland, USA) statistics software and the Astute statistics add-in for Microsoft Excel (DDU Software, University of Leeds). The distribution of data was examined by measuring the skewness and kurtosis, plotting histograms, and where necessary, estimating the significance of fit of data with a theoretical normal distribution, using the Kolmogorov-Smirnov test. For data showing a normal distribution, a paired t-test was used for statistical significance; a nonparametric test (Wilcoxon rank sum paired test) was used for skewed or non- Gaussian data. A value of p < 0.05 was taken as being statistically significant. For the regression analysis, outliers were rejected where they were outside the 95% confidence interval, or where they were clearly separated from the main data cluster (by subjective assessment), which would invalidate the regression. Bland and Altman (1986) graphs were used for further data analysis, to illustrate the degree of agreement or divergence between the two methods, as the numerical value increases. In these graphs the difference between the two values (Y-axis) was plotted against the mean of the two values (X-axis) for each data point. The Fisher exact test was used to test the significance of a difference between the observed proportions of two independent samples eg time in therapeutic range. 20 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

25 Results Patient demographics Eighty-four patients attending the clinic at UCLH, who were receiving long term oral anticoagulation were recruited to the evaluation study. These patients had been on oral anticoagulation for eight months or more. Stabilisation, or otherwise, of anticoagulant therapy was not a consideration in the selection of patients. Sixty-nine patients completed the study and 15 patients failed to complete the study (Table 1). The two groups contained similar numbers of males and females and age distribution (Table 2) Table 1: Breakdown of study groups patient consented for study 84 patients completing study 69 patients randomised to Self-testing group 44 patients randomised to control group 40 Patients who did not complete the study 15 Table 2: Patient demographics Self-testing group Control Group Male Female Mean age (years) Age range (years) Drop outs from study Fifteen patients did not complete the study. Fourteen were in the self-testing group and one from the control group. Four patients experienced difficulty performing self-testing and did not proceed onto the study following training. One further patient, randomised to the self-testing group, did not attend training. Therefore, of the 44 patients randomised to the self-testing group, 39 commenced self-testing, whereas all patients randomised to the control group entered the study. Three patients, two from the self-testing group and one from the control group were removed from the study because of poor compliance, ie repeated failure to attend clinic without a valid reason. All other drop-outs were from the selftesting study: One patient participated in the study for 1-2 months but had repeated problems obtaining adequate samples and therefore asked to withdraw, another patient self tested satisfactorily until he developed visual problems, which rendered him unable to self test, two moved from the area and one died while on the study, due to left ventricular failure and hypertension. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 21

26 Results Table 3: Reasons for not completing the study Reason for withdrawal Self-test group Control group Poor compliance** 2 1 Serious illness (pre-training) 1 NA Failed to attend training 1 NA Visual problems 1 NA Unable to obtain sample 1 NA Poor dexterity 4 NA Warfarin discontinued 1 0 Moved to another area 2 0 Patient died 1 0 Total withdrawals 14 1 ** the patients failed to attend clinic and/or self test on a regular basis Quality control results Internal quality control Patients in the self-testing group were asked to use a CoaguChek PT Control every week. The level of compliance with QC testing was measured by counting the number of QC tests performed and comparing this with the number of weekly self-tests performed and reporting this as a percentage. The median rate of QC testing was 92%, demonstrating a good level of compliance in respect to QC testing. Ten patients performed a QC test with each weekly self-test (100% testing rate), however in a few patients the rate of QC testing was as low as 30%. Data from a single lot of the CoaguChek PT Controls was analysed (Lot number ). The mean value obtained was close to the centre of the manufacturer's target range and a normal distribution was observed (Table 4). 96.5% of results were within the manufacturer's overall stated target range, although this range was exceptionally broad. However a poor level of imprecision was with an overall CV of % (Table 4). Of the seven out-ofrange QC values reported, six were marginally under the target range and one was over. The high QC result was found to be due to a defect in the instrument, which was subsequently replaced by the manufacturer. Ten vials of CoaguChek PT Controls tested by a Biomedical Scientist gave a %CV of 10.3%, although this would have been higher (16.6%) had an errant result due to an air bubble not been excluded from the analysis. There appeared to be several variables, which could account for the wide spread of QC data, including; The instructions for performing a quality control in the Quick Reference Guide and User's manual are unclear, particularly with regard to the order and timing of certain tasks. According to the instructions, the time between breaking the vial and applying the sample can vary from seconds. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer 22

27 Results Some patients, particularly elderly or arthritic patients have difficulty in crushing the glass vial. Prolonged results may be obtained if the room temperature is low or the vial does not reach room temperature prior to testing. If air bubbles are introduced onto the test strip, eg after over-vigorous shaking, discrepant results may be obtained. The package insert and user guide do state that air bubbles should be excluded. During the course of the study one instrument defect and one test strip problem (the test strips had not been kept in a refrigerator by the patient) were encountered. On both occasions the patient sample and the QC gave unexpected abnormal results. On several other occasions, abnormal QC values were obtained despite the patient's own result demonstrating adequate control of anticoagulation. No instrument or test strip defects were demonstrated on these occasions. Table 4: Internal quality Control Batch n = 199 Mean 3.19 SD 0.51 Min 2.00 Max 4.80 % CV Manufacturer's target range UK NEQAS samples Two NEQAS samples were tested by thirteen patients. The results obtained for sample NP02:07 were tightly clustered with an excellent degree of imprecision (Table 5). Two exceptionally high results were obtained for sample NP02:08 (INR = 5.1 and 4.7). One of these results was from an instrument which also gave an abnormal internal QC result (see previous section), the reason for the other abnormal result could not be ascertained. Following the exclusion of two outliers from the statistical analysis, excellent imprecision was obtained for sample NP02:08 Table 5: UK NEQAS samples (outliers excluded) Exercise NP02:07 NP02:08 Mean SD Min Max % CV Study median MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 23

28 Results INR comparability studies Two hundred and thirty four duplicate INR measurements were performed from 31 self-testing patients. When all 234 samples were studied, no significant difference was seen between the CoaguChek S and reference method (Table 6). Excellent agreement was obtained between the methods (Figure 6), and no trend was observed with increasing INRs (Figure 7). Overall, 85% of results were within 0.5 INR units of each other (Figure 7). On four occasions differences of >1 unit INR were obtained, but in each case the patient was over-anticoagulated at the time of testing. Three patients who had previously shown poor anticoagulant control, had INR results of 6.4 and 4.63, 4.7 and 5.98, 5.1 and 4.09 by the CoaguChek and reference methods respectively and had no signs of abnormal bleeding or bruising. The other patient had previously shown stable anticoagulation but a recent illness brought about changes in diet and medication resulted in an overanticoagulated state, which was accompanied by spontaneous bruising. Her INR was 6.9 by the CoaguChek S and 4.09 by the reference method. In each of these four cases, the INR was above the desired therapeutic range and would not have significantly altered patient management. The INR system is known to be unreliable above 4.5 and above this level different methods cannot be reliably compared (WHO 1983). When INR values within the therapeutic range were studied (Table 7), a small but statistically significant difference was observed between the methods. Stratification of results showed no significant differences between the methods, with the exception of a very small but statistically significant difference in the group (Table 8). However, these discrepancies were not of clinical significance. Good correlation was observed within the therapeutic range, despite the narrow range of results (Figure 8) with no significant trend or bias between the methods (Figure 9). Table 6: INR results for all oral anticoagulant samples (n = 234) CoaguChek S Reference Mean (s) SD Min Max t-test CoaguChek S v Reference NS Table 7: Oral anticoagulant samples having INR values within the therapeutic range ( ) CoaguChek S Reference Mean SD Min Max t-test CoaguChek S v Reference p = MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

29 Results Figure 6: INR for all oral anticoagulant samples, CoaguChek S v Reference Outliers y = 0.95x r = 0.95 CoaguChek S INR Reference INR Figure 7: INR for all oral anticoagulant samples, CoaguChek S v Reference (Bland and Altman diagram) 3 2 INR: CoaguChek S - reference SD 0.70 Mean SD Average INR MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 25

30 Results Figure 8: INR values for patients in the therapeutic range 5 4 y = 0.90x r = 0.85 CoaguChek INR Reference INR Figure 9: INR values for patients in the therapeutic range, CoaguChek S v Reference (Bland and Altman diagram) 2 INR: CoaguChek S - reference SD 0.51 Mean SD Average INR 26 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

31 Results Table 8: INR subgroups for oral anticoagulant control samples INR (n=26) Mean SD Min Max Wilcox Reference INR (n=39) Mean SD Min Max Wilcox v Reference INR (n=57) Mean SD Min Max Wilcox v Reference INR (n=50) Mean SD Min Max Wilcox v Reference INR (n=28) Mean SD Min Max Wilcox v Reference INR >4.00 (n=34) Mean SD Min Max Wilcox v Reference CoaguChek S Reference NS NS NS NS p = NS MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 27

32 Results Time in range The different testing frequencies used for the self-testing and control groups, as well as during the previous 6-months laboratory results made direct comparison of time spent in therapeutic range difficult, nevertheless it was felt that it was important to explore this issue. The BCSH Guidelines (1998) recommend the use of a target INR value rather than a target range. For the purposes of this exercise, the target INR ± 0.5 INR units was used as a therapeutic range. Time in range was determined using the Time in Range Calculator software (4S DAWN Clinical Software, Milnthorpe, Cumbria) using the method of Rosendaal et al (1993). Fisher s exact test was used to test the significance of a difference between the observed proportions of time in therapeutic range (measured in days) between the groups. No significant difference between percentage time in therapeutic range, measured by the CoaguChek S and reference methods, were observed in the self-testing (Table 9) or control groups (Table 10) during the study. Furthermore, similar levels of anticoagulant control were seen during the study and during the previous six months. Table 9: Percentage time in range: Self-testing group CoaguChek S Reference Previous 6 months Mean SD Fisher's exact test CoaguChek v reference NS CoaguChek v previous 6 months NS Reference v previous 6 months NS Table 10: Time in range: control group Reference Previous 6 months Mean SD Fisher's exact test Reference v previous 6 months NS Reference: self -test v control NS Previous 6 months: test v control NS Patient acceptability Patients in the self-testing group were asked to complete a Patient acceptability questionnaire three to four months into the study. Patients were asked for their views on six aspects of using the CoaguChek S: These aspects were ease of use, frequency of repeated tests, difficulty of getting an adequate sample, ease of use of quality control materials, confidence in the result and preference for home testing versus hospital testing. All patients completing the study and one patient who moved from the area after three months of testing, 28 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

33 Results were given a questionnaire. All 31 patients returned the completed questionnaire. The results are recorded in the table below: Do you find the CoaguChek S easy to use? How often did you have to repeat tests? Do you have difficulty in getting a large drop of blood? Was the quality control test easy to perform Do you have confidence in the result that the CoaguChek provides? Would you be happy to use the CoaguChek S at home rather than regularly attend the anticoagulant clinic at UCLH Table 11: patient questionnaire responses Ease of use Very Quite easy OK Difficult Very easy difficult Frequency of repeated tests Difficulty in obtaining sample Was the quality control test easy to perform Confidence in the Selftest result Testing preference Most occasion s Quite Often Sometimes Never I cannot obtain sufficient sample I still find it difficult I had problems at first I have had no problems Very easy Quite easy OK Difficult Very difficult I trust the result. I do not trust the result I have no strong feelings I prefer to test myself No strong feelings either way I prefer to be tested at clinic The majority of patients initially found it difficult to obtain an adequate sample, but with more experience, most found self-testing using the CoaguChek S reasonably easy (Table 11). Although only one patient found the CoaguChek S difficult to use, most patients found that they had to repeat tests and some still experienced some difficulty in obtaining an adequate sample. Most patients (87%) were confident in the result that they obtained and most MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 29

34 Results patients who expressed a preference, preferred self-testing to attending the hospital anticoagulant clinic. The 31 self-testing patients who completed the study were conscientious in performing and reporting their weekly tests. On the few occasions where weekly tests were not performed, this was generally due to the patient experiencing difficulty with self-testing or disruption of their anticoagulant control due to dental treatment, hospitalisation or on one occasion the loss of CoaguChek S monitor. Adverse incidents All patients were asked to report any unexpected bleeding or bruising, excessive bleeding or bruising (defined as out of proportion to trauma suffered) and hospital admissions. Five patients from each group reported adverse incidents (Table 12) all related to bleeding or bruising. In five of these incidents oral anticoagulation was thought to be a contributory factor. Table 12: Adverse incidents Self-testing group Nature of adverse Anticoagulant event control Spontaneous bruising Over - following admission to anticoagulated hospital for chest infection. Not eating well Bruising to arm and hip Well controlled following a fall Bleeding following PR Over - examination Blood filled blisters on feet following long distance walking anticoagulated Well controlled Epistaxis Over - anticoagulated Control group Haematoma secondary to Well controlled torn muscle Epistaxis Over - anticoagulated Bleeding gums after brushing teeth Spontaneous bruising on hand Peri-operative bleed during surgery for rectal polyps. Blood transfusion given Well controlled Over - anticoagulated Warfarin stopped Was warfarin a contributory factor Probably Unlikely Probably Unlikely Probably Possibly Probably Unlikely Probably No 30 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer

35 Results Carryover The test strips are designed for single use only, therefore no carryover can occur. Microbiological safety The test strips are disposable and as there are no accessible moving parts, microbiological safety could not be assessed in the usual manner (Kennedy et al 1988). In order to avoid infection, each time a blood sample is about to be taken a new lancet should be used. SOFTCLIX II was not designed for use in hospitals for testing different patients, hence the cap was not designed to be renewed after each use. On the other hand SOFTCLIX Pro has a special snap and lock mechanism which ensures that the same lancet cannot be used again. Each time the lancet is replaced the integrated platform is also removed so that those parts of the instrument coming into contact with the skin and blood of the patient are always replaced. Accidental splashing of blood onto the casing of the instrument would cause the only foreseeable microbiological hazard. Contamination should be removed by wiping with a 10% solution of sodium hypochlorite 70%, isopropanol or Sporicidin brand spray disinfectant. Cleaning the pricking device requires disinfecting the cap thoroughly about once a week by placing it for 10 minutes in a 70% alcohol solution (available at any pharmacist). Electrical safety The manufacturer supplied a self declaration of conformity to IEC , EMC limits according to EN and RMI limits according to EN A copy of this document is shown in the appendix. No independent evidence of conformity was available. MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S Monitor 31

36

37 Discussion The CoaguChek S is a small portable coagulation monitor that measures PT/INR on native venous or capillary whole blood. It is designed for use in oral anticoagulant control by non-laboratory healthcare staff and patients. The CoaguChek S was previously evaluated (MDA 01026) in a laboratory/hospital outpatient department setting, by experienced laboratory staff (MDA 01026) and was shown to give accurate, reproducible results. This was a case controlled, non-crossover study designed to assess the performance of the CoaguChek S in a patient self-testing environment. Eighty four patients receiving long term oral anticoagulation were randomised to either self-testing (intervention) or to continue traditional laboratory testing (control) groups. The two groups had similar age and sex distributions. Fifteen patients did not complete the study. Fourteen were in the self-testing group and one from the control group. Four patients experienced difficulty performing self-testing and did not proceed onto the study following training. One further patient, randomised to the self-testing group, did not attend training. Therefore, of the 44 patients randomised to the self-testing group, 38 commenced self-testing, whereas all patients randomised to the control group entered the study. When 234 duplicate INR measurements in 31 self-testing patients were studied, no significant difference was seen between the CoaguChek and reference method. Good correlation was obtained between the methods with no obvious trend observed with increasing INR. Overall, 85% of results were within 0.5 INR units of each other. On four occasions differences of >1 unit INR were obtained, but in each case the patient was over-anticoagulated at the time of testing and the differences in INR would not have significantly altered patient management. When only INR values within the therapeutic range were studied, a small but statistically significant difference was observed between the methods. Stratification of results also showed a small but statistically significant difference in the INR = group but these differences were of insufficient magnitude to be of clinical significance. The different testing frequencies used for self-testing, laboratory control and laboratory results from the previous six months laboratory results made direct comparison of time spent in therapeutic range difficult, it was important to investigate this issue. Time in range was determined using the method of Rosendaal et al (1993). No significant difference between time in therapeutic range, measured by the CoaguChek S and reference methods, were observed in the self-testing or control groups during the study. Furthermore, similar levels of anticoagulant control were seen during the study and during the previous six months. The self-testing patients were expected to test a CoaguChek PT Control every week. Compliance in this matter was assessed by counting the number of QC tests performed and comparing this with the number of weekly self-tests performed and reporting this as a percentage. Although the rate of weekly testing ranged from %, the median rate of QC testing was 92%, MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer 33

38 Discussion demonstrating a good level of compliance in respect to QC testing. Data from one Lot of the CoaguChek PT Control were analysed. Although 96.5% of results were within the manufacturer's stated range, this range was felt to be too wide and a poor level of imprecision was observed. During the course of the study one instrument defect and one test strip problem were encountered. On each occasion, both the patient's sample and the QC gave unexpected abnormal results and the problem once identified, was easily corrected. However, on many other occasions, abnormal QC values were obtained despite the patient's own result demonstrating adequate control of anticoagulation. No instrument or test strip defects were demonstrated on these occasions. It was generally felt that weekly QC testing was of little benefit, as most out-of-range QC results were due to problems with the use and preparation of the QC reagent, rather than instrument/test strip faults. Monthly testing as recommended in the BCSH guidelines (2001) may be more appropriate, with additional testing performed in the event of an unexpected INR result, following possible damage to the CoaguChek S monitor and on starting a new box of test strips. The NEQAS samples produced a narrower range of results (%CV <10%) and were generally perceived to be of more value than the CoaguChek PT Control. Although many patients initially found it difficult to obtain an adequate sample (77%), after a time most found self-testing using the CoaguChek S relatively easy, with only one patient reporting continued problems. Most patients were confident in the result that they obtained (87%), and most patients who expressed an opinion preferred self-testing to attendance at the hospital anticoagulant clinic (77%). The 31 self-testing patients who completed the study were conscientious in performing and reporting their weekly tests. A total of ten bleeding/bruising events were reported with equal numbers from each group. Anticoagulation was thought to be a contributory factor in five of these events (three in the self-testing group and two in the control group). This study found no significant safety issues associated with self-testing for oral anticoagulant control. 34 MHRA Evaluation Report: Patient self-testing using the Roche CoaguChek S coagulometer