Clinical Trials in Cornea

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Article initiated by:
Francesc March de Ribot, MD, PhD
All contributors:
Apoorva Chowdhary, Jainam Shah, Olivia Lee, MD, Vatinee Y. Bunya, MD, MSCE, Francesc March de Ribot, MD, PhD, Shu Feng, MD, Sarah Zhou, MD, Dina Abdelsalam
Assigned editor:
Review:
Assigned status Update Pending
.


Herpetic Eye Disease Study - 1 (HEDS - 1)

Ophthalmology 1994;1871-1882[1]| Ophthalmology 1994;1883-1896[2]| Arch Ophthalmol 1996;1065-1072.[3]

Objectives

The goal was to determine the role of 1) topical steroids in stromal keratitis associated with HSV; and 2) oral acyclovir in HSV stromal keratitis and HSV iridocyclitis (receiving treatment with topical trifluridine -antiviral- and topical steroids treatment).[4]

Design

3 separate controlled clinical trials, randomized, double-masked, placebo-controlled to evaluate HSV 1) Stromal keratitis with steroids, 2) without steroids, and 3) Iridocyclitis. Groups:

  1. SKN – Stromal keratitis, not on steroids: 106 patients who had not used a topical steroid in the preceding ten days were randomised to receive topical prednisolone or placebo. The drops over a ten-week period, commencing with 1% prednisolone phosphate 8 times a day, tapering to ⅛ once a day.
  2. SKS – Stromal keratitis, on steroids: 104 patients who were already using topical steroids were randomised to receive acyclovir 400 mg five times daily for ten weeks, or placebo. Topical steroid therapy was standardised for both groups as per the SKN trial.
  3. IRT – Iridocyclitis, receiving topical steroids: 50 patients who were already using topical steroids were randomised to receive acyclovir 400 mg five times daily for ten-weeks or placebo. Topical steroid and antiviral therapy were standardised for both groups.


Patients were evaluated weekly for ten weeks, fortnightly for six more weeks, and at six months.

Main outcome measures

VA, resolution of active disease, treatment failure.

Results

  1. SKN – Stromal keratitis, not on steroids: 106 patients who had not used topical steroid in the preceding ten days were randomised to receive topical prednisolone or placebo. Corticosteroid therapy had a longer time to treatment failure, reduced the risk of persistent or progressive stromal keratouveitis by 68%, and had a shorter resolution time. At 6 months, there were no differences in VA or herpetic recurrence between the groups.
  2. SKS – Stromal keratitis, on steroids: 104 patients who were already using topical steroids were randomised to receive acyclovir 400 mg five times daily for ten weeks, or placebo. The median time to treatment failure was longer in the acyclovir group 84 days, vs. to placebo 62 days. There were no differences in treatment failure (75% in acyclovir and 74% in placebo) or worsening (18% in acyclovir and 19% in placebo). However, VA improved over 6 months in more patients in the acyclovir group.
  3. IRT – Iridocyclitis, receiving topical steroids: 50 patients using topical steroids were randomised to receive acyclovir or placebo. Oral acyclovir added to topical trifluridine and prednisolone appeared to improve the recovery in HSV iridocyclitis, after the first 3 weeks of follow-up. Treatment failure in the first ten weeks was 68% in the placebo compared to 50% in the oral acyclovir group. Relapse rates were similar between the two groups. Overall, the numbers of patients in this trial were too small to have conclusions.

Limitations

Many patients got lost in the follow-up. Modern treatment involves topical acyclovir or ganciclovir.

Conclusions

Topical corticosteroid reduced persistence or progression of stromal inflammation and HSV stromal keratitis. Postponing steroids delayed resolution of stromal keratitis but had no detrimental effect in VA at 6 months. Oral acyclovir was not useful for HSV stromal keratitis already receiving topical trifluridine and topical steroids, and it was not clear the benefits in HSV iridocyclitis.

Pearls for clinical practice

Topical steroids may speed the resolution of HSV stromal keratitis.


Omega-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease, by the Dry Eye Assessment and Management (DREAM) Study Research Group

Objective

Dry eye disease (DED) is a widespread condition, affecting approximately 14% of adults in the United States. Previous clinical trials had demonstrated the efficacy of supplementation with poly-unsaturated fats, particularly omega-3 fatty acids, in mitigating inflammation. The DREAM trial sought to determine the effects of omega-3 fatty acid supplementation on dry eye disease. [5]

Design

Multi-center, double-blind randomized clinical trial. Enrolled 535 patients with DED across 27 sites in the US. Subjects randomized to 2:1 ratio to receive active or placebo supplements for 12 months. 349 patients received active supplements, and 186 received placebo.[6]

  • Active Supplement Regimen: Active capsules contained 400 mg of eicosapentaenoic acid (EPA) and 200 mg docosahexaenoic acid (DHA), for a total daily dose of 2000 mg EPA and 1000 mg of DHA.
  • Placebo Supplement Regimen: Placebo capsules contained 1000 mg of olive oil (68% oleic acid, 13% palmitic acid, 11% linoleic acid).


The regimen was reduced or suspended when patients reported gastrointestinal symptoms or when a contraindication to treatment with the full dose of active supplements developed. If these symptoms resolved, the patient could restart or increase the regimen.

  • Visits were conducted at 3, 6, and 12 months after initiation of study. Participants were also contacted via telephone at 9 months to report adverse events.

Main outcome measure

  1. Mean change from baseline in the Ocular Surface Disease Index (OSDI) score

Results

  • OSDI scores decreased between baseline and 12 months in the active supplement group and in the placebo group (P<0.001), most of the decrease occurring in the first 3 months.
  • The mean change in scores was -13.9+15.6 points in active supplement group and -12.5+18.2 points in placebo group, resulting in mean difference in change of -1.9 that was not statistically significant (95% CI, -5.0 to 1.1, p=0.21)

Limitations

According to the study design, participants were able to continue with or change their dry eye therapies during the study. Additionally, some have questioned the use of olive oil as a placebo, due to its potential anti-inflammatory properties.

Clinical Pearls

In patients with moderate-to-severe dry eye disease despite the use of other treatments, 12 months of supplementation with 3000 mg of omega-3 fatty acids did not contribute to a significant difference in improvement of dry eye disease symptoms and signs when compared to placebo.


Cornea Donor Study (CDS)

Background

Purpose: To evaluate whether survival with donors >65 years is comparable to younger donors in penetrating keratoplasty (PK) for moderate-risk endothelial disease. [7]

Design: Prospective, multicenter, double-masked, randomized non-inferiority trial

Methods:

  • Inclusion criteria: 1,090 patients age 40–80 years undergoing penetrating keratoplasty (PK) for Fuchs endothelial corneal dystrophy (FECD) or pseudophakic/aphakic corneal edema (PACE).
  • Exclusion criteria: High-risk eyes (prior failed graft, chemical burns, herpes keratitis, uncontrolled glaucoma, uveitis) and low-risk eyes (e.g., keratoconus, stromal dystrophies without edema)
  • Randomization: Randomization balanced assignment by surgeon and donor age (12–65 vs 66–75 years). Investigators and recipients were masked
  • Primary outcome: Graft failure, defined as regraft or central opacity compromising vision ≥3 months. Rejection was classified as definite (endothelial rejection line) or probable (inflammatory signs without a line).

Key Findings

Donor Age and Graft Survival

  • Cumulative probability of graft survival at 5 years was identical, and non-inferiority of donor age 12-65 compared to 66-75 years old was demonstrated. Difference in survival rate at 10 years was insignificant. [7]

At 5 years, the cumulative probability of graft survival was 86% overall, identical between corneas from younger and older donors [7]. The upper limit of the one-sided 95% CI was 4%, below the pre-specified non-inferiority margin of 8%, and adjustment for baseline ECD did not change the results. Donor age analyzed as a continuous variable showed no significant effect, although exploratory analyses suggested higher survival for the youngest donors (93% survival for donor age 12–40 years vs 85% survival for ages 41–75). At 10 years, survival was 77% for donors aged 12–65 versus 71% for donors aged 66–75. Survival remained stable for donors aged 34–71 (75%), with the greatest survival rate in donors aged 12–33 (96%) and the lowest in those aged 72–75 (62%), the latter decline emerging after year 6.

Endothelial Cell Loss and Morphometry

  • Endothelial cell density (ECD) was significantly greater at 5 years in grafts from younger (12-65 years) compared to older (66-75 years) donors with a decline in ECD from baseline by about 70% across all donor ages. [8]

The SMAS analyzed 347 eyes with clear grafts at 5 years. Median ECD declined by about 70% from baseline across all donor ages. Younger donors (12–65 years) had higher median 5-year ECD than older donors (824 vs 654 cells/mm²), corresponding to median losses of 69% and 75% (adjusted P = 0.04). At 10 years, substantial cell loss persisted at median ECD of 628 cells/mm² for younger donors and 550 cells/mm² for older donors [9]. Higher baseline ECD and larger donor tissue size were associated with better long-term ECD, though variability was wide, with 24% of grafts falling below 500 cells/mm² and only 14% above 1,000 at 10 years. Morphometric analysis revealed that cell shape and variability independently predicted endothelial failure, beyond absolute ECD counts [10]. A related analysis confirmed that low ECD alone strongly correlated with graft failure risk [11].

Causes of Graft Failure, Recipient Risk Factors, and Donor Risk Factors

  • A preoperative diagnosis of PACE and glaucoma history, especially history of both glaucoma surgery and IOP-lowering drops, were the strongest predictors of graft failure at 5 years.

By 5 years, 135 grafts (12%) failed, including 102 regrafts (76%) and 33 failures without regraft (24%) [7]. Major causes were graft rejection (48), endothelial decompensation (46), and primary donor failure (3). Other non-rejection failures included infection (15), persistent epithelial defects (6), glaucoma (3), epithelial downgrowth (2), corneal edema (1), thinning (1), hypotony (1), wound dehiscence (1), and refractive indications (8). Failure cause distribution did not differ by donor age. Among 1,090 participants, preoperative diagnosis and glaucoma history were the strongest predictors of failure [12] [13]. Risk was nearly four times higher with PACE compared with FECD (27% vs 7%). Glaucoma history markedly increased risk, especially when prior surgery and IOP-lowering medication use were both present. In FECD, lens status had little effect, whereas in pseudophakic/aphakic corneal edema, anterior chamber IOLs carried higher failure than posterior chamber IOLs. Recipient age, sex, diabetes, smoking, and graft size were not significant predictors. Elevated postoperative IOP, vitrectomy at transplant, and graft size reached significance in univariate but not multivariate models, largely confounded by diagnosis. Non-white/Hispanic recipients had higher failure risk than white non-Hispanic recipients, although subgroup sizes were small. Donor risk factors were less influential. Variables such as tissue retrieval method, cause of death, and preservation times showed no consistent effect [14]. Importantly, donor diabetes was not associated with graft failure or with greater long-term endothelial cell loss at 10 years, however analyses at 10 years may be confounded by early failure of grafts from donors with diabetes that were not included in the analysis [15].

Corneal Thickness

  • Analysis of corneal thickness measurements found that increased corneal thickness after PK independently predicted poorer long-term outcomes [16]. Thicker grafts at 1, 5, and 10 years correlated with higher failure rates, providing a practical adjunct to ECD monitoring in predicting prognosis.

ABO Compatibility

  • ABO compatibility was not a significant determinant of graft survival overall [17]. In low-risk cases, ABO incompatibility also did not meaningfully alter outcomes [18].

Graft Rejection

  • A definite rejection event was associated with lower graft survival rates compared to grafts without a rejection event.

Longer-term analyses confirmed the prognostic importance of rejection. By 10 years, a definite rejection event was strongly associated with subsequent graft failure: survival was 88% without rejection compared to 77% with definite rejection [19]. A history of glaucoma, particularly with prior filtering surgery, markedly increased rejection risk (10-year incidence 35% vs 14%). At 5 years, rejection occurred in roughly one-quarter of grafts and was more frequent in PACE than FECD, as well as in female compared with male recipients [20]. Lens status also influenced outcomes, with higher rejection in phakic FECD eyes versus pseudophakic eyes.

Clinical Implications

  • Corneal tissue from donors up to 75 years can be used safely for PK in FECD and PACE.
  • Five-year graft survival was identical between younger and older donor groups, and even at 10 years there was no significant difference (77% vs 71%), though ECL was somewhat greater in older tissue.
  • Preoperative risk stratification is key, and surgical planning may benefit more from risk stratification based on recipient characteristics rather than based on donor variables. PACE was at fourfold higher risk of graft failure compared to FECD. Glaucoma history, particularly history of filtering surgery and use of IOP-lowering medications, was strongly predictive of poor survival. In PACE, anterior chamber intraocular lenses conferred greater failure risk than posterior chamber intraocular lenses.
  • Preoperative ECD was not predictive of graft survival, whereas the 6-month ECD strongly predicted later graft survival. Increased corneal thickness during follow-up independently predicted poorer outcomes, complementing, but not replacing ECD monitoring.


Cornea Preservation Time Study (CPTS)

Background

Purpose: To provide high-quality evidence on whether preservation time (PT) up to 14 days affects endothelial cell loss (ECL) and graft success 3 years post Descemet stripping automated endothelial keratoplasty (DSAEK).

Design: Prospective, multicenter, double-masked, randomized, noninferiority trial.

Methods:

  • Inclusion criteria: Patients age 30 to 90 with Fuchs’ endothelial corneal dystrophy (FECD) or pseudophakic/aphakic corneal edema (PACE) [3].
  • Exclusion criteria: Patients with prior failed PKP or DSAEK, tube shunts, uncontrolled glaucoma or uveitis, anterior chamber intraocular lenses, and peripheral anterior synechiae measuring more than one-fourth of the anterior chamber angle were excluded.
  • Randomization: Patients were randomized 1:1 to receive donor corneas preserved in Optisol-GS for ≤7 days or 8–14 days prior to transplantation. Surgeons were required to have prior experience with at least 50 DSAEK cases, a primary donor failure rate of less than 3%, and they were masked to PT until surgery.
  • Primary outcome: Graft success at 3 years defined as a clear graft without need for regrafting. Graft failure was defined as regraft for any reason, failure to clear 8 weeks postoperatively, or initially clear graft that became and remained cloudy for 90 days.

Key Findings

Graft Success and PT

  • Success rate at 3 years after DSAEK were high regardless of PT, however noninferiority of longer PT was unable to be demonstrated. [21]

At 3 years, the cumulative probability of graft success was not significantly different between groups (95.3% in the 0-7 day group; 92.1% in the 8-14 day group), however results did not meet criteria for noninferiority of the 8-14 day group [3]. When further divided into subgroups, 3-year graft success was lowest for PT of 12-14 days compared to other preservation time subgroups. The risk of graft failure was significantly higher in the 8–14 day group. Subgroup analysis further showed that the 3-year graft success was lowest for preservation times of 12–14 days compared to graft success for PT of ≤4 days, 5–7 days, and 8–11 days.

Endothelial Cell Loss

  • Longer PT was associated with significantly greater endothelialcell loss (ECL), however, the effect of PT on endothelial cell loss was comparable from 4-13 days. Greatest ECL occurred within the first 6 postoperative months. [22]

At 3 years post DSAEK, ECD declined by 37% in the 0–7 day group and by 40% in the 8–14, with eac additional day of PT corresponding to am ean decrease of 15 cells/mm². Findings at 4 years post DSEAK were similar.

Graft Rejection

  • Overall graft failure rate from rejection was low, and younger recipient age was the only significant factor in risk of rejection. [23]

The 3-year cumulative probability of a definite rejection episode was 3.6%, with younger recipient age being the only significant factor in risk of rejection. Half of definite rejection episodes occurred within the first postoperative year. The overall graft failure rate from rejection in CPTS was low at 1%. Donor age, PT, immunization within 3 months of follow-up, and graft size, were not significantly associated with rejection risk. Contrary to the Cornea Donor Study (CDS), which found that PACE, prior use of glaucoma medications, and glaucoma filtering surgery were associated with higher risk of graft rejection following PK, CPTS found that prior use of glaucoma medications and less complex glaucoma surgery (e.g. laser trabeculoplasty, trabeculectomy) were not associated with higher risk of graft rejection following DSAEK. However, notably CPTS did not include tube shunt surgeries. Grafts that had experienced a rejection episode but were ultimately clear at 3 years had significantly higher ECL than grafts that had no history of rejection (48% vs 38%, P=0.03) but did not substantially impact overall graft survival.

Donor, Recipient, and Operative Factors

  • Donor diabetes, lower screening ECD, a recipient diagnosis of PACE, and operative complications were significantly associated with lower ECD and reduced graft survival at 3 years. [24]

Impact on ECD Mean endothelial cell loss (ECL) was 47% in recipients of corneas from diabetic donors compared with 43% without diabetes. PACE was associated with greater ECL compared with FECD (53% vs 44%). [24] Preoperative ECD was not associated with LEGF but lower ECD at 6 months was strongly predictive (p<0.001) [25] Lower baseline intraocular pressure was initially associated with reduced 3-year ECD, but this was not significant after excluding eyes with prior glaucoma treatment, suggesting baseline IOP did not independently affect long-term endothelial survival when glaucoma was well controlled and anterior chamber anatomy was well preserved. Notably, intraoperative complications were strongly associated with worse outcomes (55% ECL loss with complications, 44% without complications. [24]

Impact on graft survival The overall 3-year graft success rate in CPTS was 94.1% [26]. Donor diabetes and operative complications were independent predictors of failure. At 3 years, graft success was 95.0% for non-diabetic donors versus 90.3% for diabetic donors, and 94.6% without operative complications versus 79.5% with complications. PACE was the principal recipient factor associated with late graft failure; 3-year success rates were 83.7% in PACE and 94.3% in FECD. Other donor, recipient, and operative characteristics including donor age, sex, storage solution, cause of death, lenticule thickness, insertion method, incision size, concomitant cataract surgery, and recipient age were ultimately not independent risk factors for endothelial survival. With regards to graft success, eyes with prior glaucoma surgery showed success rates (80% vs 94%), but this did not meet the significance threshold in CPTS, and tube shunt cases were excluded. In summary, donor diabetes, lower screening ECD, a recipient diagnosis of PACE, and operative complications were significantly associated with lower ECD at 3 years. Donor diabetes, operative complications, and PACE were likewise independent predictors of reduced graft survival. Operative complications were the most clearly modifiable factor, underscoring the importance of careful surgical technique.

Postoperative Graft Attachment and Intraocular Pressure (IOP)

  • Donor diabetes, greater pre-lamellar dissection donor central corneal thickness, and intraoperative complications were associated with higher rates of graft dislocation, and graft dislocation was associated with higher risk of graft failure at 3 years postoperatively. Early acute IOP elevation was associated with higher risk of graft failure. [27]

Eight percent of eyes had at least one graft dislocation (GD) postoperatively. Donor diabetes, greater pre-lamellar dissection donor central corneal thickness, and intraoperative complications (OR, 2.97) were associated with a higher risk of GD. After accounting for donor history of diabetes, PT, recipient diagnosis, operative complications and surgeon, GD was a major determinant of long-term outcomes for graft failure compared with eyes without GD at 3 years postoperatively. These results highlight that even partial detachment carried an elevated risk of failure compared to fully attached grafts, supporting a “dose–response” effect for the severity of dislocation. GD was also associated with significantly lower 3-year postoperative ECD compared with eyes without GD [10]. Graft dislocation, but not partial detachment with interface fluid, was associated with worse ECD in clear grafts at 3 years, which the authors suggested may adversely affect longer-term graft survival. The 3-year graft success rate for 24 eyes (75%) with acute IOP elevation was significantly lower than in eyes that did not experience the acute increase in IOP (94.1%).There was a 3.4-fold higher risk of graft failure (HR, 3.42), although it did not significantly affect the mean 3-year ECD. The authors noted that this apparent discrepancy was likely due to a selection effect: grafts severely damaged by acute IOP spikes tended to fail early, leaving only surviving clear grafts available for ECD analysis at the 3 year mark [11] By contrast, elevated IOP beyond 1 month postoperatively occurred in 23% of eyes with functioning grafts, but was not significantly associated with graft success or ECD at 3 years.

Infections and Donor Rim Cultures

  • Longer PT was not associated with increased rim culture positivity for fungal or bacterial growth, and overall rate of infection was low. [28]

Donor rim cultures were performed in 59% of eyes. Positive fungal growth occurred in 2.5% of 0–7 day PT corneas and 1.3% of 8–14 day PT corneas, while positive bacterial growth occurred in 1.5% and 1.0%, respectively, with insignificant differences in percentage of positive cultures between PT groups. Surgeon-prepared tissue carried a higher risk of positive fungal cultures compared with eye bank–prepared tissue, while younger donor age and accidental death were associated with positive bacterial cultures. Postoperative infection was rare: fungal keratitis developed in 1 of 15 recipients of a cornea with a positive fungal culture (6.7%), and no infections occurred following positive bacterial cultures. With two additional infections in eyes without rim culture performed, the overall incidence across the entire CPTS cohort was 0.15% for fungal and 0.08% for bacterial infection. Longer PT was not associated with increased rim culture positivity or infection risk, and the overall rate of infection was very low.

Surgeon Attitudes and Policy Impact

  • The proportion of surgeons willing to accept donor corneas preserved for >7 days and eye bank-reported mean PT increased after publication of CPTS. [29]

A follow-up survey of American Academy of Ophthalmology members with a cornea interest assessed the impact of CPTS on surgeon attitudes toward PT. In 2012, 364 of 1,609 surgeons (22.6%) responded, and in 2018, 297 of 1,872 surgeons (15.9%) responded. The proportion of surgeons willing to accept donor corneas preserved for more than 7 days significantly increased from 32% in 2012 to 46% in 2018. A significant change was observed among surgeons with more than 10 years of experience, with acceptance rising from 28% to 47% over this period. Consistent with these shifts, eye bank-reported mean PT increased from 4.6 days in 2010 to 5.1 days in 2018, and the proportion of endothelial keratoplasty (EK)-intended donor corneas preserved for more than 7 days rose from 3% to 9%. These results suggest that CPTS influenced both surgeon acceptance patterns and eye-bank distribution practices.

Clinical Implications and Summary

  • Donor corneas can be safely preserved for up to 11 days with little influence on graft success and comparable ECL from 4–13 days
  • Overall infection incidence was low
  • Donor diabetes was consistently associated with lower 3-year ECD and higher graft failure risk, while PACE (vs FECD) conferred greater ECL and an elevated risk of late failure. Other variables including donor age, graft diameter, and insertion method were not independent predictors of outcomes within CPTS criteria.
  • Surgical technique and early postoperative events emerged as the most clearly modifiable factors. Operative complications were strongly linked to both reduced ECD and increased failure risk. Graft dislocation (GD), seen in 8% of eyes, carried a nearly eight-fold higher failure risk, with a clear dose–response relationship by detachment severity.
  • 6-month postoperative ECD, not preoperative ECD, was a critical predictor of late endothelial graft failure at 5 years, reinforcing the need to protect the endothelium early after surgery


References

  1. ↑ Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology. 1994;101(12):1871-1882. doi:10.1016/s0161-6420(13)31155-5
  2. ↑ Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology. 1994;101(12):1883-1896. doi:10.1016/s0161-6420(94)31087-6
  3. ↑ A controlled trial of oral acyclovir for iridocyclitis caused by herpes simplex virus. The Herpetic Eye Disease Study Group. Arch Ophthalmol. 1996;114(9):1065-1072. doi:10.1001/archopht.1996.01100140267002
  4. ↑ Herpetic Eye Disease Study (HEDS) I. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT00000138 Accessed May 31, 2024.
  5. ↑ Dry Eye Assessment and Management Study (DREAM). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT02128763 Accessed May 31, 2024.
  6. ↑ Dry Eye Assessment and Management Study Research Group, Asbell PA, Maguire MG, et al. n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease. N Engl J Med. 2018;378(18):1681-1690. doi:10.1056/NEJMoa1709691
  7. ↑ 7.0 7.1 7.2 7.3 Cornea Donor Study Investigator Group, gal RL, Dontchev M, et al. The effect of donor age on corneal transplantation outcome results of the cornea donor study. Ophthalmology. 2008;115(4):620-626.e6. doi:10.1016/j.ophtha.2008.01.003
  8. ↑ Cornea Donor Study Investigator Group, Lass JH, Gal RL, et al. Donor age and corneal endothelial cell loss 5 years after successful corneal transplantation. Specular microscopy ancillary study results. Ophthalmology. 2008;115(4):627-632.e8. doi:10.1016/j.ophtha.2008.01.004
  9. ↑ Writing Committee for the Cornea Donor Study Research Group, Lass JH, Benetz BA, et al. Donor age and factors related to endothelial cell loss 10 years after penetrating keratoplasty: Specular Microscopy Ancillary Study. Ophthalmology. 2013;120(12):2428-2435. doi:10.1016/j.ophtha.2013.08.044
  10. ↑ Benetz BA, Lass JH, Gal RL, et al. Endothelial morphometric measures to predict endothelial graft failure after penetrating keratoplasty. JAMA Ophthalmol. 2013;131(5):601-608. doi:10.1001/jamaophthalmol.2013.1693
  11. ↑ Lass JH, Sugar A, Benetz BA, Beck RW, Dontchev M, Gal RL, Kollman C, Gross R, Heck E, Holland EJ, Mannis MJ, Raber I, Stark W, Stulting RD; Cornea Donor Study Investigator Group. Endothelial cell density to predict endothelial graft failure after penetrating keratoplasty. Arch Ophthalmol. 2010 Jan;128(1):63-9. doi: 10.1001/archophthalmol.2010.128.63.
  12. ↑ Sugar A, Tanner JP, Dontchev M, et al. Recipient risk factors for graft failure in the cornea donor study. Ophthalmology. 2009;116(6):1023-1028. doi:10.1016/j.ophtha.2008.12.050
  13. ↑ Writing Committee for the Cornea Donor Study Research Group, Sugar A, Gal RL, et al. Factors associated with corneal graft survival in the cornea donor study. JAMA Ophthalmol. 2015;133(3):246-254. doi:10.1001/jamaophthalmol.2014.3923
  14. ↑ Sugar J, Montoya M, Dontchev M, et al. Donor risk factors for graft failure in the cornea donor study. Cornea. 2009;28(9):981-985. doi:10.1097/ICO.0b013e3181a0a3e6
  15. ↑ Lass JH, Riddlesworth TD, Gal RL, et al. The effect of donor diabetes history on graft failure and endothelial cell density 10 years after penetrating keratoplasty. Ophthalmology. 2015;122(3):448-456. doi:10.1016/j.ophtha.2014.09.012
  16. ↑ Verdier DD, Sugar A, Baratz K, et al. Corneal thickness as a predictor of corneal transplant outcome. Cornea. 2013;32(6):729-736. doi:10.1097/ICO.0b013e31827b14c7
  17. ↑ Cornea Donor Study Investigator Group. ABO blood group compatibility and corneal graft survival. Am J Ophthalmol. 2011;151(2):227-233.e1. doi:10.1016/j.ajo.2010.08.031
  18. ↑ Dunn SP, Stark WJ, Stulting RD, et al. The effect of ABO blood incompatibility on corneal transplant failure in conditions with low-risk of graft rejection. Am J Ophthalmol. 2009;147(3):432-438.e3. doi:10.1016/j.ajo.2008.09.021
  19. ↑ Dunn SP, Gal RL, Kollman C, et al. Corneal graft rejection 10 years after penetrating keratoplasty in the cornea donor study. Cornea. 2014;33(10):1003-1009. doi:10.1097/ICO.0000000000000212
  20. ↑ Stulting RD, Sugar A, Beck R, et al. Effect of donor and recipient factors on corneal graft rejection. Cornea. 2012;31(10):1141-1147. doi:10.1097/ICO.0b013e31823f77f5
  21. ↑ Rosenwasser GO, Szczotka-Flynn LB, Ayala AR, et al. Effect of Cornea Preservation Time on Success of Descemet Stripping Automated Endothelial Keratoplasty: A Randomized Clinical Trial. JAMA Ophthalmol. 2017;135(12):1401-1409. doi:10.1001/jamaophthalmol.2017.4989
  22. ↑ Lass JH, Benetz BA, Verdier DD, et al. Corneal Endothelial Cell Loss 3 Years After Successful Descemet Stripping Automated Endothelial Keratoplasty in the Cornea Preservation Time Study: A Randomized Clinical Trial. JAMA Ophthalmol. 2017;135(12):1394-1400. doi:10.1001/jamaophthalmol.2017.4970
  23. ↑ Stulting RD, Lass JH, Terry MA, et al. Factors Associated With Graft Rejection in the Cornea Preservation Time Study. Am J Ophthalmol. 2018;196:197-207. doi:10.1016/j.ajo.2018.10.005
  24. ↑ 24.0 24.1 24.2 Lass JH, Benetz BA, Patel SV, et al. Donor, Recipient, and Operative Factors Associated With Increased Endothelial Cell Loss in the Cornea Preservation Time Study. JAMA Ophthalmol. 2019;137(2):185-193. doi:10.1001/jamaophthalmol.2018.5669
  25. ↑ Patel SV, Lass JH, Benetz BA, et al. Postoperative Endothelial Cell Density Is Associated with Late Endothelial Graft Failure after Descemet Stripping Automated Endothelial Keratoplasty. Ophthalmology. 2019;126(8):1076-1083. doi:10.1016/j.ophtha.2019.02.011
  26. ↑ Terry MA, Aldave AJ, Szczotka-Flynn LB, et al. Donor, Recipient, and Operative Factors Associated with Graft Success in the Cornea Preservation Time Study. Ophthalmology. 2018;125(11):1700-1709. doi:10.1016/j.ophtha.2018.08.002
  27. ↑ Aldave AJ, Terry MA, Szczotka-Flynn LB, et al. Effect of Graft Attachment Status and Intraocular Pressure on Descemet Stripping Automated Endothelial Keratoplasty Outcomes in the Cornea Preservation Time Study. Am J Ophthalmol. 2019;203:78-88. doi:10.1016/j.ajo.2019.02.029
  28. ↑ Mian SI, Aldave AJ, Tu EY, et al. Incidence and Outcomes of Positive Donor Rim Cultures and Infections in the Cornea Preservation Time Study. Cornea. 2018;37(9):1102-1109. doi:10.1097/ICO.0000000000001654
  29. ↑ Hannush SB, Drury DC, Aldave AJ, et al. Impact of the Cornea Preservation Time Study on Donor Cornea Preservation Time and Surgeon Attitudes. Int J Eye Bank. Published online 2018. https://eyebankingjournal.org/article/impact-of-the-cornea-preservation-time-study-on-donor-cornea-preservation-time-and-surgeon-attitudes/
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