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Mid-term results of self-testing of the international normalized ratio in adults with a mechanical heart valve
Thrombosis Research 133 (2014) 149–153
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Mid-term results of self-testing of the international normalized ratio in adults with a mechanical heart valve☆ Kasra Azarnoush a,⁎, Enrica Dorigo a, Bruno Pereira b, Claire Dauphin c, Etienne Geoffroy a, Nicolas Dauphin a, Nicola D’Ostrevy a, Benoit Legault a, Lionel Camilleri a a b c
Heart surgery Department, G. Montpied Hospital, Clermont-Ferrand University Hospital, Clermont-Ferrand, France Bio-statistics unit, Délégation Recherche Clinique & Innovation, Clermont-Ferrand University Hospital, Clermont-Ferrand, France Cardiology department, G. Montpied Hospital, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
a r t i c l e
i n f o
Article history: Received 17 June 2013 Received in revised form 4 September 2013 Accepted 9 September 2013 Available online 16 September 2013
a b s t r a c t Background: Commonly the frequency of international normalized ratio (INR) monitoring with a conventional laboratory test in stable patients is once a month. When using a dedicated personal device for INR assessment, the frequency may be increased to two or more times a month. Objective: To show that INR assessed by self-measurement at home is reliable and feasible in the mid-term and improves medical care. Patients and methods: All patients in the study on INR self-measurement (clinical trial.gov: NCT00925197), conducted between 2004 and 2007, were re-contacted for mid-term follow-up. One hundred and seventy eight out of 192 patients who participated in the study answered a questionnaire. The average follow-up time was 4.2 years (±1) for the self-measurement group and 4.9 years (±1) for the laboratory-analyzed control group. Results: Only 26 patients (group A) continued to use INR self-measurement to monitor treatment with vitamin K antagonists (VKA). The main reasons to stop INR self-measurement were its high cost and difficulty in obtaining strips. There were significantly fewer bleeding complications (p = 0.04) and complications related to VKA (p = 0.01) in self-measured patients compared to the control group. Feelings of security and quality of life were also significantly better (p = 0.002) for self-measured patients. Conclusion: Many patients with a mechanical heart valve, who self-measured INR, continue to use this method for their follow-up because of its positive effects on their health and quality of life. © 2013 Elsevier Ltd. All rights reserved.
Introduction Patients who have received mechanical valve prosthesis require treatment with vitamin K antagonists (VKA) in accordance with current recommendations [1]. Dabigatran has the approval of the Food and Drug Administration (FDA) and was placed on the US market in October 2010 after publication of the results from the RE-LY study on anticoagulant therapy in patients with non-valvular atrial fibrillation [2]. It is currently not used for patients with mechanical heart valves, although studies are still investigating its effectiveness [3]. This study protocol for the use of Dabigatran in patients with mechanical valves was interrupted in December 2011 as well detailed in the brand new published article which followed [4]. With no available data from international literature and no validated randomized trial, new oral anticoagulants have currently ☆ This Work was accepted for an oral presentation in June 2013, at Venice (Society of Heart Valve disease SHVD). ⁎ Corresponding author. Tel.: +33 47 37 51 577; fax: +33 47 37 51 579. E-mail address: [email protected] (K. Azarnoush). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.09.013
no indication for a medical prescription for patients with mechanical heart valve outside clinical trials. The quality of life of patients with mechanical valve prosthesis depends mainly on the absence of unwanted events related to anticoagulation, such as thromboembolic complications by underdosing and bleeding by overdosing. This monitoring is based on strict surveillance of the INR (international normalized ratio): this can be conducted by a monthly blood test analyzed in a laboratory or by a selfmeasurement device several times every month. INR self-measurement can provide reliable and more frequent results. Improvement in the quality of life for patients with self-testing devices is usually recorded in important international publications [5]. Previously, we observed an excellent correlation (N 80%) between INR results measured using a self-monitoring device and INR assessed by a laboratory [6]. However, there were seven hospitalizations for serious unwanted events associated with VKA in patients whose samples were laboratory-assessed (control group), and this is about 32,000 Euros more expensive than the absence of hospitalization for patients within the self-measurement group (p b 0.01). Self-measurement
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devices provide greater stability of anticoagulant therapy and, thus, reduce unwanted events [7]. A randomized study of INR self-measurement was conducted between 2004 and 2007 at the University Hospital Center of ClermontFerrand (ClinicalTrials.gov identifier: NCT00925197) [6,8]. Patients who participated in this study were re-contacted to evaluate their ongoing state of health, VKA management, and INR follow-up.
Patients and Methods Patients who participated in the study were re-contacted by phone or mail, and asked to complete a simple questionnaire. In total, 178 of the 192 patients who participated in the original study completed the questionnaire. For the other 14 patients, 4 patients had died in the interval between the two studies, 4 patients were lost to follow-up, 5 patients did not reply, and 1 patient had received a heart transplant. Among the patients who replied, two had undergone surgery for endocarditis. Among the 178 patients, 83 were INR self-measuring and used either a CoaguChek® (Roche Diagnostics, Mannheim, Germany) or a INRatio® device (Hemosense, San Diego, USA), plus strips offered by the Department of Cardiovascular Surgery. Since the start of the study, 63 of these 83 patients had returned their INR self-measurement device and 20 had continued to use the device and were purchasing their own strips from the pharmacy (Fig. 1).
Among the 102 patients in the control group, 95 responded to our questionnaire. Some devices for self-measurement that were returned by self-measurement patients were distributed to 15 patients in the control group who requested one. After proper training on the use of the device for several months, nine patients discontinued the use of the self-measurement device due to the high cost of strips, whereas six patients continued to regularly use the INR self-measurement devices (Fig. 1). We divided our patients into three groups: group A: 26 patients who had a device and continued to use it; group B: 80 patients who did not use an INR self-measurement device; and group C: 72 patients who had used an INR self-measurement device but decided to quit. After the end of the first trial, patients had no further “study” contact with the research team (other than the usual patient’s questions and help with unusual events within the heart surgery department). The preoperative characteristics of the patients have been previously reported [6] and there was no statistically significant difference between the groups. All patients received information on the use of VKA during their stay in hospital and through postoperative rehabilitation services. Education related to VKA therapy was identical for the two groups. For patients in INR self-testing group, three to six additional sessions on the practical use of INR self-testing devices were organized during their hospital stay and at rehabilitation centers, just after surgery. No additional education was provided after the immediate postoperative period. Patients and physicians all followed the recommendations of the
The evolution of the number of patients and presentation of the groups
178 patients
SELF-MEASURMENT GROUP:
LABORATORY CONTROL GROUP:
83 patients
95 patients
Group A
Group C
Group B
Self-measurement continuation:
Self-measurement interruption:
Obtained one Selfmeasurement
20 patients
63 patients
device: 15 patients
CONTROL LAB: 80 patients
Group A
Group C
Self-measurement continued: 6 patients
Self-measurement interruption: 9 patients
Fig. 1. Distribution of patients in each group. Group A: 26 patients who had a device and continued to use it; group B: 80 patients who did not use an INR self-measurement device; and group C: 72 patients who had used an INR self-measurement device but no longer used it.
K. Azarnoush et al. / Thrombosis Research 133 (2014) 149–153
Department of Cardiovascular Surgery regarding the INR therapeutic target range developed for the study [6], and this was pursued as a reference for the ongoing follow-up of our patients. Statistics The population is described using numbers and percentages for categorical variables and the means (± standard deviations) for quantitative variables. These were compared between independent groups by ANOVA or the Kruskal − Wallis test if ANOVA conditions were not met (homoscedasticity checked by Bartlett's test and normality by the Shapiro − Wilk test), followed by the appropriate post hoc Tukey − Kramer or Dunn test. Categorical data were compared between groups using the chi-squared test (or Fisher's exact test) followed by the post-hoc Marascuillo procedure. Multivariate regression analyses were then performed to assess adjustments to the post-intervention period. All analyses were performed using STATA (version 12, StataCorp, College Station, TX, USA) with a two-sided type I error of 5% (considering α inflation when appropriate). Results The patients’ characteristics from the different groups are summarized in Table 1. Three patients died at the end of the study after a median follow up of 4.9 (±1) years from the self-assessment group and 4.2 (±1) years from group B. Statistical analyses compared data from patients who had never used an INR self-measurement device (group B) to those who still used it (group A). Those patients who had already used the INR self-measurement device, but had now stopped (group C), were separated from group A in order to study the effectiveness of education on self-measurement INR monitoring. One of the aims of our study was to compare patients who had used an INR selfmeasurement device (group C) with patients still using a conventional INR test (i.e., group B). Group C contained patients who had only participated in a previous study: thus, there was a selection bias (historical use of an INR self-measurement device). Consequently, this did not allow statistical evaluation of complications related to VKAs. The results from group C are, nevertheless, reported in Tables 1 and 2. Complications related to VKA and estimation of their severities are listed according to international recommendations [9]. The first thing to note is the high number of significant bleeding complications (hospitalization with or without transfusion of red blood cells) in group B (37.5%) compared to group A (15.4%), (p = 0.04) and the second element, of even more relevance, is the absence of the occurrence of significant thromboembolic events in group A, after a mean follow-up of
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4 years (Tables 1 and 3). Considering all the side effects associated with VKAs, the group of patients who regularly used an INR self-measurement device had a statistically lower risk than group B (42.5%; p = 0.01) and even than group B and C combined (35.5%; p = 0.04). It is noteworthy that there was no difference in survival of patients among the different groups and the overall survival at the end of the followup period was 97.2%. Assessment of INR dosage was made at least once a month in 96% of patients in group A and 92% of patients from group B, although group A patients had a clear tendency towards self-management of VKA (50%) in contrast to patients in group B (14.1%), who relied heavily on their treating physicians (p b 0.001). Variation in INR outside the target range is significantly higher for patients in group B (p = 0.03), and five patients in group B were hospitalized for a VKA overdose and had INR values far above the recommended therapeutic range. Table 2 summarizes the questions asked directly to patients to collect their perceptions about INR self-measurement. All patients from group A believed that the device increased their quality of life. Only 36 (45%) patients thought this way in the group B (who had never had an INR self-measurement device) (p = 0.002). The main reason for interrupting the use of INR self-measurement (group C) was the high cost of its use. Two-thirds of patients in groups B and C would have been motivated to use an INR self-measurement device if there had been financial support equivalent to that of diabetic patients. Discussion Currently, more than 900,000 patients are treated by oral anticoagulants (VKA) in France [10]. VKAs are responsible for most iatrogenic complications in France [11]. The cost of these complications is N300 million Euros per year [11]. INR variability is an independent predictive factor for decreased survival for patients with a mechanical valve [12]. Biological monitoring is essential due to the large inter-individual pharmacokinetic variability of INR [13]. The first point to note in our study is the excellent survival of patients with a mechanical valve. The recommendations of our Department of Cardiovascular Surgery are reinforced by these results, which are consistent with those reported in the international literature [14,15]. Oral anticoagulants, such as AVK, have a narrow therapeutic window, which can cause serious undesirable effects: hemorrhagic accidents by an overdose or thromboembolic accidents by underdosing [16]. The severity of bleeding complications is highlighted by a metaanalysis published in 2003 [17]. From 33 studies (4374 patient years
Table 1 Follow-up of patients and the occurrence of complications related to the use of anticoagulants. Group A: 26 patients who had a device and continued to use it; group B: 80 patients who did not use an INR self-measurement device; group C: 72 patients who had used an INR self-measurement device but no longer used it.
Gender, male, n (%) Age (years), mean (standard deviation) Post-study period (years), mean (standard deviation) INR monitoring frequency ≤1 month, n (%) INR variations outside the target area(1), n (%) Active participation in patient dose adjustment with or without the help from the doctor, n (%) VKA self-management, n (%) Bleeding, n (%) All events related to VKA, n (%)(2)
Group A (n = 26)
Group B (n = 80)
(A vs. B)
p
B+C n = 152
(A vs. B + C)
A+C n = 98
(A + C vs. B)
15 (57.7) 62.5 (10.8) 4.2 (1.0) 25 (96.2) 8 (30.8) 20 (76.9)
53 (66.2) 63.6 (8.8) 4.9 (1.0) 70 (92.1) 42 (56.0) 37 (47.4)
0.43 0.79 0.001 0.68 0.03 0.009
111 (73.0) 62.5 (9.3) 4.9 (1.1) 135 (92.5) 71 (46.7) 69 (46.6)
0.12 0.82 0.001 0.70 0.08 0.004
73 (74.5) 61.7 (10.0) 4.7 (1.1) 90 (93.8) 37 (39.4) 52 (54.2)
0.23 0.20 0.18 0.68 0.03 0.38
13 (50.0) 4 (15.4) 4 (15.4)
11 (14.1) 30 (37.5) 34 (42.5)
b0.001 0.04/0.049⁎ 0.01/0.04⁎
125 (84.5) 48 (31.6) 54 (35.5)
b0.001 0.09 0.04/0.05⁎
VKA: vitamin K antagonists. INR: international normalized ratio. (1) Other events related to VKA (significant overdoses requiring hospitalization): n = 5 in group C. (2) Thromboembolic events: n = 2 in group C and n = 2 in group B. ⁎ Adjusted p values to numbers of years of follow up.
p
25 (26.1) 22 (22.4) 24 (24.5)
p
0.05 0.03/0.04⁎ 0.01/0.02⁎
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Table 2 Opinions of patients concerning INR self-measurement. Group A: 26 patients who had a device and continue to use it; group B: 80 patients who did not use an INR self-measurement device; group C: 72 patients who had used an INR self-measurement device but no longer used it.
Self-measurement ↑comfort and quality of life, n (%) Self-measurement = INR stability, n (%) Self-measurement ↓ complications, n (%) Self-measurement gives more reliable results, n (%) Device support, n (%) Use if there is reimbursement, n (%)
Group A (n = 26)
Group B (n = 80)
P (A vs. B)
B+C n = 152
P (A vs. B + C)
A+C n = 98
P (A + C vs. B)
26 (100.0) 18 (69.2) 16 (61.5) 8 (30.8) 25 (96.1) 24 (96.0)
36 (70.9) 26 (47.3) 16 (29.1) 8 (14.5) 58 (80.6) 53 (71.6)
0.002 0.06 0.007 0.09 0.06 0.01
96 (80.0) 68 (56.7) 47 (39.5) 23 (19.2) 115 (81.6) 107 (74.3)
0.008 0.24 0.04 0.19 0.06 0.02
83 (91.1) 60 (65.9) 47 (52.2) 23 (25.3) 82 (86.3) 78 (82.1)
0.001 0.03 0.006 0.13 0.32 0.10
VKA: vitamin K antagonists. INR: international normalized ratio.
of treatment with VKA), 0.6 − 10% of hemorrhagic accidents have been reported, and 13.4% of these are fatal events. Thus, it is important to provide education and information for long-term VKA use. Although the rate of complications caused by VKA under- or overdosing in the control group was quite acceptable (within the low range), there was an even lower frequency of this type of accident in the INR self-measurement group because of the significantly improved patient follow-up. It is even more remarkable that the use of a self-measurement device seemed to actively contribute to educating patients to have more frequent INR assessments (N 96% had more than one INR assessment a month, despite the additional cost that this entails, and they either acted alone (50%) or with their treating physician to make any necessary VKA-dose adjustment. In adults, this VKA self-management is not yet officially authorized in France outside of clinical trials. For 13 years in Europe and North America (Canada and the USA), INR self-measurement systems have been used to allow patients to obtain at-home reliable [6] and more frequent measurements [18]. These devices have an important impact on the quality of life of patients [19], but also affect the stability of anticoagulation [20]. The decrease in the frequency of hemorrhagic and thromboembolic disorders under VKA, obtained after extensive education and close monitoring of INR rates by self-measurement devices, should be compared to the incidence of these complications in clinical trials that evaluate new oral anticoagulants and VKA [2,21]. This comparison is even more important if we consider that Boehringer Ingelheim Pharmaceutical Laboratories interrupted its study concerning the use of Dabigatran in patients with mechanical valves (ClinicalTrials.gov Identifier: NCT01452347) [4]. New oral anticoagulants still need to be validated by further important studies to replace conventional VKA in daily treatment of patients with mechanical heart valves. It should be noted that some rare studies have cast doubts on the advantages provided by INR self-measurement devices given to patients with a mechanical valve prosthesis receiving VKA. The study by Matchar et al. [22] presents perfect methodology and meticulous statistical analyses, but which can hardly reflect what happens in ordinary life. Indeed, the population in this study was almost exclusively composed by males (98%), recruited from military or ex-military personnel. There was no funding to enable support, even partial and because of that 234 patients who had been initially randomized to INR self-measurement, stopped the use of the device mainly for economical reasons (out of 1465). Patients under VKA in the control group were Table 3 Characteristics of patients in group A and B.
Aortic valve replacement Mitral valve replacement Double valve replacement Atrial Fibrillation Antiplatelet agents
Group A (n = 26)
Group B (n = 80)
p
21 (80.8) 4 (15.4) 1 (3.8) 4 (15.4) 22 (84.6)
62 (77.5) 12 (15.0) 6 (7.5) 10 (12.5) 68 (85.0)
0.73 0.96 1 0.71 0.96
seen again in specialized consultations every 3 months, which is impossible in France, in a population unaccustomed to this kind of military discipline. These characteristics and the judgment criteria in Matchar’s study make it impossible to directly compare their results with data from our patients. The discontinuation rate for the use of selfmeasurement devices in the Matchar et al. study [22] was significantly lower than the one in our study; however, our study had a wider range of patients and we also had a longer follow-up period. The main cause of renouncing the use of INR self-measurement devices is its funding. Indeed, the high cost of devices and even the higher cost of strips are real obstacles to their use. However, this should be compared with the situation for French paediatric patients who rightly receive (at least) partial reimbursement (limited to the number of strips required monthly) for the overall price of self-measurement devices, such as glucometers to French diabetic patients. It was not possible to quantify the extra cost induced by thromboembolic events and/or bleeding. In our initial study, this extra cost exceeded the cost induced by INR self-measurement devices. Study Limitations The team involved in the production and construction of this study are aware that there may have been selection bias of patients. Indeed, among all patients who had an INR self-measurement device, only the most motivated (and probably the better-off patients in financial terms) continued to use it. The small samples size and a significantly different follow-up time between group A and B are among other limitations of this study. However, as it indicated in statistical considerations, multivariate analysis was considered in order to take into account adjustment on numbers of years of follow-up in order to reduce the risk of statistical errors. Conclusion Specific VKA education and INR monitoring in patients who have a mechanical valve are of paramount importance. Self monitoring device support improves the quality of life of these patients and significantly reduces the number of complications caused by large variations in INR. A meticulous education program and specific education on the use of INR self-measurement devices, as well as financial support (even partial) for patients with a mechanical heart prosthesis, would facilitate the purchase of devices and strips for selected patients, and would make inestimable progress towards modern and adapted support for our patients. Conflict of Interest Statement The INR self-measurement devices from the NCT00925197 study were funded by the Hospital Clinical Research Program (HCRP) of the French Ministry of Health, the University Hospital of ClermontFerrand and St. Jude Medical Laboratories (Minnesota, USA), Roche
K. Azarnoush et al. / Thrombosis Research 133 (2014) 149–153
Diagnostics International (Roche Diagnostics, Mannheim, Germany), and Hemosense (San Diego, USA). For the current study, there is no funding to declare. All patients were contacted on the initiative of the Department of Cardiovascular Surgery at the University Hospital Center of Clermont-Ferrand. Authors’ Contributions K. Azarnoush: conceived the study and performed data acquisition, data interpretation and wrote the manuscript. E. Dorigo: patient management and data acquisition. B. Pereira: Head of independent statistics unit of the University Hospital of Clermont-Ferrand, data analysis and interpretation. C. Dauphin: protocol development. E. Geoffroy: patient management and data acquisition. N. Dauphin: patient management and data acquisition. N. D’Ostrevy: patient management and data acquisition. B. Legault: patient management and data acquisition. L. Camilleri: Head of Heart Surgery Department, study conception, final approval. Acknowledgments The authors would like to thank Ms. Valérie Batel for her precious help in data acquisition and preparation of this manuscript. Appendix A. Supplementary Data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.thromres.2013.09.013. References [1] Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, et al. Evidencebased management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl. 2):e152S–84S. [2] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139–51. [3] Van de Werf F, Brueckmann M, Connolly SJ, Friedman J, Granger CB, Härtter S, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J 2012;163(6):931–7. [4] Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;26;369(13):1206–14.
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[5] Heneghan C, Ward A, Perera R, Bankhead C, Fuller A, Stevens R, et al. Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2012;379(9813):322–34. [6] Azarnoush K, Camilleri L, Aublet-Cuvelier B, Geoffroy E, Dauphin C, Dubray C, et al. Results of the first randomized French study evaluating self-testing of the International Normalized Ratio. J Heart Valve Dis 2011;20(5):518–25. [7] Bloomfield HE, Krause A, Greer N, Taylor BC, MacDonald R, Rutks I, et al. Meta-analysis: effect of patient self-testing and self-management of longterm anticoagulation on major clinical outcomes. Ann Intern Med 2011;154(7):472–82. [8] Dauphin C, Legault B, Jaffeux P, Motreff P, Azarnoush K, Joly H, et al. Comparison of INR stability between self-monitoring and standard laboratory method: preliminary results of a prospective study in 67 mechanical heart valve patients. Arch Cardiovasc Dis 2008;101(11–12):753–61. [9] Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL, et al. Guidelines for reporting mortality and morbidity after cardiac valve interventions. Ann Thorac Surg 2008;85:1490–5. [10] Gras-Champel V, Brenet-Dufour V, Moragny J, Masson H, Davidau E, Masmoudi K, et al. Quantification of the part allocated to the preventability of vitamin K antagonists therapy bleeding events. Therapie 2010;65(3):261–8. [11] Pouyanne P, Haramburu F, Imbs JL, Bégaud B. Admissions to hospital caused by adverse drug reactions: cross sectional incidence study. French Pharmacovigilance Centres. BMJ 2000;320(7241):1036. [12] Butchart EG, Payne N, Li HH, Buchan K, Mandana K, Grunkemeier GL. Better anticoagulation control improves survival after valve replacement. J Thorac Cardiovasc Surg 2002;123:715–23. [13] Johnston M, Harrison L, Moffat K, Willan A, Hirsh J. Reliability of the international normalized ratio for monitoring the induction phase of warfarin: comparison with the prothrombin time ratio. J Lab Clin Med 1996;128(2):214–7. [14] Weber A, Noureddine H, Englberger L, Dick F, Gahl B, Aymard T, et al. Ten-year comparison of pericardial tissue valves versus mechanical prostheses for aortic valve replacement in patients younger than 60 years of age. J Thorac Cardiovasc Surg 2012 Nov;144(5):1075–83. [15] Azarnoush K, Laborde F, de Riberolles C. The Sorin Bicarbon over 15 years clinical outcomes: multicentre experience in 1704 patients. Eur J Cardiothorac Surg 2010;38(6):759–66. [16] Wong PY, Schulman S, Woodworth S, Holbrook A. Supplemental patient education for patients taking oral anticoagulants: systematic review and meta-analysis. J Thromb Haemost 2013;11(3):491–502. [17] Linkins LA, Choi PT, Ouketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139(11):893–900. [18] Fitzmaurice DA, Murray ET, McCahon D, Holder R, Raftery JP, Hussain S, et al. Self management of oral anticoagulation: randomised trial. BMJ 2005;331(7524):1057. [19] Levi M, de Peuter OR, Kamphuisen PW. Management strategies for optimal control of anticoagulation in patients with atrial fibrillation. Semin Thromb Hemost 2009;35(6):560–7. [20] Gardiner C, Williams K, Longair I, Mackie IJ, Machin SJ, Cohen H. A randomised control trial of patient self-management of oral anticoagulation compared with patient self-testing. Br J Haematol 2006;132(5):598–603. [21] Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883–91. [22] Matchar DB, Jacobson A, Dolor R, Edson R, Uyeda L, Phibbs CS, et al. Effect of home testing of international normalized ratio on clinical events. N Engl J Med 2010;363(17):1608–20.
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Mid-term results of self-testing of the international normalized ratio in adults with a mechanical heart valve☆ Kasra Azarnoush a,⁎, Enrica Dorigo a, Bruno Pereira b, Claire Dauphin c, Etienne Geoffroy a, Nicolas Dauphin a, Nicola D’Ostrevy a, Benoit Legault a, Lionel Camilleri a a b c
Heart surgery Department, G. Montpied Hospital, Clermont-Ferrand University Hospital, Clermont-Ferrand, France Bio-statistics unit, Délégation Recherche Clinique & Innovation, Clermont-Ferrand University Hospital, Clermont-Ferrand, France Cardiology department, G. Montpied Hospital, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
a r t i c l e
i n f o
Article history: Received 17 June 2013 Received in revised form 4 September 2013 Accepted 9 September 2013 Available online 16 September 2013
a b s t r a c t Background: Commonly the frequency of international normalized ratio (INR) monitoring with a conventional laboratory test in stable patients is once a month. When using a dedicated personal device for INR assessment, the frequency may be increased to two or more times a month. Objective: To show that INR assessed by self-measurement at home is reliable and feasible in the mid-term and improves medical care. Patients and methods: All patients in the study on INR self-measurement (clinical trial.gov: NCT00925197), conducted between 2004 and 2007, were re-contacted for mid-term follow-up. One hundred and seventy eight out of 192 patients who participated in the study answered a questionnaire. The average follow-up time was 4.2 years (±1) for the self-measurement group and 4.9 years (±1) for the laboratory-analyzed control group. Results: Only 26 patients (group A) continued to use INR self-measurement to monitor treatment with vitamin K antagonists (VKA). The main reasons to stop INR self-measurement were its high cost and difficulty in obtaining strips. There were significantly fewer bleeding complications (p = 0.04) and complications related to VKA (p = 0.01) in self-measured patients compared to the control group. Feelings of security and quality of life were also significantly better (p = 0.002) for self-measured patients. Conclusion: Many patients with a mechanical heart valve, who self-measured INR, continue to use this method for their follow-up because of its positive effects on their health and quality of life. © 2013 Elsevier Ltd. All rights reserved.
Introduction Patients who have received mechanical valve prosthesis require treatment with vitamin K antagonists (VKA) in accordance with current recommendations [1]. Dabigatran has the approval of the Food and Drug Administration (FDA) and was placed on the US market in October 2010 after publication of the results from the RE-LY study on anticoagulant therapy in patients with non-valvular atrial fibrillation [2]. It is currently not used for patients with mechanical heart valves, although studies are still investigating its effectiveness [3]. This study protocol for the use of Dabigatran in patients with mechanical valves was interrupted in December 2011 as well detailed in the brand new published article which followed [4]. With no available data from international literature and no validated randomized trial, new oral anticoagulants have currently ☆ This Work was accepted for an oral presentation in June 2013, at Venice (Society of Heart Valve disease SHVD). ⁎ Corresponding author. Tel.: +33 47 37 51 577; fax: +33 47 37 51 579. E-mail address: [email protected] (K. Azarnoush). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.09.013
no indication for a medical prescription for patients with mechanical heart valve outside clinical trials. The quality of life of patients with mechanical valve prosthesis depends mainly on the absence of unwanted events related to anticoagulation, such as thromboembolic complications by underdosing and bleeding by overdosing. This monitoring is based on strict surveillance of the INR (international normalized ratio): this can be conducted by a monthly blood test analyzed in a laboratory or by a selfmeasurement device several times every month. INR self-measurement can provide reliable and more frequent results. Improvement in the quality of life for patients with self-testing devices is usually recorded in important international publications [5]. Previously, we observed an excellent correlation (N 80%) between INR results measured using a self-monitoring device and INR assessed by a laboratory [6]. However, there were seven hospitalizations for serious unwanted events associated with VKA in patients whose samples were laboratory-assessed (control group), and this is about 32,000 Euros more expensive than the absence of hospitalization for patients within the self-measurement group (p b 0.01). Self-measurement
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devices provide greater stability of anticoagulant therapy and, thus, reduce unwanted events [7]. A randomized study of INR self-measurement was conducted between 2004 and 2007 at the University Hospital Center of ClermontFerrand (ClinicalTrials.gov identifier: NCT00925197) [6,8]. Patients who participated in this study were re-contacted to evaluate their ongoing state of health, VKA management, and INR follow-up.
Patients and Methods Patients who participated in the study were re-contacted by phone or mail, and asked to complete a simple questionnaire. In total, 178 of the 192 patients who participated in the original study completed the questionnaire. For the other 14 patients, 4 patients had died in the interval between the two studies, 4 patients were lost to follow-up, 5 patients did not reply, and 1 patient had received a heart transplant. Among the patients who replied, two had undergone surgery for endocarditis. Among the 178 patients, 83 were INR self-measuring and used either a CoaguChek® (Roche Diagnostics, Mannheim, Germany) or a INRatio® device (Hemosense, San Diego, USA), plus strips offered by the Department of Cardiovascular Surgery. Since the start of the study, 63 of these 83 patients had returned their INR self-measurement device and 20 had continued to use the device and were purchasing their own strips from the pharmacy (Fig. 1).
Among the 102 patients in the control group, 95 responded to our questionnaire. Some devices for self-measurement that were returned by self-measurement patients were distributed to 15 patients in the control group who requested one. After proper training on the use of the device for several months, nine patients discontinued the use of the self-measurement device due to the high cost of strips, whereas six patients continued to regularly use the INR self-measurement devices (Fig. 1). We divided our patients into three groups: group A: 26 patients who had a device and continued to use it; group B: 80 patients who did not use an INR self-measurement device; and group C: 72 patients who had used an INR self-measurement device but decided to quit. After the end of the first trial, patients had no further “study” contact with the research team (other than the usual patient’s questions and help with unusual events within the heart surgery department). The preoperative characteristics of the patients have been previously reported [6] and there was no statistically significant difference between the groups. All patients received information on the use of VKA during their stay in hospital and through postoperative rehabilitation services. Education related to VKA therapy was identical for the two groups. For patients in INR self-testing group, three to six additional sessions on the practical use of INR self-testing devices were organized during their hospital stay and at rehabilitation centers, just after surgery. No additional education was provided after the immediate postoperative period. Patients and physicians all followed the recommendations of the
The evolution of the number of patients and presentation of the groups
178 patients
SELF-MEASURMENT GROUP:
LABORATORY CONTROL GROUP:
83 patients
95 patients
Group A
Group C
Group B
Self-measurement continuation:
Self-measurement interruption:
Obtained one Selfmeasurement
20 patients
63 patients
device: 15 patients
CONTROL LAB: 80 patients
Group A
Group C
Self-measurement continued: 6 patients
Self-measurement interruption: 9 patients
Fig. 1. Distribution of patients in each group. Group A: 26 patients who had a device and continued to use it; group B: 80 patients who did not use an INR self-measurement device; and group C: 72 patients who had used an INR self-measurement device but no longer used it.
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Department of Cardiovascular Surgery regarding the INR therapeutic target range developed for the study [6], and this was pursued as a reference for the ongoing follow-up of our patients. Statistics The population is described using numbers and percentages for categorical variables and the means (± standard deviations) for quantitative variables. These were compared between independent groups by ANOVA or the Kruskal − Wallis test if ANOVA conditions were not met (homoscedasticity checked by Bartlett's test and normality by the Shapiro − Wilk test), followed by the appropriate post hoc Tukey − Kramer or Dunn test. Categorical data were compared between groups using the chi-squared test (or Fisher's exact test) followed by the post-hoc Marascuillo procedure. Multivariate regression analyses were then performed to assess adjustments to the post-intervention period. All analyses were performed using STATA (version 12, StataCorp, College Station, TX, USA) with a two-sided type I error of 5% (considering α inflation when appropriate). Results The patients’ characteristics from the different groups are summarized in Table 1. Three patients died at the end of the study after a median follow up of 4.9 (±1) years from the self-assessment group and 4.2 (±1) years from group B. Statistical analyses compared data from patients who had never used an INR self-measurement device (group B) to those who still used it (group A). Those patients who had already used the INR self-measurement device, but had now stopped (group C), were separated from group A in order to study the effectiveness of education on self-measurement INR monitoring. One of the aims of our study was to compare patients who had used an INR selfmeasurement device (group C) with patients still using a conventional INR test (i.e., group B). Group C contained patients who had only participated in a previous study: thus, there was a selection bias (historical use of an INR self-measurement device). Consequently, this did not allow statistical evaluation of complications related to VKAs. The results from group C are, nevertheless, reported in Tables 1 and 2. Complications related to VKA and estimation of their severities are listed according to international recommendations [9]. The first thing to note is the high number of significant bleeding complications (hospitalization with or without transfusion of red blood cells) in group B (37.5%) compared to group A (15.4%), (p = 0.04) and the second element, of even more relevance, is the absence of the occurrence of significant thromboembolic events in group A, after a mean follow-up of
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4 years (Tables 1 and 3). Considering all the side effects associated with VKAs, the group of patients who regularly used an INR self-measurement device had a statistically lower risk than group B (42.5%; p = 0.01) and even than group B and C combined (35.5%; p = 0.04). It is noteworthy that there was no difference in survival of patients among the different groups and the overall survival at the end of the followup period was 97.2%. Assessment of INR dosage was made at least once a month in 96% of patients in group A and 92% of patients from group B, although group A patients had a clear tendency towards self-management of VKA (50%) in contrast to patients in group B (14.1%), who relied heavily on their treating physicians (p b 0.001). Variation in INR outside the target range is significantly higher for patients in group B (p = 0.03), and five patients in group B were hospitalized for a VKA overdose and had INR values far above the recommended therapeutic range. Table 2 summarizes the questions asked directly to patients to collect their perceptions about INR self-measurement. All patients from group A believed that the device increased their quality of life. Only 36 (45%) patients thought this way in the group B (who had never had an INR self-measurement device) (p = 0.002). The main reason for interrupting the use of INR self-measurement (group C) was the high cost of its use. Two-thirds of patients in groups B and C would have been motivated to use an INR self-measurement device if there had been financial support equivalent to that of diabetic patients. Discussion Currently, more than 900,000 patients are treated by oral anticoagulants (VKA) in France [10]. VKAs are responsible for most iatrogenic complications in France [11]. The cost of these complications is N300 million Euros per year [11]. INR variability is an independent predictive factor for decreased survival for patients with a mechanical valve [12]. Biological monitoring is essential due to the large inter-individual pharmacokinetic variability of INR [13]. The first point to note in our study is the excellent survival of patients with a mechanical valve. The recommendations of our Department of Cardiovascular Surgery are reinforced by these results, which are consistent with those reported in the international literature [14,15]. Oral anticoagulants, such as AVK, have a narrow therapeutic window, which can cause serious undesirable effects: hemorrhagic accidents by an overdose or thromboembolic accidents by underdosing [16]. The severity of bleeding complications is highlighted by a metaanalysis published in 2003 [17]. From 33 studies (4374 patient years
Table 1 Follow-up of patients and the occurrence of complications related to the use of anticoagulants. Group A: 26 patients who had a device and continued to use it; group B: 80 patients who did not use an INR self-measurement device; group C: 72 patients who had used an INR self-measurement device but no longer used it.
Gender, male, n (%) Age (years), mean (standard deviation) Post-study period (years), mean (standard deviation) INR monitoring frequency ≤1 month, n (%) INR variations outside the target area(1), n (%) Active participation in patient dose adjustment with or without the help from the doctor, n (%) VKA self-management, n (%) Bleeding, n (%) All events related to VKA, n (%)(2)
Group A (n = 26)
Group B (n = 80)
(A vs. B)
p
B+C n = 152
(A vs. B + C)
A+C n = 98
(A + C vs. B)
15 (57.7) 62.5 (10.8) 4.2 (1.0) 25 (96.2) 8 (30.8) 20 (76.9)
53 (66.2) 63.6 (8.8) 4.9 (1.0) 70 (92.1) 42 (56.0) 37 (47.4)
0.43 0.79 0.001 0.68 0.03 0.009
111 (73.0) 62.5 (9.3) 4.9 (1.1) 135 (92.5) 71 (46.7) 69 (46.6)
0.12 0.82 0.001 0.70 0.08 0.004
73 (74.5) 61.7 (10.0) 4.7 (1.1) 90 (93.8) 37 (39.4) 52 (54.2)
0.23 0.20 0.18 0.68 0.03 0.38
13 (50.0) 4 (15.4) 4 (15.4)
11 (14.1) 30 (37.5) 34 (42.5)
b0.001 0.04/0.049⁎ 0.01/0.04⁎
125 (84.5) 48 (31.6) 54 (35.5)
b0.001 0.09 0.04/0.05⁎
VKA: vitamin K antagonists. INR: international normalized ratio. (1) Other events related to VKA (significant overdoses requiring hospitalization): n = 5 in group C. (2) Thromboembolic events: n = 2 in group C and n = 2 in group B. ⁎ Adjusted p values to numbers of years of follow up.
p
25 (26.1) 22 (22.4) 24 (24.5)
p
0.05 0.03/0.04⁎ 0.01/0.02⁎
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Table 2 Opinions of patients concerning INR self-measurement. Group A: 26 patients who had a device and continue to use it; group B: 80 patients who did not use an INR self-measurement device; group C: 72 patients who had used an INR self-measurement device but no longer used it.
Self-measurement ↑comfort and quality of life, n (%) Self-measurement = INR stability, n (%) Self-measurement ↓ complications, n (%) Self-measurement gives more reliable results, n (%) Device support, n (%) Use if there is reimbursement, n (%)
Group A (n = 26)
Group B (n = 80)
P (A vs. B)
B+C n = 152
P (A vs. B + C)
A+C n = 98
P (A + C vs. B)
26 (100.0) 18 (69.2) 16 (61.5) 8 (30.8) 25 (96.1) 24 (96.0)
36 (70.9) 26 (47.3) 16 (29.1) 8 (14.5) 58 (80.6) 53 (71.6)
0.002 0.06 0.007 0.09 0.06 0.01
96 (80.0) 68 (56.7) 47 (39.5) 23 (19.2) 115 (81.6) 107 (74.3)
0.008 0.24 0.04 0.19 0.06 0.02
83 (91.1) 60 (65.9) 47 (52.2) 23 (25.3) 82 (86.3) 78 (82.1)
0.001 0.03 0.006 0.13 0.32 0.10
VKA: vitamin K antagonists. INR: international normalized ratio.
of treatment with VKA), 0.6 − 10% of hemorrhagic accidents have been reported, and 13.4% of these are fatal events. Thus, it is important to provide education and information for long-term VKA use. Although the rate of complications caused by VKA under- or overdosing in the control group was quite acceptable (within the low range), there was an even lower frequency of this type of accident in the INR self-measurement group because of the significantly improved patient follow-up. It is even more remarkable that the use of a self-measurement device seemed to actively contribute to educating patients to have more frequent INR assessments (N 96% had more than one INR assessment a month, despite the additional cost that this entails, and they either acted alone (50%) or with their treating physician to make any necessary VKA-dose adjustment. In adults, this VKA self-management is not yet officially authorized in France outside of clinical trials. For 13 years in Europe and North America (Canada and the USA), INR self-measurement systems have been used to allow patients to obtain at-home reliable [6] and more frequent measurements [18]. These devices have an important impact on the quality of life of patients [19], but also affect the stability of anticoagulation [20]. The decrease in the frequency of hemorrhagic and thromboembolic disorders under VKA, obtained after extensive education and close monitoring of INR rates by self-measurement devices, should be compared to the incidence of these complications in clinical trials that evaluate new oral anticoagulants and VKA [2,21]. This comparison is even more important if we consider that Boehringer Ingelheim Pharmaceutical Laboratories interrupted its study concerning the use of Dabigatran in patients with mechanical valves (ClinicalTrials.gov Identifier: NCT01452347) [4]. New oral anticoagulants still need to be validated by further important studies to replace conventional VKA in daily treatment of patients with mechanical heart valves. It should be noted that some rare studies have cast doubts on the advantages provided by INR self-measurement devices given to patients with a mechanical valve prosthesis receiving VKA. The study by Matchar et al. [22] presents perfect methodology and meticulous statistical analyses, but which can hardly reflect what happens in ordinary life. Indeed, the population in this study was almost exclusively composed by males (98%), recruited from military or ex-military personnel. There was no funding to enable support, even partial and because of that 234 patients who had been initially randomized to INR self-measurement, stopped the use of the device mainly for economical reasons (out of 1465). Patients under VKA in the control group were Table 3 Characteristics of patients in group A and B.
Aortic valve replacement Mitral valve replacement Double valve replacement Atrial Fibrillation Antiplatelet agents
Group A (n = 26)
Group B (n = 80)
p
21 (80.8) 4 (15.4) 1 (3.8) 4 (15.4) 22 (84.6)
62 (77.5) 12 (15.0) 6 (7.5) 10 (12.5) 68 (85.0)
0.73 0.96 1 0.71 0.96
seen again in specialized consultations every 3 months, which is impossible in France, in a population unaccustomed to this kind of military discipline. These characteristics and the judgment criteria in Matchar’s study make it impossible to directly compare their results with data from our patients. The discontinuation rate for the use of selfmeasurement devices in the Matchar et al. study [22] was significantly lower than the one in our study; however, our study had a wider range of patients and we also had a longer follow-up period. The main cause of renouncing the use of INR self-measurement devices is its funding. Indeed, the high cost of devices and even the higher cost of strips are real obstacles to their use. However, this should be compared with the situation for French paediatric patients who rightly receive (at least) partial reimbursement (limited to the number of strips required monthly) for the overall price of self-measurement devices, such as glucometers to French diabetic patients. It was not possible to quantify the extra cost induced by thromboembolic events and/or bleeding. In our initial study, this extra cost exceeded the cost induced by INR self-measurement devices. Study Limitations The team involved in the production and construction of this study are aware that there may have been selection bias of patients. Indeed, among all patients who had an INR self-measurement device, only the most motivated (and probably the better-off patients in financial terms) continued to use it. The small samples size and a significantly different follow-up time between group A and B are among other limitations of this study. However, as it indicated in statistical considerations, multivariate analysis was considered in order to take into account adjustment on numbers of years of follow-up in order to reduce the risk of statistical errors. Conclusion Specific VKA education and INR monitoring in patients who have a mechanical valve are of paramount importance. Self monitoring device support improves the quality of life of these patients and significantly reduces the number of complications caused by large variations in INR. A meticulous education program and specific education on the use of INR self-measurement devices, as well as financial support (even partial) for patients with a mechanical heart prosthesis, would facilitate the purchase of devices and strips for selected patients, and would make inestimable progress towards modern and adapted support for our patients. Conflict of Interest Statement The INR self-measurement devices from the NCT00925197 study were funded by the Hospital Clinical Research Program (HCRP) of the French Ministry of Health, the University Hospital of ClermontFerrand and St. Jude Medical Laboratories (Minnesota, USA), Roche
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Diagnostics International (Roche Diagnostics, Mannheim, Germany), and Hemosense (San Diego, USA). For the current study, there is no funding to declare. All patients were contacted on the initiative of the Department of Cardiovascular Surgery at the University Hospital Center of Clermont-Ferrand. Authors’ Contributions K. Azarnoush: conceived the study and performed data acquisition, data interpretation and wrote the manuscript. E. Dorigo: patient management and data acquisition. B. Pereira: Head of independent statistics unit of the University Hospital of Clermont-Ferrand, data analysis and interpretation. C. Dauphin: protocol development. E. Geoffroy: patient management and data acquisition. N. Dauphin: patient management and data acquisition. N. D’Ostrevy: patient management and data acquisition. B. Legault: patient management and data acquisition. L. Camilleri: Head of Heart Surgery Department, study conception, final approval. Acknowledgments The authors would like to thank Ms. Valérie Batel for her precious help in data acquisition and preparation of this manuscript. Appendix A. Supplementary Data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.thromres.2013.09.013. References [1] Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, et al. Evidencebased management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th edn: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl. 2):e152S–84S. [2] Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139–51. [3] Van de Werf F, Brueckmann M, Connolly SJ, Friedman J, Granger CB, Härtter S, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: The Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J 2012;163(6):931–7. [4] Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;26;369(13):1206–14.
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