Voriconazole has been used in the treatment and prophylaxis of invasive fungal infections (IFIs) while its wide use was limited by some frequent adverse events, especially neurotoxicity, hepatotoxicity and even renal disruption. The aim of this study was to comprehensively compare voriconazole-induced toxicity, including tolerability, neurotoxicity, visual toxicity, hepatotoxicity and nephrotoxicity with the composite of other antifungals commonly used in clinic.
Methods
Bibliography databases were searched to select randomized controlled trials providing information about the incidence of toxicity referred above. A total of 4122 patients from 16 studies were included in the meta-analysis.
Results
Analysis of individual types of toxicity showed that there was a significant difference between voriconazole and the composite of other antifungal agents. The primary outcome, the tolerability of voriconazole was slightly inferior (OR = 1.71, 95% CI = 1.21–2.40, P = 0.002) and it is noteworthy that the probabilities of neurotoxicity and visual toxicity were around twice higher and six-fold for voriconazole compared with the counterpart (OR = 1.99, 95% CI = 1.05–3.75, P = 0.03 and OR = 6.50, 95% CI = 2.93–14.41, P < 0.00001, respectively). Hepatotoxicity was more common in voriconazole group (OR = 1.60, 95% CI = 1.17–2.19, P = 0.003) whereas its pooled risk of nephrotoxicity was about half of the composite of other five antifungal agents (OR = 0.46, 95% CI = 0.26–0.84, P = 0.01).
Conclusion
Our analysis has revealed differences in multiple types of toxicity induced by VRC versus other antifungals and quantified the corresponding pooled risks, which could provide an alternative for patients with a certain antifungal intolerance and help the clinician to select the optimal intervention.
European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group
FLU
fluconazole
FN
febrile neutropenia
HM
hematological malignancy
IFIs
invasive fungal infections
ISA
isavuconazole
ITRA
itraconazole
LAMB
liposome amphotericin B
MCF
micafungin
MDS
myelodysplastic syndrome
N
No
NA
not available
OR
Odds ratios
P
prophylaxis
RCTs
randomized controlled trials
SOT
solid organ transplantation
VRC
voriconazole
VRC
voriconazole
Y
Yes
Background
Invasive fungal infections (IFIs) remain a leading cause of morbidity and mortality in immunodeficient critically ill patients. Prophylaxis usually recommended for those patients with unidentified diagnosis but with high risk factors. Empirical antifungal therapy is usually suggested to treat probable and possible IFIs. A definitive therapy is permitted only for the definitive diagnosis as proven fungal infection. The abovementioned three levels of IFI diagnosis were defined according to the EORTC/MSG criteria [1].
Amphotericin B (AMB), triazoles including itraconazole, voriconazole (VRC), posaconazole, isavuconazole as well as combination antifungal therapy with voriconazole and an echinocandin are preferred agents for treatment and prevention of invasive aspergillosis in most patients [2]. Fluconazole and echinocandin including caspofungin, micafungin and anidulafungin are usually recommended for invasive candidiasis while some triazole and AMB are also recommended if there is intolerance limited availability, or resistance to other antifungal agents [3].
Anzeige
Voriconazole is a second-generation triazole antifungal agent that is effective against an IDSA diverse array of fungi, including Candida, Aspergillus, Scedosporium, and Fusarium spp. It is recommended as the first-line treatment for invasive aspergillosis by the Infectious Diseases Society of America [2, 4] and is also used in definitive and prophylatic therapies for Candida spp. and other molds [3, 5]. However, the universal use of this agent has been restricted by the high frequency of adverse events such as neurotoxicity, visual toxicity, and hepatotoxicity and the potential for nephrotoxicity caused by a cyclodextrin-based vehicle in its intravenous formulation; any of these types of toxicity may lead to discontinuation during treatment [6‐8].
While individual reviews of different antifungals have been reported [8‐15], there has been no systematic comprehensive comparison of the safety of VRC and other antifungal agents. A systematic review from 2010 individually compared the risk of discontinuation and hepatotoxicity of six antifungals in definitive and empirical therapies for IFIs [4]. Due to its indirect parallels between VRC and other antifungal agents as well as the limited toxicity, its findings need to be clarified and updated. We therefore performed a comprehensive meta-analysis of all relevant data in randomized controlled trials (RCTs) in order to gain a better understanding of the main toxicity profiles for VRC and other antifungals used in definitive, empirical, and prophylactic therapies for IFIs.
Methods
Search strategy
We conducted a literature search of PubMed, Embase, and the Cochrane Library from their inceptions up to December 15, 2016. An additional manual literature search was performed by checking the reference lists in eligible articles. The MeSH terms used for keyword and text-word searches were “antifungal agents” and “voriconazole”. The search was limited to human studies.
Selection criteria
Two reviewers independently evaluated each study and identified whether they met the predefined inclusion criteria. We used the PRISMA criteria for searching and selecting studies (Fig. 1). The following inclusion criteria were applied to identify eligible studies: (i) published in the English language before December 15, 2016; (ii) designed as an RCT; (iii) comparing the safety between VRC and other antifungal agents in definitive, empirical, or prophylactic therapy for IFIs; and (iv) providing the incidence of toxicity at least one term among discontinuation, neurotoxicity, visual toxicity, hepatotoxicity, or nephrotoxicity. We excluded studies that enrolled only pediatric patients, studies only focusing on superficial or mucocutaneous fungal infection, and studies of pharmacokinetics, clinical efficacy, and mycology.
×
Anzeige
Safety outcomes
The primary outcome was the proportion of patients who discontinued antifungal therapy due to adverse events. The secondary outcome of interest was the cumulative incidence of adverse events related to neurotoxicity, including headache, dizziness, restlessness, hallucination, insomnia and depression and some other nervous system disorders and psychiatric disorders according to version 4.0 of the Common Terminology Criteria for Adverse Events (CTCAE) [16]. Another secondary outcome is visual toxicity which was defined as the occurrence of abnormal vision, photophobia, chromatopsia and some other eye disorders according to CTCAE. We also evaluated the cumulative incidence of laboratory tests of liver dysfunction (serum transaminase, alanine transaminase, alkaline phosphatase, or bilirubin levels) and renal dysfunction (serum creatinine), which represented the safety outcomes of hepatotoxicity and nephrotoxicity. We directly used the laboratory test cutoff values reported for individual studies, since the criteria varied among the different studies.
Data extraction and quality assessment
Two reviewers independently extracted specific information from studies, including year of publication, authors, study design, therapeutic purposes, antifungals administered, sample size, age, underlying diseases, dose and duration of administration, and safety outcomes including tolerability, neurotoxicity, visual toxicity, hepatotoxicity, and nephrotoxicity. Disagreements about the specific data between two reviewers were resolved through consensus. We attempted to contact the authors by email to seek required data that were missing from the original reports.
Two investigators independently appraised the sources of bias in RCTs according to the Cochrane Collaboration guidelines, and classified each RCT into low, unclear, or high risk by evaluating the following domains: random sequence generation, allocation concealment, blinding of participants and outcome assessment, incomplete outcome data, selective outcome reporting, and other issues [17]. Discrepancies were resolved by discussion with a third investigator. RCTs for which two or more domains were judged as having a high or unclear risk were regarded as having a high overall risk of bias.
Statistical analysis
We compared the following five safety outcomes between VRC and other antifungal agents: (1) the proportion of antifungal discontinuations due to adverse events, and the cumulative incidences of neurotoxic events related to (2) nervous system and psychiatric disorders and (3) eye disorders (4) liver and (5) renal dysfunction. We performed subgroup analysis to determine if the final results were influenced by certain factors, including different antifungals, therapeutic purpose (definitive, empirical, or prophylactic therapy), and duration (<14 days and ≥14 days). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for subgroups with more than two studies. We also performed a sensitivity analysis to examine the stability of the results by excluding a single or multiple studies that were classified by a specific criterion, such as a small sample (n < 50), single-center design, or high risk of bias.
A two-sided P value of <0.05 was considered indicative of statistical significance. All statistical analyses were performed using RevMan (version 5.3) and Stata (version 12.0, StataCorp, College Station, TX).
Results
Study selection and characteristics of included researches
The electronic and manual searches identified 6547 studies, of which 16 RCTs [18‐33] involving 4122 randomized patients met the criteria and so were entered into the final analysis (Table 1). A flow diagram of the study selection process is shown in Fig. 1 (see more detailed searching strategy in Additional file 1). The safety outcomes for tolerability, neurotoxicity, visual toxicity, hepatotoxicity, and nephrotoxicity were reported for 12, 10, 13, 14, and 9 studies, respectively. The main underlying disease of patients in the included RCTs was hematological malignancy, followed by solid cancers and other diseases with a high risk of fungal infection. The antifungal agents used in the counterpart groups included fluconazole (n = 3), amphotericin B (n = 3), itraconazole (n = 4), micafungin (n = 4), isavuconazole (n = 1), and a combination of fluconazole and AMB (n = 1). There were eight, three, and five studies that had definitive, empirical, and prophylactic treatment purposes, respectively. The duration of drug therapy was at least 2 weeks in 12 RCTs, less than 2 weeks in 3 RCTs, and unknown in the remaining RCTs.
Table 1
Characteristics of included studies
Year
Author
Multicenter
Therapeutic purpose
Antifungals
Sample size
Age
Underlying Disease
Dosing regimen
Duration
2001
Ally
Y
D
VRC
200
18–75
Esophageal Candidiasis, AIDS
200 mg, oral, bid
14d
FLU
191
18–76
Esophageal Candidiasis, AIDS
200 mg, oral, qd
15d
2002
Lazarus
Y
P
VRC
18
23–61
HM & solid tumor
200/300 mg, oral, q12h
14d
FLU
6
23–62
HM & solid tumor
400 mg, oral, qd
14d
2002
Herbrecht
Y
D
VRC
144
48.5
HM, SOT, AIDS
200 mg, oral/i.v., bid
77d
AMBD
133
50.5
HM, SOT, AIDS
1–1.5 mg/kg, i.v., qd
10d
2002
Walsh
Y
E
VRC
415
46.3
FN, HM or other cancers
200 mg, oral, q12h
7d
LAMB
422
45
FN, HM or other cancers
3 mg/kg, i.v. qd
7d
2005
Kullberg
Y
D
VRC
248
53.6
Candidaemia
200 mg, bid
15d
AMB/FLU
122
53.3
Candidaemia
AMB 0.7–1.0 mg/kg, oral/i.v., qd,
15d
Flu, 400 mg, oral/i.v. qd
2007
Queiroz-Telles
Y
D
VRC
35
48.3
Paracoccidioidomycosis
200 mg, oral, bid
169d
ITRA
18
48.7
Paracoccidioidomycosis
100 mg, oral, bid
200d
2010
Wingard
Y
P
VRC
305
43
AHSCT
200 mg, oral, bid
100d
FLU
295
43
AHSCT
400 mg, oral, qd
100d
2010
Kohno.
Y
D
VRC
54
69.9
Tuberculosis sequelae
4 mg/kg, i.v., bid
3w
MCF
53
72.1
Tuberculosis sequelae
150–300 mg, i.v., qd
3w
2010
Oyake 1
Y
E
VRC
46
NA
FN patients with AML
4 mg/kg, i.v., bid
9d
MCF
49
NA
FN patients with AML
150 mg, i.v., qd
10d
2011
Bansal
N
D
VRC
15
36.3
CISA
200 mg (adults), 100 mg (children), oral, q12h;
12w
AMB
18
36.3
CISA
1 mg/kg, i.v., qd
14w
2011
Mattiuzzi
N
P
VRC
71
36.3
AML + MDS
300 mg, i.v., bid
20d
ITRA
52
60
AML + MDS
200 mg, i.v., qd
21d
2012
Shang
Y
D
VRC
34
37.5
Kidney transplant
4 mg/kg, i.v., q12h
2.9 m
MCF
31
39.2
Kidney transplant
100 mg (<60 kg), qd;
3.8 m
150 mg (>60 kg), i.v., qd
2013
Gao
Y
P
VRC
224
42.3
AHSCT
200/100 mg, oral/i.v., bid
96d
ITRA
241
42.3
AHSCT
200 mg, oral/i.v., bid
68d
2014
Hayashi
Y
P
VRC
33
NA
AHSCT
200 mg, oral, bid
NA
ITRA
33
NA
AHSCT
2.5 mg/kg, oral/i.v., bid
NA
2016
Maertens
Y
D
VRC
258
51.2
HM
4 mg/kg/200 mg, oral/i.v., bid
47d
ISA
258
51.1
HM
200 mg, oral/i.v., qd
45d
2016
Oyake 2
Y
E
VRC
50
53
FN with hematopathy
4 mg/kg, i.v., bid
9d
MCF
50
53
FN with hematopathy
150 mg, i.v., qd
12d
Y Yes, N No, NA not available, D definitive treatment, E empirical treatment, P prophylaxis, VRC voriconazole, FLU fluconazole, AMBD amphotericin B deoxycholate, LAMB liposome amphotericin B, AMB amphotericin B, ITRA itraconazole, MCF micafungin, ISA isavuconazole, HM hematological malignancy, SOT solid organ transplantation, FN febrile neutropenia, AHSCT allogeneic hematopoietic stem cell transplantation, AML acute myeloid leukemia, CISA chronic invasive sinus aspergillosis, MDS myelodysplastic syndrome
Bias assessment
Figure 2 presents the results of the systematic bias analysis. There was a low risk of bias for most items, except for the presence of performance and detection bias due to the lack of a double-blind design and blind outcome assessment in four studies [18, 22, 27, 32].
×
Safety outcomes
Tolerability
Tolerability could be analyzed for 12 RCTs involving 2146 patients [20, 21, 23, 24, 26‐33]. VRC was associated with a higher probability of discontinuation due to adverse events compared with the composite of other antifungal agents (13.2% vs. 9.8%) (OR = 1.71, 95% CI = 1.21–2.40, P = 0.002; I2 = 32%) (Fig. 3).
×
Neurotoxicity
Neurotoxicity could be analyzed for 10 RCTs involving 3036 patients [19, 21, 24, 26, 28‐33]. Compared with other antifungal agents, the use of VRC significantly increased the probability of neurotoxicity, from 13.1% to 16.1% (OR = 1.99, 95% CI = 1.05–3.75, P = 0.03; I2 = 55%) (Fig. 4).
×
Visual toxicity
Visual toxicity could be analyzed for 13 RCTs involving 3940 patients [19‐26, 28, 29, 31‐33]. The pooled risk of an incidence of visual toxicity was 15.7% in the VRC group and 4.2% in the counterparts group (comprising combinations of various antifungals) (OR = 6.50, 95% CI =2.93–14.41, P < 0.00001; I2 = 77%) (Fig. 5).
×
Hepatotoxicity
Hepatotoxicity could be analyzed for 14 RCTs involving 3529 patients [18‐24, 26, 28‐33]. The pooled risk of an elevation in liver enzyme levels was 13.6% in the VRC group and 17.7% in the counterparts group (comprising combinations of various antifungals) (OR = 1.60, 95% CI =1.17–2.19, P = 0.003; I2 = 39%) (Fig. 6).
×
Nephrotoxicity
Nephrotoxicity could be analyzed for 9 RCTs involving 2530 patients [20‐22, 28‐32]. The rate of the abnormal renal function was significantly lower in the VRC group than in the counterparts group (10.0% vs. 17.1%) (OR = 0.46, 95% CI = 0.26–0.84, P = 0.02; I2 = 67%) (Fig. 7).
×
Subgroup analysis
In a further subgroup analysis by types of antifungal agents, therapeutic purpose, and duration, the risk of adverse events differed between treatment with VRC and other antifungals (Table 2).
Table 2
Summary of subgroup analysis for the safety of voriconazole and other antifungals
Outcome
Subgroup
Variables
No. of studies
No. of patients
OR (95% CI)
I2%
P
VRC
counterpart
Tolerability
Antifungals
FLU
2
5/218
2/197
0.86 (0.02, 38.38)
73
0.94
AMB
1
19/415
23/422
0.83 (0.45, 1.55)
NA
0.56
ITRA
3
91/330
70/311
1.42 (0.98, 2.06)
0
0.06
MCF
4
52/184
24/183
3.19 [1.77, 5.76]
0
0.0001
ISA
1
35/259
21/257
1.76 (0.99, 3.11)
NA
0.05
Therapeutic purpose
definitive
6
69/830
31/672
1.87 [1.20, 2.92]
0
0.005
empirical
3
63/511
44/521
2.10 (0.72, 6.15)
80
0.18
prophylaxis
3
87/313
71/299
1.35 (0.67, 2.69)
34
0.40
Duration
<14d
3
63/511
44/521
2.10 (0.72, 6.15)
80
0.18
≥14d
9
156/1143
102/971
1.54 [1.16, 2.05]
0
0.003
Neurotoxicity
Antifungals
FLU
1
10/200
13/191
0.72 [0.31, 1.69]
NA
0.45
AMB
2
20/609
3/607
6.87 [2.04, 23.16]
21
0.002
ITRA
3
29/330
15/311
1.62 [0.84, 3.14]
52
0.15
MCF
3
13/138
0/134
10.28 [1.91, 55.44]
0
0.007
ISA
1
175/259
165/257
1.16 [0.81, 1.67]
NA
0.42
Therapeutic purpose
definitive
6
208/776
182/735
1.27 [0.93, 1.73]
26
0.13
empirical
2
22/465
2/472
9.57 [2.57, 35.60]
0
0.0008
prophylaxis
2
17/295
12/293
1.40 [0.66, 2.97]
69
0.39
Duration
≥14d
8
225/1071
194/1028
1.29 [0.97, 1.72]
29
0.08
<14d
2
22/465
2/472
9.57 [2.57, 35.60]
0
0.0008
Visual toxicity
Antifungals
FLU
3
77/523
35/492
2.11 [1.38, 3.24]
66
0.0006
AMB
3
97/624
4/625
28.83 [10.84, 76.64]
75
<0.00001
ITRA
2
37/259
0/259
46.57 [5.89, 368.06]
0
0.0003
MCF
3
31/138
0/134
26.63 [5.15, 137.62]
0
<0.0001
ISA
1
69/259
39/257
2.03 [1.31, 3.15]
NA
0.002
Therapeutic purpose
definitive
8
175/1039
57/875
3.33 [2.41, 4.59]
49
<0.00001
empirical
2
103/465
2/472
53.85 [15.23, 190.37]
0
<0.00001
prophylaxis
3
44/547
20/542
1.93 [1.11, 3.36]
68
0.02
Duration
<14d
11
219/1586
77/1417
2.92 [2.21, 3.85]
57
<0.00001
≥14d
2
103/465
2/472
53.85 [15.23, 190.37]
0
<0.00001
Hepatotoxicity
Antifungals
FLU
2
14/218
7/197
1.76 (0.71, 4.36)
0
0.22
AMB
3
128/624
131/625
0.99 (0.74, 1.32)
0
0.95
ITRA
4
46/363
21/344
2.19 (1.27, 3.76)
0
0.005
MCF
3
35/138
15/134
2.78 (1.38, 5.60)
4
0.004
ISA
1
42/259
23/257
1.97 (1.15, 3.38)
NA
0.01
Therapeutic purpose
definitive
8
156/1039
76/875
1.79 (1.18, 2.71)
29
0.006
empirical
2
128/465
132/472
0.98 (0.73, 1.30)
0
0.88
prophylaxis
4
44/346
21/332
2.11 (1.22, 3.63)0
0
0.07
Duration
<14d
2
128/465
132/472
0.98 (0.73, 1.30)
0
0.88
≥14d
11
194/1352
93/1174
1.82 (1.31, 2.54)
19
0.0003
Nephrotoxicity
Antifungals
FLU
0
NA
NA
NA
NA
NA
AMB
3
45/624
110/625
0.15 (0.03, 0.84)
78
0.03
ITRA
1
1/71
0/52
2.23 (0.09, 55.94)
NA
0.62
MCF
3
8/138
10/134
0.70 (0.25, 1.94)
0
0.49
ISA
1
58/259
55/257
1.06 (0.70, 1.61)
NA
0.79
Therapeutic purpose
definitive
6
89/804
122/666
0.36 (0.14, 0.91)
78
0.03
empirical
2
44/465
81/472
0.50 (0.34, 0.74)
0
0.0006
prophylaxis
1
1/71
0/52
2.23 (0.09, 55.94)
NA
0.62
Duration
<14d
2
44/465
81/472
0.50 (0.34, 0.74)
0
0.0006
≥14d
7
90/875
122/718
0.41 (0.17, 0.98)
74
0.05
NA not applicable
Anzeige
The risk of discontinuation did not differ significantly between VRC and each single individual antifungal except for micafungin, which was associated with significantly reduced odds of discontinuation compared with VRC. According to the subgroup analysis of various treatment purposes, we found that VRC showed a significant poor tolerance in the definitive treatment compared with the empirical and prophylaxis treatment. Concerning the duration of treatment, VRC was more likely to be discontinued than other antifungal agents in patients treated for longer than 14 days. VRC was associated with significantly high risk of neurotoxicity compared with AMB and micafungin while other triazoles including fluconazole, itraconazole and isavuconazole failed to provide a significant reduction or increase in the incidence rate of neurotoxicity. Additionally, we also identified statistically significance in the odd of neurotoxicity in VRC versus other antifungal agents in the subgroup of empirical treatment and duration less than 14 days. Of notes, the studies involved in these two groups are the same, including the counterparts of AMB and micafungin, which may lead to this significant diffference owing to the antifungal type. However, there was no statistically significant difference in the group of definitive and prophylactic treatment as well as duration ≥14 days. The high risk of visual toxicity during VRC treatment was consistent across all analyzed subgroups and the heterogeneity was also reduced attribute to the stratification of three subgroups analysis. For the outcome of hepatotoxicity, VRC showed a higher risk of abnormal liver enzyme levels compared with itraconazole, micafungin, and isavuconazole, but not for fluconazole or AMB. Patients who were diagnosed as definitive IFIs had a high risk of the elevation of liver enzyme levels in the VRC group. In addition, a duration of at least 2 weeks seemed to be a risk factor for liver injury when patients were treated with VRC rather than other antifungals. The heterogeneity of hepatotoxicity was also reduced by stratifying the data by all three subgroups. The occurrence of abnormal renal function did not differ significantly between VRC and the other antifungal agents except AMB, which was associated with a higher risk of nephrotoxicity. The probability of abnormal renal function in definitive and empirical fungal therapies was lower for VRC than for the composite of the other five antifungals. However, the risk of nephrotoxicity was significantly higher for patients treated with other antifungals than for VRC for treatment durations shorter than 14 days.
Sensitivity analysis
The sensitivity analysis verified the robustness of the findings for each outcome. A leave-one-out sensitivity analysis showed that no individual study excessively influenced the pooled effect in our meta-analysis except for the outcome of neurotoxicity (see Additional file 2: Figs. S1–S5), which was affected by removing 5 single study (including studies of Walsh, Queiroz-Telles, Kohno, Mattiuzzi and Oyake 2 [21, 26, 29, 30, 32]). In addition, the results for each outcome remained stable after excluding RCTs with samples smaller than 50, with a single-center design or with a high risk of bias (see in Additional file 3: Table S1).
Discussion
This meta-analysis found that the pooled risks of the primary and other four secondary safety outcomes differed significantly between VRC and the composite of other antifungal treatments. VRC was associated with higher risks of treatment discontinuation, neurotoxicity, visual toxicity, and hepatotoxicity but a lower risk of nephrotoxicity compared with the other antifungals.
The combined discontinuation rate of VRC was 13.2% in our meta-analysis. Wang found a discontinuation rate of 9.5%, but this slight discrepancy could have been due to that study involving only three RCTs [4]. According to the results of the present meta-analysis of the primary outcome of tolerability, patients treated with VRC were more likely to discontinue therapy compared with the composite of the other five antifungals. However, the significant difference between these two groups could disappear when they were grouped according to specific drugs. The heterogeneity associated with multiple drugs could explain this change, while the therapeutic purpose and duration of therapy might also have influenced the final results. Patients with definitive IFIs and longer treatment durations were more vulnerable to discontinuation of VRC than the counterparts, which could be due to the severe underlying condition and long-term drug accumulation. Sensitivity analysis based on the small sample size (n < 50), single center and high risk of bias did not significantly change the results. However, it should be noted that all of the outcomes in our results need to be interpreted with caution since the counterpart of the VRC group was defined as a composite of antifungal agents rather than a single antifungal.
Anzeige
VRC-associated neurotoxicity, especially hallucination, is a common type of toxicity that is considered to significantly limit its application in the clinic [5, 11, 34]. Our findings indicated that the pooled risk of neurotoxicity for patients treated with VRC was almost twice higher than for those treated with other antifungals. Subgroup analysis indicated that VRC had similar incidence of neurotoxicity with trizoles (excluded of posaconazole) while a higher risk of neurotoxicity compared with AMB and micafungin. Zonios [34] exclusively investigated the incidence of hallucinations associated with VRC therapy, and found a rate of 16.6%, which is similar as our result (16.1% for the pooled incidence of neurotoxicity).
VRC-associated visual disturbance is also a common type of toxicity according to clinical observation [21, 24, 28, 35, 36]. Our main findings indicated that the pooled risk of visual events for patients treated with VRC was 6.5 fold higher than for those treated with other antifungals. Subgroup analysis demonstrated that the incidence of visual disturbance still differed significantly between VRC and other antifungals in each single subgroup even though there were some variations in ORs. The pooled risk of visual toxicity showed the highest gap (15.7% in VRC vs. 4.2% in the counterpart) among all of the observed toxicity outcomes. These two adverse events, neurotoxic and visual adverse events, although usually reversible, often lead to premature discontinuation of VRC [28].
The pooled risk of VRC-associated hepatotoxicity in our analysis (17.7%) was similar to that found by Wang (19.7%) [4]. We found that the risk of hepatotoxicity was higher for VRC than for any combination of the other five antifungals. VRC was involved in occurrence of hepatotoxicity in the definitive treatment group but not in the empirical and prophylactic treatment groups; the severe underlying condition and infectious situation may have contributed to this difference. A longer treatment duration also influenced the risk of hepatotoxicity.
The risk of nephrotoxicity was lower in the VRC group, but only AMB showed a significant higher risk of nephrotoxicity in the subgroup analysis, which was consistent with other studies [6, 37]. Unexpectedly, the nephrotoxicity risk was found to differ significantly between these two groups when the treatment duration was shorter than 14 days [21, 32]. These two studies compared VRC with liposomal AMB and micafungin, respectively. The probability of nephrotoxicity was the same in the RCT comparing VRC and micafungin, meaning that the result was due to the RCT comparing VRC with AMB [21]. A high AMB-induced nephrotoxicity could explain this result. The small number of studies and the combination of heterogeneous antifungals in the counterparts group could be the root cause of the unexpected results and the significant heterogeneity in nephrotoxicity outcomes.
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Another newly released triazole antifungal agent, posaconazole, showed similar treatment–related adverse events with fluconazole for prophylaxis in severe Graft-versus-Host Disease [38]. Additionally, patient receiving voriconazole was proved to have more treatment-related adverse events than those receiving fluconazole [39]. Thus posaconazole seems to cause less adverse events than voriconazole according to this indirect evidence. There were also some studies which use posaconazole as a substitution of voriconazole due to its intolerance [40, 41]. However, there is no RCT comparing voriconazole and posaconazole in safety area. Further studies are needed in this respect.
Strengths and weaknesses
The previous meta-analysis regarding the status of voriconazole among all antifungal agents mostly focused on the efficacy and pharmacoeconomics [42‐44]. To our knowledge, this is the first study to have comprehensively compared five common adverse events induced by VRC and other antifungals by systematically reviewing RCTs. The results can be used by clinicians to avoid unnecessary adverse effects and select a better antifungal therapeutic scheme for patients. Furthermore, we also quantified the specific outcomes concerning different antifungals, treatment purposes, and durations by subgroup analysis for four safety outcomes.
Several limitations of our study should be considered. First, as is inevitable for any meta-analysis, our study shares the limitations of the original studies. However, we performed the largest pooled comparison of the toxicity profiles of VRC and a composite of other common antifungal agents based on RCTs. Second, we directly used the criteria applied in each study because the thresholds for abnormal liver and renal enzyme levels varied between them. Finally, the combination of various antifungals in the counterparts group may have been responsible for the moderate heterogeneity and a certain degree of publication bias among the studies (see in Additional file 4: Figure S6). The present findings therefore need to be confirmed in future high-quality studies.
Conclusion
This meta-analysis provides a comprehensive synthesis of the evidence of harm that voriconazole is associated with higher pooled risk of treatment discontinuation, neurotoxicity, visual toxicity, hepatotoxicity but a lower risk of nephrotoxicity compared with other antifungal agents based on the evidence of current RCTs. The results could point to alternative treatments for a patient with a certain antifungal intolerance, thereby helping the clinician select the optimal intervention.
Acknowledgements
Not applicable.
Funding
This work was supported by the Chinese Medical Association (No. 16010120628) and the 17th “Tengfei Cup” extracurricular academic science and technology works competition of Xi ‘an Jiaotong University.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its additional files].
Ethics approval and consent to participate
No ethical approval was sought, because approval was deemed unnecessary for this meta-analysis.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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