会计谨慎性原则
Influence of the American Society of Hematology Guidelines on the Management of Newly Diagnod Childhood Immune Thrombocytopenia
Corinna L.Schultz,MD,MSHP;Nandita Mitra,PhD;Marilyn M.Schapira,MD,MPH;Michele P.Lambert,MD,MTR
Author Affiliations:Children’s
Hospital of Philadelphia,Philadelphia,Pennsylvania (Schultz,Lambert);currently with Alfred I.duPont Hospital for Children,Wilmington,Delaware (Schultz);Department of Biostatistics and Epidemiology,University of Pennsylvania,
Philadelphia (Mitra);Leonard Davis Institute of Health Economics,University of Pennsylvania,Philadelphia (Mitra,Schapira);Perelman School of Medicine,University of Pennsylvania,
牛尾的做法大全Philadelphia (Schapira,Lambert);Center for Health Equity Rearch &Promotion,Philadelphia VA Medical Center,Philadelphia,Pennsylvania (Schapira).
关于诚信的故事
Corresponding Author:Corinna L.Schultz,MD,MSHP,Department of Hematology,34th and Civic Cente
r Boulevard,Philadelphia,PA 19104(schultzc1@email.chop.edu).
Rearch
Original Investigation
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I mmune thrombocytopenia(ITP)is an autoimmune disor-
der characterized by immunologic destruction of other-wi normal platelets affecting1in20000children annu-ally in the United States.The International Working Group defines ITP as a platelet count less than100×103/μL(to con-vert to×109per liter,multiply by1)in the abnce of other caus.1Immune thrombocytopenia is often considered a lf-limited dia without significant medical complications but can rarely be associated with life-threatening bleeding includ-ing intracranial hemorrhage.2,3Pharmacologic treatments may temporarily increa the platelet count but do not appear to decrea the time to resolution of ITP.2,4,5
Treatment recommendations for childhood ITP have been the subject of debate.Although guidelines in the United King-dom have long supported a watch and wait approach,6,7the American Society of
Hematology(ASH)did not universally adopt that approach until2011.The ASH recommends that “children with no bleeding or mild bleeding(defined as skin manifestations only,such as bruising and petechiae)be man-aged with obrvation alone regardless of platelet count.”1Our objective was to understand the impact that the2011ASH guidelines had on practice patterns at the Children’s Hospital of Philadelphia(CHOP),a large,urban,pediatric tertiary care hospital in the United States.
Methods
We conducted a retrospective cohort study.The initial cohort was developed by querying the hospital data system for pa-tients ages0to17years en in inpatient and outpatient loca-tions at CHOP between January1,2007,and December31,2012, using the International Classification of Dias,Ninth Revi-sion(ICD-9)code for ITP(287.31).Manual medical record re-view was ud to refine the cohort.The clinical data ex-tracted included year of diagnosis,age and platelet count at diagnosis,x,residence zip code,attending physician,pres-ence and type of bleeding symptoms,and documented rea-son for pharmacotherapy as stated in the asssment and plan for the encounter.Bleeding symptoms included any subjec-tive or objective documented bleeding symptoms aside from bruising or petechiae.Euclidian distance from the patient’s home zip code to the CHOP zip code was calculated in kilo-meters.Pharmacy data included all platelet-increasing therapy (intrav
enous immunoglobulin[IVIG],Rho[D]immune globu-lin,and corticosteroids)given at diagnosis or arranged for ad-ministration within1week.Blood bank data included any packed red blood cells or platelets given at the diagnosis en-counter.Diagnosis encounter was determined by the pres-ence of platelet count less than100×103/μL in the abnce of other caus,with physician documentation of new or likely ITP.For tho diagnod as having ITP between2010and 2012,we recorded bleeding symptoms and management during the6months postdiagnosis.This study was approved by the institutional review board of CHOP;informed connt was waived.
We compared clinical and demographic variables be-tween patients receiving pharmacotherapy and obrvation.Additionally,we compared patients managed in the preguide-line change period(2007-2010)and postguideline change pe-riod(2011-2012).Categorical variables were compared using the χ2test and continuous variables were compared using the t test or Wilcoxon rank-sum test for heavily skewed distributions.
We ud multivariable logistic regression to asss the as-sociation between management type at diagnosis(pharmaco-therapy vs obrvation alone)and age(years),platelet count (×103/μL),period of diagnosis(preguideline change vs post-guideline change period),x,and distance(kilometers).Odds ratios(ORs)and95%CIs are prented.In condary analy-s,we ud a generalized estimating equ
ations approach to account for patient clustering by attending physician.Thirty attending physicians were reprented,with8accounting for most study participants.Additionally,we evaluated interac-tions between period of diagnosis and age or platelet count by including multiplicative interaction terms in our models.The prence of bleeding symptoms correlated perfectly with re-ceiving pharmacotherapy(ie,every patient who had docu-mented bleeding symptoms received pharmacotherapy).Be-cau of this,only1of the variables could be included in the regression models and,therefore,the prence of bleeding symptoms was excluded.The condary outcome,manage-ment within6months after diagnosis,was analyzed via mul-tivariable logistic regression accounting for clustering by at-tending physician and included management at diagnosis, age,platelet count,time of diagnosis,x,and distance.All sta-tistical tests were2sided and statistical significance was con-sidered to be P<.05.Analys were conducted using Stata12.0 (Stata Corp).
Results
Study Cohort Development
An initial cohort of502patients was developed via ICD-9code. Medical record review then excluded patients owing to treat-ment at another institution(n=69),diagnosis prior to2007 (n=68),and alternativ
e diagnosis(n=41).Evan syndrome (n=8),autoimmune lymphoproliferative syndrome(n=5), and neonatal alloimmune thrombocytopenia(n=3)were the most common alternative diagnos.Twelve patients were ex-cluded owing to age older than17years or diagnosis unable to be confirmed.The final cohort included311patients.
Study Population Characteristics
Distribution of age and platelet count were skewed toward younger age and lower platelet count.The mean(SD)age at di-agnosis was6.1(5.1)years and the median age was4years (range,0.1-17years).The mean(SD)platelet count was16.9 (18.7)×103/μL and the median was9×103/μL(range,1-96×103/μL).Fifty-five percent of patients prented with a platelet count less than10×103/μL.Forty-ven percent were male.Ad-ditionally,19.6%had bleeding symptoms,all with a platelet count less than23×103/μL and80%with a platelet count less than10×103/μL.The most common bleeding symptoms were epistaxis(n=25),wet purpura(n=20),gastrointestinal bleed-ing(n=5),hematuria(n=4),and menstrual bleeding(n=4).
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Intracranial hemorrhage at diagnosis was rare (n =2,0.6%),with 1incidentally found on imaging.
New diagnos ranged from 34to 51and 59to 63per year in 2007-2009and 2010-2012,respectively.Overall,55%of pa-tients were managed with pharmacotherapy at diagnosis,with 98.8%of tho receiving IVIG,4.6%receiving glucocorti-coids,0.6%receiving Rho(D)immune globulin,and 3.5%re-ceiving blood products.Every patient who received blood prod-ucts also received another pharmacotherapy type.The proportion of patients managed with obrvation alone at di-agnosis incread significantly during the study from 34%of patients in 2007-2010to 49.2%in 2011(P <.02)and 71%in 2012(P <.001)(Figure ).
Comparison by Management Type at Diagnosis
When compared bad on management type (pharmaco-therapy vs obrvation alone),there was a statistically signifi-cant difference in age,platelet count,and bleeding symp-toms (Table 1).Sex and distance were not different between groups.Tho receiving pharmacotherapy were significantly younger (mean [SD],5[4.5]years;median,3years)than tho obrved (mean [SD],7.4[5.5]years;median,6years)(P <.001).Additionally,tho who received pharmacotherapy had si
g-nificantly lower platelet counts (mean [SD],7.9(5.8)×103/μL;median,6×103/μL;range,1-42×103/μL)than tho obrved (mean [SD],28.2(22.7)×103/μL;median,21×103/μL;range,1-96×103/μL)(P <.001).Of tho with a platelet count less than 10×103/μL,79%(n =136)received pharmacotherapy.Addition-ally,every patient with bleeding symptoms received pharma-cotherapy (P <.001).
Comparison by Period of Diagnosis
When looked at across periods (Table 2),patients were sig-nificantly younger in the postguideline change period (mean [SD],5.2[4.6]years;median,3years)than in the preguide-line change period (mean [SD],6.7[5.3]years;median,4years)(P =.02).Similarly,patients lived further from the hospital in the postguideline change period (39.2km)than in the preguideline change period (32.3km)(P =.03).Neither age nor distance differed between management types in the postguideline change period.Platelet count and bleeding symptoms remained significantly different between man-agement types during both periods.Most importantly,there was a significant change in the proportion of patients with a platelet count less than 10×103/μL who were obrved in the preguideline change period (9%)vs postguideline change period (41%)(P <.001).
Multivariable Model
Consistent with univariate analysis,younger age,lower platelet count,and preguideline change period were associ-ated with incread odds of pharmacologic treatment (Table 3).In other words,with all other variables held con-stant,for every 1-year increa in age,a patient has 8%lower odds of receiving pharmacotherapy (OR,0.92;95%CI,0.87-0.99)and for every 1-×103/μL increa in platelet count,a
Figure.Pharmacologic Treatment at Diagnosis
P a t i e n t s R e c e i v i n g P h a r m a c o t h e r a p y , %
Year
20072008
20092010
2011
2012
Percentage of patients each year receiving pharmacologic treatment divided into the portion with bleeding symptoms (light portion of bar)and without bleeding symptoms (dark portion of bar).The asterisk reprents approximate timing of management guideline change.
SI conversion factor:To convert platelet count to ×109per liter,multiply by 1.
a
红烧肉怎么烧Continuous variables analyzed via t test and categorical variables via χ2test.
b Noncutaneous bleeding symptoms.c
N =310.
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给予的英文patient has 14%lower odds of receiving pharmacotherapy (OR,0.86;95%CI,0.83-0.89).Additionally,as compared with the preguideline change period,tho diagnod as having ITP in the postguideline change period have 85%lower odds of receiving pharmacotherapy (OR,0.17;95
%CI,0.09-0.34).When variation bad on attending physician was taken into account or period interaction terms were included,ORs were nearly identical.
Management Within 6Months Postdiagnosis
During 2010and 2012,23%(27of 119)of patients received phar-macotherapy within 6months after diagnosis,with no signifi-cant difference by year or initial management type (P =.54).Of tho receiving pharmacotherapy in the 6months after diagno-sis,47%(n =7)in 2010and 42%(n =5)in 2012had also received pharmacotherapy at initial diagnosis.Despite this,the percent-age of patients who were obrved alone at diagnosis and who later received pharmacotherapy decread from 40%to 16%from 2010to 2012,respectively.Tho receiving pharmaco-therapy in the 6months after diagnosis were treated,on aver-age,1.2months after diagnosis (range,0.25-5months),with 68%within 1month of diagnosis and no difference between 2010and 2012.Age,platelet count,x,and distance of tho receiving later pharmacotherapy were consistent with the larger cohort.
In a multivariable logistic model,only older age was sig-nificantly associated with incread odds of pharmacologic treatment within 6months after diagnosis when all other vari-ables were held constant (OR,1.08;95%CI,1.00-1.17;P =.04).Accounting for clustering by attending physician and includ-ing interaction terms produced nearly identical results.
Documented Reasons for Pharmacotherapy
Almost half who received pharmacotherapy at diagnosis had a reason documented for receiving pharmacotherapy,with the most common being epistaxis,activity level of the child,and wet purpura (Table 4).All children receiving pharmaco-therapy within 6months after diagnosis had a reason docu-mented,with the most common being thrombocytopenia,bruis-ing,activity level,or gastrointestinal bleeding.One child,initially treated with IVIG,prented with a small intracranial hemor-rhage from direct head trauma 1.5months after diagnosis.Over-all,35%of tho treated at diagnosis and 31%of tho treated within 6months had potentially significant bleeding symp-toms as the reason documented for pharmacotherapy.
Discussion
Over the past 20years,national and international groups have created practice guidelines for the management
of
SI conversion factor:To convert platelet count to ×109per liter,multiply by 1.a
Continuous variables analyzed via t test and categorical variables via χ2
test.Overall P value is bad on comparison between totals from the preguideline change and postguideline change period.
b Noncutaneous bleeding symptoms only.c
端午由来N =
310.
a
Postguideline change period (2011-2012)compared with preguideline change period
(2007-2010).
破解游戏网站a
Total percentage of tho treated with documented bleeding symptoms was 35%at diagnosis (2007-2012)and 31%within the first 6months postdiagnosis (2010-2012).
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childhood ITP.Despite the cooperative efforts,manage-ment practices vary,with the most notable difference between the United Kingdom and the United States.Start-ing in1992and reaffirmed in2003,guidelines in the United Kingdom have supported a watch and wait approach,stat-ing that treatment should be bad on symptoms and not platelet count,opting for obrvation alone over pharmaco-therapy when feasible.6,7This contrasts with the1996rec-ommendation by ASH that management be bad on symp-toms and platelet count becau“current evidence is inadequate to recommend which groups of children with ITP can be safely managed without therapy.”8The recom-mendations by ASH suggested,via opinion statement,that it may be appropriate to withhold treatment for tho who are asymptomatic with platelet counts in the range of20to 30×103/μL.Althou
木里大寺gh most of the recommendations from ASH were bad on symptoms and platelet count,they did recommend that children younger than3years with a plate-let count less than20×103/μL,regardless of symptoms, undergo pharmacotherapy to increa the platelet count to a normal range.8
Over time,there have been natural history studies of ITP indicating that most children do not experience significant bleedingatfollow-up,regardlessoftheinitialmanagement.2,5,9-12 This led to guidelines,such as the2010International Conn-sus Report,which states that“the majority of children with newly diagnod ITP lack significant bleeding symptoms and may be managed without therapy directed at raising platelet count,”13and to the2011ASH guideline,which“moved away from recommendations for treatment bad on platelet number”1(p4195)and now states that“children with no bleed-ing or mild bleeding(defined as skin manifestations only,such as bruising and petechiae)be managed with obrvation alone regardless of platelet count(grade1B).”1
Without a national US registry,practice patterns of US physicians toward childhood ITP are not well described.Sur-veys of pediatric hematologists by the American Society for Pediatric Hematology/Oncology in1997and2001attempted to asss practice patterns.When given hypothetical patient situations,pediatric hematologists endord obrvation 16%of the time.14,15This mirrored2single-center retrospec-tive studies in Alabama and Indiana showing obr
vation alone as first-line treatment ud in17%and14%of patients older than10and4years,respectively.16,17In2008,an Ital-ian group noted a25%obrvation rate,18while another large US tertiary care hospital obrved31%of patients over a similar period.19The rates of obrvation alone have dra-matically incread in the United Kingdom from39%in1995 to62%in2000and84%in2009,20where recommendations for watch and wait have been in place for nearly20years.In one survey done since the2011ASH guideline update,5of12 (42%)Oklahoma pediatric hematologists endord obrva-tion alone for management when given a hypothetical situation.21To our knowledge,there have been no studies looking at US trends after the publication of the2011ASH guidelines to date.
Using a single pediatric tertiary care institution,we described practice patterns in newly diagnod childhood ITP surrounding guideline changes.We found a significant change in the u of obrvation alone at diagnosis of ITP at CHOP between2007and2012,with its rate reaching71% in2012.Although we cannot prove causation,this significant change demonstrates a strong association with the timing of the2011ASH guidelines and the possible influence of the guidelines on practice.At CHOP,management decisions can be discusd at routine weekly divisional patient care con-ferences but ultimately remains at the discretion of the treat-ing physician.While the hematology
department has not had a written policy addressing management of newly diagnod ITP,the ASH guidelines were prented at this meeting after publication.The relative influence of the2011 ASH guidelines,clinical opinion leaders,treating physician, and patient preference has yet to be determined.Further rearch is also needed to investigate whether this increa in obrvation rate is unique to this large,rearch-bad institution or whether obrvation rates have incread nationwide.
We demonstrated a significant difference in age,platelet count,and bleeding symptoms between tho receiving pharmacotherapy and obrvation alone at diagnosis.In our multivariable analysis,children who are younger,with a lower platelet count,and prenting during the preguide-line change period had incread odds of receiving pharma-cotherapy.However,over time,age became less significant between the2management types despite an overall decreas-ing age.
When looking across periods,the most significant change was the increa in the u of obrvation alone among tho with a platelet count less than10×103/μL becau this is a plate-let count often evoking fear of bleeding in parents and attend-ing physicians.Although most of tho who prented with bleeding symptoms had a platelet count less than10×103/μL, there remains a substantial number of children with lower platelet count who continue to receive pharmacotherapy in the abnc
e of bleeding symptoms.This reprents a group that is potentially over treated and leaves room for improvement in management practices.
Additionally,cost savings from elimination of hospitaliza-tion,unnecessary medication administration,and evalua-tion of adver effects of pharmacotherapy(ie,computed to-mographic scan to evaluate headache post-IVIG)could be significant.22Despite this,we anticipate that practice will con-tinue to vary from guidelines owing to parent and referring physician’s expectations and managing hematologist’s deci-sion-making approach.23
Of concern was whether we delayed initial treatment of childhood ITP.Evaluating management within6months af-ter diagnosis,we did not e an increa in the proportion of children receiving later pharmacotherapy or returning with bleeding symptoms after initial obrvation.Although the number of children receiving later pharmacotherapy was small, there was not a significant increa during our study.In fact, the percentage obrved at diagnosis who received later phar-macotherapy decread across time,reprenting perhaps an incread comfort with obrvation alone as first-line man-agement in children with ITP.
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