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Risk difference plots (random effects). Pooled risk difference, −0.23
(95% confidence interval, −0.15 to −0.32).

Risk difference plots (random effects). Pooled risk difference, −0.23 (95% confidence interval, −0.15 to −0.32).

Table 1. 
Oral Antimycotic Treatments vs Placebo
Oral Antimycotic Treatments vs Placebo
Table 2. 
Oral Antimycotic 4-Arm Trials
Oral Antimycotic 4-Arm Trials
Table 3. 
Dose-Finding Studies
Dose-Finding Studies
Table 4. 
Oral Antimycotic 2-Arm Trials
Oral Antimycotic 2-Arm Trials
Table 5. 
Oral Antimycotic 3-Arm Trials
Oral Antimycotic 3-Arm Trials
Table 6. 
Definitions of Clinical Cure in Onychomycosis Trials
Definitions of Clinical Cure in Onychomycosis Trials
1.
Crawford  FHart  RBell-Syer  STorgerson  DYoung  PRussell  I Topical treatments for fungal infections of the skin and nails of the foot [Cochrane Review on CD-ROM].  Oxford, England Cochrane Library, Update Software2000; (2)
2.
Harris  J Treatment of toenail onychomycosis: do crinkly toenails really matter? [letter]. BMJ. 1999;3191197Article
3.
Roberts  DT Prevalence of dermatophyte onychomycosis in the United Kingdom: results of an omnibus survey. Br J Dermatol. 1992;126 (suppl 39) 23- 37Article
4.
Crawford  FYoung  PGodfey  C  et al.  Oral treatments for fungal infections of the toenails [protocol for a Cochrane Review].  Oxford, England Cochrane Library, Update Software2001; (2)
5.
Jadad  ARMoore  RACarroll  D  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;171- 12Article
6.
Moher  DJadad  ARNichol  G  et al.  Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials. 1995;1662- 73Article
7.
Begg  CCho  MEastwood  S  et al.  Improving the quality of randomized controlled trials: the CONSORT statement. JAMA. 1996;276637- 639Article
8.
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials. 1986;7177- 188Article
9.
Honeyman  JFTalarico  FSArruda  LHF  et al.  Itraconazole versus terbinafine (LAMISIL): which is better for the treatment of onychomycosis? J Eur Acad Dermatol Venereol. 1997;9215- 221
10.
Shemer  ANathansohn  NKaplan  BGilat  DNewman  NTrau  H Open randomized comparison of different itraconazole regimens for the treatment of onychomycosis. J Dermatol Treatment. 1999;10245- 249Article
11.
Gupta  AKMaddin  SArlette  JGiroux  JMShear  NH Itraconazole pulse therapy is effective in dermatophyte onychomycosis of the toenail: a double blind placebo controlled study. J Dermatol Treatment. 2000;1133- 37Article
12.
Jones  EJZaias  N Double-blind randomized comparison of itraconazole capsules and placebo in onychomycosis of toenail. Int J Dermatol. 1996;35589- 590Article
13.
Elewski  BScher  RKAly  R  et al.  Double-blind randomized comparison of itraconazole capsules vs placebo in the treatment of toenail onychomycosis. Cutis. 1997;59217- 220
14.
Goodfield  MJAndrew  LEvans  EGV Short term treatment of dermatophyte onychomycosis. BMJ. 1992;3041151- 1154Article
15.
Watson  AMarley  JEllis  DWilliams  T Terbinafine in onychomycosis of the toenail: a novel treatment protocol. J Am Acad Dermatol. 1995;33775- 779Article
16.
Svejgaard  ELBrandrup  FKragballe  K  et al.  Oral terbinafine in toenail dermatophytosis: a double blind placebo controlled multi-centred study with 12 months' follow-up. Acta Derm Venereol. 1997;7766- 69
17.
Evans  EGVSigurgeirsson  B Double blind, randomized study of continuous terbinafine compared with intermittent itraconazole in the treatment of toenail onychomycosis. BMJ. 1999;3181031- 1035Article
18.
Alpsoy  EYilmaz  EBasaran  E Intermittent therapy with terbinafine for dermatophyte toe-onychomycosis: a new approach. J Dermatol. 1996;23259- 262
19.
Tausch  IBrautigam  MWeidinger  GJones  TC Evaluation of 6 weeks treatment of terbinafine in tinea unguium in a double-blind trial comparing 6 and 12 weeks therapy. Br J Dermatol. 1997;136737- 742Article
20.
De Doncker  PDecroix  JPierard  GE  et al.  Antifungal pulse therapy for onychomycosis: a pharmacokinetic and pharmacodynamic investigation of monthly cycles of 1 week pulse therapy with itraconazole. Arch Dermatol. 1996;13234- 41Article
21.
Havu  VBrandt  HHeikkila  H  et al.  A double blind randomized study comparing itraconazole pulsed therapy with continuous dosing for the treatment of toenail onychomycosis. Br J Dermatol. 1997;136230- 234Article
22.
Drake  LAShear  NHArlette  JP  et al.  Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J Am Acad Dermatol. 1997;37740- 745Article
23.
Van der Schroeff  JGCirkel  PKSCrijns  MB  et al.  A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol. 1992;126 (suppl 39) 36- 39Article
24.
Ling  MRSwinyer  LJTaylor Jarrett  M  et al.  Once weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998;38 (6 Pt 2) S95- S102Article
25.
Scher  RKBreneman  DRich  P  et al.  Once weekly fluconazole (150, 300 or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998;38S77- S86Article
26.
Svejgaard  E Oral ketoconazole as an alternative to griseofulvin in recalcitrant dermatophyte infections and onychomycosis. Acta Derm Venereol. 1985;65143- 149
27.
Cullen  SICullen  MK Ketoconazole and griseofulvin in the treatment of toenail dermatophyte onychomycosis. Curr Ther Res. 1987;4124- 29
28.
Piepponen  TBlomqvist  KBrandt  H  et al.  Efficacy and safety of itraconazole in the long-term treatment of onychomycosis. J Antimicrob Chemother. 1992;29195- 205Article
29.
Walsoe  IStrangerup  MSvejgaard  E Itraconazole in onychomycosis: open and double blind studies. Acta Derm Venereol. 1990;70137- 140
30.
Brautigam  MNolting  SSchopf  REWeindinger  G German randomized double blind multicentre comparison of terbinafine and itraconazole for the treatment of toenail tinea infection. BMJ. 1995;311919- 922Article
31.
Arenas  RDominguez-Cherit  JFernandez  L Open randomized comparison of itraconazole versus terbinafine in onychomycosis. Int J Dermatol. 1995;34138- 143Article
32.
Baran  RBelaich  SBeylot  C  et al.  Comparative multicentre double blind study of terbinafine (250 mg per day) versus griseofulvin (1 g per day) in the treatment of dermatophyte onychomycosis. J Dermatol Treatment. 1997;893- 97Article
33.
Faergernann  JAnderson  CHersle  K  et al.  Double-blind parallel group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis. J Am Acad Dermatol. 1995;32750- 753Article
34.
Hofmann  HBrautigam  MWeidinger  G  et al.  Treatment of toenail onychomycosis: a randomized double blind study with terbinafine and griseofulvin. Arch Dermatol. 1995;131919- 922Article
35.
Kavli  GMidelfart  KMoseng  D  et al.  Trichophyton-rubrum infected toenails treated with ketoconazole and partial nail avulsion. Dermatologica. 1984;169191- 193Article
36.
Korting  HCSchafer-Korting  MZienicke  H  et al.  Treatment of tinea unguium with medium and high doses of ultramicrosize griseofulvin compared with that with itraconazole. Antimicrob Agents Chemother. 1993;372064- 2068Article
37.
Haneke  ETajerbashi  MDe Doncker  PHeremans  A Itraconazole in the treatment of onychomycosis: a double blind comparison with miconazole. Dermatology. 1998;196323- 329Article
38.
Tosti  APiraccini  BMStinchi  C  et al.  Treatment of dermatophyte nail infections: an open randomized study comparing intermittent terbinafine therapy with continuous terbinafine treatment and intermittent itraconazole therapy. J Am Acad Dermatol. 1996;34595- 600Article
39.
Billstein  SKianifard  FJustice  A Terbinafine vs placebo for onychomycosis in black patients. Int J Dermatol. 1999;38377- 379Article
40.
De Backer  MDe Keyser  PDe Vroey  CLesaffre  E A 12-week treatment for dermatophyte toe onychomycosis: terbinafine 250 mg/day vs itraconazole 200 mg/day—a double-blind comparative trial. Br J Dermatol. 1996;13416- 17Article
41.
Arenas  RFernandez  GDominguez  L Onychomycosis treated with itraconazole or griseofulvin alone with and without a topical antimycotic or keratolytic agent. Int J Dermatol. 1991;30586- 589Article
42.
Brautigam  MNolting  SSchopf  REWeidinger  G German randomized double blind multicentre comparison of terbinafine and itraconazole for the treatment of toenail tinea infection. Br J Dermatol. 1996;13418- 21Article
43.
Brautigam  M Terbinafine versus itraconazole: a controlled clinical comparison in onychomycosis of the toenails. J Am Acad Dermatol. 1998;38 (5 Pt 3) S53- S56Article
44.
Degreef  HDel Palacio  AMygind  SGinter  GPinto Soares  AZuluga  A Randomized double-blind comparison of short-term itraconazole and terbinafine therapy for toenail onychomycosis. Acta Derm Venereol. 1999;79221- 223Article
45.
Chien  R-NYang  L-JLin  P-YLiaw  Y-F Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study. Hepatology. 1997;25103- 107Article
46.
De Backer  MDe Vroey  CLesaffre  EScheys  IDe Keyser  P Twelve weeks of continuous oral therapy for toenail onychomycosis caused by dermatophytes: a double-blind comparative trial of terbinafine 250 mg/day versus itraconazole 200 mg/day. J Am Acad Dermatol. 1998;38S57- S63Article
47.
Chen  JLiao  WWen  HWu  JYao  Z A comparison among four regimens of itraconazole treatment in onychomycosis. Mycoses. 1999;4293- 96Article
48.
Ellis  DHWatson  ABMarley  JEWilliams  TG Non-dermatophytes in onychomycosis of the toenails. Br J Dermatol. 1997;136490- 493Article
49.
Ellis  DHMarley  JEWatson  ABWilliams  TG Significance of non-dermatophyte moulds and yeasts in onychomycosis. Dermatology. 1997;19440- 42Article
50.
Warwick  DChurch  L Continuous terbinafine versus intermittent itraconazole for toenail onychomycosis. J Fam Pract. 1999;48492- 493
51.
Friedman-Birnbaum  RCohen  AShemer  A  et al.  Treatment of onychomycosis: a randomized double blind comparison study with topical bifonazole-urea ointment alone and in combination with short-duration oral griseofulvin. Int J Dermatol. 1997;3667- 69Article
52.
Goodfield  MJRowell  NRForster  RA  et al.  Treatment of dermatophyte infection of the finger- and toe-nails with terbinafine, an orally active fungicidal agent. Br J Dermatol. 1989;121753- 757Article
53.
Goodfield  MJD Short duration therapy with terbinafine for dermatophyte onychomycosis: a multicentre trial. Br J Dermatol. 1992;12633- 35Article
54.
Kedja  J Itraconazole pulsed therapy vs continuous terbinafine dosing for toenail onychomycosis. Postgraduate Medicine: A Special Report: Update on Superficial Fungal Infections New York, NY McGraw-Hill Co July1999;12- 15
55.
Russell  BFrain-Bell  WStevenson  CJ  et al.  Chronic ringworm infection of the skin and nails treated with griseofulvin: report of a therapeutic trial. Lancet. 1960;11141- 1147Article
56.
Schatz  FBrautigam  MDobrowolski  E  et al.  Nail incorporation kinetics of terbinafine in onychomycosis patients. Clin Exp Dermatol. 1995;20377- 383Article
57.
Zaidi  ZJafri  NKhan  KAHassan  P Randomized double blind trial of the efficacy and tolerability of terbinafine 250 mg once daily versus 250 mg twice daily in the treatment of toenail onychomycosis for 16 weeks. Shuster  SJafary  MHeds.Royal Society of Medicine Services International Congress Series, No. 205. London, England Royal Society of Medicine Services Ltd1993;49- 54
58.
Havu  VHeikkila  HKuokkanen  K  et al.  Double-blind randomized study to compare the efficacy and safety of terbinafine (Lamisil) with fluconazole (Diflucan) in the treatment of onychomycosis. Br J Dermatol. 2000;14297- 102Article
Evidence-Based Dermatology: Original Contribution
June 2002

Oral Treatments for Toenail OnychomycosisA Systematic Review

Author Affiliations
 

DamianoAbeniMD, MPHRosamariaCoronaDSc, MDPaoloPasquiniMD, MPHMichael E.BigbyMDMoysesSzkloMD, MPH, DrPHHywelWilliamsMD

Arch Dermatol. 2002;138(6):811-816. doi:10.1001/archderm.138.6.811
Abstract

Objective  To identify and synthesize the evidence for the efficacy of oral treatments for fungal infections of the toenails.

Design  Systematic review of randomized controlled trials.

Interventions  Oral treatments for dermatophyte infections of the toenails.

Main Outcome Measures  Cure confirmed by microscopy and culture results in patients with clinically diagnosed fungal infections. Data relating to the clinical cure rates were also extracted from the trials.

Results  A pooled analysis of 2 trials comparing mycological cure rates from continuous treatment with terbinafine (250 mg/d for 12 weeks) and continuous treatment with itraconazole (200 mg/d for 12 weeks) found a statistically significant difference in 11- and 12-month outcomes in favor of terbinafine (risk difference, −0.23 [95% confidence interval, −0.32 to −0.15]; number needed to treat, 5 [95% confidence interval, 4 to 8]). An analysis of clinical cure rates was not possible because of the diversity of definitions used in researching the effectiveness of oral antifungal drugs for onychomycosis. Only 3 trials gave a clear definition of clinical cure and presented data for these outcomes.

Conclusions  There is good evidence that a continuous regimen of terbinafine (250 mg/d) for 3 months is the most effective oral treatment for fungally infected toenails. Consensus among researchers evaluating oral antifungal drugs for onychomycosis is needed to establish meaningful definitions of clinical cure. Most trials were funded by the pharmaceutical industry; we found little independent research, and this may have introduced bias to the review.

ORAL TREATMENT may be the only effective treatment for infected toenails. A previous systematic review of topical compounds for fungal toenail infections found little evidence of effectiveness for topical therapies.1

Griseofulvin, for many years the only oral therapy, is inexpensive but has a protracted administration time. The newer drugs, azoles and allylamines, have improved cure rates of nail infections but are vastly more expensive than griseofulvin, and some general physicians believe that these resources might be more beneficially used to treat potentially life-threatening conditions.2

The ingredient costs of oral antifungal drugs alone accounted for £30 million of the National Health Service (NHS) prescribing budget in 1998 (personal communication, Department of Health, Statistics Division, Branch SD1E, September 1, 1999). Because 5% of UK adults older than 55 years have infected toenails, the prescribing costs—coupled with consultation costs—represent substantial NHS expenditure if all those affected sought treatment.3

Trials of oral antifungal drugs for toenail infections have described a variety of cure rates for the drugs that are prescribed. The present systematic review examines all available data from evaluations of these therapies and includes a statistical summary of their clinical effectiveness.

METHODS
SEARCH STRATEGY

We searched the following 5 databases up to March 2000: MEDLINE, EMBASE, CINAHL, Bath Information and Data Services (BIDS), and the Cochrane Controlled Trials Register. The MEDLINE search strategy is published elsewhere.4 The following 2 economic databases were searched up to January 2000: NHS Economic Evaluation Database (NEED) and ECONLIT. Four other databases were searched up to January 1997: CAB Health Abstracts, HEALTHSTAR, and Database of Abstracts of Reviews of Effectiveness (DARE) but did not identify any additional randomized clinical trials. The following 3 podiatry journals not listed in these databases were searched manually: The Foot, Journal of British Podiatric Medicine, and British Journal of Podiatric Medicine and Surgery. We obtained the Cochrane Skin Group's partial hand search of the British Journal of Dermatology. We searched the bibliographies of all review articles identified and contacted all schools of podiatry in the United Kingdom and pharmaceutical companies to identify unpublished or unlisted trials.

SELECTION CRITERIA

We considered all randomized clinical trials that evaluated oral treatments for dermatophyte infections of the toenails. We included trials that used microscopy and culture to confirm the presence of dermatophytes. We included duplicate trials only once. We excluded trials that also evaluated the treatment of fungal infections of the fingernails in which the foot-specific data were not presented and trials that included patients with yeast and mold infections of the toenails. Four reviewers working in pairs (F.C. and E.B.; R.H. and S.E.M.B.S.) independently applied these criteria to each trial located. There were no European language restrictions.

DATA EXTRACTION AND QUALITY ASSESSMENT

All reviewers independently summarized the included trials and appraised their quality of reporting based on items from published checklists.46 The 12-quality criteria included the following: aims clearly defined, prior sample size calculation reported, inclusion and exclusion criteria defined, subjects blinded, method of randomization defined, baseline comparability of groups reported (age, sex, and duration of complaint), interventions defined, outcome assessment blinded, compliance assessed, and trial analyzed by intention to treat.

MYCOLOGICAL AND CLINICAL CURE RATES (OUTCOMES)

Reports were scrutinized for cure rates from mycological investigations (microscopy and culture) and clinical cure rates. The definition(s) of clinical cure was noted, and data that could be used in a reanalysis (absolute numbers or means and a measure of variance) sought.

STATISTICAL ANALYSIS

For each trial we calculated the cure rates at follow-up (3, 6, 9, and 12 months) from the reported mycological results, with "cure" defined as negative results on microscopy and no growth of dermatophyte in culture. We also collected data regarding clinical cure. We estimated the difference in the proportion of patients cured with 95% confidence intervals in the unpaired proportions that constitute the risk difference.7 We also calculated the numbers needed to treat for those comparisons that were statistically significantly different. To estimate differences between treatments, we pooled trials that evaluated similar interventions and controls. Because there was clear evidence of heterogeneity between trials (P<.001 for the Q-combinability test [part of the DerSimonian-Laird random effects analysis], which is known to have low power) we used a random effects model.8 Finally, we combined the evidence of direct "head-to-head" treatment comparisons.

RESULTS

We identified 50 trials evaluating treatment efficacy,958 32 of which we included940 (Table 1, Table 2, Table 3, Table 4, and Table 5). Eighteen trials were excluded for the following reasons: duplicate reports,42,43,46,4850,52,53 combined hand and feet data or combined with topical data,41,47,51,54,55,57 no mycology assessment,56 protocol deviation,45 and data not clearly presented.44,58

MYCOLOGICAL CURE RATES AND EFFECTIVENESS
Itraconazole vs Terbinafine: 12-Week Outcomes After 12 Weeks of Treatment

We found 6 placebo-controlled trials of terbinafine and itraconazole that presented outcomes at 12 weeks1116: 3 trials evaluating itraconazole vs placebo (N = 433) found that itraconazole had greater effectiveness,1113 and 3 trials evaluating terbinafine vs placebo (N = 337) found that terbinafine was more effective.1416 We regarded outcomes at 3 months as clinically irrelevant; a more clinically meaningful assessment of the treatment were outcomes at 9 months.

Itraconazole vs Terbinafine: 11- and 12-Month Outcomes After 12 Weeks of Treatment

Only 2 trials of direct comparisons between treatment with itraconazole (200 mg/d) and terbinafine (250 mg/d) gave data on outcomes at 11 and 12 months. These were pooled in a meta-analysis using a random effects model, which showed a risk difference in favor of terbinafine (−0.23 ([95% CI, −0.15 to −0.32]) (N = 501) (Figure 1).30,40 Both trialists found terbinafine to produce clinically significant improvements in the length of the unaffected nail in great toenails.

Dose-Finding Studies of Itraconazole and Terbinafine Treatments

Two studies compared different regimens of itraconazole with terbinafine.17,38 Tosti et al38 compared intermittent treatment with itraconazole (400 mg/d) with intermittent treatment with terbinafine (500 mg/d) and continuous treatment with terbinafine (250 mg/d) (N = 60), while Evans and Sigurgeirsson17 compared 12- and 16-week regimens of continuous terbinafine (250 mg/d) with intermittent itraconazole (400 mg/d) for 12 and 16 weeks (N = 421). The resultant data from these 2 trials lie within the confidence intervals for the dose-finding analysis, which suggest no advantage in higher or prolonged dosages.

Only 1 trial investigated the use of terbinafine in a dosing schedule.18 Alpsoy et al18 did not detect a difference in cure rates when comparing a continuous regimen of terbinafine (79%) with an intermittent regimen (74%), but the trial population was small (N = 47).

Three trials evaluated the value of continuous and intermittent dosage schedules of itraconazole. Havu et al21 found that the cure rate was not significantly different between 3 months of continuous treatment with itraconazole (200 mg/d) and an intermittent (1 week of treatment in every 4 [1:4]) regimen of 400 mg/d (N = 121). De Doncker et al20 evaluated 2 different intermittent schedules of itraconazole of 3 and 4 months (400 mg/d; 1:4 weeks) and found that the cure rates at 24 weeks were 64% for patients who received the shorter treatment and 72% for those who received 4 months of treatment.20 The trial had a small number of patients (N = 50), and no significant difference was detected between the treatments. Shemer et al10 also did not find that a higher long-term cure rate was associated with a 200-mg/d continuous regimen of itraconazole compared with either of the 2 intermittent regimens (1:4 weeks) for 12 or 16 weeks (N = 64).10

Griseofulvin vs Itraconazole

Three studies comparing the effectiveness of itraconazole and griseofulvin produced poor cure rates.28,29,36 Two studies with small numbers of patients (N = 80) did not detect a difference in patient outcomes with griseofulvin (500 mg/d) and itraconazole (100 mg/d) taken for 24 to 36 weeks: Walsoe et al29 found that none of their 19 patients were cured with either drug while the 61 patients in the trial by Piepponen et al28 had cure rates of 30% in the griseofulvin arm and 36% in the itraconazole arm. Korting et al36 compared 2 different dosages of griseofulvin (660 mg/d and 990 mg/d) with 100-mg/d dosage of itraconazole taken for 18 months but detected no difference in the cure rates (N = 108). The cure rates were 6% in both griseofulvin arms and 8% in the itraconazole arm.

Griseofulvin vs Terbinafine

Two studies compared terbinafine (250 mg/d) and griseofulvin (1000 mg/d) for 6 to 12 months of treatment and concluded that the 250-mg/d dosage of terbinafine is the superior treatment at 12- and 18-month outcomes.32,34 Faergenann et al33 reported that 500 mg of griseofulvin taken daily for 1 year had a significantly poorer cure rate than 250 mg of terbinafine taken daily for 3 months.33 The cure rates were 84% in the terbinafine arm compared with 45% in the griseofulvin arm.

Griseofulvin vs Ketoconazole

Poor cure rates also occurred after 6 to 11 months of treatment with ketoconazole (200 mg/d) and treatments with griseofulvin (1000 mg/d and 500 mg/d).26,27 These small trials did not detect differences between the cure rates of the 3 different treatments.

Dose-Finding Studies for Fluconazole

We included 2 dose-finding studies evaluating fluconazole. Ling et al24 compared treatment with fluconazole (450 mg/wk) for 4, 6, and 9 months vs placebo. Cure rates were 61% for 9 months of treatment, with significantly lower rates for shorter treatment times (4 months, 34%). Scher et al25 detected improved cure rates associated with higher dosages of 150 mg, 300 mg, and 450 mg of fluconazole (once weekly) were compared with placebo, and the 450-mg/wk dosage produced the highest cure rate (62%) after a maximum of 12 months.

CLINICAL CURE RATES

A great deal of variation in the definition of clinical cure was found between the included trial reports. Table 6 gives the various definitions stated in the methods sections of each of the included trials. Table 6 also specifies whether the clinical cure data presented in the reports are complete or incomplete.

The reviewers found deviations from the stated methods in most trial reports for clinical cure data. Sometimes deviations occurred when undefined clinical cure data were presented.13,31,37,39 In most reports the reverse was true: authors stated their intention to evaluate the effect of the drug of interest on certain clinical signs and symptoms but failed to present separate data for them. Instead, an estimate of "clinical success" was made without explicit reference to any individual clinical feature.9,12,2023,25,26,29,30,32 Some authors simply failed to present data for all intended outcomes.15,36,38 The use of line graphs, means without measures of variance, and P values to present clinical cure data hampered the production of a coherent data summary of clinical cure rates.13,16,18,19,28,34,40

Only Ling et al,24 Evans and Sigurgeirsson,17 and Gupta et al11 presented data in absolute numbers for clinical cures they defined a priori. These authors evaluated different drugs. Ling et al24 found that people who took fluconazole, 450 mg once weekly for 9 months, had the highest percentage of clinically normal nail with complete regrowth of healthy tissue at 6-month follow-up (37%). Evans and Sigurgeirsson17 found that a higher proportion of people who took terbinafine, 250 mg/d for 16 weeks, had 100% clear toenail and at least 5 mm of unaffected nail growth compared with people randomized to either 250 mg/d of terbinafine for 12 weeks or a 1 week in 3- or 4-intermittent cycle of itraconazole (400 mg/d). In both these trials the clinical cure rates were consistent with the mycological cure rates. Gupta et al11 compared intermittent itraconazole treatment (400 mg/d) with placebo and found that the proportion of patients who were clear of all signs of infection or markedly improved reflected the rates determined by mycological investigation. However, the proportion deemed clinically cured in the placebo arm was much lower than the proportion found to be cured using the mycological outcome criteria (1% and 28%, respectively).

MICROORGANISMS

Trichophyton rubrum was the most commonly identified infecting organism in all the included studies, with proportions reported to be from 68% to 100% of the identified fungi. Others species included Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton interdigital, Trichophyton soudanense, and Epidermophyton floccosum. The review included trials with patients who had dermatophyte infection only; therefore, we cannot make conclusions about the efficacy of oral antifungals in the treatment of nondermatophyte onychomycosis.

QUALITY SCORES

The average score for all trials included in the review was 6.7 of 12.0. Blinded outcome assessment was only reported in 1 study,34 and the method used to conceal the random allocation from the researchers was reported in 4.1719,32 In 2 trials the inclusion/exclusion criteria were unclear,19,34 but all of the included trials re ported clear aims. Only half of the included trials reported comparable populations of patients at baseline for the duration of infection.13,1622,24,25,30,31,33,37

ADVERSE EVENTS

With the exception of 1 trial,9 all reported adverse events. The frequency of adverse events was not significantly different between treatment and placebo arms for terbinafine, itraconazole, and fluconazole.1215,2226 The data from dose-finding studies do not suggest that shorter treatment times (including intermittent regimens) result in fewer reported adverse events. No trials with placebo controls were identified for evaluations of griseofulvin and ketoconazole.

COMMENT

We found 32 randomized evaluations of terbinafine, itraconazole, griseofulvin, fluconazole, and ketoconazole that met our inclusion criteria. No difference in outcomes was detected between terbinafine (250 mg/d) and itraconazole (400 mg/d) at 3 months. However, a pooled analysis of mycological cure rates taken at 11 and 12 months (Figure 1) showed that terbinafine (250 mg/d) was more effective than itraconazole (400 mg/d) in the treatment of fungally infected toenails in the longer term.

The 1999 trial by Evans and Sigurgeirsson17 was not included in the meta-analysis because it compared continuous dosages of terbinafine (250 mg/d) with intermittent regimens of itraconazole (400 mg/d). The cure rates achieved in the terbinafine arms of the trial, relative to the itraconazole arms, are consistent with the meta-analysis in Figure 1 and provide evidence that continuous treatment with terbinafine (250 mg/d) is significantly more effective than an intermittent regimen of itraconazole (400 mg/d). The small trial by Alpsoy et al18 and data from the arm of the trial evaluating intermittent and continuous dosages of terbinafine in the study by Tosti et al38 both suggest that high levels of effectiveness can be achieved using a intermittent regimen of terbinafine, but this needs to be evaluated in a large randomized controlled trial.

There is no evidence that intermittent regimens of itraconazole produce statistically different cure rates from continuous schedules. Nor is there evidence that intermittent regimens or shorter treatment times result in fewer reported adverse events.

There was no evidence of significantly different rates of effectiveness in direct comparisons between itraconazole and griseofulvin or between itraconazole and ketoconazole, but the sample sizes in these trials were small. Fluconazole also produced only modest cure rates after particularly prolonged treatment times.

A large variety of signs and symptoms are used in dermatology research to establish the clinical cure rates of drugs used in the management of toenail onychomycosis. The lack of standardization of definitions for clinical cure, together with fairly arbitrary methods of data collection and presentation, render these outcomes meaningless in a systematic review of the literature. Future researchers of effective oral treatments for onychomycosis should clearly define the outcomes of interest, specify the mode of measurement, and ensure a clear presentation of the data. Consensus among the dermatology community about the most important signs and symptoms of clinical cure and methods of measurement for onychomycosis would be particularly helpful.

Twenty-two trials included in this systematic review were supported by pharmaceutical companies. All produced data to endorse the use of the sponsor's product, and it is possible that the conclusions of the present systematic review are compromised by a publication bias. The small number of trials in the meta-analysis for 11- and 12-month outcomes (Figure 1) make it difficult to use a funnel plot, but commercial influence and small sample sizes are 2 features frequently associated with such bias. This only serves to reinforce the need for a trial amnesty in which unpublished data are made available, otherwise independently funded research may be the only route to unbiased estimates of the effects of oral antifungal drugs.

CONCLUSIONS

Based on the mycological cure rates in our systematic review, it appears that a continuous regimen of terbinafine (250 mg/d) is the most effective oral therapy for the long-term management of fungally infected toenails. A standardization of methods regarding the collection and presentation of data regarding complete clinical cure is required to allow future researchers to compare the effect of oral antifungal agents on clinical outcomes in the treatment of onychomycosis. A consensus between clinicians and researchers regarding the best way to collect and present those secondary outcomes is needed.

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Article Information

Accepted for publication January 30, 2002.

A cooperative effort of the Clinical Epidemiology Unit of the Istituto Dermopatico dell'Immacolata–Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS) and the Archives of Dermatology

Corresponding author and reprints: Fay Crawford, PhD, The Dental Health Services Research Unit, The University of Dundee, Park Place, Dundee DD1 4MR, Scotland (e-mail: f.crawford@dundee.ac.uk).

References
1.
Crawford  FHart  RBell-Syer  STorgerson  DYoung  PRussell  I Topical treatments for fungal infections of the skin and nails of the foot [Cochrane Review on CD-ROM].  Oxford, England Cochrane Library, Update Software2000; (2)
2.
Harris  J Treatment of toenail onychomycosis: do crinkly toenails really matter? [letter]. BMJ. 1999;3191197Article
3.
Roberts  DT Prevalence of dermatophyte onychomycosis in the United Kingdom: results of an omnibus survey. Br J Dermatol. 1992;126 (suppl 39) 23- 37Article
4.
Crawford  FYoung  PGodfey  C  et al.  Oral treatments for fungal infections of the toenails [protocol for a Cochrane Review].  Oxford, England Cochrane Library, Update Software2001; (2)
5.
Jadad  ARMoore  RACarroll  D  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;171- 12Article
6.
Moher  DJadad  ARNichol  G  et al.  Assessing the quality of randomized controlled trials: an annotated bibliography of scales and checklists. Control Clin Trials. 1995;1662- 73Article
7.
Begg  CCho  MEastwood  S  et al.  Improving the quality of randomized controlled trials: the CONSORT statement. JAMA. 1996;276637- 639Article
8.
DerSimonian  RLaird  N Meta-analysis in clinical trials. Control Clin Trials. 1986;7177- 188Article
9.
Honeyman  JFTalarico  FSArruda  LHF  et al.  Itraconazole versus terbinafine (LAMISIL): which is better for the treatment of onychomycosis? J Eur Acad Dermatol Venereol. 1997;9215- 221
10.
Shemer  ANathansohn  NKaplan  BGilat  DNewman  NTrau  H Open randomized comparison of different itraconazole regimens for the treatment of onychomycosis. J Dermatol Treatment. 1999;10245- 249Article
11.
Gupta  AKMaddin  SArlette  JGiroux  JMShear  NH Itraconazole pulse therapy is effective in dermatophyte onychomycosis of the toenail: a double blind placebo controlled study. J Dermatol Treatment. 2000;1133- 37Article
12.
Jones  EJZaias  N Double-blind randomized comparison of itraconazole capsules and placebo in onychomycosis of toenail. Int J Dermatol. 1996;35589- 590Article
13.
Elewski  BScher  RKAly  R  et al.  Double-blind randomized comparison of itraconazole capsules vs placebo in the treatment of toenail onychomycosis. Cutis. 1997;59217- 220
14.
Goodfield  MJAndrew  LEvans  EGV Short term treatment of dermatophyte onychomycosis. BMJ. 1992;3041151- 1154Article
15.
Watson  AMarley  JEllis  DWilliams  T Terbinafine in onychomycosis of the toenail: a novel treatment protocol. J Am Acad Dermatol. 1995;33775- 779Article
16.
Svejgaard  ELBrandrup  FKragballe  K  et al.  Oral terbinafine in toenail dermatophytosis: a double blind placebo controlled multi-centred study with 12 months' follow-up. Acta Derm Venereol. 1997;7766- 69
17.
Evans  EGVSigurgeirsson  B Double blind, randomized study of continuous terbinafine compared with intermittent itraconazole in the treatment of toenail onychomycosis. BMJ. 1999;3181031- 1035Article
18.
Alpsoy  EYilmaz  EBasaran  E Intermittent therapy with terbinafine for dermatophyte toe-onychomycosis: a new approach. J Dermatol. 1996;23259- 262
19.
Tausch  IBrautigam  MWeidinger  GJones  TC Evaluation of 6 weeks treatment of terbinafine in tinea unguium in a double-blind trial comparing 6 and 12 weeks therapy. Br J Dermatol. 1997;136737- 742Article
20.
De Doncker  PDecroix  JPierard  GE  et al.  Antifungal pulse therapy for onychomycosis: a pharmacokinetic and pharmacodynamic investigation of monthly cycles of 1 week pulse therapy with itraconazole. Arch Dermatol. 1996;13234- 41Article
21.
Havu  VBrandt  HHeikkila  H  et al.  A double blind randomized study comparing itraconazole pulsed therapy with continuous dosing for the treatment of toenail onychomycosis. Br J Dermatol. 1997;136230- 234Article
22.
Drake  LAShear  NHArlette  JP  et al.  Oral terbinafine in the treatment of toenail onychomycosis: North American multicenter trial. J Am Acad Dermatol. 1997;37740- 745Article
23.
Van der Schroeff  JGCirkel  PKSCrijns  MB  et al.  A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol. 1992;126 (suppl 39) 36- 39Article
24.
Ling  MRSwinyer  LJTaylor Jarrett  M  et al.  Once weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998;38 (6 Pt 2) S95- S102Article
25.
Scher  RKBreneman  DRich  P  et al.  Once weekly fluconazole (150, 300 or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998;38S77- S86Article
26.
Svejgaard  E Oral ketoconazole as an alternative to griseofulvin in recalcitrant dermatophyte infections and onychomycosis. Acta Derm Venereol. 1985;65143- 149
27.
Cullen  SICullen  MK Ketoconazole and griseofulvin in the treatment of toenail dermatophyte onychomycosis. Curr Ther Res. 1987;4124- 29
28.
Piepponen  TBlomqvist  KBrandt  H  et al.  Efficacy and safety of itraconazole in the long-term treatment of onychomycosis. J Antimicrob Chemother. 1992;29195- 205Article
29.
Walsoe  IStrangerup  MSvejgaard  E Itraconazole in onychomycosis: open and double blind studies. Acta Derm Venereol. 1990;70137- 140
30.
Brautigam  MNolting  SSchopf  REWeindinger  G German randomized double blind multicentre comparison of terbinafine and itraconazole for the treatment of toenail tinea infection. BMJ. 1995;311919- 922Article
31.
Arenas  RDominguez-Cherit  JFernandez  L Open randomized comparison of itraconazole versus terbinafine in onychomycosis. Int J Dermatol. 1995;34138- 143Article
32.
Baran  RBelaich  SBeylot  C  et al.  Comparative multicentre double blind study of terbinafine (250 mg per day) versus griseofulvin (1 g per day) in the treatment of dermatophyte onychomycosis. J Dermatol Treatment. 1997;893- 97Article
33.
Faergernann  JAnderson  CHersle  K  et al.  Double-blind parallel group comparison of terbinafine and griseofulvin in the treatment of toenail onychomycosis. J Am Acad Dermatol. 1995;32750- 753Article
34.
Hofmann  HBrautigam  MWeidinger  G  et al.  Treatment of toenail onychomycosis: a randomized double blind study with terbinafine and griseofulvin. Arch Dermatol. 1995;131919- 922Article
35.
Kavli  GMidelfart  KMoseng  D  et al.  Trichophyton-rubrum infected toenails treated with ketoconazole and partial nail avulsion. Dermatologica. 1984;169191- 193Article
36.
Korting  HCSchafer-Korting  MZienicke  H  et al.  Treatment of tinea unguium with medium and high doses of ultramicrosize griseofulvin compared with that with itraconazole. Antimicrob Agents Chemother. 1993;372064- 2068Article
37.
Haneke  ETajerbashi  MDe Doncker  PHeremans  A Itraconazole in the treatment of onychomycosis: a double blind comparison with miconazole. Dermatology. 1998;196323- 329Article
38.
Tosti  APiraccini  BMStinchi  C  et al.  Treatment of dermatophyte nail infections: an open randomized study comparing intermittent terbinafine therapy with continuous terbinafine treatment and intermittent itraconazole therapy. J Am Acad Dermatol. 1996;34595- 600Article
39.
Billstein  SKianifard  FJustice  A Terbinafine vs placebo for onychomycosis in black patients. Int J Dermatol. 1999;38377- 379Article
40.
De Backer  MDe Keyser  PDe Vroey  CLesaffre  E A 12-week treatment for dermatophyte toe onychomycosis: terbinafine 250 mg/day vs itraconazole 200 mg/day—a double-blind comparative trial. Br J Dermatol. 1996;13416- 17Article
41.
Arenas  RFernandez  GDominguez  L Onychomycosis treated with itraconazole or griseofulvin alone with and without a topical antimycotic or keratolytic agent. Int J Dermatol. 1991;30586- 589Article
42.
Brautigam  MNolting  SSchopf  REWeidinger  G German randomized double blind multicentre comparison of terbinafine and itraconazole for the treatment of toenail tinea infection. Br J Dermatol. 1996;13418- 21Article
43.
Brautigam  M Terbinafine versus itraconazole: a controlled clinical comparison in onychomycosis of the toenails. J Am Acad Dermatol. 1998;38 (5 Pt 3) S53- S56Article
44.
Degreef  HDel Palacio  AMygind  SGinter  GPinto Soares  AZuluga  A Randomized double-blind comparison of short-term itraconazole and terbinafine therapy for toenail onychomycosis. Acta Derm Venereol. 1999;79221- 223Article
45.
Chien  R-NYang  L-JLin  P-YLiaw  Y-F Hepatic injury during ketoconazole therapy in patients with onychomycosis: a controlled cohort study. Hepatology. 1997;25103- 107Article
46.
De Backer  MDe Vroey  CLesaffre  EScheys  IDe Keyser  P Twelve weeks of continuous oral therapy for toenail onychomycosis caused by dermatophytes: a double-blind comparative trial of terbinafine 250 mg/day versus itraconazole 200 mg/day. J Am Acad Dermatol. 1998;38S57- S63Article
47.
Chen  JLiao  WWen  HWu  JYao  Z A comparison among four regimens of itraconazole treatment in onychomycosis. Mycoses. 1999;4293- 96Article
48.
Ellis  DHWatson  ABMarley  JEWilliams  TG Non-dermatophytes in onychomycosis of the toenails. Br J Dermatol. 1997;136490- 493Article
49.
Ellis  DHMarley  JEWatson  ABWilliams  TG Significance of non-dermatophyte moulds and yeasts in onychomycosis. Dermatology. 1997;19440- 42Article
50.
Warwick  DChurch  L Continuous terbinafine versus intermittent itraconazole for toenail onychomycosis. J Fam Pract. 1999;48492- 493
51.
Friedman-Birnbaum  RCohen  AShemer  A  et al.  Treatment of onychomycosis: a randomized double blind comparison study with topical bifonazole-urea ointment alone and in combination with short-duration oral griseofulvin. Int J Dermatol. 1997;3667- 69Article
52.
Goodfield  MJRowell  NRForster  RA  et al.  Treatment of dermatophyte infection of the finger- and toe-nails with terbinafine, an orally active fungicidal agent. Br J Dermatol. 1989;121753- 757Article
53.
Goodfield  MJD Short duration therapy with terbinafine for dermatophyte onychomycosis: a multicentre trial. Br J Dermatol. 1992;12633- 35Article
54.
Kedja  J Itraconazole pulsed therapy vs continuous terbinafine dosing for toenail onychomycosis. Postgraduate Medicine: A Special Report: Update on Superficial Fungal Infections New York, NY McGraw-Hill Co July1999;12- 15
55.
Russell  BFrain-Bell  WStevenson  CJ  et al.  Chronic ringworm infection of the skin and nails treated with griseofulvin: report of a therapeutic trial. Lancet. 1960;11141- 1147Article
56.
Schatz  FBrautigam  MDobrowolski  E  et al.  Nail incorporation kinetics of terbinafine in onychomycosis patients. Clin Exp Dermatol. 1995;20377- 383Article
57.
Zaidi  ZJafri  NKhan  KAHassan  P Randomized double blind trial of the efficacy and tolerability of terbinafine 250 mg once daily versus 250 mg twice daily in the treatment of toenail onychomycosis for 16 weeks. Shuster  SJafary  MHeds.Royal Society of Medicine Services International Congress Series, No. 205. London, England Royal Society of Medicine Services Ltd1993;49- 54
58.
Havu  VHeikkila  HKuokkanen  K  et al.  Double-blind randomized study to compare the efficacy and safety of terbinafine (Lamisil) with fluconazole (Diflucan) in the treatment of onychomycosis. Br J Dermatol. 2000;14297- 102Article
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