EMPoWarMENT: Edmonton Pediatric Warfarin Self-Management Pilot Study in Children with Primarily Cardiac Disease

Thrombosis Research 126 (2010) e110–e115

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Regular Article

EMPoWarMENT: Edmonton Pediatric Warfarin Self-Management Pilot Study in Children with Primarily Cardiac Disease☆ M.E. Bauman a,⁎, K. Black b, M.L. Bauman c, A.A.K. Bruce d, S. Kuhle e, L. Bajzar c, M.P. Massicotte a a

Stollery Children's Hospital, University of Alberta, Edmonton, AB, Canada Stollery Children's Hospital, Edmonton, AB, Canada University of Alberta, Edmonton, AB, Canada d FRCPC University of Alberta, Edmonton, AB, Canada e School of Public Health, University of Alberta, Edmonton, AB, Canada b c

a r t i c l e

i n f o

Article history: Received 28 January 2010 Received in revised form 20 May 2010 Accepted 28 May 2010 Available online 2 July 2010 Keywords: Home INR monitoring Point of care monitoring Warfarin Vitamin K antagonists Quality of life Children Warfarin Self-management Heart disease

a b s t r a c t Increasing numbers of children require warfarin thromboprophylaxis. Home INR testing by the patient (PST) has revolutionized warfarin management. However, the family/patient must contact the health team for guidance for warfarin dosing. Patient self management(PSM) prepares a patient performing PST to take an active role in warfarin dosing. Adult studies demonstrate that PSM is safe and effective with improved adherence and treatment satisfaction quality of life (QOL). Objective: To estimate the safety and efficacy in children performing PSM or PST, to evaluate warfarin dose decision making in PSM, and warfarin related QOL. Methods: Warfarinized children performing PST for N 3 m were randomized to PST or PSM. The PSM group underwent warfarin management education and assumed independent warfarin management. INRs were collected for a year prior to and for 1 year of study to determine TTR and warfarin decision making. QOL was assessed through inventory completion and interviews. Results: 28 children were randomized and followed for 12 months. TTR was (83.9% pre/ post), and 77.7% pre to 83.0% post for PST and PSM (p = 0.312). Appropriate warfarin decision making was 90% with no major bleeding episodes and no thromboembolic events. PSM was preferred by families. Conclusions: PSM for children may be a safe and effective management strategy for warfarinized children. Clinical studies with larger sample size are required. © 2010 Elsevier Ltd. All rights reserved.

Introduction Pediatric medical and surgical advances have resulted in increased survival of infants and children with conditions previously considered fatal. However, a common sequela is the need for anticoagulation therapy for treatment of deep venous thrombosis or long-term primary thromboprophylaxis, most commonly in children with heart disease[1–4]. The cohorts of children requiring primary thromboprophylaxis in the setting of mechanical prosthetic heart valves and following the Fontan procedure are challenging due to their lifelong need for thromboprophylaxis. Warfarin, a narrow therapeutic index drug, is commonly used but must be closely monitored using a Abbreviations: INR, International normalized ratio; PST, patient self testing; PSM, Patient self management; QOL, Quality of life; TTR, Time in therapeutic range; VPaT, Vascular Patency and Thrombosis; KIDCLOT PAC QL, Kids informed decrease complications, Learning on Thromboembolism Pediatric Anticoagulation Quality of Life Inventory. ☆ Funding in part by Health Quality Council of Alberta and CIHR. ⁎ Corresponding author. Stollery Children's Hospital, 8440 112 Street, WMC 4H2.11, Edmonton, AB, Canada T6G 2B7. Tel.: + 1 780 407 1070; fax: + 1 780 407 1787. E-mail address: [email protected] (M.E. Bauman). 0049-3848/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2010.05.024

prothrombin time converted to an international normalized ratio (INR) to avoid both thrombotic and bleeding complications[5]. Warfarin management is difficult in children as they usually have complex underlying health problems, are receiving multiple medications, have inconsistent nutritional intake, and venipuncture is often difficult. In addition, the need to go to the laboratory for testing causes interruption of school and parent work attendance, and may have issues of adherence, especially in teenagers. Patient self testing (PST) using a point of care (POC) INR monitor revolutionized warfarin management in children[6]. The POC INR monitor requires a blood sample obtained by fingerstick, is performed at the patients’ convenience, eliminates the need for the patient to visit the laboratory for regular INR testing, produces an INR result within one minute, enables timely drug dosage adjustment, and prompt attention to critical values. The CoaguChek meter (CoaguChek XS® (Roche Diagnostics, Basel Switzerland) is most studied in children with the most recent model the CoaguChek XS® providing improved accuracy[7–9]. In general, POC coagulometers authorized for use have demonstrated accuracy and reliability. The CoaguChek XS® meter used in this study is demonstrated to be accurate and precise for use in children prescribed warfarin therapy[7–9]. For

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quality assurance, the Vascular Patency and Thrombosis (VPaT) program standards require evaluation of user proficiency in meter testing technique with laboratory comparisons yearly to ensure continued accuracy of coagulometer results[10]. Time in therapeutic range (TTR) is a commonly used surrogate for safety and efficacy. Published pediatric data indicate that TTR with patient self testing (PST) using a POC INR meter is as high as 83%. Patient self testing also decreases clinically important events[7,10–14] resulting in outcomes equal to or better than those achieved with conventional management by physician or anticoagulation clinics[21] utilizing laboratory INR. Patient self management (PSM) is a concept where a patient performing PST takes an active role in managing their treatment. Warfarinized patients are educated about warfarin management and dosing, and subsequently self-adjust their warfarin dose through application of dosing guidelines to the self tested INR result. Patient self management provides the potential for improving warfarin management through increased knowledge and participation in their healthcare. This concept is demonstrated to improve adherence and subsequently translate into better outcomes[10,15]. The primary objective of this pilot study was to estimate safety (bleeding) and efficacy (TTR, new or recurrent thromboembolic events) in children performing PSM or PST prior to implementation of a larger cohort study. The secondary objectives were the following: firstly, to evaluate warfarin dose decision making in PSM based on the warfarin dose adjustment algorithm; secondly, to qualitatively identify changes in warfarin related quality of life in PST and PSM; and thirdly, to identify characteristics of patients successful at PSM.

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as previously described. Demographic and clinical characteristics were collected. Participants were followed for a period of 12 months from time of randomization. Children randomized to the PST arm continued PST with warfarin dose adjustments and patient logs (diaries) completed by the nurse practitioner or physician within the VPaT program (Fig. 2). Participants randomized to PSM attended a one hour standardized intensive education group session[17] which focused on:[18–20] 1. Review of basic information on blood coagulation 2. Theoretical principles of individual interactions between warfarin and other medications, nutrition and illness 3. Warfarin dose adjustments using a standardized algorithm[4] appropriate for the patient target INR (Fig. 2) 4. Applying knowledge and critical thinking to optimize decision making for warfarin dose adjustments when deviations from the algorithm are reasonable 5. Recognition and reporting of adverse events i.e. thrombosis (under-dose) and hemorrhage (overdose) to the VPaT program 6. Information on the frequency of INR monitoring 7. Diary record completion and submission for quality control

The VPaT program is a dedicated subspecialty program within Stollery Children's Hospital, Edmonton, Canada. The VPaT program manages outpatient warfarinized children across Western Canada. Within this program, PST using the CoaguChek XS® meter following standardized validated warfarin education (KIDCLOT©)[6] is usual care. The Stollery Children's Hospital provided financial support in part for the INR meters and strips due to an objective improvement in clinical care for warfarinized children performing PST compared with those attending the laboratory for INR testing[6]. All children 0- 19 years (and their caregivers) followed by the VPaT program requiring long-term warfarin and who have been performing PST for greater than 3 months and able to attend the local Edmonton VPaT clinic between April-August 2008 were eligible for participation in this study (Fig. 1). Families were approached during their scheduled clinic visit. Consenting children and their families were enrolled in the trial and block randomized to either continue PST or to receive the intervention, PSM. A priori, a decision was made to have odd and even numbers from 1 to X assigned to PST or PSM, respectively; with X being the total number of consenting patients. The numbers were placed in an opaque, sealed envelope and following consent, the envelope was opened and a number was blindly chosen by the patient. All participants attended their annual thrombosis clinic appointment and underwent clinical assessment, educational review for PST, and completed the validated KIDCLOT© knowledge retention questionnaire [6] to ensure children and their caregivers sustained adequate knowledge (score N80%) about their warfarin therapy. Patients performed a point of care INR test to re-evaluate testing technique to ensure competency while at the same time a laboratory INR was performed to ensure meter accuracy [22,23].

Participants applied their new knowledge and began PSM, a two phase process: The initial 3 months (Phase 1) were supportive, where PSM participants communicated their recommendations for warfarin dose adjustment to the VPaT program. During Phase 2, participants made warfarin dose adjustments independently with 24 h VPaT support available as required. Participants completed and submitted INR diaries to the VPaT Program once a month during Phase 1 and then every two months during Phase 2. Submitted diaries were reviewed by the VPaT staff as a safety measure. The data obtained from patient diaries/logs was used to determine TTR, adverse events, adherence and warfarin dose decision making during the study period. Participant INRs and warfarin dosing decisions were collected for each participant for a year prior to study start as a within patient comparator. Adverse events were defined as objectively confirmed thrombosis and/or bleeding that involved/ required medical assessment and / or intervention. As part of the standardized JKIDCLOT© education parents and children were instructed on how to manage minor bleeding events by applying 10 minutes of firm pressure to cuts and for nosebleeds and to page the VPaT practitioner and to seek medical attention for any major bleeding or bleeding that they are concerned about. This education is reinforced and participants re-tested for knowledge retention yearly. Bruises were assessed every eight hours. If bleeding did not stop after 10 minutes of firm pressure, or if bruises increased in size over time or developed a subcutaneous lump (hematoma) they were instructed to page the VPaT practitioner on call and to seek medical attention. Reported events were documented in the patient files. In addition, PSM participants were instructed to document all (minor and major) bleeding events on their diaries at the time of the event, and were thereby included on their submissions. PST patients were questioned about any events with by telephone with each INR performed and documented by the practitioner. A formal Data Safety Monitoring Board (DSMB) was assembled (MC, AKC, JH) to review all adverse events. Stopping rules were determined according to the following. The study was insufficiently powered to determine efficacy, and PST is an acceptable method of warfarin monitoring in children[4], therefore, stopping rules only pertained to safety within the intervention group (PSM). A priori, the decision was that if 2 children experienced adverse events that may have been attributed to improper warfarin decision making, the study would be closed.

Interventions

Quality of Life

All participants participated in focus groups and completed and validated a baseline[16] quality of life inventory (KIDCLOT PAC QL©)

Quality of life (QOL) for PST and PSM participants is reported qualitatively from two sources. Firstly, the KIDCLOT PAC QL© parent-

Methods

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Fig. 1. EMPoWarMENT Study Methods. ITT + Intention to treat. mo = months, POC = point of care, KIDCLOT© QL = KIDCLOT© quality of life, PST = patient self testing, PSM = patient self management, TTR = time in therapeutic range, QOL = health related quality of life.

proxy (parents QOL and their assessment of child's’ QOL) and child teen KIDCLOT PAC QL© were completed pre and post intervention to evaluate potential change in quality of life related to warfarin use. Differences pre/post intervention were analyzed then compared between groups to identify any trends. Secondly, open ended questionnaires were completed and used as a platform for conducting semi-structured interviews at study conclusion. To interpret the semistructured interviews a conventional content analysis approach was taken[21]. The open-ended questionnaires were reviewed multiple times, and coded to identify potential themes by two researchers independently. Together the two researchers identified the key recurrent themes and compared them across the data set. Finally,

the data from the semi-structured interviews was analyzed to ensure a complete understanding of the underlying concept. As this is a pilot study with a small sample size and as such, was not registered with clinicaltrials.gov. The study was approved by the Health Research Ethics Board of the University of Alberta, Stollery Children's Hospital, Protocol # 2196. Statistical Analysis Given the limited number of eligible patients (n = 28) before the initiation of the study, no sample size calculation was performed. Patients in each assigned group were followed for one year. Neither

Fig. 2. EMPoWarMENT Trial: Edmonton Pediatric Warfarin Self-Management Study Warfarin Algorythm.

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participants nor the study team were blinded to the intervention. The statistician was blinded to the group assignments. The patients’ and their families’ baseline characteristics are reported descriptively. The TTR for each group and study phase was calculated using linear interpolation between INR values. The postintervention TTRs in each group (adjusting for baseline TTRs) were compared using Analysis of Covariance[28]. Warfarin decision making was evaluated through review of patient diaries to determine if the dose decision was consistent with education provided and dosing algorithm and described as a mean of the percentage of correct decisions. Data were analyzed as per Intention-To-Treat. Stata 11 (Stata Corp, College Station, TX) was used for the statistical analysis. Results All 28 of the eligible children followed by the VPaT program consented to participate in the study. Of the 28 patients (median age 10 years, range 1-19 years), 14 were randomized to PST and 14 to PSM. The groups appeared to be evenly distributed for the most common diagnosis (congenital or acquired heart disease), indication for anticoagulation, age, household income, parent educational and adults living in the home (Table 1). Twenty-six patients (93%) were followed for 12 months. Early withdrawal occurred in two children within the PSM group. One patient relocated after 9 months and a second child had their therapeutic warfarin discontinued 6 months after study start. Safety and Efficacy Evaluation of safety and efficacy revealed no reported bleeding events or new / recurrent thromboembolic events in either PST or PSM. These do not account for any events that may be brief, self-limiting, and deemed not worth mentioning by parents. Within the study period there were 584 and 587 INRs performed in the PST and PSM group. Twelve (0.02%) INRs and 8 (0.014%) INRs were greater than 5.0 in the PST and PSM, respectively. The INRs greater than 5 and were nonrelated to warfarin dosing decision and related to unexpected illness. The TTR remained unchanged in the PST group (83.9% pre and post), while the TTR in the PSM group changed from 77.7% pre to 83.0% post (p= 0.312). After adjusting for baseline differences in TTR, patients in the self-management group had a 1% (95%CI -7.7%; 9.7%) higher postintervention TTR compared to those in the self-testing group. The mean number of INR tests over the study period for PST and PSM was 22.6 and 22.7 respectively. Patients performing PSM made warfarin dose decisions consistent with the guidelines 90% of the time. The decisions that were inconsistent with the guidelines were entirely related to frequency of INR testing where the interval between INR testing was extended beyond recommendations for 1 week. Of the total 318 INRs performed in the PSM group there were 10 calls from participants requesting information and/or warfarin dosing support. Participant requests for support were to acquire reaffirmation of their decision and reasons for request are presented in Table 2. There appeared to be no identifiable patient characteristics that would identify patients that would be most successful at PSM.

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Table 1 PST (n = 14) Age group 1 to 5 years 6 to 12 years 13 years and older Underlying diagnosis Congenital heart disease Acquired heart disease Other Reason for anticoagulation Fontan Mechanical mitral valve Mechanical aortic valve Giant coronary aneurysms Other Therapeutic range 2.5-3.5 2.0-3.0 Household income b $30,000 $30,000 - $50,000 N $60,000 Missing Parental education Secondary school or less College/Technical institute Undergraduate university Graduate university Missing # of adults living in household 1 2 3 Missing # of full-time employed adults in household 0 1 2 3 Missing # of children in household 1 2 3 or more Missing # of school-aged children in household 0 1 2 3 or more Missing TTR

PSM (n = 14)

p value 0.61

3 6 5

5 6 3

12 1 1

11 1 2

5 4 4 0 1

5 3 3 1 2

5 9

3 11

2 3 5 4

2 3 6 3

7 4 1 1 1

4 4 4 0 2

3 9 1 1

4 7 1 2

0.83

0.81

0.4

0.98

0.31

0.84

0.62 1 6 6 0 1

2 5 4 1 2

4 7 2 1

4 5 3 2

0 6 6 1 1 83.9

1 4 5 2 2 77.7

0.62

0.35

0.32

• They became more confident that their child would not clot, but less secure in controlling their ability to control the INR. • Increased difficulty with warfarin dose adjustments • There was a positive trend in the parent-child relationship. These changes were not observed in the PST group.

Quality of Life The KIDCLOT PAC QL identified no change in “tasks” associated with warfarin use (i.e. remembering to give the pill, finger pokes, etc) between groups. Participants reported an overall preference for PSM. However, the following trends were identified to be influenced by PSM. Parents reported: • Their child's activities were altered due to warfarin (positive and negative).

Table 2 Support Requests. Total INRs for PSM n = 318

Number of requests n = 10

Reason for support request

Frequency

missed dose Warfarin reversal for dental extraction Warfarin management while on holiday INR N 5 INR b 1.4 Illness

1 1 1 1 1 5

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Children N8 years of age and teens did not report any differences in the tasks associated with warfarin use or in their activities (staying with friends, school trips, etc) pre post intervention or between PST and PSM. Yet for PSM, an increased sense of safety that they would not clot, more confidence in their INR, less worry that they would forget to take a warfarin pill, that their parents were less overprotective, and less associated stress due to warfarin was reported. Families preferred PSM and all but one indicated their preference for PSM. Open-ended questionnaires and semi-structured interviews identified recurrent themes (Table 3). Responses to PSM were: • “At first I didn't think I would want to. I thought I would want the protection of the VPaT program but it worked out well” • “I like self management better”. • “Made us more aware of why we were changing warfarin dosing and testing more often.” • “Inspires cooperation between family members” • “Shared responsibility for managing health.” • “More involved.” • “Makes things simpler.” • “Less stress.” One single parent of a 16 year male did not prefer PSM. Increased anxiety (anxiety/stress related to INR value) was the only identifiable negative theme. Discussion This study is the first randomized study evaluating warfarin PSM in children. There were no hemorrhagic or thromboembolic events. Children randomized to PSM demonstrated TTR and warfarin dose decision making was as appropriate as for those children on PSM with the VPaT program providing warfarin management decisions. There was no significant difference between PST and PSM in TTR, 83.9 and 83.0% respectively, with the frequency of INR testing being 22.6 and 22.7, respectively. Importantly, participants reported preference for PSM and enhanced QOL associated with an increased understanding of warfarin management. Baseline TTR for the PSM group was 77.7%, less than the PST group (83.9%). The lower baseline TTR for PSM group was attributable to poor adherence in four participants. Based on their level of adherence these four participants would not have been selected for PSM based on their TTR or ‘adherence to date. Interestingly, these non-adherent participants, when randomized to PSM demonstrated the greatest improvement in warfarin management (mean 31.06%, range 17%-55%). The results of this study are consistent with publications describing PSM of anticoagulant therapy among adults when a standardized comprehensive education program precedes PSM[18–20,22]. Adult

studies demonstrate comparable TTR between PSM and usual warfarin management with increased treatment satisfaction[18–20,22]. However, adult warfarin PSM studies are often biased by including only highly selected groups of patients considered to be ‘suitable’[18]. Within this study all patients were eligible for PSM regardless of their anticoagulation history which avoided the bias of patient selection as all participants were considered eligible for PSM. There is increasing awareness of the need to report “patientcentered” outcomes with the intent of improving patient centered care and long term outcomes for patients. Measurement of patient health related quality of life strengthens the measure of the effect of management interventions. The EmPoWarMent study is the first study to formally evaluate Health Related QOL in warfarinized children. Patient input was obtained on the influence of PSM on the family and patient to ensure the family benefited. Patient self management is not a new modality in chronically ill patients. Glucose monitoring and self adjustment of the insulin dose and diabetic diet are accepted worldwide in well-trained diabetic children and are an indispensable part of diabetic therapy[23–28]. Increased patient understanding and involvement in their disease is the result of the self management approach. Health theorists believe self management improves patient motivation, treatment related QOL, provides a sustained improvement in disease control, and possibly reduces complications[15,26–29]. Overall, participants in the PSM group were satisfied with the intervention and reported a positive change on their life. Furthermore, active participation in managing their health condition improved their motivation and empowered them to manage their warfarin effectively. Increased awareness related to warfarin management, communication, flexibility, and in family relationships were recurrent themes identified. These themes correlate well with the changes in QOL from the KIDCLOT PAC QL inventory© data with a positive change in parent-child relationships (parents were deemed as less over protective by the children and there was less discrepancy of how the parents treated their child in comparison to their other children). There was an increased sense of security reported by the children (an increased sense of safety that they would not clot, more confidence in their INR, less worry that they would forget to take a warfarin pill, and less associated stress due to warfarin. Open-ended questionnaires and interviews suggested that families’ experienced increased anxiety related to changes in the INR described (i.e. “I became worried when my INR is too low or high”). The KIDCLOT PAC QL© demonstrated a decline in the parents confidence in the INR. The increased concern might be appropriate when INRs are outside of the target range and potentially decline with more experience in PSM. One single parent of a 16 year old male did not prefer PSM as she reported anxiety related to her child making

Table 3 PSM Interview Responses. “Able to make decisions based on guidelinesknowing why INR changes” Communication “Increases communication with parents and others...” Relationship between “Brought us closer” parent and child Awareness

Flexibility

“convenient and flexible”

Anxiety

“become alerted when my INR is out of range – it causes more stress”

“more aware of why we are changing the dose, “it was a good experience (PSM), why we are testing more often” because it has empowered me with knowledge about the INR & Coumadin doses” “it has become my responsibility as a patient to “being able to relay that information to other family members…” look after all of my own warfarin treatments such as communicating with INR doctor/nurse” “Inspires cooperation between us” “XX is more aware of where INR is and why they may need testing more often” “It makes things simpler” “Gives a little more freedom and I feel confident they is doing well” “become worried when INR is too high or too low”

“little stress(ful)”

“being more involved heightens our awareness of the particulars”

“the information is helpful”

“we have become closer”

“we have that leeway, know that we have plus or minus a day, we can test whenever we want…” “more anxious"

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independent dosing decisions; however this motivated teen improved his TTR by 21% while on PSM. ‘Sick’ days from school were not evaluated within this study. There appeared to be no identifiable patient characteristics to recognize patients that would be most successful as PSM. Participants with low education levels appeared to be equally successful (Table 1) and participants who performed poorly on PST did well on PSM. Within this study all children had access to socialized health care removing the barrier of the cost of the meter and test strips to success. In addition, the VPaT program has a long established home monitoring program with validated education strategies which may contribute to the success of PSM, and may impact on the generalizability of the results to other centers Limitations to this study include patient inclusion at a single centre resulting in the small sample size, compounded by two patients not completing the full 12 month study period. Multinational studies are required to increase sample size and power of these results. This study suggests that self management is an effective method for warfarin management and has the potential to improve patient participation in their health care. Further prospective studies are required with larger samples to evaluate safety, efficacy, and changes in QOL over time. Conclusions PSM for children may be a safe and effective management strategy. When preceded by structured education and knowledge evaluation by trained health care professionals, children and their caregivers appear to be able to adjust their warfarin doses safely and accurately. PSM may be as effective as PST improving QOL through patient knowledge and autonomy. Pediatric patients with chronic diseases beginning in childhood have significant patient years ahead of them therefore, optimizing patient knowledge and self-directed health management is one way to improve adherence and long term outcomes[15,26–29]. However, further studies with larger samples are required to formally evaluate long term outcomes and sustainability of warfarin PSM. Conflict of Interest Disclosures ME Bauman – none K Black – none ML Bauman-none AAK Bruce - none S Kuhle- none L Bajzar-none MP Massicotte – none References [1] Andrew M. Indications and drugs for anticoagulation therapy in children. Thromb Res 1996;81(2 Suppl):S61–73. [2] Andrew M, David M, Adams M, Ali K, Anderson R, Barnard D, et al. Venous thromboembolic complications (VTE) in children: First analyses of the Canadian registry of VTE. Blood 1994;83(5):1251–7. [3] Andrew M, Marzinotto V, Brooker LA, Adams M, Ginsberg J, Freedom R, et al. Oral anticoagulation therapy in pediatric patients: a prospective study. Thromb Haemost Mar 1994;71(3):265–9. [4] Ignjatovic V, Barnes C, Newall F, Hamilton S, Burgess J, Monagle P. Point of care monitoring of oral anticoagulant therapy in children: comparison of CoaguChek Plus and Thrombotest methods with venous international normalised ratio. J Thromb Haemost Oct 2004;92(4):734–7.

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