pediatric warfarin practice and pharmacogenetic testing
TRANSCRIPT
Thrombosis Research 126 (2010) e144–e146
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Thrombosis Research
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Letter to the Editors-in-Chief
Pediatric warfarin practice and pharmacogenetic testing☆
Abbreviations: CYP, cytochrome P450; VKORC1, vitampharmacogenetic; HTRS, Hemophilia and Thrombosis R☆ The work was presented at the 2009 American SoOncology Annual Meeting.
0049-3848/$ – see front matter © 2010 Elsevier Ltd. Aldoi:10.1016/j.thromres.2009.12.022
Keywords:
ChildrenGenetic testingAnticoagulant therapyPolymorphisms in cytochrome P450 (CYP) 2C9 and vitamin Kepoxide reductase (VKORC1) are associated with warfarin dose [1,2].Warfarin dosing algorithms that incorporate pharmacogenetic (PGx)testing have been developed for adults and are being testing in clinicaltrials [3–5]. In 2007, the FDA updated warfarin prescribing informa-tion, recommending PGx testing forCYP2C9 andVKORC1, but questionsremain regarding the clinical utility of the PGx algorithms and howthey will be integrated into clinical care, especially pediatric practice.
Despitemore thana dozen PGx algorithms to guidewarfarin therapyin adults, there are few data related to the contribution of CYP2C9 andVKORC1 to pediatric dosing. Pediatric specific algorithms must accountfor differences in many factors including: body size; developmentaldifferences in the coagulation system; [6,7] physiologic developmentthatmay influencewarfarin distribution, binding, or clearance; [6,8] useof interactingmedications (e.g. antibiotics); differences in dietary intakeand eating patterns; and treatment non-adherence [9–11].
We developed an on-line questionnaire based on literature reviewand expert opinion. Our goalwas todetermine currentwarfarin practiceand knowledge, attitudes and behavior regarding PGx testing. Thequestionnairewas designed to answer the following questions: (1) howand when do pediatric hematologists initiate warfarin?; (2) are theyfamiliar with PGx testing and do they order it?; and (3) are theyinterested in using this approach and for whom? The questionnairecontained 10 multiple choice questions and 13 Likert-scale questions.We asked respondents to provide warfarin doses for a hypothetical10-year-old, 40-kg (75thile for age) child initiating warfarin for acutedeep vein thrombosis. We assessed face validity by having thequestionnaire reviewed by 4 clinicians prior to administration. Weassessed internal validity by comparing consistency between similaritems and quantified this metric using Cronbach's alpha.
To obtain opinions from pediatric hematologists with expertise inwarfarin management, we surveyed members of HTRS–a researchsociety of adult and pediatric hematologists with specific interests inhemophilia and thrombosis (N=176). HTRS estimated that 38%(N=67) of its membership is pediatric. HTRS sent an e-mail to theirmembership that described the purpose of the study and included alink to complete the questionnaire via Survey Monkey©.
in K epoxide reductase; PGx,esearch Society.ciety of Pediatric Hematology/
l rights reserved.
Descriptive statistics were performed. Fisher's exact tests (for N≤5)were used for categorical comparisons andMcNemar's test was used tocompare response proportions to similar items on the questionnaire.
Forty-two responses were received from (self-reported) pediatrichematologists who treat children with warfarin. The response ratewas 63% (42/67) of the targeted physicians. Cronbach's alpha forsimilar questionnaire items was 0.68.
Warfarin Practice Patterns. Thirty-seven percent (14/38) of respon-dents treat ≤10 children taking warfarin per year, 45% (17/38) treat11–30 per year, and 18% (7/38) treat more than 30 per year. Variousservices are involved in pediatric warfarin management: pediatrichematologist-oncologist (14/39; 36%), pediatric hematologist (9/39;23%), pediatric coagulation specialist (13/39; 33%), and other (antic-oagulation service, nurse, and pediatric cardiologist) (3/39; 8%). Eighty-eight percent (37/42) indicated that they sometimes (20–60%), usually(61–95%) or always (N95%) treat a child 5–18 years old with warfarin ifthe child needs anticoagulant therapy for ≥6 months compared to 52%(22/42) of respondents who indicated that they sometimes, usually oralways treat a child with warfarin if the child needs anticoagulanttherapy for ≤3 months (McNemar's test; pb0.01). On a 5-point Likertscale, 82% (31/38) agreed or strongly agreed with the statement “Therisks of warfarin warrant better dosing strategies”. Agreementwith thisstatement did not depend on experience with warfarin initiation(Fisher's exact test; p=0.19). Eight percent (3/38) of respondentsagreedwith the statement “I avoid prescribingwarfarin, because it takestoo long to achieve a therapeutic dose”. There was great heterogeneityin warfarin dosing recommendations (Fig. 1), including use of a loadingdose: loading doses (8–10 mg in the 40-kg, hypothetical patient) wererecommended by 46% (17/37) of respondents.
Ninety-two percent (35/38) report interest in participating inclinical research to develop a new pediatric warfarin dosing algorithmto aid warfarin initiation.
Warfarin PGx Testing. Respondents were familiar with warfarin PGxtesting, and 74% (29/39) had attended a presentation on the subjectwithin the last 2 years. Seventy-two percent (28/39) agreed orstrongly agree that they know where to send samples for VKORC1 orCYP2C9 testing, and 59% (23/39) agreed or strongly agreed that theyhave enough information about warfarin PGx testing to incorporate itinto clinical practice. However, only 2% (1/42) reported orderingVKORC1 and/or CYP2C9 testing for N95% of cases of pediatricanticoagulation management compared to 38% (16/42; 38%) whoreported that they always test their pediatric patients for Factor VLeiden as part of anticoagulant management (McNemar's test;pb0.001) (Table 1).
Forty-two percent (16/38) reported that they would sendwarfarinsensitivity testing for a child with multiple medical problems withacute DVT who will be bridged to warfarin compared to 18% (7/38)who reported that they would send warfarin sensitivity testing for ahealthy child with acute DVT who will be bridged to warfarin(McNemar's test; pb0.01) (Table 1).
No respondents agreed or strongly agreed with the statement“There are significant risks associated with warfarin sensitivitytesting”. However, thirty-seven percent (14/38) agreed or strongly
Fig. 1. Recommended warfarin doses from 42 pediatric hematologists for a hypothetical10-year-old child weighing 40 kg with given INRs between initiation (day 0) and day90. Recommended warfarin doses are shown at each time point along with the givenINR. All doses ≥10 mg were recommended by one respondent.
e145Letter to the Editors-in-Chief
agreed that it takes too long to get the results of warfarin sensitivitytesting; 21% (8/38) disagreed or strongly disagreed with thestatement “I expect warfarin sensitivity testing to be cost-effective”;and only 13% (5/38) agreed or strongly agreed that that theavailability of warfarin PGx testing will increase their prescription ofwarfarin compared to other anticoagulants.
Our questionnaire provides the first data regarding currentwarfarin practice and knowledge, attitudes and behavior regardingPGx testing among pediatric hematologists.
Warfarin Practice Patterns. Pediatric hematologists have variableexperience with warfarin initiation, but, in general, they are morelikely to prescribe warfarin in children requiring long-term antic-oagulation. Dosing recommendations were variable and respondentsindicated a need for better dosing algorithms. Loading doses wererecommended by almost 50% of respondents. Although this strategyconflicts with adult dosing recommendations, [12] pediatric guide-lines suggest loading doses, [9,13] because they may decrease thedelay until the INR is therapeutic by 1 or 2 days [14]. PGx testing canidentify children with high warfarin requirements who might benefitfrom greater initial doses [15]. The variation in use of loading doses forthe hypothetical patient highlights the heterogeneous approach towarfarin dosing, likely resulting in suboptimal dosing strategy inchildren. Although anticoagulation clinics can facilitate the manage-ment of children on warfarin, [16] use of PGx algorithms may furtherimprove INR control [5,15,17].
Table 1Pediatric hematologists' practices related to warfarin therapy.
Question N(#yes/# responses)
p
Always test for Factor V Leiden for anticoagulantmanagement?
16/42 b0.001
Always test for VKORCI and/or CYP2C9 foranticoagulant management?
1/42
Use warfarin for child needing 0–3 months oftherapy?
22/42 b0.01
Use warfarin for child needing N6 months oftherapy?
37/42
Would order PGx testing in healthy child startingwarfarin?
7/38 b0.01
Would order PGx testing in child with multiplemedical problems starting warfarin?
16/38
Warfarin PGx Testing. Pediatric hematologists are familiar withwarfarin PGx testing, but have not incorporated it into practice.Although testing for Factor V Leiden has not been shown to improveclinical outcome, [18] significantly more hematologists order Factor VLeiden testing than order PGx testing. Concerns likely relate to lack ofpediatric-specific evidence as well as concerns about feasibility ofobtaining PGx results in a timely manner and the cost-effectiveness ofPGx based dosing [19]. We hypothesize that use of PGx will change,once PGx testing become cheaper and pediatric warfarin dosingalgorithms that incorporate PGx data are developed and prospectivelyvalidated.
Respondents did not identify risks associated with PGx testing.Future studies, should specifically determine potential risks of PGxtesting in children: delay in therapy initiation while waiting forgenotype, limiting access to warfarin to those with certain genotypes,privacy of and access to genetic data, impact on insurability,psychological stress, implications for family members, and identifyinginformation about other medical conditions, [20] prognosis andresponse to other drugs [21].
We also found enthusiasm for a clinical trial to develop a pediatricwarfarin dosing algorithm. Since respondents were more likely to usewarfarin in children requiring long-term anticoagulation and use PGxtesting in children with complex medical conditions, these childrenshould be enrolled in future studies. Therefore, pediatric studieswill differfromprior (adult) PGx studies that sometimes excludedpatientswhohadmultiple medical problems [5]. Pediatric anticoagulant trials haveencountered substantial obstacles in the past, such as small studypopulations. Thus, efficient approaches are needed to successfully studywarfarin PGx testing in children [22–24]. A study that includes carefullyphenotyped children should require fewer subjects than the thousands ofadults enrolled in development of adult PGx algorithms [25].
Our studymay be limited by amoderately low response rate (63%)and that we queried a national rather than international academicsociety. Generalizability of our findings to other clinicians caring forchildren is unknown. However, in comparison to adults (who oftenaremanaged by primary care physicians), children takingwarfarin aretypically managed by pediatric hematologists, pediatric cardiologists,and cardiothoracic surgeons. Thus, our findings may be used as thebasis for future queries of these physicians.
In summary, pediatric hematologists identify a need for betterwarfarin dosing algorithms. Such algorithms may incorporate warfa-rin PGx testing. Pediatric hematologists are knowledgeable about suchtesting but rarely order it. As algorithms with PGx components aredeveloped, investigators should consider the optimal target popula-tions as well as potential barriers to PGx testing.
Discloser of Conflicts of Interest
The authors have no relevant conflicts of interest to declare.
Acknowledgements
We thank the Hemophilia and Thrombosis Research Society forsending the study questionnaire to its membership on our behalf andMr. Agustin Calatroni for statistical analysis and graphic design. Weacknowledge partial support from the American Heart Association.
References
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Courtney D. ThornburgDepartment of Pediatrics, Duke University Medical Center,
Durham, NC, United StatesCorresponding author. Duke University Medical Center Box 102382,Durham, NC 27710. Tel.: +1 919 684 3401; fax: +1 919 681 7950.
E-mail address: [email protected].
Emma JonesLisa Bomgaars
Department of Pediatrics, Baylor College of Medicine,Houston, TX
Brian F. GageDepartment of Medicine, Washington University in St. Louis,
St. Louis, MO
27 July 2009