Comparison of Antifungal Prophylaxis Drugs in Patients With Hematological Disease or Undergoing Hematopoietic Stem Cell Transplantation

Key Points Question 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.


Introduction
Invasive fungal infections (IFIs) have emerged as important causes of morbidity and mortality in patients receiving myelosuppressive chemotherapy, immunosuppressive therapy, or hematopoietic stem cell transplantation (HSCT). Because of the difficulty in obtaining a timely diagnosis as well as the high morbidity and mortality associated with IFIs, antifungal prophylaxis remains a high priority in these populations at high risk of IFIs. 1 Over the past decade, clinical benefits from antifungal prophylaxis have been demonstrated. [2][3][4] However, there is no clear consensus on antifungal prophylaxis treatment between different centers and groups, particularly in the choice of the antifungal prophylaxis agents. Conventional pairwise meta-analyses based on a direct comparison are relatively limited and difficult to use to investigate antifungal prophylaxis agents. We performed a systematic review and network meta-analysis 5 to gain a better understanding of the outcomes associated with and tolerance to current antifungal agents.

Protocol and Registration
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic 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 Search
Medline, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials were searched to collect all published evidence from randomized clinical trials from inception to October 2019 that assessed 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 all included studies and reviews were screened to identify potentially relevant evidence.

Study Inclusion Criteria
All available randomized clinical trials that aimed to compare any antifungal agent with a placebo, no antifungal agent, or another antifungal agent for prophylaxis in patients with hematological disease or undergoing HSCT were included. In this analysis, we assumed that there was no difference between placebo and no antifungal agent. deep tissue); (4) incidence of invasive candidiasis; (5) incidence of invasive aspergillosis; (6) fungirelated death; and (7) withdrawal because of adverse effects of the drug.

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

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

Characteristics of the Studies
The flowchart of study selection for this network meta-analysis is shown in eFigure 1 in the Supplement. 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 basic characteristics of the included studies are summarized in Table 1. The randomization process and selection of the reported results were not reported clearly in most trials (eFigure 2 in the Supplement).

Network Geometry and Synthesis of Results
The network geometry for each outcome is shown in eFigure 3 in the Supplement: fungal infections included 12 groups, 69 studies, and 14 789 patients; IFIs included 12 groups (Figure 1)         placebo (Figure 2

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

Heterogeneity, Inconsistency, and Small-Study Effects
Heterogeneity and inconsistency are shown in Table 3. Heterogeneity was low for IFIs and mortality.
In contrast, heterogeneity was reasonable for the other outcomes (τ 2 values from 0.1 to 0.4). Loop inconsistency 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 a funnel 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 to compare antifungal prophylaxis options for patients with hematological disease or undergoing HSCT.
Our analysis may provide some important information for clinical decision-making for antifungal prophylaxis in these patients. We derived 2 principal findings from our analysis: voriconazole may be the best choice for patients undergoing HSCT, and posaconazole may be the best prophylactic option for patients with AML or MDS. Posaconazole is recommended for IFIs during remission induction chemotherapy for AML and MDS, according to the Guidelines from the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology. 83 Overall, posaconazole and voriconazole are recommended as the most reasonable options for the prevention of IFIs. The difference between agents may be meaningful and is not available from single trials, to our knowledge. For instance, voriconazole has not been directly compared with other drugs except for placebo, 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 most commonly reported treatment-related adverse effects of oral posaconazole were digestive tract symptoms, including nausea, vomiting, and gastrointestinal upset. 84 The most common cause for discontinuation was severe nausea or gastrointestinal upset. 85 We noticed that the incidence of withdrawal was different in patients with AML or MDS and patients undergoing HSCT. We assumed that in patients undergoing HSCT, especially allo-HSCT, a high-dose pretreatment scheme, the use of cyclosporin and the incidence of gastrointestinal acute graft-vs-host disease (GVHD) would decrease the tolerance of posaconazole. The rate of adverse events that led to the discontinuation of  posaconazole was 40% in the study by Chatter et al. 22 In the posaconazole group, the rate of diarrhea was 67%, of nausea was 67%, and of vomiting was 29%. The rate of gastrointestinal adverse events was similar between the liposomal amphotericin B and posaconazole groups. A new route of administration through injection may be an option for patients who are unable to swallow or are intolerant of oral posaconazole.

JAMA Network Open | Infectious Diseases
Caspofungin is recommended to prevent invasive candidiasis, and the same results were confirmed 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 clinical practice guidelines for the management of candidiasis from the Infectious Diseases Society of America. 86 In our analysis, posaconazole was ranked the best choice for preventing invasive Aspergillus infections, followed by caspofungin. According to the guidelines for the diagnosis and management of aspergillosis from the Infectious Diseases Society of America, posaconazole, voriconazole, and micafungin are recommended for invasive aspergillosis prevention. 87 However, in our analysis, it appeared that caspofungin treatment was associated with a better outcome than micafungin and voriconazole in preventing aspergillosis. Concerning the prevention of fungi-related death, treatment with liposomal amphotericin B might be associated with a better outcome, followed by posaconazole and voriconazole. There was no significant difference in fungi-related death with posaconazole.
Some previous studies have summarized the data from the literature on antifungal prophylaxis in hematological disease. [88][89][90] These network meta-analyses did not take into account antifungal prophylaxis in other high-risk groups, such as patients with GVHD. 91 With regard to GVHD, the risk of IFIs appears particularly prominent in patients with high-grade acute GVHD or steroid-dependent chronic GVHD. 91 Our network meta-analysis has taken into account antifungal prophylaxis in patients with GVHD. A high number of patients with solid tumor without HSCT therapy were included in previous network meta-analyses. In the study by Ninane et al, 92 solid tumors were present in more than 20% of patients. We did not consider this study appropriate for a network meta-analysis for antifungal prophylaxis, as routine antifungal prophylaxis is not recommended in patients with solid tumors. 91 The evidence shown by Leonart et al 88   treatment was used. When this study was excluded from the analysis, the difference between direct and 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 being clinically useful. The uncertainty present in the rankings may be neglected in considering the best treatment, and the rankings may give a false sense that some interventions are superior to others. A PRISMA-NMA statement has suggested that more attention should be paid to the relative effect estimates, rather than the rankings, because a good rank does not necessarily translate to a clinically relevant effect. 6 Although the usefulness of rankings is currently debated, rankings will probably continue to be reported. Reporting all probabilities for each intervention with each possible rank is one way to convey the uncertainty in the rank ordering. 94 The treatment effects and rankings also depend on the number of treatments and trials in the network. 95

Limitations
Our study has some limitations. First, an improved understanding of antifungal pharmacology, pharmacokinetics, and pharmacodynamics has resulted in therapeutic drug monitoring becoming a valuable adjunct to the administration of some antifungal agents. We could not perform an analysis of therapeutic drug monitoring to evaluate the efficacy and adverse effects of antifungal prophylaxis or justify why therapeutic drug monitoring should not be performed with antifungal prophylaxis if it is strongly recommended with antifungal treatment because of the limited data. Second, the follow-up time of most studies was too short to determine the survival benefits from antifungal prophylaxis. Third, a limited number of head-to-head trials have investigated posaconazole and voriconazole. Fourth, the characteristics of patients and treatments were heterogeneous among the various randomized clinical trials. Although our subgroup analyses found different results among different patient populations, the data did not allow us to perform more detailed analyses, such as those for different ages and races/ethnicities. We also could not perform a more stratified analysis taking into consideration the dosage form and dose of agents. Therefore, the evidence derived from this meta-analysis should be used with caution for shared decision-making. However, our study provides 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 in patients with hematological disease or undergoing HSCT. Our findings suggest that, in terms of the prevention of IFIs and tolerance, voriconazole may be the best prophylactic option for patients undergoing HSCT, and posaconazole may be the best prophylactic option for patients with AML or MDS.