Antimetabolites as an adjunct to dacryocystorhinostomy for nasolacrimal duct obstruction

What is the aim of the review?
Dacryocystorhinostomy (DCR) is a type of surgery that creates a new tear drainage pathway between the eyelid and nose to relieve tearing symptoms (functional success), improve openness of the tear duct to irrigation (anatomic success), and increase the size of the opening into the nose (ostium size). Our aim was to assess whether antiscarring medications (antimetabolites) can increase the functional success, anatomic success, and ostium size of DCR.

Key results
We found that antimetabolites may improve functional and anatomic success (relative to DCR alone) at a follow-up time longer than six months. Antimetabolites may also improve ostium size at six months.

What was studied in the review?
The lacrimal system of the eye produces tears, which nourish the eye surface and keep it moist. After passing along the eye surface, tears drain into the nose through the lacrimal drainage apparatus. Nasolacrimal duct obstruction (NLDO) is the blockage of this canal, which can cause an overflow of tears. NLDO is usually painless and can affect one or both eyes. NLDO can also lead to infection of the eye. NLDO is treated surgically with a procedure known as dacryocystorhinostomy (DCR), which establishes a new pathway by creating a pathway between the tear sac and the nose. Antimetabolites have been used to improve success rates of this procedure. We wanted to learn whether DCR in combination with antimetabolites can improve outcomes for functional success, anatomic success, and ostium size than DCR alone. We collected and analyzed all relevant randomized controlled trials to answer this question.

What are the main results of the review?
We identified 31 relevant studies for inclusion, most of which originated in South and East Asia and involved predominantly women. These studies compared participants who underwent DCR with metabolites versus participants who underwent DCR alone. Twenty-three of these studies (1309 participants) provided data on our outcomes of interest.

DCR with antimetabolites may improve functional and anatomic success when patients are followed more than six months after surgery; the certainty of this evidence was moderate. There was no difference in functional and anatomic success at six months among participants who underwent DCR with antimetabolites compared to participants who underwent DCR alone; the certainty of evidence is low.

At six months, participants who underwent DCR with antimetabolites may have increased ostium size compared to those receiving DCR alone. However, beyond six months, there is no evidence of a difference between participants who underwent DCR with antimetabolites compared to participants who underwent DCR alone. The certainty of the evidence was low due to substantial variability among the studies that assessed this outcome. Adverse effects of antimetabolites were minimal.

How up-to-date is this review?
We reviewed studies published up to 6 September 2019.

Authors' conclusions: 

There is moderate-certainty evidence that application of antimetabolites at the time of DCR increases functional and anatomic success of DCR when patients are followed for more than six months after surgery, but no evidence of a difference at six months, low-certainty of evidence. There is low-certainty evidence that combining antimetabolite with DCR increases the size of the lacrimal ostium at six months. However, beyond six months, the evidence remain uncertain. Adverse effects of the application of antimetabolites were minimal.

Read the full abstract...
Background: 

Nasolacrimal duct obstruction (NLDO) is a condition that results in the overflow of tears (epiphora) or infection of the nasolacrimal sac (dacryocystitis). The etiology of acquired NLDO is multifactorial and is not fully understood. Dacryocystorhinostomy (DCR) is the surgical correction of NLDO, which aims to establish a new drainage pathway between the lacrimal sac and the nose. The success of DCR is variable; the most common cause of failure is fibrosis and stenosis of the surgical ostium. Antimetabolites such as mitomycin-C (MMC) and 5-fluorouracil (5-FU) have been shown to be safe and effective in reducing fibrosis and improving clinical outcomes in other ophthalmic surgery settings (e.g. glaucoma and cornea surgery). Application of antimetabolites at the time of DCR has been studied, but the utility of these treatments remains uncertain.

Objectives: 

Primary objective: To determine if adjuvant treatment with antimetabolites improves functional success in the setting of DCR compared to DCR alone.

Secondary objectives: To determine if anatomic success of DCR is increased with the use of antimetabolites, and if the surgical ostium is larger in participants treated with antimetabolites.

Search strategy: 

We searched the Cochrane Register for Controlled Trials (CENTRAL) (which contains the Cochrane Eye and Vision Trials Register) (2019, Issue 9), Ovid MEDLINE, Embase.com, PubMed, LILACS (Latin American and Caribbean Health Sciences Literature database), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic searches. We last searched the electronic databases on 6 September 2019.

Selection criteria: 

We only included randomized controlled trials. Eligible studies were those that compared the administration of antimetabolites of any dose and concentration versus placebo or another active treatment in participants with NLDO undergoing primary DCR and reoperation. We only included studies that had enrolled adults 18 years or older. We also included studies that used silicone intubation as part of the DCR procedure.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. Two review authors independently screened the search results, assessed risk of bias, and extracted data from the included studies using an electronic data collection form.

Main results: 

We included 31 studies in the review, of which 23 (1309 participants) provided data relating to our primary and secondary outcomes. Many of the 23 studies evaluated functional success, while others also assessed our secondary outcomes of anatomic success or ostium size, or both.

Study characteristics

Participant characteristics varied across studies, with the age of participants ranging from 30 to 70 years. Participants were predominantly women. These demographics correspond to those most frequently affected by nasolacrimal duct obstruction. Almost all of the studies utilized MMC as the antimetabolite, with only one using 5-FU. We assessed most trials as at unclear risk of bias for most domains. Conflicts of interest were not frequently reported, although the antimetabolites used are generic medications, and studies were not likely to be conducted for financial interest.

Findings

Twenty studies provided data on the primary outcome of functional success, of which 7 (356 participants) provided data at 6 months and 14 (909 participants) provided data beyond 6 months. At six months, the results showed no evidence of effect of antimetabolite on functional success (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.98 to 1.29; low-certainty evidence). Beyond six months, the results favored the antimetabolite group (RR 1.15, 95% CI 1.07 to 1.25; moderate-certainty evidence).

Fourteen studies reported data on the secondary outcome of anatomic success, of which 4 (306 participants) reported data at 6 months and 12 (831 participants) provided data beyond 6 months. Results at six months showed no evidence of effect of antimetabolite on anatomic success (RR 1.02, 95% CI 0.95 to 1.11; low-certainty evidence). Beyond six months, participants in the antimetabolite group were more likely to achieve anatomic success than those receiving DCR alone (RR 1.09, 95% CI 1.04 to 1.15; moderate-certainty evidence).

At six months and beyond six months follow-up, two studies reported mean change in ostium size. We did not conduct meta-analysis for the various follow-up periods due to clinical, methodological, and statistical heterogeneity. However, point estimates from these studies at six months consistently favored participants in the antimetabolite group (low-certainty evidence). Beyond six months, while point estimates from one study favored participants in the antimetabolite group, estimates from another study showed no evidence of a difference between the two groups. The certainty of evidence at both time points was low.

Adverse events

Adverse events were rare. One study reported that one participant in the MMC group experienced delayed wound healing. Other studies reported no significant adverse events related to the application of antimetabolites.

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