comparisonofantifungalprophylaxisdrugsinpatientswithhematological ... ·...

Original Investigation | Infectious Diseases

Comparison of Antifungal Prophylaxis Drugs in Patients With HematologicalDisease or Undergoing Hematopoietic Stem Cell TransplantationA Systematic Review and Network Meta-analysisJing Wang, MD, PhD; Min Zhou, MD, PhD; Jing-Yan Xu, MD, PhD; Rong-Fu Zhou, MD, PhD; Bing Chen, MD, PhD; Yuan Wan, PhD

Abstract

IMPORTANCE Several antifungal drugs are available for antifungal prophylaxis in patients withhematological disease or who are undergoing hematopoietic stem cell transplantation (HSCT).

OBJECTIVE To summarize the evidence on the efficacy and adverse effects of antifungal agentsusing an integrated comparison.

DATA SOURCES Medline, EMBASE, and the Cochrane Central Register of Controlled Clinical Trialswere searched to collect all relevant evidence published in randomized clinical trials that assessedantifungal prophylaxis in patients with hematological disease. Sources were search from inception upto October 2019.

STUDY SELECTION Studies that compared any antifungal agent with a placebo, no antifungal agent,or another antifungal agent among patients with hematological disease or undergoing HSCT wereincluded. Of 39 709 studies identified, 69 met the criteria for inclusion.

DATA EXTRACTION AND SYNTHESIS The outcome from each study was estimated using therelative risk (RR) with 95% CIs. The Mantel–Haenszel random-effects model was used. The reliabilityand validity of the networks were estimated by addressing inconsistencies in the evidence fromcomparative studies of different treatments. Data were analyzed from December 2019 to February2020. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analysesfor Network Meta-analysis (PRISMA-NMA) guideline.

MAIN OUTCOMES AND MEASURES The primary outcomes were invasive fungal infections (IFIs)and mortality. The secondary outcomes were fungal infections, proven IFIs, invasive candidiasis,invasive aspergillosis, fungi-related death, and withdrawal owing to adverse effects of the drug.

RESULTS We identified 69 randomized clinical trials that reported comparisons of 12 treatmentswith at total of 14 789 patients. Posaconazole was the treatment associated with the best probabilityof success against IFIs (surface under the cumulative ranking curve, 86.7%; mean rank, 2.5).Posaconazole treatment was associated with a significant reduction in IFIs (RR, 0.57; 95% CI, 0.42-0.79) and invasive aspergillosis (RR, 0.36; 95% CI, 0.15-0.85) compared with placebo. Voriconazolewas associated with a significant reduction in invasive candidiasis (RR, 0.15; 95% CI, 0.09-0.26)compared with placebo. However, posaconazole was associated with a higher incidence ofwithdrawal because of the adverse effects of the drug (surface under the cumulative ranking curve,17.5%; mean rank, 9.2). In subgroup analyses considering efficacy and tolerance, voriconazole mightbe the best choice for patients undergoing HSCT, especially allogenic HSCT; however, posaconazole

(continued)

Key PointsQuestion What primary antifungal

prophylaxis drugs for patients with

hematological disease or undergoing

hematopoietic stem cell transplantation

perform best in randomized

clinical trials?

Findings In this systematic review and

network meta-analysis of 69

randomized clinical trials that performed

comparisons of individual antifungal

agents in 14 789 patients, voriconazole

was recommended for patients

undergoing HSCT and posaconazole was

recommended for patients with acute

myeloid leukemia or myelodysplastic

syndrome.

Meaning These findings may help

clinicians to make antifungal prophylaxis

treatment decisions.

+ Supplemental content

Author affiliations and article information arelisted at the end of this article.

Open Access. This is an open access article distributed under the terms of the CC-BY License.

JAMA Network Open. 2020;3(10):e2017652. doi:10.1001/jamanetworkopen.2020.17652 (Reprinted) October 8, 2020 1/19

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Abstract (continued)

was ranked as the best choice for patients with acute myeloid leukemia or myelodysplasticsyndrome.

CONCLUSIONS AND RELEVANCE These findings suggest that voriconazole may be the bestprophylaxis option for patients undergoing HSCT, and posaconazole may be the best prophylaxisoption for patients with acute myeloid leukemia or myelodysplastic syndrome.

JAMA Network Open. 2020;3(10):e2017652. doi:10.1001/jamanetworkopen.2020.17652

Introduction

Invasive fungal infections (IFIs) have emerged as important causes of morbidity and mortality inpatients receiving myelosuppressive chemotherapy, immunosuppressive therapy, or hematopoieticstem cell transplantation (HSCT). Because of the difficulty in obtaining a timely diagnosis as well asthe high morbidity and mortality associated with IFIs, antifungal prophylaxis remains a high priority inthese populations at high risk of IFIs.1 Over the past decade, clinical benefits from antifungalprophylaxis have been demonstrated.2-4 However, there is no clear consensus on antifungalprophylaxis treatment between different centers and groups, particularly in the choice of theantifungal prophylaxis agents. Conventional pairwise meta-analyses based on a direct comparisonare relatively limited and difficult to use to investigate antifungal prophylaxis agents. We performed asystematic review and network meta-analysis5 to gain a better understanding of the outcomesassociated with and tolerance to current antifungal agents.

Methods

Protocol and RegistrationThis systematic review was conducted in accordance with the Preferred Reporting Items forSystematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA) reporting guideline.6

This protocol has been registered at PROSPERO under registration number CRD42020161748.

Literature SearchMedline, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials were searched tocollect all published evidence from randomized clinical trials from inception to October 2019 thatassessed primary antifungal prophylaxis in patients with hematological disease or undergoing HSCT.The search strategy is detailed in the eAppendix in the Supplement. The reference lists from allincluded studies and reviews were screened to identify potentially relevant evidence.

Study Inclusion CriteriaAll available randomized clinical trials that aimed to compare any antifungal agent with a placebo, noantifungal agent, or another antifungal agent for prophylaxis in patients with hematological diseaseor undergoing HSCT were included. In this analysis, we assumed that there was no differencebetween placebo and no antifungal agent.

Data ExtractionFrom each relevant study, the following data were extracted: authors’ names, year of publication,number of patients, age, use and dosage of drugs, categories of disease. Extracted outcomesincluded (1) incidence of fungal infections (superficial and IFI); (2) incidence of IFIs (possible,probable, and proven IFIs); (3) incidence of proven IFIs (positive histological results on biopsy from

JAMA Network Open | Infectious Diseases Antifungal Prophylaxis Drugs in Patients With Hematological Disease or Undergoing HSCT




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deep tissue); (4) incidence of invasive candidiasis; (5) incidence of invasive aspergillosis; (6) fungi-related death; and (7) withdrawal because of adverse effects of the drug.

Quality AssessmentTwo of us (M.Z. and J.-Y.X.) independently participated in the quality assessment, and disagreementswere resolved by a third reviewer (B.C.) until consensus was obtained. The quality of the evidencewas assessed using the revised tool for risk of bias in randomized trials.7

Statistical AnalysisWe compared different agents through network meta-analyses performed under a frequentistframework using a random-effects model. The analysis was performed using the network andmvmeta packages in Stata statistical software version 14.0 (StateCorp).8,9 We estimated the outcomefrom each study using the relative risk (RR) with 95% CIs. A 95% CI of an RR not covering 1 indicateda statistically significant association. Forest plots and league tables were used to visually present theresults of the network meta-analysis. For each outcome, the surface under the cumulative rankingcurve (SUCRA) was used to separately rank each agent.10 The larger the SUCRA value, the better therank. The reliability and validity of the networks were estimated by addressing the inconsistenciesand heterogeneity in the evidence from comparative studies of different treatments.11 The overalland loop inconsistencies were evaluated.8,12 Heterogeneity was estimated by the restrictedmaximum likelihood method. A τ2 value less than 0.1 indicated a very low level of heterogeneity, anda τ2 value from 0.1 to 0.5 indicated a reasonable level; a τ2 value greater than 0.5 was considered toindicate high heterogeneity.13 Additional subgroup analyses were performed restricted to data fromdifferent patient populations. Small-study effects were described with a funnel plot. Each funnel plotwas tested using the Begg test to assess the small-study effects. A 2-sided P < .05 was consideredstatistically significant. Data were analyzed from December 2019 to February 2020.

Results

Characteristics of the StudiesThe flowchart of study selection for this network meta-analysis is shown in eFigure 1 in theSupplement. In total, 69 trials with 14 789 patients were included,14-82 including 12 groups: placebo,polyene, conventional amphotericin B, liposomal amphotericin B, miconazole, ketoconazole,fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and micafungin. The basiccharacteristics of the included studies are summarized in Table 1. The randomization process andselection of the reported results were not reported clearly in most trials (eFigure 2 in theSupplement).

Network Geometry and Synthesis of ResultsThe network geometry for each outcome is shown in eFigure 3 in the Supplement: fungal infectionsincluded 12 groups, 69 studies, and 14 789 patients; IFIs included 12 groups (Figure 1), 64 studies,and 12 943 patients; proven IFIs included 11 groups, 37 studies, and 7179 patients; invasive candidiasisincluded 12 groups, 45 studies, and 9838 patients; invasive aspergillosis included 12 groups, 40studies, and 7958 patients; mortality included 12 groups, 69 studies, and 14 789 patients; fungi-related deaths included 12 groups, 45 studies, and 8636 patients; and withdrawal included 11 groups,39 studies, and 9056 patients. Indirect and mixed-treatment comparisons are shown as forest plots(eFigure 4 in the Supplement).

The SUCRA value and rank of each agent for each outcome are shown in Table 2. Regarding IFIs,posaconazole was the approach with the highest ranking (SUCRA, 86.7%; mean rank, 2.5). The 2approaches with the next-highest rankings were caspofungin (SUCRA, 84.2%) and micafungin(SUCRA, 76.4%). Posaconazole was associated with a significant reduction in IFIs (RR, 0.57; 95% CI,0.42-0.79) and invasive aspergillosisus infections (RR, 0.36; 95% CI, 0.15-0.85) compared with








Table 1. Basic Characteristics of Included Studies

Source Country Population

Interventions

Patients, No.Mean age,(range), y RoB2A B

Akiyama et al,14 1993 Japan Patients with hematological malignant neoplasmsreceiving chemotherapy

FLCZ 200 mgorally every d

AMB 800 mgorally 3×/d

130 43.32(15-67)

2

Annaloro et al,15 1995 Italy Bone marrow transplant recipients (allogeneic andautologous HSCT)


ITCZ 400 mgpo/IV every d

59 33.62(13-56)

2

Behre et al,16 1995 Germany Patients with hematological diseases receivingchemotherapy or undergoing HSCT

AMB 10 mg INH2×/d

Placebo 115 43.00(18-81)

2

Benhamou et al,17 1991 France Bone marrow transplant recipients (allogeneic andautologous HSCT)

KTCZ 200-600mg orally every d

Placebo 125 7.00 (NA) 2

Bodey et al,18 1994 United States Patients with acute leukemia receivingchemotherapy


AMB 0.5 mg/kgIV 3×/wk

77 46.47(17-80)

2

Boogaerts et al,19 2001 Finland Patients with hematological diseases receivingchemotherapy or HSCT

ITCZ 400 mgorally 2×/d

AMB 500 mgorally 3×/dNystatin 2 mIUorally 4×/d

277 46.92(NA)

2

Brincker,20 1978 Denmark Patients with hematological malignant neoplasmsreceiving chemotherapy

MICZ 500 mgorally 4×/d

Placebo 30 NA 2

Brincker,21 1983 Denmark Patients with acute leukemia receivingchemotherapy

KTCZ 400 mgorally every d

Placebo 38 58.50(NA)

2

Chaftari et al,22 2012 United States Hematopoietic stem cell transplant recipients(allogeneic HSCT)

POCZ 200 mgorally 3×/d

AMBL 7.5 mg/kgIV 1×/wk

40 55.48(20-69)

2

Chandrasekar andGatney,23 1994

United States Patients with acute leukemia receivingchemotherapy or HSCT


Placebo 46 38.00(NA)

3

Choi et al,24 2005 Korea Hematopoietic stem cell transplant recipients(allogeneic HSCT)


ITCZ 200 mgorally every d

78 34.43(18-56)

3

Cornely et al,25 2007 International Patients with AML or MDS receiving chemotherapy POCZ 200 mgorally 3×/d

FLCZ 400 mgorally every d orITCZ 200 mgorally 2×/d

602 49.44(13-82)

2

Donnelly et al,26 1984 UK Patients with acute leukemia receivingchemotherapy or HSCT



36 37.38(13-63)

2

Egger et al,27 1995 Switzerland Patients with hematological diseases receivingchemotherapy or HSCT


Polyene, nystatin8 mIU orally 3×/d

89 38.42(14-73)

3

Ellis et al,28 1994 Saudi Arabia Patients with hematological malignancies receivingchemotherapy or HSCT


Polyene,clotrimazole 10mg 2×/d

90 23.33(12-70)

2

Epstein et al,29 2018 United States Patients with hematological malignant neoplasmsreceiving chemotherapy


MCFG 100 mg IVevery d

113 60.02(26-75)

2

Estey et al,30 1984 United States Patients with acute leukemia receivingchemotherapy

KTCZ 200 mgorally 2×/d

Placebo 70 37.22(16-78)

3

Fisher et al,31 2019 United States Patients with acute myeloid leukemia receivingchemotherapy


CASP 50 mg IVevery d

510 9.49(0-26)

2

Glasmache et al,32 2006 Germany Patients with hematological malignancies receivingchemotherapy or HSCT


ITCZ 2.5mg/kgorally 2×/d

494 48.94(NA)

1

Goodman et al,33 1992 United States Bone marrow transplant recipients (allogeneic andautologous HSCT)


Placebo 356 NA 2

Hansen et al,34 1987 United States Patients with hematological malignant neoplasmsreceiving chemotherapy or HSCT


Placebo 56 NA 2

Harousseau et al,35 2000 International Patients with hematological malignant neoplasmsreceiving chemotherapy or HSCT

ITCZ 2.5 mg/kgorally 2×/d


557 48.74(15-82)

1

Hayashi et al,36 2014 Japan Patients with grade II-IV acute GVHD or chronicGVHD receiving corticosteroid treatment


VOCZ 200 mgorally 2×/d

66 NA 2

Hiemenz et al,37 2005 United States Hematopoietic stem cell transplant recipients(allogeneic and autologous HSCT)

FLCZ 400 mg IVevery d

MCFG 5 mg/kg IV2×/d

74 43.24(19-65)

3

Hiramatsu et al,38 2008 Japan Hematopoietic stem cell transplant recipients(allogeneic and autologous HSCT)



100 46.90(16-67)

2

Huang et al,39 2012 China Hematopoietic stem cell transplant recipients(allogeneic and autologous HSCT)

ITCZ 5 mg/kgorally every d


283 32.72(18-70)

3

Huijgens et al,40 1999 Netherlands Patients with hematological malignant neoplasmsreceiving chemotherapy or HSCT

FLCZ 50 mgorally 2×/d


202 45.15(NA)

2

Ito et al,41 2007 Japan Patients with AML or MDS receiving chemotherapy FLCZ 200 mgorally every d

ITCZ 200 mgorally every d

218 55.46(16-80)

3

Kaptan et al,42 2003 Turkey Patients with acute leukemia receivingchemotherapy


Placebo 97 35.58(20-73)

3

Kelsey et al,43 1999 International Hematopoietic stem cell transplant recipients(allogeneic and autologous HSCT)

AMBL 2 mg/kg IV3×/wk

Placebo 161 39.92(15-65)

1

(continued)




Table 1. Basic Characteristics of Included Studies (continued)


Interventions


Kern et al,44 1998 International Patients with AML receiving chemotherapy FLCZ 400 mgorally every d

AMB 40 mg orallyevery 4 h (6×/d)

68 48.71(17-73)

2

Koh et al,45 2002 Singapore Hematopoietic stem cell transplant recipients(allogeneic and autologous HSCT)


AMB 0.2 mg/kgIV every d

186 29.69(4-63)

2

Lass-Florl et al,46 2003 Austria Patients with hematological malignant neoplasmsreceiving chemotherapy

ITCZ 5 mg/kgorally 2×/d


106 43.94(NA)

3

Laverdiere et al,47 2000 Canada Patients with hematological malignant neoplasmsreceiving chemotherapy or undergoingtransplantation

FKCZ 400 mgorally every d

Placebo 266 46.31(17-80)

2

Mahmoud et al,48 2016 Egypt Patients with acute leukemia receivingchemotherapy

MCFG 1 mg/kg IVevery d

Placebo 70 7.35(0-18)

2

Marks et al,49 2011 International Hematopoietic stem cell transplant recipients(allogeneic HSCT)



465 42.78(11-70)

3

Marr et al,50 2004 United States Hematopoietic stem cell transplant recipients(allogeneic HSCT)

FLCZ 400 mgorally or IV everyd

ITCZ 2.5 mg/kgorally 3×/d or200 mg IV everyd

299 NA 2

Mattiuzzi et al,51 2003 United States Patients with AML or MDS receiving chemotherapy AMBL 3 mg/kg IV3×/wk

FLCZ 200 mgorally 2×/d andITCZ 200 mg/kgorally 2×/d

137 60.57(19-84)

2

Mattiuzzi et al,52 2006 United States Patients with AML or MDS receiving chemotherapy ITCZ 200 mg IVevery d

CASP 50 mg IVevery d

200 62.17(17-82)

2

Mattiuzzi et al,53 2011 United States Patients with AML or MDS receiving chemotherapy ITCZ 200 mg IVevery d

VOCZ 300 mg IV2×/d

123 59.42(21-83)

2

Menichetti et al,54 1999 Italy Patients with hematological malignant neoplasmsreceiving chemotherapy or HSCT


Placebo 405 44.00(17-79)

2

Morgenstern et al,55 1999 UnitedKingdom

Patients with hematological malignanct neoplasmsreceiving chemotherapy or HSCT



445 44.55(16-81)

2

Nucci et al,56 2000 Brazil Patients with hematological malignant neoplasmsreceiving chemotherapy or HSCT


Placebo 210 27.7(5-67)

2

Oren et al,57 2006 Israel Patients with hematological diseases receivingchemotherapy or HSCT


ITCZ 200 mgorally or IV everyd

195 49.49(17-75)

3

Palmblad et al,58 1992 Sweden Patients with acute leukemia receivingchemotherapy


Placebo 107 50.47(15-74)

2

Park et al,59 2016 Korea Hematopoietic stem cell transplant recipients(allogeneic and autologous HSCT)



250 46.66(20-64)

2

Penack et al,60 2006 Germany Patients with hematological diseases receivingchemotherapy or HSCT

AMBL 50 mg IVevery other d

Placebo 132 53.76(21-77)

3

Perfect et al,61 1992 United States Bone marrow transplant recipients (autologousHSCT)


Placebo 182 38.75(24-55)

2

Philpott-Howardet al,62 1993

International Patients with hematological diseases receivingchemotherapy or HSCT


Polyene, nystatin1 mIU orally 4×/dor AMB 500 mgorally 4×/d

536 45.9(11-87)

3

Rijnders et al,63 2008 Netherlands Patients with hematological diseases receivingchemotherapy or HSCT

AMBL 12.5 mgINH every d

Placebo 271 49.49(18-74)

1

Riley et al,64 1994 United States Bone marrow transplant recipients (allogeneic andautologous HSCT)


Placebo 35 38.00(10-52)

3

Rotstein et al,65 1999 Canada Patients with hematological malignant neoplasmsreceiving chemotherapy or undergoing HSCT


Placebo 304 46.40(17-80)

2

Sawada et al,66 2009 Japan Patients with hematological diseases receivingchemotherapy or HSCT

FlCZ 10 mg/kg IVevery d

MCFG 2 mg/kg IVevery d

107 6.01 (NA) 2

Schaffner andSchaffner,67 1995

Swizerland Patients with AML or NHL receiving chemotherapyor HSCT


Placebo 151 39.5(17-71)

2

Schwartz et al,68 1999 Germany Patients with hematological malignantneoplasmscies receiving chemotherapy or HSCT

AMB 10 mg INH2×/d

Placebo 382 46.81(16-81)

1

Shen et al,69 2013 China Patients with AML or MDS receiving chemotherapy FLCZ 400 mgorally every d

POCZ 200 mgorally TID

234 40.00(15-68)

3

Slavin et al,70 1995 Australia Bone marrow transplant recipients (allogeneic andautologous HSCT)


Placebo 300 36.35(13-65)

2

Tollemar et al,71 1993 Sweden Bone marrow transplant recipients (allogeneic andautologous HSCT)

AMBL 1 mg/kg IVevery d

Placebo 53 58.3 (NA) 2

(continued)




Figure 1. Schematic of the Network of Evidence Used in Network Meta-analysis for Invasive Fungal Infections

ITCZ

VOCZ

POCZ

CASP

MCFG

Placebo

Polyene

AMB

AMBL

MICZ

KTCZ

FLCZ

AMB indicates conventional amphotericin B; AMBL,liposomal amphotericin B; KTCZ, ketoconazole; FLCZ,fluconazole; ITCZ, itraconazole; VOCZ, voriconazole;POCZ, posaconazole; CASP, caspofungin; and MCFG,micafungin.

Table 1. Basic Characteristics of Included Studies (continued)


Interventions


Ullmann et al,72 2007 International Patients with grade II-IV acute GVHD or chronicGVHD



600 41.30(13-72)

2

Van Burik et al,73 2004 United States Hematopoietic stem cell transplant recipients(allogeneic and autologous HSCT)



882 42.52(0-73)

2

Vehreschild et al,74 2007 Germany Patients with AML receiving chemotherapy VOCZ 200 mgorally 2×/d

Placebo 25 53.60(18-73)

3

Vreugdenhil et al,75 1993 Netherlands Patients with hematological malignant neoplasmsreceiving chemotherapy


Placebo 92 49.5(15-75)

2

Wingard et al,76 1987 United States Patients with hematological diseases receivingchemotherapy or HSCT

MICZ 5 mg/kg IVevery d

Placebo 208 33.93(6-75)

2

Wingard et al,77 2010 United States Hematopoietic stem cell transplant recipients(allogeneic HSCT)



600 43.00(2-65)

3

Winston et al,78 1993 United States Patients with acute leukemia receivingchemotherapy

FLCZ 400 mgorally every d or200 mg IV 2×/d

Placebo 256 43.47(17-82)

2

Winston et al,79 2003 United States Hematopoietic stem cell transplant recipients(allogeneic HSCT)


ITCZ 200 mg IVevery d

138 39.54(14-63)

1

Wolff et al,80 2000 United States Bone marrow transplant recipients (allogeneic andautologous HSCT)



355 42.55(18-68)

2

Yamac et al,81 1995 Turkey Patients with hematological diseases receivingchemotherapy


Placebo 70 49.41(16-68)

2

Young et al,82 1999 International Patients with leukemia receiving chemotherapy FLCZ 200 mgorally every d

Polyene, nystatin8 mIU orallyevery d

164 43.23(17-80)

2

Abbrevations: AMB, amphotericin B; AMBL, liposomal amphotericin B; CASP,caspofungin; FLCZ, fluconazole; KTCZ, ketoconazole; ITCZ, itraconazole; INH, inhalation;

IV, intravenously; MCFG, micafungin; NA, not available; POCZ, posaconazole; RoB2,revised tool for risk of bias; VOCZ, voriconazole.




Table 2. SUCRA Values and Mean Rank for All Outcomes

MeasureFungalinfections IFIs Proven IFIs

Invasivecandidiasis

Invasiveaspergillosis Mortality

Fungi-relateddeath Withdrawal

Overall

Placebo

SUCRA, % 6.2 19.2 25.3 11.6 40.9 38.0 33.7 45.2

Mean rank 11.3 9.9 8.5 10.7 7.5 7.8 8.3 6.5

Polyene

SUCRA, % 27.5 12.6 37.0 31.0 18.0 15.0 22.6 72.0

Mean rank 9.0 10.6 7.3 8.6 10.0 10.4 9.5 3.8

Amphotericin B

SUCRA, % 37.5 41.0 14.1 3.6 69.3 42.7 28.3 50.5

Mean rank 7.9 7.5 9.6 11.6 4.4 7.3 8.9 5.9

Liposomal amphotericin B

SUCRA, % 46.8 61.5 59.7 44.2 37.8 61.8 78.8 4.3

Mean rank 6.8 5.2 5.0 7.1 7.8 5.2 3.3 10.6

Miconazole

SUCRA, % 76.6 55.2 NA 60.7 42.3 44.5 58.5 NA

Mean rank 3.6 5.9 NA 5.3 7.3 7.1 5.6 NA

Ketoconazole

SUCRA, % 58.4 17.1 6.3 26.6 63.4 15.4 7.5 63.0

Mean rank 5.6 10.1 10.4 9.1 5.0 10.3 11.2 4.7

Fluconazole

SUCRA, % 48.8 45.8 60.5 67.1 24.2 49.0 51.6 41.0

Mean rank 6.6 7.0 4.9 4.6 9.3 6.6 6.3 6.9

Itraconazole

SUCRA, % 28.4 64.6 75.4 80.5 22.4 47.1 64.3 38.0

Mean rank 8.9 4.9 3.5 3.1 9.5 6.8 4.9 7.2

Voriconazole

SUCRA, % 30.5 36.9 81.5a 67.1 51.2 73.8 75.0 78.1a

Mean rank 8.6 8.4 2.9 4.6 6.4 3.9 3.8 3.2

Posaconazole

SUCRA, % 82.9 86.7a 78.6 62.6 87.8a 68.5 76.2a 17.5

Mean rank 2.9 2.5 3.1 5.1 2.3 4.5 3.6 9.2

Caspofungin

SUCRA, % 84.9a 84.2 35.1 88.5a 78.6 54.2 36.9 67.6

Mean rank 2.7 2.7 7.5 2.3 3.4 6.0 7.9 4.2

Micafungin

SUCRA, % 71.4 75.0 76.4 56.6 64.0 90.0a 66.6 72.7

Mean rank 4.1 3.7 3.4 5.8 5.0 2.1 4.7 3.7

Transplantation

Placebo

SUCRA, % 8.5 7.4 4.5 2.3 41.8 25.7 25.6 45.8

Mean rank 8.3 7.5 7.7 6.9 4.5 5.5 4.7 4.8

Polyene

SUCRA, % NA NA NA NA NA NA NA NA

Mean rank NA NA NA NA NA NA NA NA

Amphotericin B

SUCRA, % 44.1 48.2 44.5 75.9 22.6 94.2a 23.4 48.0

Mean rank 5.5 4.6 4.9 2.4 5.6 1.3 4.8 4.6


SUCRA, % 14.3 25.2 40.7 30.7 40.7 36.3 32.7 6.4

Mean rank 7.9 6.2 5.1 5.2 4.6 4.8 4.4 7.6

(continued)




Table 2. SUCRA Values and Mean Rank for All Outcomes (continued)


Invasivecandidiasis



Miconazole



Ketoconazole

SUCRA, % 42.8 NA NA NA NA NA NA NA

Mean rank 5.6 NA NA NA NA NA NA NA

Fluconazole

SUCRA, % 48.3 44.2 44.2 56.8 37.8 44.5 59.0 62.3

Mean rank 5.1 4.9 4.9 3.6 4.7 4.3 3.0 3.6

Itraconazole

SUCRA, % 69.7 66.9 59.5 77.8a 54.2 32.3 72.7 35.0

Mean rank 3.4 3.3 3.8 2.3 3.7 5.1 2.4 5.6

Voriconazole

SUCRA, % 75.1a 68.4 71.6a 60.9 70.5 49.2 NA 89.4a

Mean rank 3.0 3.2 3.0 3.3 2.8 4.0 NA 1.7

Posaconazole

SUCRA, % 73.0 76.3a 69.5 NA NA NA NA 28.2

Mean rank 3.2 2.7 3.1 NA NA NA NA 6.0

Caspofungin



Micafungin

SUCRA, % 74.2 63.4 65.5 45.6 82.3a 67.7 86.6a 84.9

Mean rank 3.1 3.6 3.4 4.3 2.1 2.9 1.7 2.1

AML or MDS

Placebo

SUCRA, % 73.5 74.0 NA NA NA 22.5 NA NA

Mean rank 2.9 2.8 NA NA NA 6.4 NA NA

Polyene



Amphotericin B

SUCRA, % 11.9 14.3 54.2a 45.8 43.5 66.7 55.9 NA

Mean rank 7.2 7.0 2.4 3.7 3.8 3.3 3.6 NA


SUCRA, % 18.0 11.5 NA 21.0 55.4 44.4 59.4 44.6

Mean rank 6.7 7.2 NA 4.9 3.2 4.9 3.4 3.8

Miconazole



Ketoconazole



Fluconazole

SUCRA, % 52.0 53.1 49.0 50.0 26.5 56.1 59.8 71.9

Mean rank 4.4 4.3 2.5 3.5 4.7 4.1 3.4 2.4

Itraconazole

SUCRA, % 42.4 43.5 53.4 55.7 14.6 28.5 18.2 28.5

Mean rank 5.0 5.0 2.4 3.2 5.3 6.0 5.9 4.6

Voriconazole

(continued)




Table 2. SUCRA Values and Mean Rank for All Outcomes (continued)


Invasivecandidiasis



SUCRA, % 82.7 83.1 NA NA NA 55.8 58.5 6.8

Mean rank 2.2 2.2 NA NA NA 4.1 3.5 5.7

Posaconazole

SUCRA, % 83.4a 83.3a NA 46.4 84.0a 80.1a 83.0a 89.5a

Mean rank 2.2 2.2 NA 3.7 1.8 2.4 2.0 1.5

Caspofungin

SUCRA, % 35.9 37.2 43.4 81.1a 76.0 45.8 15.4 58.7

Mean rank 5.5 5.4 2.7 1.9 2.2 11.0 6.1 3.1

Micafungin



Allo-HSCT

Placebo



Polyene



Amphotericin B






Miconazole



Ketoconazole



Fluconazole

SUCRA, % 4.4 4.7 10.3 27.9 15.9 60.1 22.4 50.8

Mean rank 2.9 2.9 2.8 2.4 2.7 1.8 1.8 2.0

Itraconazole

SUCRA, % 65.3 66.0 64.6 85.8a 40.9 14.5 77.6a 0.0

Mean rank 1.7 1.7 1.7 1.3 2.2 2.7 1.2 3.0

Voriconazole

SUCRA, % 80.3a 79.3a 75.1a 36.3 93.3a 75.4a NA 99.2a

Mean rank 1.4 1.4 1.5 2.3 1.1 1.5 NA 1.0

Posaconazole



Caspofungin



Micafungin



Abbreviations: AML, acute myeloid leukemia; HSCT, hematopoietic stem celltransplantation; MDS, myelodysplastic syndrome; NA, not available; SUCRA, surfaceunder the cumulative ranking curve.

a Ranking first among agents.




placebo (Figure 2). Regarding mortality, the treatment ranked highest was micafungin (SUCRA,90.0%; mean rank, 2.1). Voriconazole ranked second (SUCRA, 73.8%), and posaconazole rankedthird (SUCRA, 68.5%).

Caspofungin (SUCRA, 84.9%) treatment ranked the highest for reducing fungal infections.Posaconazole ranked highest in preventing invasive aspergillosis (SUCRA, 87.8%). Caspofungin wasranked highest for preventing invasive candidiasis (SUCRA, 88.5%), and liposomal amphotericin Branked the highest for reducing fungi-related deaths (SUCRA, 78.8%). Voriconazole was associatedwith a significant reduction in invasive candidiasis (RR, 0.15; 95% CI, 0.09-0.26) compared withplacebo (eFigure 5 in the Supplement). Voriconazole was ranked highest for having the lowestincidence of withdrawal (SUCRA, 78.1%). Posaconazole was associated with a higher incidence ofwithdrawal because of the adverse effects of the drug (SUCRA, 17.5%; mean rank, 9.2) (eFigure 6 inthe Supplement).

Subgroup AnalysesBecause extensive categories of patients were included, we evaluated whether the prophylacticoutcomes and tolerance of agents varied in different patient populations (patients with acutemyeloid leukemia [AML] or myelodysplastic syndrome [MDS] or undergoing HSCT or allo-HSCT).Considering efficacy and tolerance, voriconazole was ranked as the best choice for patientsundergoing HSCT; this result was also found in the allo-HSCT population. However, posaconazole wasranked as the best choice for patients with AML or MDS.

Heterogeneity, Inconsistency, and Small-Study EffectsHeterogeneity and inconsistency are shown in Table 3. Heterogeneity was low for IFIs and mortality.In contrast, heterogeneity was reasonable for the other outcomes (τ2 values from 0.1 to 0.4). Loopinconsistency for placebo, amphotericin B, and fluconazole was found for invasive candidiasis(indirect effect estimate, 2.53; 95% CI, 1.07-3.98; P = .001) (eFigure 7 in the Supplement). We used afunnel plot to visually demonstrate small-study effects (eFigure 8 in the Supplement).

Discussion

In this systematic review and network meta-analysis, we combined direct and indirect evidence tocompare antifungal prophylaxis options for patients with hematological disease or undergoing HSCT.Our analysis may provide some important information for clinical decision-making for antifungalprophylaxis in these patients. We derived 2 principal findings from our analysis: voriconazole may bethe best choice for patients undergoing HSCT, and posaconazole may be the best prophylactic optionfor patients with AML or MDS. Posaconazole is recommended for IFIs during remission inductionchemotherapy for AML and MDS, according to the Guidelines from the Infectious Diseases WorkingParty of the German Society for Haematology and Medical Oncology.83 Overall, posaconazole andvoriconazole are recommended as the most reasonable options for the prevention of IFIs. Thedifference between agents may be meaningful and is not available from single trials, to ourknowledge. For instance, voriconazole has not been directly compared with other drugs except forplacebo, fluconazole, and itraconazole; however, this network meta-analysis compared voriconazole,as well as posaconazole, with other drugs indirectly.

Posaconazole is recommended for the prevention of IFIs regardless of tolerance. The mostcommonly reported treatment-related adverse effects of oral posaconazole were digestive tractsymptoms, including nausea, vomiting, and gastrointestinal upset.84 The most common cause fordiscontinuation was severe nausea or gastrointestinal upset.85 We noticed that the incidence ofwithdrawal was different in patients with AML or MDS and patients undergoing HSCT. We assumedthat in patients undergoing HSCT, especially allo-HSCT, a high-dose pretreatment scheme, the use ofcyclosporin and the incidence of gastrointestinal acute graft-vs-host disease (GVHD) would decreasethe tolerance of posaconazole. The rate of adverse events that led to the discontinuation of








Figure 2. Forest Plot of Invasive Fungal Infections

RR (95% CI) [95% Prl]Treatment effectPolyene vs placebo

VOCZ vs placebo

AMB vs placebo 1.30 (0.58-2.89) [0.48-3.51]0.65 (0.35-1.20) [0.28-1.51]0.44 (0.26-0.74) [0.20-0.95]0.47 (0.10-2.28) [0.08-2.63]1.08 (0.11-10.58) [0.10-12.16]

0.92 (0.41-2.07) [0.34-2.52]1.35 (0.32-5.73) [0.27-6.64]

0.54 (0.08-3.70) [0.07-4.25]0.57 (0.41-0.79) [0.30-1.10]0.74 (0.30-1.83) [0.25-2.19]0.58 (0.30-1.10) [0.24-1.38]0.50 (0.18-1.37) [0.15-1.63]0.34 (0.13-0.87) [0.11-1.04]0.36 (0.06-2.13) [0.05-2.45]1.04 (0.20-5.44) [0.17-6.27]0.44 (0.21-0.92) [0.17-1.13]0.57 (0.23-1.42) [0.19-1.70]0.58 (0.10-3.44) [0.08-3.96]0.06 (0.00-1.47) [0.00-1.70]0.16 (0.04-0.57) [0.04-0.67]0.19 (0.03-1.13) [0.03-1.30]0.68 (0.31-1.51) [0.25-1.84]0.72 (0.13-3.94) [0.12-4.54]2.08 (0.43-10.01) [0.37-11.56]0.88 (0.44-1.76) [0.36-2.18]1.14 (0.53-2.42) [0.43-2.97]1.16 (0.21-6.37) [0.18-7.33]0.12 (0.01-2.82) [0.00-3.27]0.31 (0.09-1.11) [0.08-1.30]0.39 (0.07-2.09) [0.06-2.40]1.06 (0.20-5.61) [0.18-6.47]3.06 (0.66-14.21) [0.57-16.43]1.30 (0.72-2.33) [0.57-2.96]1.67 (0.85-3.30) [0.68-4.10]1.70 (0.32-9.06) [0.28-10.45]0.18 (0.01-3.74) [0.01-4.33]0.46 (0.14-1.55) [0.12-1.82]0.57 (0.11-2.97) [0.09-3.42]2.87 (0.34-24.48) [0.29-28.11]1.22 (0.24-6.12) [0.21-7.07]1.57 (0.30-8.10) [0.26-9.34]1.60 (0.17-15.06) [0.15-17.30]0.17 (0.01-5.39) [0.00-6.28]0.43 (0.06-3.00) [0.05-3.44]0.53 (0.06-4.95) [0.05-5.69]0.42 (0.10-1.87) [0.08-2.17]0.55 (0.12-2.49) [0.10-2.88]0.56 (0.06-4.79) [0.06-5.50]0.06 (0.00-1.77) [0.00-2.06]0.15 (0.02-0.94) [0.02-1.08]0.19 (0.02-1.58) [0.02-1.81]1.29 (0.72-2.23) [0.58-2.86]1.31 (0.26-6.65) [0.22-7.67]0.14 (0.01-3.05) [0.01-3.53]0.36 (0.12-1.03) [0.10-1.22]0.44 (0.09-2.18) [0.08-2.51]1.02 (0.20-5.31) [0.17-6.12]0.11 (0.00-2.41) [0.00-2.80]0.28 (0.08-0.91) [0.07-1.07]0.34 (0.07-1.74) [0.06-2.01]0.11 (0.00-3.39) [0.00-3.95]0.27 (0.04-1.89) [0.03-2.17]0.33 (0.04-3.13) [0.03-3.59]2.54 (0.10-66.10) [0.08-76.84]3.12 (0.10-98.03) [0.09-114.37]1.23 (0.18-8.43) [0.16-9.68]

AMBL vs placeboMICZ vs placeboKTCZ vs placeboFLCZ vs placeboITCZ vs placebo

AMBL vs placebo

POCZ vs placeboCASP vs placeboMCFG vs placeboAMB vs placebo

VOCZ vs placebo

MICZ vs placeboKTCZ vs placeboFLCZ vs placeboITCZ vs placebo

MICZ vs AMB

POCZ vs placeboCASP vs placeboMCFG vs placeboAMBL vs AMB

POCZ vs AMB

KTCZ vs AMBFLAC vs AMBITCZ vs AMBVOCZ vs AMB

ITCZ vs AMBL

CASP vs AMBMCFG vs AMBMICZ vs AMMLKTCZ vs AMBLFLCZ vs AMBL

KTCZ vs MICZ

VOCZ vs AMBLPOCZ vs AMBLCASP vs AMBLMCFG vs AMBL

CASP vs MICZ

FLCZ vs MICZITCZ vs MICZVOCZ vs MICZPOCZ vs MICZ

POCZ vs KTCZ

MCFG vs MICZFLCZ vs KTCZITCZ vs KTCZVOCZ vs KTCZ

POCZ vs FLCZ

CASP vs KTCZMCFG vs KTCZITCZ vs FLCZVOCZ vs FLCZ

CASP vs FLCZMCFG vs FLCZVOCZ vs ITCZPOCZ vs ITCZCASP vs ITCZMCFG vs ITCZPOCZ vs VOCZCASP vs VOCZMCFG vs VOCZCASP vs POCZMCFG vs POCZMCFG vs CASP

0 1101RR (95% CI) [95% Pri]

Event was more commonin the intervention group

Event was more commonin the reference group

The dotted line indicates null effect; diamonds, relativerisk (RR); and black whiskers, 95% CI; red whiskers,95% predicted interval (PrI); AMB, conventionalamphotericin B; AMBL, liposomal amphotericin B;KTCZ, ketoconazole; FLCZ, fluconazole; ITCZ,itraconazole; VOCZ, voriconazole; POCZ,posaconazole; CASP, caspofungin; and MCFG,micafungin.




posaconazole was 40% in the study by Chatter et al.22 In the posaconazole group, the rate ofdiarrhea was 67%, of nausea was 67%, and of vomiting was 29%. The rate of gastrointestinal adverseevents was similar between the liposomal amphotericin B and posaconazole groups. A new route ofadministration through injection may be an option for patients who are unable to swallow or areintolerant of oral posaconazole.

Caspofungin is recommended to prevent invasive candidiasis, and the same results wereconfirmed in patients with AML or MDS. There were no relevant data from patients undergoing HSCT.An echinocandin drug is recommended as the initial therapy for candidemia, according to the clinicalpractice guidelines for the management of candidiasis from the Infectious Diseases Society ofAmerica.86 In our analysis, posaconazole was ranked the best choice for preventing invasiveAspergillus infections, followed by caspofungin. According to the guidelines for the diagnosis andmanagement of aspergillosis from the Infectious Diseases Society of America, posaconazole,voriconazole, and micafungin are recommended for invasive aspergillosis prevention.87 However, inour analysis, it appeared that caspofungin treatment was associated with a better outcome thanmicafungin and voriconazole in preventing aspergillosis. Concerning the prevention of fungi-relateddeath, treatment with liposomal amphotericin B might be associated with a better outcome,followed by posaconazole and voriconazole. There was no significant difference in fungi-relateddeath with posaconazole.

Some previous studies have summarized the data from the literature on antifungal prophylaxisin hematological disease.88-90 These network meta-analyses did not take into account antifungalprophylaxis in other high-risk groups, such as patients with GVHD.91 With regard to GVHD, the risk ofIFIs appears particularly prominent in patients with high-grade acute GVHD or steroid-dependentchronic GVHD.91 Our network meta-analysis has taken into account antifungal prophylaxis in patientswith GVHD. A high number of patients with solid tumor without HSCT therapy were included inprevious network meta-analyses. In the study by Ninane et al,92 solid tumors were present in morethan 20% of patients. We did not consider this study appropriate for a network meta-analysis forantifungal prophylaxis, as routine antifungal prophylaxis is not recommended in patients with solidtumors.91 The evidence shown by Leonart et al88 focused on double-blind trials, and the study byZhao et al89 focused on triazole agents. Therefore, the conclusions of the comparisons in thosereports cannot be compared with the results in this meta-analysis.

Inconsistency refers to the differences between direct and various indirect effect estimates forthe same comparison. Stata tests for inconsistency have 2 levels12: overall inconsistency, in whichthe level of inconsistency is computed according to the type of between-treatment comparison forall cases and a local approach, in which each treatment is individually examined. Local inconsistencybecause of loop inconsistency in placebo, amphotericin B, and fluconazole was found for invasivecandidiasis in our analysis. There are 4 causes of inconsistency: chance, bias in head-to-headcomparisons, bias in indirect comparisons, and genuine diversity.93 According to Higgins et al11 loopinconsistency refers to a difference between direct and indirect comparisons. The study by Behreet al16 may be the source of the loop inconsistency because aerosol amphotericin B inhalation

Table 3. Tests for Inconsistency, Heterogeneity, and Small-Study Effects

Outcome

Inconsistency at the overall level

Heterogeneity (τ2) Begg test P valueχ2 P valueFungal infections 13.97 .45 0.118 .06

IFIs 10.04 .75 0.069 .40

Proven IFIs 8.77 .11 0.112 .40

Invasive candidiasis 13.51 .09 0.284 .35

Invasive aspergillosis 8.60 .48 0.192 .91

Mortality 6.20 .91 0.016 .48

Fungi-related death 13.05 .16 0.303 .93

Withdrawal 13.67 .06 0.334 .51Abbreviation: IFI, invasive fungal infection.




treatment was used. When this study was excluded from the analysis, the difference between directand indirect comparisons of the treatments for invasive candidiasis was not significant.

The interpretations of the results were based on SUCRA values and ranking in our study.Although rankings are appealing, they may be incorrectly emphasize particular treatments as beingclinically useful. The uncertainty present in the rankings may be neglected in considering the besttreatment, and the rankings may give a false sense that some interventions are superior to others. APRISMA-NMA statement has suggested that more attention should be paid to the relative effectestimates, rather than the rankings, because a good rank does not necessarily translate to a clinicallyrelevant effect.6 Although the usefulness of rankings is currently debated, rankings will probablycontinue to be reported. Reporting all probabilities for each intervention with each possible rank isone way to convey the uncertainty in the rank ordering.94 The treatment effects and rankings alsodepend on the number of treatments and trials in the network.95

LimitationsOur study has some limitations. First, an improved understanding of antifungal pharmacology,pharmacokinetics, and pharmacodynamics has resulted in therapeutic drug monitoring becoming avaluable adjunct to the administration of some antifungal agents. We could not perform an analysisof therapeutic drug monitoring to evaluate the efficacy and adverse effects of antifungal prophylaxisor justify why therapeutic drug monitoring should not be performed with antifungal prophylaxis ifit is strongly recommended with antifungal treatment because of the limited data. Second, thefollow-up time of most studies was too short to determine the survival benefits from antifungalprophylaxis. Third, a limited number of head-to-head trials have investigated posaconazole andvoriconazole. Fourth, the characteristics of patients and treatments were heterogeneous among thevarious randomized clinical trials. Although our subgroup analyses found different results amongdifferent patient populations, the data did not allow us to perform more detailed analyses, such asthose for different ages and races/ethnicities. We also could not perform a more stratified analysistaking into consideration the dosage form and dose of agents. Therefore, the evidence derived fromthis meta-analysis should be used with caution for shared decision-making. However, our studyprovides important data from which future practice-changing prospective trials can be designed.

Conclusions

This network meta-analysis assessed the performance of various antifungal prophylaxis treatment inpatients with hematological disease or undergoing HSCT. Our findings suggest that, in terms of theprevention of IFIs and tolerance, voriconazole may be the best prophylactic option for patientsundergoing HSCT, and posaconazole may be the best prophylactic option for patients with AMLor MDS.

ARTICLE INFORMATIONAccepted for Publication: July 3, 2020.

Published: October 8, 2020. doi:10.1001/jamanetworkopen.2020.17652

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Wang J et al.JAMA Network Open.

Corresponding Authors: Bing Chen, MD, PhD, Department of Hematology, Affiliated Drum Tower Hospital ofNanjing University Medical School, 321 Zhongshan Rd, Nanjing, 210008, China ([email protected]); YuanWan, PhD, The Pq Laboratory of Micro/Nano BiomeDx, Department of Biomedical Engineering, BinghamtonUniversity – SUNY, Binghamton, Biotechnology Building, 65 Murray Hill Rd, Vestal, NY 13850 ([email protected]).

Author Affiliations: Department of Hematology, Affiliated Drum Tower Hospital of Nanjing University MedicalSchool, Nanjing, China (Wang, M. Zhou, Xu, R.-F. Zhou, Chen); The Pq Laboratory of Micro/Nano BiomeDx,





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mailto:[email protected]



Department of Biomedical Engineering, Binghamton University – SUNY, Binghamton, New York (Wang, Wan).

Author Contributions: Drs Wang and Wan had full access to all of the data in the study and take responsibility forthe integrity of the data and the accuracy of the data analysis.

Concept and design: Chen, Wan.

Acquisition, analysis, or interpretation of data: Wang, M. Zhou, Xu, R.-F. Zhou, Wan.

Drafting of the manuscript: M. Zhou, Wan.

Critical revision of the manuscript for important intellectual content: Wang, Xu, R.-F. Zhou, Chen, Wan.

Statistical analysis: Wang, M. Zhou, Wan.

Obtained funding: M. Zhou, Xu, Wan.

Administrative, technical, or material support: Wang, Xu, R.-F. Zhou, Wan.

Supervision: Chen, Wan.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was partially supported by Binghamton University Faculty Start-up Fund (grant No.910252-35), Binghamton University S3IP Award (No. ADLG195), and Nanjing Medical Science and TechniqueDevelopment Foundation (grant Nos. YKK15068 and YKK17074).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; anddecision to submit the manuscript for publication.

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SUPPLEMENT.eAppendix. Search StrategyeFigure 1. PRISMA FlowcharteFigure 2. Quality AssessmenteFigure 3. Network Geometry of All OutcomeseFigure 4. Forest Plots of All OutcomeseFigure 5. League Tables of All OutcomeseFigure 6. Cluster Rank Combined the SUCRAeFigure 7. Inconsistency Plot of All OutcomeseFigure 8. Funnel Plots of All Outcomes




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