Haematologica 2003 - Supplements - Haematologica
Haematologica 2003 - Supplements - Haematologica Haematologica 2003 - Supplements - Haematologica
Self-testing and self-monitoring of oral anticoagulant therapywithin range (78% vs 60%) and a lower prevalenceof adverse effects (9.5% vs 15%, p=0.03) than did295 patients followed as usual care.More recently, two controlled and randomizedstudies compared self-management to the anticoagulationclinics model of management. In a Dutchstudy with a cross-over design (Cromheecke 2000),50 patients were randomized either to self-managementor to be followed by a clinic for a periodof 3 months; then each group switched to the othertype of model for another 3-month period. Theglobal quality of the two management systems wassimilar: patients remained within the therapeuticrange 55% and 49% of the time spent in self-managementand AC, respectively (p=0.06). However,the patients’ level of satisfaction was higher withself-management. In another German study(Watkze 2000), 49 self-management patients followedweekly were compared to 53 patients followedin an AC, where they were seen on averageevery 4-8 weeks. The self-management group hada higher percentage of checks within the rangethan did the AC group (84% vs 74%). Neither oneof these two studies was, however, extensiveenough to evaluate possible differences in the clinicalcomplications of the different groups.In conclusion, several studies have now establishedthat OAT self-management is feasible andthat in some cases it yields results that are betterthan usual care and at least similar to the ones ofanticoagulation clinics. It must, however, bestrongly stressed that these studies were carriedout on a limited number of patients, who werehighly selected from a very large number of anticoagulationpatients. Furthermore, none of thesestudies has so far demonstrated a clinical advantageof self-management over anticoagulationclinics, that is over the current reference standardin OAT management. The (possible) improvement ofthe time spent within the therapeutic range, mostlikely due to the increased frequency of the checks,and the patients’ greater satisfaction are interestingresults achieved by self-management; theseshould, however, be regarded as surrogate endpointswhen compared to the real objective of OAT,that is the prevention of thromboses with the minimumrisk of hemorrhage.2. Portable coagulometers to determineINRA new family of small, easy-to-use, portablecoagulometers (monitors) based on dry-chemistrytechnology are now available. These monitors allowthe determination of the INR also outside the laboratory(local hospital, community-based, generalpractitioners and patients), thus offering greaterflexibility in managing anticoagulated patients.2.1 How monitors workMonitors consist of a small measuring unit andof a reactive strip (or cartridge) incorporatingthromboplastin and calcium chloride in freezedriedform. The sample to be tested consists of anunmeasured drop of capillary or venous bloodwithout anticoagulant that is placed by the operatorson the reactive part of the strip. The blood,carried inside the strip by capillarity, mixes withand rehydrates the thromboplastin, thus startingthe coagulation reactions. The end-point recordedas a conventional prothrombin time (PT) is causedby the fibrin formation which stops blood flowwithin the capillaries, or by the thrombin generationwhich is quantitated by a specific probe. Inother devices the thromboplastin preparation ismixed with iron particles that are kept in motionby a magnet. When the first fibrin strand is formed,the trapped iron particles stop moving and causethe timer to stop. Whatever the end-point, the PTis eventually converted into INR by means of thecalibration parameters [international sensitivityindex (ISI) and mean normal prothrombin time(MNPT)] encoded in the test strip.2.2 Calibration of monitorsAccording to the World Health Organization(WHO), the calibration parameters (ISI and MNPT)needed to convert PT into INR must be determinedthrough a process of calibration, which is detailedin the specific guidelines issued in 1999 (WHOExpert Committee on Biological Standardization,1999). Although the above guidelines deal with thecalibration of conventional INR measuring systems,they can be adapted also for the calibration of themonitors (Tripodi 1993, 1997, 2001). The calibrationmodel proposed for the monitors in the early ‘90(Tripodi 1993) has recently been subjected to amulticenter study sponsored by the EuropeanUnion. This study confirmed the reliability and recommendedthe proposed model as the standardmodel to calibrate all monitors used for the laboratorycontrol of patients on oral anticoagulants(Poller 2002). The responsibility of calibration restsentirely on the manufacturers, who should complywith the requirement and calibrate the devicesaccording to the above recommendation.2.3 Accuracy of INR measurementIndividual monitors (even though they have beencalibrated) must be checked before release to thepatient in order to assess their reliability. Theassessment should be carried out by comparing theINR values on display with those obtained with areference system. The reference system may beeither an international standard for thromboplastincoupled with the manual technique to recordcoagulation time, or a system calibrated againstone of the international standard for thrombo-Haematologica/journal of hematology vol. 88(supplement 3):February 2003 3
Italian Federation of Anticoagulation Clinicsplastin (WHO Expert Committee on Biological Standardization1999, Tripodi 2001). Although all monitorsare designed and built to measure the INRand many of them are based on the same principle,generalization is not possible and their accuracyshould be evaluated individually through specificstudies (Biasiolo 2000, Cosmi 2000a, Tripodi2001). At variance with the conventional INR measuringsystems, the monitors bear the advantage ofa simpler blood drawing, which makes testing possiblealso for unskilled operators such as the patienthimself. However, this advantage may be obscuredby the risk of increasing the variability in drawingcapillary blood as opposed to venous blood. It istherefore mandatory to pay as much attention aspossible in drawing capillary blood by finger stick(Biasiolo 2000) and to train the operator, especiallyif he/she is not a laboratory worker.2.4 Evaluation of the quality of resultsReliability of INR measurement must be continuouslychecked through quality assurance programsthat must include both internal and external(regional or national) schemes.2.4.1 Internal quality control schemeThis can be carried out by the operator justbefore testing by using quality control materials atdifferent levels of anticoagulation. These materialsare usually supplied by the manufacturers and consistof freeze-dried samples. The user should test adrop of material (after proper preparation ifrequired) on the test strip and compare the resulton display with that specified by the manufacturer.In some monitors the above control can be preceded(or replaced) by an electronic control thatchecks all electronic functions of the monitor. Theresponsibility of the internal quality control schemerests on the operator, who must be fully aware onthe relevance of the scheme, on the way it must becarried out and on the action to be taken in caseresults are out of control. Before performing themeasurement on blood sample, the operator mustcheck whether the results of control samples arewithin the range of values supplied by the manufacturer.Results of internal quality controls shouldbe entered in a file to allow for periodical statisticalanalysis. Further information to be recorded isthe operator identity, the date and timing of testing,the lot numbers of the control materials andof the strips used for testing. The statistical analysiscan be performed by the operator himself (if alaboratory worker, or general practitioner), or bythe anticoagulant clinic if the operator is thepatient or his/her own relative.2.4.2 External quality control schemeThe purpose of this scheme is to assess periodicallythe performance of the monitor through theanalysis of unknown samples distributed by anexternal organizer, who is also independent fromthe manufacturer of the monitor. If the unknownsamples are shared by many participants it is alsopossible to assess the relative performance ofgroups of monitors and estimate the agreement ofthe INR measurement among users that operatewithin the same country or region. To this endresults obtained with individual monitors may becompared with the general (consensus) mean ofall the participants in the same way as for theexternal quality assessment of conventional INRmeasurement. However, external quality assessmentfor the monitors represents a special case notyet fully addressed where the experience is stilllimited. Most monitors accept only non-citratedwhole blood or plasma as testing material. Therefore,it would be impossible to supply all users withthe same non-citrated sample. As an alternative,operators might be trained on how to reconstitutefreeze-dried citrated plasmas with appropriatereconstitution fluids containing optimal amountsof calcium chloride. Calcium chloride would serveto antagonize the trisodium citrate used as anticoagulant,thus making testing possible even forcitrated plasma. Although possible this systemwould not be applicable to all types of monitors assome of them accept only whole blood as testingmaterial. While waiting for more appropriate solution,an acceptable (though demanding) alternativefor the external quality assessment would be torecall periodically (two-three time/year) individualmonitors and operators to the anticoagulant clinicwhere the INR for the same patients could bemeasured in parallel with the monitor and the laboratoryreference system. Comparison of thesepaired values could be taken as the basis for assessingthe monitor performance. Differences in excessof 20% should be regarded as unacceptable andthe procedure repeated. If the difference persiststhe user should refer to the manufacturer for furtherinvestigation on the causes of failure.3. Instructions to use portablecoagulometersPortable coagulometers are the result of technologicaladvances applied to the measurement ofprothrombin time; they can potentially simplify andimprove oral anticoagulation therapy in selectedpatients. A wide variety of these systems are commerciallyavailable. They allow the prothrombintime to be measured from a drop of capillary blood(similarly to how diabetic patients check theirglycemia). Portable coagulometers are light, handy,easily transportable and, especially the newestones, small. Determining prothrombin time requiresa suitable drop of blood; this can be obtained by4 Haematologica/journal of hematology vol. 88(supplement 3):February 2003
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Self-testing and self-monitoring of oral anticoagulant therapywithin range (78% vs 60%) and a lower prevalenceof adverse effects (9.5% vs 15%, p=0.03) than did295 patients followed as usual care.More recently, two controlled and randomizedstudies compared self-management to the anticoagulationclinics model of management. In a Dutchstudy with a cross-over design (Cromheecke 2000),50 patients were randomized either to self-managementor to be followed by a clinic for a periodof 3 months; then each group switched to the othertype of model for another 3-month period. Theglobal quality of the two management systems wassimilar: patients remained within the therapeuticrange 55% and 49% of the time spent in self-managementand AC, respectively (p=0.06). However,the patients’ level of satisfaction was higher withself-management. In another German study(Watkze 2000), 49 self-management patients followedweekly were compared to 53 patients followedin an AC, where they were seen on averageevery 4-8 weeks. The self-management group hada higher percentage of checks within the rangethan did the AC group (84% vs 74%). Neither oneof these two studies was, however, extensiveenough to evaluate possible differences in the clinicalcomplications of the different groups.In conclusion, several studies have now establishedthat OAT self-management is feasible andthat in some cases it yields results that are betterthan usual care and at least similar to the ones ofanticoagulation clinics. It must, however, bestrongly stressed that these studies were carriedout on a limited number of patients, who werehighly selected from a very large number of anticoagulationpatients. Furthermore, none of thesestudies has so far demonstrated a clinical advantageof self-management over anticoagulationclinics, that is over the current reference standardin OAT management. The (possible) improvement ofthe time spent within the therapeutic range, mostlikely due to the increased frequency of the checks,and the patients’ greater satisfaction are interestingresults achieved by self-management; theseshould, however, be regarded as surrogate endpointswhen compared to the real objective of OAT,that is the prevention of thromboses with the minimumrisk of hemorrhage.2. Portable coagulometers to determineINRA new family of small, easy-to-use, portablecoagulometers (monitors) based on dry-chemistrytechnology are now available. These monitors allowthe determination of the INR also outside the laboratory(local hospital, community-based, generalpractitioners and patients), thus offering greaterflexibility in managing anticoagulated patients.2.1 How monitors workMonitors consist of a small measuring unit andof a reactive strip (or cartridge) incorporatingthromboplastin and calcium chloride in freezedriedform. The sample to be tested consists of anunmeasured drop of capillary or venous bloodwithout anticoagulant that is placed by the operatorson the reactive part of the strip. The blood,carried inside the strip by capillarity, mixes withand rehydrates the thromboplastin, thus startingthe coagulation reactions. The end-point recordedas a conventional prothrombin time (PT) is causedby the fibrin formation which stops blood flowwithin the capillaries, or by the thrombin generationwhich is quantitated by a specific probe. Inother devices the thromboplastin preparation ismixed with iron particles that are kept in motionby a magnet. When the first fibrin strand is formed,the trapped iron particles stop moving and causethe timer to stop. Whatever the end-point, the PTis eventually converted into INR by means of thecalibration parameters [international sensitivityindex (ISI) and mean normal prothrombin time(MNPT)] encoded in the test strip.2.2 Calibration of monitorsAccording to the World Health Organization(WHO), the calibration parameters (ISI and MNPT)needed to convert PT into INR must be determinedthrough a process of calibration, which is detailedin the specific guidelines issued in 1999 (WHOExpert Committee on Biological Standardization,1999). Although the above guidelines deal with thecalibration of conventional INR measuring systems,they can be adapted also for the calibration of themonitors (Tripodi 1993, 1997, 2001). The calibrationmodel proposed for the monitors in the early ‘90(Tripodi 1993) has recently been subjected to amulticenter study sponsored by the EuropeanUnion. This study confirmed the reliability and recommendedthe proposed model as the standardmodel to calibrate all monitors used for the laboratorycontrol of patients on oral anticoagulants(Poller 2002). The responsibility of calibration restsentirely on the manufacturers, who should complywith the requirement and calibrate the devicesaccording to the above recommendation.2.3 Accuracy of INR measurementIndividual monitors (even though they have beencalibrated) must be checked before release to thepatient in order to assess their reliability. Theassessment should be carried out by comparing theINR values on display with those obtained with areference system. The reference system may beeither an international standard for thromboplastincoupled with the manual technique to recordcoagulation time, or a system calibrated againstone of the international standard for thrombo-<strong>Haematologica</strong>/journal of hematology vol. 88(supplement 3):February <strong>2003</strong> 3
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