Internal Limiting Membrane Peeling in Macular Hole Surgery

What clinical and economic evidence exists to support ILM peeling?

Noemi Lois, MD, PhD, FRCS(ED) • Kurt Spiteri-Cornish, MD, FRCOphth • Laura Ternent, PhD

Full-thickness macular hole (FTMH) is one of the retinal conditions most commonly encountered by vitreoretinal surgeons. Based on data from randomized, clinical trials (RCTs),^1,2 it is clear that surgery is effective and should be offered to patients with FTMH stages 2-4, based on the classification of Donald Gass, MD.³

Since vitrectomy surgery was first proposed by Kelly and Wendell in 1991 for the treatment of FTMH,⁴ many strategies have been developed in an attempt to improve the anatomical and functional outcomes of the procedure. Of these, only internal limiting membrane peeling has been generally adopted by vitreoretinal surgeons.

PEELING PROS AND CONS

Following the introduction of ILM peeling to macular hole surgery,⁵ many case series and some case control studies appeared to support the performance of this maneuver in the treatment of patients with FTMH.⁶

Concerns, however, existed for the routine use of ILM peeling. First, ILM peeling is a challenging surgical maneuver when undertaken without the aid of retinal dyes. If dyes are used, ILM peeling is greatly facilitated; however, the risk of any potential toxicity related to the dye should be taken into consideration. In addition, some data suggest that there may be potential deleterious effects of peeling the ILM. Thus, paracentral visual field defects have been described and attributed to the performance of ILM peeling.⁷

Furthermore, an abnormal functional recovery of the B wave of the focal macular electroretinogram has been observed following ILM peeling.⁸ As a result, and given that it appeared that good results could be obtained in eyes with small FTMHs without undertaking ILM peeling,⁹ many vitreoretinal surgeons opted to use ILM peeling only in cases of large holes or cases identified as having a high risk of failure, such as long-standing ones. Other surgeons, nonetheless, have been performing ILM peeling routinely in all their cases, although they have been unable to back up their preference with the best evidence-based data.

Recently conducted RCTs have now provided strong evidence favoring the performance of ILM peeling in all cases of idiopathic stage 2-4 FTMH. Four RCTs undertaken in China (n=49),¹⁰ Denmark (n=75),¹¹ France (n=80),¹² and the United Kingdom (n=141)¹³ have demonstrated the superiority of ILM peeling compared with no peeling to achieve macular hole closure with a single procedure with no increased risk of intraoperative or postoperative complications.

FILMS

In the largest of these RCTs, FILMS (the Full-thickness macular hole and Internal Limiting Membrane peeling Study),^12,13 in addition to the evaluation of the status of the macular hole, a detailed functional analysis, which included distance and near vision, contrast sensitivity, and reading speed, was undertaken. Furthermore, patient reported outcomes (PROs) and cost effectiveness of the treatment were also assessed.

In FILMS, phakic patients underwent phacoemulsification and vitrectomy, detachment, and removal of the posterior hyaloid with 12% C3F8 gas. Depending upon randomization, patients could receive trypan blue-assisted ILM peeling or no ILM peeling.

FILMS did not detect a statistically significant difference in distance visual acuity at six months, which was considered the primary outcome of the study, although an adjusted mean difference of five ETDRS letters favoring ILM peeling was detected. No statistically significant differences in any other functional parameters or in the PROs, which included results of EQ-5D and VFQ-25 questionnaires, were observed between randomized groups.

On the interpretation of these findings, however, it is important to consider that, given ethical considerations and following standard clinical practice, patients in the no ILM peeling arm were allowed to receive ILM peeling if the FTMH had not closed after the initial surgery. Hence, the majority of patients in the no ILM peeling group would have received ILM peeling by the time that the primary outcome of the study and PROs were evaluated.

In FILMS, patients in the ILM peel arm were found to have a statistically significantly higher rate of macular hole closure, and they less frequently required further surgery than those in the no ILM peeling arm.

Economic Results

The economic analysis undertaken in FILMS¹⁴ revealed the mean total cost of care of patients with idiopathic FTMH (including intervention costs and other primary and secondary care costs) to be £2,550 (~$4,000) in the ILM peeling arm and £2,974 (~$4,700) in the no ILM peeling arm. The main determinant of this difference in cost was the increased need for additional surgery in the no ILM peeling group. Quality-adjusted life years (QALYs) were very slightly higher, on average, in the peeling arm (mean difference of 0.002 additional QALYs in the peel arm).

The economic analysis suggested that it is likely that ILM peeling is cost effective compared with no ILM peeling. For this analysis, bootstrapping was used. Bootstrapping is a nonparametric technique commonly used within economic evaluations to produce confidence intervals around differences in costs and QALYs.¹⁵

Using bootstrapping, repeated random samples of the same size as the original sample are drawn with replacements from the original data (Figure 1). The number of samples required is typically 1,000.

Figure 1. Process of bootstrapping

Figure 2 shows the scatter plot of the bootstrapped costs and effects, presented on an incremental cost-effectiveness plane. The cost-effectiveness plane illustrates how an economic evaluation brings together information on both costs and effects. The vertical axis represents the difference in costs between ILM peeling and no ILM peeling, and the horizontal axis represents the differences in effects (QALYs) between ILM peeling and no ILM peeling.

Figure 2. Bootstrapped costs and effects

IMAGE FROM TERNENT L, VALE L, BOACHIE C, BURR JM, LOIS N, FOR THE FILMS GROUP. COST-EFFECTIVENESS OF INTERNAL LIMITING MEMBRANE PEELING VERSUS NO PEELING FOR PATIENTS WITH AN IDIOPATHIC FULL-THICKNESS MACULAR HOLE: RESULTS FROM A RANDOMISED CONTROLLED TRIAL. BR J OPHTHAMOL. 2012:96:438-443. REPRINTED WITH PERMISSION OF BMJ JOURNALS.

For each bootstrap iteration, we produced an estimate of the differences in costs and effects, and each circle in Figure 2 represents one such pair of data. The average of the 1,000 bootstrap iterations from FILMS (pair comparisons of mean costs and effects [QALYs] between the ILM peeling and no ILM peeling arms) dropped in the southeast (bottom right) quadrant of the cost-effectiveness plane, indicating that ILM peeling dominated because it was both less costly and more effective than no ILM peeling (Figure 2).

Furthermore, a cost-effectiveness acceptability curve (CEAC) was constructed using FILMS data. The CEAC was constructed by plotting the proportion of cost and QALY pairs that were cost effective at different willingness to pay thresholds.¹⁶ It can be thought of a little like a one-sided statistical test in that we showed the probability (the P value) that an intervention would have a cost per QALY no greater than a particular value. This proportion can be identified from the cost-effectiveness plane.

All points in the southeast quadrant (new treatment is both less costly and more effective) were considered cost effective. All points in the northwest quadrant (new treatment is more costly and less effective) were not considered cost-effective. Depending on willingness-to-pay values (eg, £0, £20,000, and £30,000 per QALY — roughly, $0, $32,000, and $47,000), points in the northeast (new treatment is more costly and more effective) and points in the southwest quadrant (new treatment is less costly and less effective) may be considered cost effective.

In FILMS, it was found that ILM peeling had a 90% chance of being cost effective when society's willingness to pay for a QALY was £20,000 — the threshold used by the National Institute of Clinical Excellence (NICE). In fact, even in cases in which society was not willing to pay anything for an additional QALY, it was found that there would be a 90% chance for ILM peeling still to be cost effective (Figure 3), as 90% of the bootstrapped iterations were found to be cost-saving, where ILM peeling was less costly than no ILM peeling.

Figure 3. Cost-effectiveness acceptability curve constructed with FILMS data

IMAGE FROM TERNENT L, VALE L, BOACHIE C, BURR JM, LOIS N, FOR THE FILMS GROUP. COST-EFFECTIVENESS OF INTERNAL LIMITING MEMBRANE PEELING VERSUS NO PEELING FOR PATIENTS WITH AN IDIOPATHIC FULL-THICKNESS MACULAR HOLE: RESULTS FROM A RANDOMISED CONTROLLED TRIAL. BR J OPHTHAMOL. 2012;96:438-443. REPRINTED WITH PERMISSION OF BMJ JOURNALS.

CONCLUSION

A forthcoming systematic review and an individual patient data (IPD) meta-analysis, which includes data from the four above-mentioned RCTs evaluating ILM peeling in macular hole surgery,^10-13 are currently being undertaken. This study will provide the best available evidence with regards to the use of ILM peeling for the treatment of patients with FTMH. RP

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