Key clinical studies related to patient self-testing of INR and point-of-care INR testing

Verret L et al. Pharmacotherapy. 2012;32(10):871–879.

Summary: The VERRET study was undertaken to evaluate the quality of life of warfarin patients who self-test and self-manage their anticoagulation therapy vs. patients who test in a clinic.

Patients were given a quality of life questionnaire before and after the study period. Quality of anticoagulation control was assessed using time in therapeutic range (TTR). After four months, TTR was slightly higher in the patient self-testing group than in the control group. Patient satisfaction with treatment was also significantly higher in the self-managed group than in the control group.

Singer DE et al. J Am Heart Assoc. 2013;2(1):1–15.

Summary: The study found that there are geographical differences in time in therapeutic range (TTR). The conclusion stated by the authors is that regional differences in TTR are associated with reduced frequency of INR testing. The more frequently testing occurs, the higher the resultant TTR.

Plesch W et al. Int J Lab Hematol. 2009;31:20–25.

Summary: This study was performed to confirm the correct INR results received from two routinely manufactured lots of test strips when compared with the international reference preparations (IRP) rTF/95 and ERM-AD149.

The results of the study confirm the successful calibration of two lots of the CoaguChek^® XS system, demonstrate the validity of the calibration concept, and prove the accuracy of the system in comparison with the IRP. Clinical decisions in oral anticoagulation therapy may be reliably made upon the INR results of the system.

Wann LS et al. J Am Coll Cardiol. 2011;57(11):1330–1337.

Summary: Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal-to-permanent atrial fibrillation (AF) and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance < 15 mL/min), or advanced liver disease (impaired baseline clotting function).

Selection of patients with AF and at least one additional risk factor for stroke who could benefit from treatment with dabigatran as opposed to warfarin should consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program to sustain routine monitoring of INR, patient preferences, cost, and other factors.

Atay JK et al. Clin Appl Thromb Hemost. 2012;18(2):181–184.

Summary: The aim of the study was to assess hospital budget implications of substituting dabigatran for warfarin in patients enrolled in a large anticoagulation service. Substituting dabigatran for warfarin will result in increased expense due to drug cost.

Medical Advisory Secretariat. Ont Health Technol Assess Ser. 2009;9(12):1–114.

Summary: Hemorrhagic events, thromboembolic events, all-cause mortality, anticoagulation control as assessed by proportion of time or values in the therapeutic range, patient-reported outcomes including satisfaction, quality of life (QoL), compliance, acceptability, and convenience.

Plesch W et al. Thromb Res. 2008;123(2):381–389.

Summary: The first paper reporting a performance verification study of a point-of-care monitor for prothrombin time (PT) testing according to the requirements given in Chapter 8 of the International Organization for Standardization (ISO) 17593:2007 standard “Clinical laboratory testing and in vitro medical devices – Requirements for in vitro monitoring systems for self-testing of oral anticoagulant therapy.”

The system demonstrated a high level of trueness and accuracy, and low imprecision in INR testing. It can be concluded that the CoaguChek^® XS system complies with the requirements in Chapter 8 of the ISO standard 17593:2007.

Wan Y et al. Circ Cardiovasc Qual Outcomes. 2008;1(2):84–91.

Summary: Until 2008, there has been no systematic examination of the relationship between international normalized ratio (INR) control measurements and the prediction of adverse events in patients with atrial fibrillation on oral anticoagulation.

In atrial fibrillation patients receiving orally administered anticoagulation treatment, time in therapeutic range (TTR) and percentage of INRs in range effectively predict INR control. Data from retrospective studies support the use of TTR to accurately predict reductions in adverse events.

Heneghan C et al. Lancet. 2006;367(9813):404–411.

Summary: The meta-analysis published in the Lancet in 2006 shows the superiority of coagulation self-testing (and even better coagulation self-management) vs. usual care. One-third reduction in deaths and 55% reduction in thromboembolism (yet no increase in hemorrhage) are the most obvious clinical benefits.

Researchers identified 14 randomized trials of self-monitoring: pooled estimates showed significant reductions in thromboembolic events (odds ratio 0.45; 95% CI 0.30–0.68), all-cause mortality (0.61; 0.38–0.98), and major hemorrhage (0.65; 0.42–0.99). Trials of combined self-monitoring and self-adjusted therapy showed significant reductions in thromboembolic events (0.27; 0.12–0.59) and death (0.37; 0.16–0.85), but not major hemorrhage (0.93; 0.42–2.05). No difference was noted in minor hemorrhage. Eleven trials reported improvements in the mean proportion of international normalized ratios in range.

Self-management improves the quality of oral anticoagulation. Patients capable of self-monitoring and self-adjusting therapy have fewer thromboembolic events and lower mortality than those who self-monitor alone. However, self-monitoring is not feasible for all patients, and it requires identification and education of suitable candidates.

Menendez-Jandula B et al. Ann Intern Med. 2005;142(1):1–10.

Summary: This is a prospective, single-centre, controlled, randomized trial to compare the clinical outcomes of patient self-management (PSM) with conventional management (CM).

Outcome: In comparison with an anticoagulation clinic, PSM of oral anticoagulant therapy (OAT) reduces the incidence of major complications, minor hemorrhages, and possibly mortality.

Methodology: A total of 737 patients with different indications for OAT were randomized. The PSM group received simple instructions on how to use a portable coagulometer and to adjust the dose of OAT weekly. The CM group received the usual care in our anticoagulation clinic with monthly international normalized ratio (INR) controls and management by specialized hematologists.

Results and benefits: PSM of OAT yields better results than CM performed by specialized physicians:

The percentage of in-range INR values of the PSM group was significantly better than in CM (58.1% vs. 54.0%) in the intention-to-treat analysis.

Trend to reduced mortality (CM: 4.3%; PSM: 1.7%): In the CM group, 3 of 15 deaths were associated directly to OAT. In the PSM group, 6 patients died, but none of the deaths were related to OAT.

60% mortality reduction

A large proportion of patients are candidates to use the PSM model, since old age and low educational level do not seem to be major inconveniences. An ideal model to manage OAT should be PSM with the specialized support of an anticoagulation clinic (ACC) for as many patients as possible.

Woods K et al. Thromb Res. 2004;114(3):161–165.

Summary: Although previous studies suggest that capillary blood monitoring of the international normalized ratio (INR) is rapid and reliable, patient preferences for the method of blood drawing have not been investigated.

The findings support the routine use of capillary blood testing using a portable monitor for the management of patients in outpatient anticoagulation clinics.

Koertke H et al. Circulation. 2003;108(Suppl 1):II75–78.

Summary: Measuring on your own reduces risk of bleeding. The Early Self-Controlled Anticoagulation Trial (ESCAT) Study demonstrates advantages of monitoring coagulation yourself.

Self-monitoring one’s coagulation values in conjunction with an INR value that is as low as possible reduces the risk of bleeding without increasing the danger of thrombosis. This enables heart valve patients to attain similar low rates of complications as to a non-anticoagulated comparative group. The ESCAT Study demonstrates this. It was a wide-scope empirical study in which about 1,820 patients with prosthetic heart valves adapted their oral anticoagulation therapy via their blood INR values.

The degree of blood coagulation is determined by measuring the INR value. When values are above or below the individual therapeutic range, the oral anticoagulant dosage is adjusted. Patients that have mechanical heart valves aim for an INR value between 2.5 and 4.5 INR. Values > 3.5 INR indicate a greater thrombogenicity. Conventionally, the general practitioner takes care of the INR monitoring and of the dosage adjustment.

The ESCAT I Study with heart valve patients had already demonstrated that a significantly higher therapy reliability could be achieved via INR self-monitoring using a coagulation monitoring device and the patient's self-adjustment of the anticoagulant dosage. 80% of the self-monitoring group were able to maintain their INR values long term within the therapeutic range. The control group monitored by doctors had a rate of only 65%.

The follow-up ESCAT II Study aimed to investigate how adjusting for an INR value that was as low as possible in conjunction with coagulation self-monitoring would facilitate further minimization of bleeding risk. “The initial results are absolutely promising,” stated Professor Dr. Reiner Körfer, director of the clinic for thorax and cardiovascular surgery at the Heart and Diabetes Center of NRW in Bad Oeynhausen, Germany, and one of the study’s authors. “A low INR adjustment and measuring the INR by the patient him-/herself lead to a significant reduction of the risk of bleeding, without increasing the danger of a thromboembolism.”

For the investigation, two groups of 910 and 908 patients were formed. One group had their INR value set from 2.5 to 4.5 (conventional group), and the second at values of 1.8 to 2.8 for aortic valves or 2.5 to 3.5 INR for mitral valves (low-dosage group). Both groups were trained in self-monitoring their coagulation and were given the CoaguChek^® S (predecessor of the CoaguChek^® XS) coagulation monitor. “According to the interim results we now have, 72% of the low-dosage group and 74.4% of the conventional group were able to maintain their INR values within the therapeutic range,” Körfer observed.

Particularly encouraging: 13 bleeding complications occurred in the conventional group vs. only 6 in the group with the low INR values, and there were only 3 thromboembolic events in both groups. “The relative bleeding risk is thus 1.6% lower," Körfer stated, succinctly stating the advantages of a low INR value. “However, this only works if this value can be maintained over the long term in a much narrower and lower therapeutic range—and that is done most reliably via self-monitoring by well-trained patients.”

Gadisseur AP et al. Arch Intern Med. 2003;163(21):2639–2646.

Summary: In this randomized study by two Dutch anticoagulation clinics, 341 patients aged between 18 and 75 years who were receiving long-term oral anticoagulant therapy (OAT) were divided into four groups: an existing routine care group of patients untrained in self-management; a routine care group of trained patients; a group managed weekly at an anticoagulation clinic where international normalized ratios (INRs) were measured by trained patients; and weekly patient self-management. A two-step randomization procedure was followed: first, a Zelen-design randomization was performed to distribute patients (without informing them) to the existing care group or to receive training in self-management; second, trained patients were randomized to the three other study groups.

Preiss M et al. Eur Heart J Suppl. 2001;3(Suppl Q):Q50–Q53.

Summary: GELIA (German Experience with Low Intensity Anticoagulation) is a multicentre study that was conducted in parallel in 29 centres in Germany. The purpose of the GELIA 6 study was to ascertain which form of oral anticoagulation monitoring is most beneficial to the patient. In an initial phase, 355 patients were supervised by their family doctors and then changed to patient self-management. The INR values and the patients’ ability to stay within their therapeutic corridor were measured for all patients under family doctor supervision and, subsequently, through self-management. The change from family doctor to self-management highlighted the significant benefits the patients enjoy (11% more INR values within the therapeutic corridor). Also, a clear tendency towards fewer complications was observed. Patient self-management improves individual clinical outcomes. It leads to more consistent, regular checking and to improved maintenance of the set values.

Cromheecke ME et al. Lancet. 2000;356(9224):97–102.

Summary: 50 patients receiving long-term oral anticoagulation were included in the study that was directed by Dr. Marcel Levi at the Academic Medical Centre in Amsterdam. The patients were randomly assigned to two groups: one group self-managed its own anticoagulation, while the other received hospital supervision. After three months, the patients swapped strategies. INR was measured at intervals of one to two weeks without it being known which method the patients were using. Altogether, there was no significant difference between the two methods. The percentage of patients remaining in the therapeutic corridor for longer was higher in the self-management group than in the reference group.

Patient satisfaction surveys showed that the self-management patients considered themselves to have a better quality of life.

Heidinger KS et al. Thromb Res. 2000;98(4):287–293.

Sawicki PT. JAMA 1999;281(2):145–150.

Summary: A study directed by Dr. Peter T. Sawicki of Düsseldorf University Hospital published in 1999 in JAMA (Journal of the American Medical Association) concluded that patient anticoagulation self-management training programs make for greater precision and so improve patient quality of life.

A total of 179 patients receiving long-term oral anticoagulation were included in the study conducted at five centres in Germany. The patients were assigned to two groups: one group took part in the patient self-management training program (learning how to measure INR and adjust anticoagulation accordingly) and subsequently self-managed, while the control group continued to receive medical supervision.

After three and six months, deviations in the measured INR/Quick values vs. the target values were much lower in the self-management group than in the control group. Readings were also within the optimum therapeutic range much more frequently.

Bernardo A. Z Kardiol. 1998;87(Suppl 4):75–81.

Summary: Between August 1986 and December 1996, 1,244 patients received instruction in anticoagulation self-monitoring at the Herz-Krauslauf-Klinik in Bad Berleburg. A team headed by Dr. Angelika Bernardo investigated the benefits of this course of instruction with regard to the patients’ ability to stay within their therapeutic corridor and the complications they experienced. Of the 1,244 patients, 387 were studied in the follow-up period with regard to their self-monitored values. The results were convincing: In weekly anticoagulation checks, 81.5% of self-monitored values were within the therapeutic corridor, and only 18.5% outside. The complication rate was 0.33% per year for bleeding, and 0.25% per year for thromboembolic events. The results show that patients can be instructed in self-management at reasonable cost, enabling them to do so reliably in the long term. The active participation of patients in their treatment is conducive to optimum long-term anticoagulation and the avoidance of life-threatening complications. Anticoagulation self-management can be assumed to lower the risk of bleeding and thromboembolism while improving prognoses and quality of life.

Bernardo A et al. J Thromb Thrombolysis. 1996;2(4):321–325.

Summary: Long-term oral anticoagulation requires careful patient monitoring in order to optimize results and to limit hemorrhagic or thromboembolic complications of treatment. For this reason, any improvement in anticoagulant control and management can be expected to have far-reaching consequences in extending longevity and decreasing complications in anticoagulated patients after heart valve surgery. Because one attractive means of improving anticoagulant management is to give patients a share of the responsibility, a program was designed to encourage patients to take an active role in monitoring their own prothrombin time (PT) and managing their own oral anticoagulation. During the period from August 1986 to February 1992, 600 patients requiring long-term anticoagulation, mainly after heart valve replacement, were trained to measure their own PT at the Cardiac Rehabilitation Center (Herz-Krauslauf-Klinik, Bad Berleburg, Germany) and to manage their own therapy: 216 patients could be followed with regard to their self-determined PTs. The results were within the target range in 83.1% of the PT determinations (n=12,306 measurements) taken by the patients themselves. Neither major bleeding nor thromboembolic complications were observed in 205 patient-years of self-monitoring of PT and self-management of oral anticoagulation.