Key Clinical Studies

List of key clinical studies regarding warfarin therapy with anticoagulation monitoring.

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1. Accuracy of the point-of-care coagulometer CoaguChek XS in the hands of patients.

Nagler, M.; Raddatz-Muller, P; Schmid, P; Bachmann LM; Wuillemin, WA.

Journal of Thrombosis and Haemostasis 2013; 11: 197.

Summary: This study titled, “Accuracy of the point-of-care coagulometer CoaguChek XS in the hands of patients” assessed the value of patient self-testing for anticoagulation therapy management using the CoaguChek XS.

Stated results showed that the accuracy of patient selftesting with the CoaguChek XS is adequate for clinical use in anticoagulation therapy management.

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2. Impact of a pharmacist-led warfarin self-management program on quality of life and anticoagulation control: a randomized trial.2

Verret L. et al

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy; 2012 Oct;32(10):871-9

Summary: The VERRET study was undertaken to evaluate the quality of life of warfarin patients who self-test and self-manage their anticoagulation therapy versus patients who are tested 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.  After 4 months TTR was slightly higher in the PST group than in the control group.  Patient satisfaction with their treatment was also significantly higher in the self-managed group than in the control group.

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2. Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial3

Singer D.E., et al

J Am Heart Assoc. 2013; 2: e000067 originally published February 19, 201

Summary: The study found that there are geographical differences in 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.

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3. Validation of the international normalized ratio (INR) in a new point-of-care system designed for home monitoring of oral anticoagulation therapy.

Plesch W, van den Besselaar AM PH.

Int. Jnl. Lab. Hem. 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.

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4. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

Wann LS, Curtis AB, Ellenbogan KA, Estes DAM, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG and Tracy CM.

J Am Coll Cardiol 2011;57:1330-1337

Summary : Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent 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 1 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.

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5. Hospital budget implications of substituting dabigatran for warfarin in an anticoagulation service. Clin Appl Thromb Hemost.

Atay JK, Fiumara K, Piazza G, Fanikos J and Goldhaber SZ

Electronic version published August, 2011

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.

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6. Point of care international normalized ratio (INR) monitoring devices for patients on long-term oral anticoagulation therapy: an evidence-based analysis.

Medical Advisory Secretariat, Ontario Health Technology Assessment Series 2009; 9(12)

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, QoL, compliance, acceptability, convenience.

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7. Results of the performance verification of the CoaguChek XS system.

Plesch W, Wolf T, Breitenbeck N, Dikkeschei LD, Cervero A ., Perez PL, van den Besselaar AM HP.

Thromb Res. 2008;123(2):381-9. 

Summary: The first paper reporting a performance verification study of a point-of-care (POC) 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.

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8. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review.

Wan Y, Heneghan C, Perera R, Roberts N, Hollowell J, Glasziou P, Bankhead C and Xu Y.

Circ Cardiovasc Qual Outcomes 2008;1:84-91

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, 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.

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9. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis.

Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Meats E and Glasziou P.

Lancet 2006;367:404-411

Summary: The meta-analysis published in the Lancet in 2006 shows the superiority of Coagulation Self-Testing (and even better Coagulation Self-Management) versus usual care. One-third reduction in deaths and 55 % reduction in thromboembolism (yet no increase in hemorrhage) are the most obvious clinical benefits.

They 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 selfmonitoring 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. 11 trials reported improvements in the mean proportion of international normalization 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 requires identification and education of suitable candidates.

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10. Comparing Self-Management of Oral Anticoagulant Therapy with Clinic Management- A Randomized Trial

Barbara Menendez-Jandula; Juan Carlos Souto; Arturo Oliver; Isabel Montserrat; Mireia Quintana; Ignasi Gich; Xavier Bonfill; and Jordi Fontcuberta.

Ann Intern Med. 2005; 142:1-10¨

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

Outcome: In comparison with an Anticoagulation Clinic, PSM of 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 INR controls and management by specialized hematologists.

Results & Benefits: PSM of OAT yields superior 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 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 ACC for as many patients as possible.

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11. Patient preferences for capillary vs. venous INR determination in an anticoagulation clinic: a randomized controlled trial.

Woods, K., Douketis, J.D., Schnurr, T., Kinnon, K., Powers, P. et al. (2004).

Thromb Res 114(3), 161-165.

Summary: Although previous studies suggest that capillary blood monitoring of the international normalize 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.

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INR self-management permits lower anticoagulation levels after mechanical heart valve replacement.

Koertke H, et al.

Circulation. 2003; 108 Suppl 1: II75-78.

Summary: Measuring on your own reduces risk of bleeding. The ESCAT Study demonstrates advantages of monitoring coagulation yourself

Monitoring one's coagulation values oneself 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 (Early Self Controlled Anticoagulation Trial) Study demonstrates this. It was a wide scope, empirical study in which about 1,820 patients with prothetic heart valves who adapted their oral anticoagulation therapy via their blood INR values.

The degree of blood coagulation is determined by measuring the INR value (International Normalized Ratio). 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 at investigating 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. med. Reiner Körfer contentedly, Director of the Clinic for Thorax and Cardiovascular Surgery of 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 thrombo-embolism."

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), 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 percent of the Low Dosage Group and 74.4 percent of the Conventional Group that were able to maintain their INR values within the therapeutic range", Körfer observed.

Particularly encouraging: 13 bleeding complications occured in the conventional group versus only 6, in the group with the low INR values, and only 3 thrombo-embolic events in both groups. "The relative bleeding risk is thus 1.6 percent 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."

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12. Comparison of the quality of oral anticoagulant therapy through patient self-management versus management by specialised anticoagulation clinics in the Netherlands.

Gadisseur APA, Breukink – Engbers WGM, van der Meer FJM, Rosendaal FR.

Thromb Haemost 2001; 86(Suppl): Abst # OC 161.

Summary: In this randomized study by 2 Dutch anticoagulation clinics 341 patients aged between 18 and 75 years and receiving long-term OAT were divided into 4 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 were measured by trained patients; and weekly patient self-management. A 2-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 3 other study groups.

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13. Additional information from the GELIA database: analysis of benefit from self-management of oral anticoagulation (GELIA 6)

Preiss M, Bernet F, Zerkowski HR.

Eur Heart J Supplements 2001; 3 (Suppl Q): Q 50– Q 53.

Summary: GELIA (German Experience with Low Intensity Anticoagulation) is a multi centre 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, more regular checking and so to improved maintenance of the set values.

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14. Self-management of oral anticoagulation

Levi M, Büller H.

Lancet, Vol 356, July 8, 2000; 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 2 groups. One group self-managed its own anticoagulation, while the other received hospital supervision. After 3 months the patients swapped strategies. INR was measured at intervals of 1 to 2 weeks, without it being known which method the patients were using at this time. 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.

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15. Clinical outcome of self-management of oral anticoagulation in patients with atrial fibrillation or deep vein thrombosis.

Heidinger KS, Bernardo A, Taborski U, Müller – Berghaus G.

Thromb Res 2000; 98: 287 - 293.

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16. A structured teaching and self-management program for patients receiving oral anticoagulation: a randomized controlled trial

Sawicki T., et al

JAMA, January 13, 1999 – Vol 28 1, No. 2

A study directed by Dr. Peter T. Sawicki of Düsseldorf University Hospital and 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 patients’ quality of life.

A total of 179 patients receiving long-term oral anticoagulation were included in the study conducted at 5 centres in Germany. The patients were assigned to 2 groups .One group took part in the SPOG patient self-management training program (learning how to measure INR and adjust anti coagulation accordingly) and subsequently self-managed, while the control group continued to receive medical supervision.

After 3 and 6 months deviations in the measured INR / Quick values versus 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.

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17. Optimization of long-term anticoagulation through patient self-management

Bernardo A.

Z Kardiol. 1998;87 Suppl 4:75-81.

Between August 1986 and December 1996, 1,244 patients received instruction in anticoagulation self – monitoring at the Herz – Kreislauf – 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 thrombo – embolic 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 thrombo - embolism, while improving prognoses and quality of life.

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18. Experience with Patient Self- Management of Oral Anticoagulation. (Conference Session)

Bernardo A .Post J.

Thromb Thromboly 1996; 2: 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 prothrombin times. 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.

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