Effect of Unilateral Endothelial Keratoplasty on Vision-Related Quality-of-Life Outcomes in the Descemet Endothelial Thickness Comparison Trial (DETECT): A Secondary Analysis of a Randomized Clinical Trial

Key Points

Question  Do unilateral ultrathin Descemet stripping automated endothelial keratoplasty and Descemet membrane endothelial keratoplasty affect vision-related quality of life?

Findings  In this secondary analysis of a randomized clinical trial, no significant differences in patient-reported quality of life outcomes at 3 and 12 months between the 2 groups were noted, with both groups experiencing substantially improved outcomes after unilateral endothelial keratoplasty.

Meaning  Despite a greater improvement in visual acuity, improvement in patient-reported vision-related quality of life was not shown to be greater with Descemet membrane endothelial keratoplasty compared with ultrathin Descemet stripping automated endothelial keratoplasty.

Importance  Vision-related quality of life can be a valuable outcome for some interventions in ophthalmology. In the primary Descemet Endothelial Thickness Comparison Trial (DETECT), Descemet membrane endothelial keratoplasty (DMEK) had superior postoperative visual acuity compared with ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK). It is of interest to determine whether this trend extends to quality of life.

Objective  To determine the effect of UT-DSAEK and DMEK on vision-related quality of life.

Design, Setting, and Participants  A prespecified secondary analysis of a 2-surgeon patient- and outcome-masked randomized clinical trial was conducted at the Casey Eye Institute in Portland, Oregon, and Byers Eye Institute in Palo Alto, California. The study was conducted between January 20, 2015, and April 26, 2017. DETECT enrolled 38 individuals and included 50 eyes with isolated endothelial dysfunction; for this analysis, the second eye from a single participant was excluded along with any questionnaires in the first eye after second eye surgery for evaluation of 38 eyes at baseline and 3 months and 26 eyes at 12 months. Mean (SD) baseline visual acuity was 0.35 (0.31) logMAR in the DMEK arm and 0.28 (0.22) logMAR in the UT-DSAEK arm. Each arm consisted of 19 participants: 18 individuals with Fuchs dystrophy and 1 participant with pseudophakic bullous keratopathy.

Interventions  Study eyes were randomized to receive either UT-DSAEK or DMEK.

Main Outcomes and Measures  Responses to the National Eye Institute (NEI) Visual Function Questionnaire-39 (VFQ-39) administered at baseline and 3 and 12 months postoperatively were analyzed using the NEI-defined traditional subscales and composite score on a 100-point scale and with a Rasch-refined analysis.

Results  There were more women in both arms of the study (UT-DSAEK, 12 [63%]; DMEK, 11 [58%]); mean (SD) age was 68 (11) years in the UT-DSAEK arm and 68 (4) years in the DMEK arm. Overall, study participants experienced a 9.1-point improvement in NEI VFQ-39 composite score at 3 months compared with baseline (N = 38; 95% CI, 4.9-13.3; P < .001), and an 11.6-point improvement at 12 months compared with baseline (n = 26; 95% CI, 6.8-16.4; P < .001). Eyes randomized to DMEK had 0.9 points more improvement in NEI VFQ-39 composite score at 3 months compared with UT-DSAEK after controlling for baseline NEI VFQ-39 (95% CI, −6.2 to 8.0; P = .80).

Conclusions and Relevance  Improvement in vision-related quality of life was not shown to be greater with DMEK compared with UT-DSAEK.

Trial Registration  ClinicalTrials.gov identifier: NCT02373137

Vision-related quality-of-life is an important outcome in ophthalmic clinical trials.¹ Current objective measurements of vision, such as visual acuity, may incompletely characterize the effect of a treatment or intervention on a patient’s functional vision.¹ The study of the association between objective measurements of vision, vision-related functioning, and therapeutic interventions is encouraged by the US Food and Drug Administration.¹ The National Eye Institute (NEI) has developed the validated, 39-question Visual Function Questionnaire (VFQ-39), which has been used widely to evaluate vision-related quality-of-life outcomes in various ocular diseases, including age-related macular degeneration, diabetic retinopathy, glaucoma, dry eye, and corneal transplantation.^2-6

Endothelial keratoplasty (EK) is the most commonly performed type of corneal transplantation in the United States.⁷ The Descemet Endothelial Thickness Comparison Trial (DETECT) was a randomized, controlled, 2-surgeon (W.C. and C.C.L.) clinical trial comparing outcomes of 2 endothelial keratoplasty techniques: ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) vs Descemet membrane endothelial keratoplasty (DMEK). The UT-DSAEK technique is regarded by many to be the standard for selective endothelial transplantation owing to its relative ease and good outcomes.^8,9 In this procedure, the diseased endothelium and Descemet membrane are replaced with donor endothelium and Descemet membrane supported by a thin layer of stroma. Traditional DSAEK donor tissue is approximately 150 μm, whereas ultrathin DSAEK donor grafts are prepared with a thinner layer of supportive stroma and are generally less than 100 μm.⁸ UT-DSAEK has been shown to have superior visual acuity results compared with traditional DSAEK.⁸ DMEK is a newer technique where only Descemet membrane and endothelium are transplanted. Typical graft thickness in DMEK is 10 to 15 μm and studies have shown the procedure to have the potential to further improve visual acuity outcomes and decrease rejection rates.^10-14 However, DMEK is technically more challenging and requires a significant learning curve; surgeons often have difficulty with donor preparation, donor attachment, and primary graft failure.^15-17

The DETECT study found DMEK to have superior visual acuity outcomes compared with UT-DSAEK at 3, 6, and 12 months postoperatively in study participants with isolated endothelial cell dysfunction. Those randomized to DMEK had 1.5 lines better best spectacle-corrected visual acuity (BSCVA) at 3 months (95% CI, 0.6-2.5 lines better; P = .002), 1.8 lines better BSCVA at 6 months (95% CI, 1.0-2.8 lines better; P < .001), and 1.4 lines better BSCVA at 12 months (95% CI, 0.7-2.2 lines better; P < .001).¹⁸ In this secondary analysis, we examine the results of the NEI VFQ-39 administered to study participants preoperatively, 3 months postoperatively, and 12 months postoperatively to evaluate vision-related quality-of-life outcomes.

The methods of DETECT have been reported in detail in the primary article.¹⁸ The research protocol is available in the Supplement. In brief, patients with isolated endothelial dysfunction from Fuchs endothelial dystrophy or pseudophakic bullous keratopathy were block randomized in a 1:1 fashion to DMEK or UT-DSAEK. Exclusion criteria included prior intraocular surgery other than cataract surgery; other corneal pathologic factors, such as keratoconus or stromal scar; presence of a predisposing condition that increased the risk of graft failure, such as corneal vascularization or uveitis; abnormal anterior segment anatomy, such as aphakia, anterior chamber intraocular lens, or peripheral anterior synechiae involving more than 3 clock hours; hypotony or elevated intraocular pressure (defined as >25 mm Hg); or visually significant optic nerve or macular pathologic changes. The primary outcome for the overall trial was BSCVA at 6 months.

The data safety and monitoring committee performed ongoing review for safety, data quality, and ethical conduct throughout the study. Institutional review board approval was obtained through the University of California, San Francisco; Oregon Health Sciences University, Portland; and Stanford University, Stanford, California. Written informed consent was obtained from all participants and the trial conformed to the tenets of the Declaration of Helsinki.¹⁹ Participants did not receive financial compensation.

For this prespecified secondary analysis, the NEI VFQ-39 was administered preoperatively and at 3 and 12 months postoperatively. The primary outcome was postoperative NEI VFQ-39 composite score at 3 months; this outcome was chosen so that the effect of unilateral EK on vision-related quality of life could be assessed in the event that the participant had second eye surgery later. Once a study participant had second eye surgery, their subsequent NEI VFQ-39 data were excluded because it would be difficult to assess which eye was contributing to vision-related quality of life. In this analysis we also excluded NEI VFQ-39 data from all second eyes for this same reason.

The NEI VFQ-39 scores were analyzed in 2 ways. The first was according to published recommendations of the NEI and the second was according to a psychometrically validated Rasch analysis.⁵ The purpose of Rasch analysis is to use mathematical modeling to reduce questionnaire redundancy without reducing the quality of information obtained, thereby generating simple, more valid measures. For the traditional approach, we converted numeric values to a 0- to 100-point scale so that they represented a percentage. Questions were then grouped into NEI-predefined subscales and, for each subscale, questions were averaged to create 12 subscale scores. The overall composite score was calculated per NEI guidelines by averaging the 12 subscale scores, thus giving equal weight to each subscale. For the Rasch analysis approach, numeric responses were converted to logits on a linear scale. According to this approach, the NEI VFQ-39 had superior unidimensionality when sorted into only 2 subscales (visual function and socioemotional quality of life). Table 1 indicates which items from the NEI VFQ-39 were included in the traditional NEI subscales and in the Rasch analysis subscales.

Univariate descriptive analysis was used to summarize demographic and baseline participant characteristics. Linear regression was used to analyze the association between BSCVA in logMAR units and NEI VFQ-39 composite score. The mean composite and subscale scores were compared at specified time points using paired t tests for UT-DSAEK and DMEK arms together and separately for both traditional and Rasch-refined scoring systems. We also assessed whether there was a difference in postoperative vision-related quality of life between treatment arms using linear regression with covariates for baseline NEI VFQ-39 composite score and treatment arm.

The sample size of 50 eyes for the trial was chosen based on the primary outcome of BSCVA. After excluding second eyes, the sample size for this analysis was 38 eyes. Given this fixed sample size and an SD in NEI VFQ-39 composite score of 12.5 points at 3 months, we estimated that we had 80% power to detect a 12-point difference in NEI VFQ-39 composite score between treatment arms. Findings were considered significant at P < .05. All analyses were conducted using Stata, version 15.1 (StataCorp).

Thirty-eight study participants were enrolled, with 50 eyes included in DETECT between January 20, 2015, and April 26, 2017, at either the Casey Eye Institute at Oregon Health Sciences University (n = 43 eyes, n = 31 study participants [86%]) or the Byers Eye Institute at Stanford University (n = 7 eyes, n = 7 participants [14%]) (Figure 1). Twenty-six participants had only 1 eye included and 12 participants had a second eye surgery at least 3 months after first eye surgery. This difference created a unilateral EK subgroup of 38 eyes (100%) at the baseline and 3-month points. After removing all participants with a second eye surgery before administration of the 12-month NEI VFQ-39, 12-month NEI VFQ-39 results were available for 26 first eye/unilateral EK eyes (96%). There were slightly more women than men in both arms: UT-DSAEK, 12 women (63%) and DMEK, 11 women (58%). Mean (SD) age was 68 (11) years in the UT-DSAEK arm and 68 (4) years in the DMEK arm. Each arm was made up of 18 participants with Fuchs endothelial dystrophy and 1 patient with pseudophakic bullous keratopathy. The mean (SD) BSCVA was 0.28 (0.22) logMAR (approximate Snellen equivalent, 20/40; 95% CI, 0.17-0.39) in the UT-DSAEK arm and 0.35 (0.31) logMAR (approximate Snellen equivalent, 20/50; 95% CI, 0.20-0.51) in the DMEK arm. Mean baseline NEI VFQ-39 composite score was 72.5 (95% CI, 66.1-79.0) in the UT-DSAEK arm and 72.3 in the DMEK arm (95% CI, 65.0-79.7) (Table 2).

We found that visual acuity was associated with vision-related quality of life as measured by the NEI VFQ-39. Participants had a mean of 1.7 points lower NEI VFQ-39 composite score for each line decrease in visual acuity at 3 months after EK after controlling for baseline NEI VFQ-39 results and treatment arm (n = 38; 95% CI, 0.8 to 33.2; P = .04). Compared with baseline, study participants had a 9.1-point improvement in NEI VFQ-39 composite score at 3 months after unilateral EK (n = 38; 95% CI, 4.9 to 13.3; P < .001) and an 11.6-point improvement in NEI VFQ-39 composite score at 12 months (n = 26; 95% CI, 6.8 to 16.4; P < .001). Those in the DMEK arm had 0.9 points more improvement in NEI VFQ-39 composite score at 3 months compared with UT-DSAEK after controlling for baseline NEI VFQ-39 score; however, this finding was not statistically significant (95% CI, −6.2 to 8.0; P = .80). At 12 months, the DMEK arm had 0.3 points more improvement in NEI VFQ-39 composite score compared with the UT-DSAEK cohort after controlling for baseline NEI VFQ-39, and this was also not statistically significant (95% CI, −7.5 to 8.1; P = .93).

Comparable results were found when analyzing these data using the Rasch analysis (Table 3). In the UT-DSAEK arm, mean composite NEI VFQ-39 scores improved from 72.5 at baseline to 81.2 at 3 months (n = 19; difference, 8.6; 95% CI, 3.5-13.7; P = .002) and to 85.9 at 12 months (unilateral surgery only, n = 14; difference, 12.6; 95% CI, 6.7-18.5; P < .001). In the DMEK arm, mean composite NEI VFQ-39 scores improved from 72.3 at baseline to 81.9 at 3 months (n = 19; difference, 9.6; 95% CI, 2.3-16.9; P = .01) and to 87.3 at 12 months (unilateral surgery only, n = 12; difference, 10.5; 95% CI, 1.5-19.5; P = .03) (Figure 2).

Given that cataract surgery has been shown to improve vision-related quality of life, we analyzed its effect in the setting of EK in this study. Of the 38 eyes included in the 3-month analysis, 13 eyes (34%) had an EK only with a mean baseline logMAR visual acuity of 0.40 (0.20; approximate Snellen equivalent, 20/50) and 25 (66%) had cataract surgery in addition to EK (the so-called triple EK) with mean baseline logMAR visual acuity of 0.26 (0.21; approximate Snellen equivalent, 20/36). Baseline mean (SD) NEI VFQ-39 composite score was 66.0 (14.3) in those undergoing only EK vs 75.8 (13.1) in those undergoing triple EK, and this difference was statistically significant between groups (P = .04). Those who underwent triple EK had a mean of just 1.5 points lower NEI VFQ-39 composite score at 3 months compared with EK only after controlling for baseline NEI VFQ-39 composite score and treatment arm (95% CI, −9.5 to 6.5; P = .71). Composite NEI VFQ-39 scores improved by an average of 13.4 points (mean [SD], 79.4 [13.8]) in those undergoing EK only by 3 months and 6.9 points (mean [SD], 82.7 [11.7]) in those undergoing triple EK by 3 months.

In this prespecified secondary analysis of a randomized patient- and outcome-masked clinical trial comparing different EK techniques, we found no significant difference in vision-related quality of life as measured by the NEI VFQ-39 between participants undergoing DMEK and UT-DSEAK. However, we observed both a clinically significant and statistically significant improvement in vision-related quality of life at 3 and 12 months in those undergoing either DMEK or UT-DSAEK (P < .001). The most notable improvements were in the general vision, mental health, and role difficulties subscale scores. The NEI and the US Food and Drug Administration recommend that vision-related quality-of-life measures be used to assess interventions in ophthalmology.¹ Given that a 4-point change in overall NEI VFQ-39 score is considered to be a small clinically relevant change, an increase of approximately 12 points, on average, from baseline to 12 months is important.²⁰ A previous study of vision-related quality of life in traditional Descemet stripping EK established that Descemet stripping EK had superior vision-related quality-of-life outcomes compared with penetrating keratoplasty.²¹ This previous study demonstrated a similar degree of improvement in NEI VFQ-39 composite score after traditional Descemet stripping EK compared with our outcomes after DMEK and UT-DSAEK.

Our results are comparable to the vision-related quality-of-life improvement after first eye cataract surgery.²² Herein, we were unable to find an additional improvement in vision-related quality of life among those undergoing cataract surgery at the time of EK. This finding may be because study participants in the EK-only group had significantly worse baseline NEI VFQ-39 composite scores and therefore had more room for improvement.

Although DETECT demonstrated that study participants undergoing DMEK had approximately 1.4 lines better visual acuity on average at 12 months than those undergoing UT-DSAEK (P = .001), we were unable to find a statistically significant difference in vision-related quality of life between the 2 groups. The reason for this discrepancy is unclear and may be related to the fact that quality-of-life measures have high variance and our study was powered to detect a difference in visual acuity NEI VFQ-39 scores. However, other issues to consider include the fact that participants in our study had overall excellent visual acuity after either type of EK with an average Snellen visual acuity of 20/20 after DMEK and 20/30 after UT-DSAEK, and that this small difference did not result in a significant quality-of-life improvement. This finding would be important because if there is a small visual acuity improvement in DMEK but no improvement in vision-related quality of life, corneal surgeons who have not yet adopted DMEK may not be as motivated to learn a new, challenging technique.⁷ Objective measurements, such as visual acuity, are key to the ongoing process of improving techniques for corneal transplantation from the corneal surgeon’s perspective; however, we believe that vision-related quality of life is still an important outcome to consider as patients place great emphasis on their functional vision.

Limitations to our study include a preferential selection of patients with isolated endothelial dysfunction, primarily Fuchs endothelial dystrophy. It is not known whether these results can be generalized to patients with more complicated anterior segment anatomy or to those who have had multiple previous surgeries, such as several glaucoma surgeries or prior vitrectomy. Twelve of our participants had second eye surgery prior to the administration of the 12-month NEI VFQ-39. We decided to eliminate NEI VFQ-39 results from study participants after the second eye surgery because the results would be difficult to interpret once the participants had undergone surgery in both eyes, although further assessment of NEI VFQ-39 improvement after second-eye vs first-eye EK is a topic of future study. This exclusion reduced the number of study participants with unilateral keratoplasty at both the 3- and 12-month points, thereby reducing our overall number of participants and power. Three-month NEI VFQ-39 score is a short-term outcome in the setting of corneal transplant and it would be interesting to have a larger subset of patients to measure longer-term patient reported outcomes in the future.

Vision-related quality-of-life improves clinically and statistically significantly in patients undergoing a unilateral EK with either UT-DSAEK or DMEK. Despite a greater improvement in visual acuity, we did not find increased improvement in patient-reported vision-related quality of life with DMEK compared with UT-DSAEK.

Accepted for Publication: February 14, 2019.

Corresponding Author: Jennifer Rose-Nussbaumer, MD, Francis I. Proctor Foundation, University of California, San Francisco, 513 Parnassus, S334H, San Francisco, CA 94143 (jennifer.rose@ucsf.edu).

Published Online: May 2, 2019. doi:10.1001/jamaophthalmol.2019.0877

Author Contributions: Dr Rose-Nussbaumer and Ms Austin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Chamberlain, Austin, Rose-Nussbaumer.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ang, Pickel, Austin.

Critical revision of the manuscript for important intellectual content: Chamberlain, Lin, Pickel, Austin, Rose-Nussbaumer.

Statistical analysis: Ang, Pickel, Austin, Rose-Nussbaumer.

Administrative, technical, or material support: Chamberlain, Lin, Pickel, Austin.

Supervision: Chamberlain, Austin, Rose-Nussbaumer.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work received financial support from grant K23 EY025025 from the National Eye Institute (Dr Rose-Nussbaumer) and an unrestricted grant from Research to Prevent Blindness.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Lions VisionGift in Portland, Oregon, served as the eye bank for this trial, in which they randomized eyes, provided tissue, and assisted in study design and implementation.