8-year results of LASIK combined with simultaneous LASIK-Xtra compared with conventional LASIK were analyzed.
Abstract
Purpose:
To analyze the 8-year results of femtosecond laser–assisted in situ keratomileusis (LASIK) combined with simultaneous accelerated corneal crosslinking (LASIK-Xtra) compared with conventional LASIK (convLASIK).
Setting:
Department of Ophthalmology, Goethe-University, Frankfurt am Main, Germany.
Design:
Prospective, randomized fellow eye–controlled clinical trial.
Methods:
Patients who received randomized treatment with the LASIK-Xtra (30 mW/cm2, 90 seconds with continuous UV-A) in 1 eye and convLASIK in the fellow eye were subjected 1 year (pos1y), and 8 years postoperatively (pos8y) to subjective refraction, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), endothelial cell count (ECC), biomechanical evaluation, and tomographic examination.
Results:
26 eyes (−7.07 ± 1.86 diopter [D]) from 13 patients (mean age 30.7 ± 10.4 years) were included. UDVA and CDVA were insignificantly different at pos1y and pos8y between convLASIK and LASIK-Xtra (each P > .28). The safety index at pos8y was 1.09 for convLASIK and 1.15 for LASIK-Xtra (P = .799), and the efficacy index 0.91 and 0.94 (P = .875), respectively. Significant myopic shift in spherical equivalent between pos1y (−0.30 ± 0.40 D) and pos8y (−0.80 ± 0.86 D) was found in the convLASIK group (P = .018), compared the LASIK-Xtra group (−0.25 ± 0.49 D and −0.40 ± 0.86 D; P = .261), respectively. However, these refractive changes cannot be fully attributed to corneal alterations alone and may also reflect other factors. Insignificant differences in mean keratometry, corneal thickness, and ECC were found at pos8y (P > .05). The stress–strain index was the only biomechanical parameter that was significantly higher in the LASIK-Xtra group at pos8y (P = .034).
Conclusions:
After 8 years, no substantial disparities in efficacy and safety indices were observed between the 2 groups. There were no substantial differences in most of the evaluated postoperative corneal biomechanical parameters between the 2 groups. However, these findings need to be validated by further studies with larger sample sizes.
In recent decades, keratorefractive surgery has undergone substantial development, with its initial procedures being performed over 3 decades ago.1 Laser in situ keratomileusis (LASIK) has emerged as the predominant refractive surgical technique, surpassing photorefractive keratectomy (PRK).2 The primary benefits of LASIK include its expeditious visual rehabilitation, the assurance of predictable refractive outcomes, minimal postoperative discomfort, and its overall safety with a very low incidence of corneal haze.3 Nevertheless, a notable disadvantage of LASIK is the necessity of creating a flap, which can be accomplished either manually with a microkeratome or using a femtosecond laser, resulting in a considerable reduction in corneal biomechanics.4–10 This loss of corneal rigidity has the potential to elevate the risk of iatrogenic keratectasia, a rare but grave complication in refractive surgery.11–14 This condition can manifest as irregular astigmatism and compromised visual acuity.11,12,14 Consequently, the assessment of corneal biomechanics has become increasingly imperative.5–7,9 In the interest of preventing the development of iatrogenic keratectasia, it is crucial to identify risk factors preoperatively to select the appropriate procedure.12,14 In addition, one option is prophylactic simultaneous corneal crosslinking (CXL) in combination with refractive surgery.10,15–18 The CXL treatment, initially developed for the management of ectatic diseases (eg, keratoconus), involves the interaction of vitamin B2 (riboflavin), UV-A light, and oxygen, leading to the photopolymerization of corneal collagen fibers resulting in the biomechanical stiffening of the cornea.19 CXL was initially performed in combination with LASIK (LASIK-Xtra) before being used in other keratorefractive techniques.20 However, given the potential complications associated with CXL, including corneal haze, scarring, sterile and microbial infiltrates, delayed wound healing, and corneal flattening with subsequent hyperopic shift, this combination should only be used after a careful risk–benefit assessment.21 To date, there have been several studies that have investigated and compared combined CXL with different protocols with various keratorefractive procedures.10,15–18 Given the potential for iatrogenic keratectasia to develop within a period ranging from a few days to several years postoperatively, the necessity for long-term results is imperative.12,22 However, only a limited number of studies have published results from follow-up periods of several years.22
The objective of this study was to investigate the results with a follow-up period of 8 years of patients who have been randomized to receive the combined LASIK-Xtra procedure in 1 eye and conventional femtosecond laser–assisted LASIK (convLASIK) without simultaneous CXL in the fellow eye.
METHODS
This follow-up analysis of a prospective, randomized, fellow eye–controlled, comparative clinical case study was performed at the Department of Ophthalmology, Goethe University, Frankfurt am Main, Germany. The study's participants included 26 patients with high myopia and/or myopic astigmatism ranging from −6 to −12 diopters (D) who received LASIK-Xtra in 1 eye and convLASIK in the fellow eye. Twenty-three of 26 patients successfully completed the 12-month follow-up period (pos1y). The results of the study with a 1-year follow-up have already been published by our research group.4,17 Of these 23 participants, 10 were no longer contactable for the 8-year follow-up visit because of outdated contact information or international relocation. Finally, 26 eyes from 13 patients completed the follow-up after 8 years (pos8y) and were included in the present analysis. The study protocol was approved by the local ethics committee (institutional review board number 2024-1899) and adhered to the tenets of the Declaration of Helsinki. All patients signed an informed consent form. The study was registered at ClinicalTrials.gov (registration number: NCT 03913338).
Inclusion and Exclusion Criteria
Included were patients older than 18 years of age who had healthy eyes suitable for bilateral myopic FS-LASIK with a refractive error of −6 to −12 D and an astigmatism of up to 5 D. Exclusion criteria were incomplete or poor-quality measurements, prior corneal surgery, keratoconus, scarring or other corneal pathologies, recurrent ocular inflammation, or vitamin C intake within 1 week before treatment.
Surgical Technique
The surgical technique has been described in detail in previous publications.4,17 One eye was randomly selected for convLASIK treatment, while the fellow eye underwent the LASIK-Xtra procedure, which combines FS-LASIK with intraoperative accelerated UV-A riboflavin crosslinking. Following the creation of the FS-LASIK flap (Intralase FS60, Abbott Medical Optics, Inc.) and ablation with the excimer laser (Armaris 750 excimer laser platform, Schwind eye-tech-solutions GmbH & Co. KG), the corneal bed was soaked with 5 drops of a dextran-free riboflavin solution (VibeX Xtra, Avedro, Inc.) and thoroughly rinsed with a 0.9% sodium chloride solution after 90 seconds of exposure (Supplemental Table 1, available at http://links.lww.com/JRS/B503). Subsequently, the flap was folded back (under-the-flap approach), and the cornea was irradiated through the applied flap with UV-A light (30 mW/cm2) for 90 seconds using the KXL system (Avedro, Inc.) according to the accelerated CXL protocol. The amount and duration of UV-A irradiation was selected according to the planned total amount of radiation exposure of 2.7 J/cm2. No nomogram adjustment was used. Both convLASIK and LASIK-Xtra were performed by a single surgeon (T.K.) at the Department of Ophthalmology, Goethe University, Frankfurt am Main, Germany.
Outcome Measures
The primary objectives of the study included the safety and efficacy indices, as well as the manifest refraction at pos1y and pos8y. The safety index was calculated as the mean corrected distance visual acuity (CDVA) in decimal at pos8y divided by the preoperative CDVA (decimal). The efficacy index was calculated as the mean uncorrected distance visual acuity (UDVA) in decimal at pos8y divided by the mean preoperative CDVA (decimal). For this purpose, visual acuity was converted from logMAR to decimal. All refractions and visual testing were performed by the same experienced study optician (J.W.), who remained blinded of which eye received each treatment.
Secondary objectives included corneal biomechanics assessed using the Corvis ST (Oculus Optikgeräte GmbH), endothelial cell count (ECC [cells/mm2]), as well as mean keratometry and central corneal thickness (CCT [µm]) measured by a multifunctional device using Scheimpflug technology (Pentacam, Oculus Optikgeräte GmbH). The ECC was measured using the Nidek CEM-530 (Nidek Co., Ltd.) 3 times in the central cornea per eye, and the mean of these measurements was used for analysis. The Pentacam was used to assess corneal tomography. The Corvis ST is a noncontact tonometer that analyzes the corneal response to an air pressure pulse using an ultra-high-speed Scheimpflug camera. All measurements were performed with the patient in a seated position and the pupil undilated. A total of 3 consecutive measurements were conducted, and the mean was calculated for analysis. In this study, 5 biomechanical parameters were analyzed: (1) the stiffness parameter at first applanation (SP-A1), calculated as the difference between the adjusted air puff pressure at first applanation and biomechanically corrected intraocular pressure divided by the deflection amplitude at the first applanation. (2) The integrated inverse radius (IIR), defined as the integrated sum of the inverse concave radii between the first and second applanation. (3) The deformation amplitude (DA) quantifies the maximum displacement of the corneal apex under the action of an air puff, and (4) the ratio between the deformation amplitude 2 mm from the apex and the apical deformation (DARatio2mm) was calculated. (5) Furthermore, the age-independent stress–strain index (SSI) was ascertained. The SSI quantifies the stiffness of the cornea from the deformity response to a defined air impulse from the Corvis ST.5 This value is intended to characterize the nonlinear stress–strain behavior and thus the tangent modulus at each intraocular pressure value.5 Consequently, the SSI is particularly relevant for assessing the biomechanical properties of the cornea after keratorefractive surgery.
Statistical Analysis
All required data were collected and entered into an Excel spreadsheet (v. 16.79.1, Microsoft Corp.). The Q-Q plots and Shapiro-Wilk test was used to test for normal distribution. Data were presented as median and interquartile range or mean ± SD, depending on data distribution. Parameters were compared using the paired t test (if normally distributed) or Wilcoxon-Mann-Whitney test (if not normally distributed). P values below 0.05 were considered statistically significant. The statistical analysis and graphical representation were conducted using SPSS software (v. 29.0.1.0, IBM Corp.).
RESULTS
This study includes 26 eyes of 13 patients (7 women, 6 men). The mean age at surgery was 30.7 ± 10.4 years (range, 18 to 56 years). Seven right and 6 left eyes received LASIK-Xtra. The preoperative UDVA, CDVA, manifest spherical (MRESph) and cylindrical refractive errors (MRECyl), and spherical equivalent (SEQ) of the convLASIK and LASIK-Xtra groups, as well as the differences between the 2 groups, are given in Table 1. No statistically significant difference was found in ablation depth between the convLASIK and LASIK-Xtra groups (116.71 ± 18.41 µm and 120.63 ± 17.75 µm, respectively; P = .480). Mean postoperative follow-up time was 8 years (pos8y; range, 7 to 10 years).
Table 1.
Preoperative, pos1y and pos8y data of the convLASIK and LASIK-Xtra group
| Parameters | Procedure | Preop | pos1y | pos8y | P value (pos1y vs pos8y)a |
| UDVA (logMAR) | convLASIK | 1.29 ± 0.23, 1.3 | −0.01 ± 0.14, 0.0 | 0.06 ± 0.31, −0.1 | .386 |
| LASIK-Xtra | 1.24 ± 0.18, 1.3 | −0.04 ± 0.18, −0.1 | 0.05 ± 0.31, 0.0 | .025* | |
| P value (convLASIK vs LASIK-Xtra)a | .285 | .609 | .636 | ||
| CDVA (logMAR) | convLASIK | −0.05 ± 0.05, −0.1 | −0.13 ± 0.06, −0.1 | −0.08 ± 0.86, −0.1 | .208 |
| LASIK-Xtra | −0.04 ± 0.07, 0.0 | −0.12 ± 0.08, −0.1 | −0.07 ± 0.18, −0.1 | .344 | |
| P value (convLASIK vs LASIK-Xtra)a | .317 | .408 | .858 | ||
| SEQ (D) | convLASIK | −7.07 ± 1.10, −6.75 | −0.30 ± 0.40, −0.25 | −0.80 ± 0.86, −0.62 | 0.018* |
| LASIK-Xtra | −7.07 ± 0.59, −7.12 | −0.25 ± 0.49, −0.12 | −0.40 ± 0.86, −0.25 | 0.261 | |
| P value (convLASIK vs LASIK-Xtra)a | .332 | .858 | .109 | ||
| MRESph (D) | convLASIK | −6.81 ± 1.03, −6.50 | −0.23 ± 0.37, −0.25 | −0.67 ± 0.91, −0.50 | .045* |
| LASIK-Xtra | −6.85 ± 0.64, −7.00 | −0.12 ± 0.44, 0.00 | −0.19 ± 0.82, −0.25 | .261 | |
| P value (convLASIK vs LASIK-Xtra)a | .550 | .308 | .031* | ||
| MRECyl (D) | convLASIK | −0.52 ± 0.35, −0.50 | −0.13 ± 0.19, 0.00 | −0.25 ± 0.31, −0.25 | 0.272 |
| LASIK-Xtra | −0.44 ± 0.33, −0.50 | −0.27 ± 0.30, −0.25 | −0.07 ± 0.18, −0.25 | 0.119 | |
| P value (convLASIK vs LASIK-Xtra)a | .582 | .084 | .203 |
convLASIK = conventional femtosecond laser–assisted in situ keratomileusis; LASIK-Xtra = LASIK combined with accelerated corneal crosslinking; MRECyl = cylindrical manifest refractive error; MRESph = spherical manifest refractive error; pos1y = 1 year postoperatively; pos8y = 8 years postoperatively; SEQ = spherical equivalent;
Values presented as mean ± SD, median
Statistically significant
P values have been calculated using the Wilcoxon signed-rank test
Visual Acuity and Manifest Refractive Error
The UDVA, DCVA, MRESph, MRECyl, and SEQ of the convLASIK and LASIK-Xtra groups are given in Table 1. The CDVA, UDVA, and SEQ of both groups are shown graphically in Figure 1. In the convLASIK group, axial length (AL) increased from 24.34 ± 1.26 mm at 1 year to 25.53 ± 1.37 mm at 8 years, whereas in the LASIK-Xtra group, AL changed only slightly from 25.28 ± 1.00 mm at 1 year to 25.44 ± 1.10 mm at 8 years, exhibiting an increase of 0.19 ± 0.21 mm and 0.16 ± 0.15 mm between pos1y and pos8y in the convLASIK and LASIK-Xtra groups, respectively, with no statistically significant difference (P = .242) observed. The safety index at pos8y was 1.09 for convLASIK and 1.15 for LASIK-Xtra (P = .799), and the efficacy index was 0.91 and 0.94 at pos8y (P = .875), respectively.
Figure 1.
Mean and SD (error bars) of the UDVA (A) and CDVA (B), spherical equivalent (C), and mean keratometry (D) of the convLASIK group and the LASIK-Xtra group preoperatively (0), as well as 1 and 8 years postoperatively. convLASIK = conventional femtosecond laser–assisted in situ keratomileusis; LASIK-Xtra = femtosecond laser in situ keratomileusis combined with accelerated crosslinking
Corneal Changes and Endothelial Cell Count
In the convLASIK group, Kmean decreased from 44.98 ± 1.44 D (range, 42.1 to 48.8 D) preoperatively to 39.62 ± 1.85 D (range, 36.1 to 43.4 D) at pos1y, with a further increase to 39.95 ± 1.89 D (range, 36.2 to 43.7 D) at pos8y (P = .026). In the LASIK-Xtra group, Kmean decreased from 44.92 ± 1.46 D (range, 42.15 to 47.90 D) preoperatively to 39.58 ± 1.80 D (35.9 to 43.0 D) at pos1y and showed only a minimal increase to 39.78 ± 1.76 D (36.4–43.2 D) at pos8y (P = .115 between pos1y and pos8y). Statistically insignificant differences were found between the differences of the 2 groups (P = .399) between pos1y and pos8y. The Kmean of both groups preoperatively, pos1y, and pos8y is shown graphically in Figure 1. The CCT exhibited a decrease of −2.85 ± 6.39 µm in the convLASIK group and −6.08 ± 12.5 µm in the LASIK-Xtra group (P = .455) between pos1y and pos8y (Table 2 and Figure 2). At pos8y, the median ECC was 2643 (range, 2347 to 3317) cells/mm2 in the convLASIK group and 2669 (range, 2311 to 3328) cells/mm2 in the LASIK-Xtra group (P = .308).
Table 2.
Biomechanical parameters preoperatively, pos1y, and pos8y of surgery
| Parameter | Surgical procedure | Preop | pos1y | pos8y | P value (pos1y vs pos8y)a |
| CCT (µm) | convLASIK | 551.38 ± 25.09, 549 | 445.46 ± 31.93, 437 | 442.61 ± 35.45, 434 | .134 |
| LASIK-Xtra | 553.77 ± 24.40, 556 | 445.23 ± 32.91, 441 | 439.15 ± 31.59, 432 | .105 | |
| P value (convLASIK vs LASIK-Xtra)a | .462 | .963 | .520 | ||
| SP-A1 (mm Hg/mm) | convLASIK | 105.12 ± 12.35, 105.2 | 70.48 ± 18.47, 71.6 | 82.61 ± 17.64, 77.5 | .031* |
| LASIK-Xtra | 103.92 ± 12.13, 102.3 | 68.65 ± 15.24, 71.4 | 87.71 ± 14.63, 87.0 | <.001* | |
| P value (convLASIK vs LASIK-Xtra)a | .731 | .559 | .154 | ||
| IIR (mm−1) | convLASIK | 8.76 ± 0.72, 9.2 | 11.44 ± 0.84, 11.7 | 12.44 ± 0.97, 12.6 | <.001* |
| LASIK-Xtra | 8.69 ± 0.89, 8.65 | 11.48 ± 1.14, 12.0 | 12.10 ± 1.05, 12.3 | <.001* | |
| P value (convLASIK vs LASIK-Xtra)a | .606 | .850 | .084 | ||
| DA (mm) | convLASIK | 1.13 ± 0.06, 1.15 | 1.24 ± 0.09, 1.22 | 1.22 ± 0.08, 1.20 | .441 |
| LASIK-Xtra | 1.13 ± 0.06, 1.14 | 1.24 ± 0.06, 1.24 | 1.19 ± 0.06, 1.18 | .045* | |
| P value (convLASIK vs LASIK-Xtra)a | .926 | .793 | .119 | ||
| DARatio2mm | convLASIK | 4.40 ± 0.36, 4.4 | 5.57 ± 0.50, 5.44 | 6.02 ± 0.55, 6.07 | .006* |
| LASIK-Xtra | 4.48 ± 0.40, 4.45 | 5.69 ± 0.59, 5.9 | 5.95 ± 0.62, 5.97 | .004* | |
| P value (convLASIK vs LASIK-Xtra)a | .226 | .449 | .404 | ||
| SSI | convLASIK | 0.82 ± 0.09, 0.81 | 0.87 ± 0.24, 0.78 | 0.74 ± 0.08, 0.73 | .035* |
| LASIK-Xtra | 0.84 ± 0.15, 0.78 | 0.80 ± 0.09, 0.77 | 0.77 ± 0.07, 0.76 | .098 | |
| P value (convLASIK vs LASIK-Xtra)a | .555 | .262 | .034* |
CCT = central corneal thickness; convLASIK = conventional femtosecond laser–assisted in situ keratomileusis; DA = deformation amplitude; DARatio2mm = deformation amplitude ratio at 2 mm; IIR = integrated inverse radius; LASIK-Xtra = LASIK combined with accelerated corneal crosslinking; pos1y = 1 year postoperatively; pos8y = 8 years postoperatively; SP-A1 = stiffness parameter at first applanation; SSI = stress–strain index
Values presented as mean ± SD, median
Statistically significant
P values have been calculated using the paired t test
Figure 2.
Mean and SD (error bars) of the convLASIK group and the LASIK-Xtra group preoperatively (0), and 1 and 8 years postoperatively for the following biomechanical measures: central corneal thickness (A), stress–strain index (B), SP-A1 (C), IIR (D), DA (E), and the DARatio2mm (F). P values indicating statistically significant differences are marked with an asterisk (*). convLASIK = conventional femtosecond laser–assisted in situ keratomileusis; DA = deformation amplitude; DARatio2mm = deformation amplitude ratio at 2 mm; IIR = integrated inverse radius; LASIK-Xtra = femtosecond laser in situ keratomileusis combined with accelerated crosslinking; SP-A1 = stiffness parameter at first applanation
Retreatments and Postoperative Complications
In the present 8-year follow-up analysis including 13 patients, none of them had undergone additional ocular surgery or underwent retreatment. The study found no evidence of post-LASIK ectasia, and no patient developed a postoperative infection, flap complications, or corneal scarring.
Corneal Biomechanical Evaluation
Table 2 summarizes the comparison between the 5 corneal biomechanical parameters and CCT at pos1y and pos8y within the group, as well as between the 2 groups (convLASIK vs LASIK-Xtra) preoperatively, pos1y, and pos8y. Figure 2 shows a graphical representation of the disparities in CCT and biomechanical parameters between the 2 groups at the different timepoints. A statistically significant decrease between preoperative and pos8y values in CCT and SP-A1, and an increase in IIR, DA, and DARatio2mm was observed in the convLASIK and LASIK-Xtra groups (each P < .05), indicating a decrease in cornea stiffness. However, when analyzing SSI, a statistically significant decrease was only observed in the convLASIK group (preoperative mean 0.82 ± 0.09 and 0.74 ± 0.08 at pos8y, P = .004), whereas no statistically significant decrease was demonstrated in the LASIK-Xtra group (preoperative mean 0.84 ± 0.15 and 0.77 ± 0.07 at pos8y, P = .076). Furthermore, a statistically significant difference at pos8y between the convLASIK and LASIK-Xtra groups was found only for SSI (P = .034). The effect size with Hedges' correction was d = 0.620, which corresponds to a medium effect. All other biomechanical parameters showed no statistically significant difference between the 2 groups at pos8y (each P > .1).
DISCUSSION
Numerous clinical studies have consistently reported that combined keratorefractive surgery (keratorefractive lenticule exchange, LASIK, and PRK) in combination with CXL is an effective procedure, producing good refractive outcomes.5,10,17 Comparative analyses have indicated that the combined procedures have similar efficacy compared with stand-alone keratorefractive procedures.10 Notably, to our knowledge, this study is the first to delineate the long-term outcomes including the effect on corneal biomechanics that extend beyond a 5-year period. The main outcomes of this 8-year follow-up analysis are as follows: (1) both groups exhibited comparable safety and efficacy indices and (2) the biomechanics of the cornea after LASIK-Xtra do not differ significantly from those after convLASIK, with only the SSI at pos8y showing statistical significance.
A recently published meta-analysis examined the differences between refractive surgery with and without CXL.10 The analysis revealed an insignificantly higher efficacy index in the convLASIK group compared with the LASIK-Xtra group after 12 months of follow-up (mean difference [MD] = −0.02).10 Our analysis demonstrated an efficacy index of 0.92 in the convLASIK group and 0.94 in the LASIK-Xtra group after an 8-year period (0 = 0.875). The minimal inferiority of the efficacy index in the convLASIK group can be primarily attributed to the more pronounced myopic shift (−0.30 ± 0.40 D at pos1y and −0.80 ± 0.86 D at pos8y) leading to a reduction in UDVA. Myopic progression was statistically significant higher (P = .018) when compared with the LASIK-Xtra group, which exhibited a mean refractive change of −0.25 ± 0.49 D at pos1y and −0.40 ± 0.86 D at pos8y (P = .261). In the meta-analysis by Hira et al., no difference in postoperative SEQ was observed between LASIK-Xtra and convLASIK eyes (MD = 0.02), with the caveat that the studies considered had a maximum follow-up of 2 years.10
The minimal increase in Kmean in the LASIK-Xtra group (39.58 ± 1.80 D to 39.78 ± 1.76 D; P = .115) compared with the convLASIK group (39.62 ± 1.85 D to 39.95 ± 1.89 D; P = .026) between pos1y and pos8y, together with the insignificant change in AL over the same period in both groups, suggests that the slightly greater myopic shift observed in the convLASIK group may not necessarily indicate biomechanical progression. Instead, it could be influenced by factors such as age-related lens changes (eg, early nuclear sclerosis). Although routine slitlamp examinations were performed, subtle early lens changes cannot be entirely excluded in this small, aging cohort.
This study revealed no statistically significant differences (P = .963) between LASIK-Xtra and convLASIK in the CCT at pos1y (445.46 µm vs 445.23 µm, respectively). At pos8y, a thinner mean CCT was found in the LASIK-Xtra group; however, this finding did not reach statistical significance (P = .154). The study by Chen et al. reached a similar conclusion, finding no differences in CCT 6 months postoperatively between the 2 groups.5 Hira et al. demonstrated a decrease in CCT in eyes that have undergone LASIK combined with CXL compared with convLASIK (MD = −13.24 µm).10 It has been documented that corneal thinning also occurs in keratoconic eyes after CXL, particularly within the first months of postsurgery, but may persist for many years.10,23,24
A multitude of studies have proposed that LASIK-Xtra is a safe procedure for myopic eyes. In essence, complications are minimal, rare, and usually transient.10 In the present analysis, the safety index was 1.09 for convLASIK and 1.15 for LASIK-Xtra at pos8y (P = .799). By comparison, the meta-analysis by Hira et al. revealed an inferiority in the safety index (MD = −0.02, P = .01) in the LASIK-Xtra group compared with convLASIK.10 Again, most included eyes' follow-up was approximately 6 months (5.7 to 24 months). Therefore, this decrease was attributed to the poorer DCVA in the LASIK-Xtra group, which could be caused primarily by corneal interface haze, which is a common complication after LASIK-Xtra with a reported greater incidence compared with convLASIK.15,25–27 The rationale provided for this observation is that the LASIK-Xtra procedure entails a greater degree of surgical corneal manipulation, as well as the exposure to the inflammatory agent riboflavin. In our cases, no corneal haze was observed at either pos1y or pos8y. This outcome may be attributable to the utilization of dextran-free riboflavin (0.22%) in our study, which was administered for a duration of 90 seconds. It is noteworthy that alternative studies may have used divergent CXL protocols. This discrepancy may be a contributing factor to the varying incidence of haze formation. In the 26 eyes included in the present analysis, no long-term complications (eg, corneal iatrogenic ectasia) occurred in the follow-up period of 8 years.
A well-known postoperative aspect is the decrease of corneal stiffness after keratorefractive surgery.4–7,9,28 The rationale behind the combination of refractive surgery with CXL is to increase corneal biomechanics and thus prevent iatrogenic ectasia. To evaluate the influence of LASIK-Xtra in comparison with convLASIK on corneal stiffness, 5 deformation parameters were analyzed provided by the Corvis ST. Statistically significant differences to pos8y between both procedures were only found in SSI (P = .034). The SSI parameter was developed to represent the material stiffness of the cornea, independent of intraocular pressure and corneal geometry.5,29 This distinguishes it from the other 4 Corvis ST parameters (SP-A1, DA, IIR, and DARatio2mm), which evaluate the overall stiffness of the cornea. From preoperative to pos1y, the SSI value decreased for the LASIK Xtra group and increased for the convLASIK group. This suggests that the modulus or stiffness measurement was contrary to expectations. This unexpected result affects the trend between pos1y and pos8y, where the values reverse. At pos8y, there was a statistically significant reduction in SSI compared with preoperative levels in the convLASIK eyes. The findings of this study stand in contrast to those reported by Chen et al., who observed an increase in SSI in the LASIK-Xtra group from 0.87 ± 0.12 preoperatively to 0.91 ± 0.12 6 months postoperatively, a phenomenon that was reverse in the convLASIK group (from 0.98 ± 0.13 to 0.85 ± 0.09, respectively). However, a key limitation of this study is the small number of patients completing the 8-year visit (13 eyes in each group), which limits statistical power. Post hoc power analysis (G*Power test v. 3.1.9.6) showed only approximately 54% power to detect the observed medium effect on SSI (Hedges' d = 0.62), and with 13 pairs, the study could only reliably detect fairly large paired effects (d ≳ 0.85) at the conventional 80% power level. Therefore, the lack of statistically significance between-group differences for the biomechanical parameters may reflect limited power (type II error, false-negative results) rather than the true absence of a difference; these results should be interpreted cautiously, and larger samples sizes are needed to validate the findings.
The approach used in this study, wherein the corneal exposure to UV-A light occurred subsequently to the reattachment of the flap without prior epithelial debridement, resulted in a reduction of the biomechanical effect due to the protective shield provided by the epithelium, as shown by Wollensak et al.30 Furthermore, it can be postulated that the interaction of oxygen and riboflavin is constrained by the applied flap. No oxygen supply or pulsed protocol was used during accelerated CXL with high fluence, which can be considered as a further factor responsible for the lower impact on biomechanical parameters. It is noteworthy that a range of CXL protocols, characterized by varying fluence, exposure duration, and exposure time, have previously been documented.5,10
To the authors' knowledge, this randomized, fellow eye–controlled study is the first of its kind with results including a long follow-up of 8 years. However, it is important to exercise caution when interpreting the results of this study because there are certain limitations that must be considered. These limitations include the small sample size, which was recruited from a single institution, thereby limiting the assessment of the development of keratectasia. Furthermore, the statistical power regarding possible minor changes in corneal biomechanics is limited. One more limitation is that an accelerated CXL protocol and the “under the flap-approach” were used in this study, which may not lead to a sufficient increase in corneal stiffness. The evaluation of biomechanical corneal effects by the Corvis ST device used in this study may not be adequate for the analysis of only subtle effects of LASIK-Xtra compared with convLASIK.
In this 8-year follow-up analysis, the findings indicate that LASIK-Xtra and convLASIK exhibit comparable safety and efficacy profiles. Regarding corneal biomechanics, over the course of many years, there were no substantial differences in most of the evaluated postoperative corneal biomechanical parameters between the 2 groups, with the exception of the SSI parameter, which was statistically significant. Further studies are necessary to investigate the occurrence of postoperative ectasia, biomechanical differences, and safety and efficacy, including a long follow-up with a larger sample size and different CXL protocols.
WHAT WAS KNOWN
Refractive surgery combined with prophylactic crosslinking seems to be as safe as refractive surgery alone with a similar efficacy.
The impact of LASIK combined with crosslinking (LASIK-Xtra) on the biomechanical weakening of the cornea seems to vary depending on the used protocol in comparison with conventional LASIK.
WHAT THIS PAPER ADDS
After an 8-year follow-up, LASIK with or without prophylactic crosslinking were found to demonstrate comparable safety and efficacy indices.
Subsequent to LASIK-Xtra, there was no substantial increase in corneal rigidity compared with conventional LASIK over the course of an 8-year follow-up period.
Footnotes
The costs for the surgical procedures were paid by Avedro, Inc. (Waltham, Massachusetts).
Presented at the 2025 Annual Congress of the ESCRS, Copenhagen, Denmark, September 2025, and at the 2025 Congress of the German Ophthalmic Surgery (DOC), Nuremberg, Germany, May 2025.
Disclosures: K.P. Kaiser: lecture fees from Oculus Optikgeräte GmbH. T. Kohnen: consultant, research, and lecturing for Alcon Laboratories, Inc., Oculus Optikgeräte GmbH, Schwind eye-tech-solutions GmbH & Co. KG, and STAAR Surgical AG; consultant and lecturing for Tarsus and Ziemer Ophthalmology GmbH; research and lecturing for Teleon Surgical; consulting for Abbvie, Geuder AG, LensGen, Santen GmbH, Stadapharm, Thieme Compliance GmbH, and Carl Zeiss Meditec AG; lecturing for Allergan, Inc., Bausch & Lomb GmbH, Johnson & Johnson Vision, MedUpdate, and streamedup. None of the other authors have any financial or proprietary interest in any material or method mentioned.
First author:
Klemens Paul Kaiser, MD
Department of Ophthalmology, Goethe-University, Frankfurt am Main, Germany
Contributor Information
Klemens Paul Kaiser, Email: klemens.kaiser@icloud.com.
Jakob Wend, Email: jakob.wend@ukffm.de.
Petra Davidova, Email: petradavid2312@gmail.com.
Tyll Jandewerth, Email: tjh101@onlinehome.de.
Zubeida H. Omerovic, Email: Zubeida.Homerovic@ukffm.de.
Eva Hemkeppler, Email: eva.hemkeppler@ukffm.de.
Christoph Lwowski, Email: ch.lw@hotmail.de.
Myriam Böhm, Email: myriam.boehm@ukffm.de.
REFERENCES
- 1.Seiler T, Wollensak J. Myopic photorefractive keratectomy with the excimer laser. One-year follow-up. Ophthalmology. 1991;98(8):1156–1163 [DOI] [PubMed] [Google Scholar]
- 2.Solomon KD, Fernández de Castro LE, Sandoval HP, Biber JM, Groat B, Neff KD, Ying MS, French JW, Donnenfeld ED, Lindstrom RL; Joint LASIK Study Task Force. LASIK world literature review: quality of life and patient satisfaction. Ophthalmology. 2009;116(4):691–701 [DOI] [PubMed] [Google Scholar]
- 3.Kohnen T, Schwarz L, Remy M, Shajari M. Short-term complications of femtosecond laser-assisted laser in situ keratomileusis cuts: review of 1210 consecutive cases. J Cataract Refract Surg. 2016;42(12):1797–1803 [DOI] [PubMed] [Google Scholar]
- 4.Kaiser KP, Biller ML, Jandewerth T, Davidova P, Hemkeppler E, Lwowski C, Böhm M, Kohnen T. Biomechanical corneal effects of LASIK Xtra compared with conventional FS-LASIK in high myopic eyes. J Cataract Refract Surg. 2025;51(2):106–112 [DOI] [PubMed] [Google Scholar]
- 5.Chen W, Bao F, Roberts CJ, Zhang J, Wang C, Li X, Wang J, Abu Said AZM, Mayopa KN, Chen Y, Zheng X, Eliasy A, Elsheikh A, Chen S. Effect of corneal cross-linking on biomechanical changes following transepithelial photorefractive keratectomy and femtosecond laser-assisted LASIK. Front Bioeng Biotechnol. 2024;12:1323612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Pedersen IB, Bak-Nielsen S, Vestergaard AH, Ivarsen A, Hjortdal J. Corneal biomechanical properties after LASIK, ReLEx flex, and ReLEx smile by Scheimpflug-based dynamic tonometry. Graefes Arch Clin Exp Ophthalmol. 2014;252(8):1329–1335 [DOI] [PubMed] [Google Scholar]
- 7.Xin Y, Lopes BT, Wang J, Wu J, Zhu M, Jiang M, Miao Y, Lin H, Cao S, Zheng X, Eliasy A, Chen S, Wang Q, Ye Y, Bao F, Elsheikh A. Biomechanical effects of tPRK, FS-LASIK, and SMILE on the cornea. Front Bioeng Biotechnol. 2022;10:834270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Yang K, Xu L, Fan Q, Gu Y, Song P, Zhang B, Zhao D, Pang C, Ren S. Evaluation of new Corvis ST parameters in normal, Post-LASIK, Post-LASIK keratectasia and keratoconus eyes. Sci Rep. 2020;10(1):5676. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Frings A, Linke SJ, Bauer EL, Druchkiv V, Katz T, Steinberg J. Effects of laser in situ keratomileusis (LASIK) on corneal biomechanical measurements with the Corvis ST tonometer. Clin Ophthalmol. 2015;9:305–311 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hira S, Heffel KK, Mehmood F, Sehgal K, Felix De Farias Santos AC, Del Valle GS. Comparison of refractive surgeries (SMILE, LASIK, and PRK) with and without corneal cross-linking: a systematic review and meta-analysis. J Cataract Refract Surg. 2024;50(5):523–533 [DOI] [PubMed] [Google Scholar]
- 11.Bohac M, Koncarevic M, Pasalic A, Biscevic A, Merlak M, Gabric N, Patel S. Incidence and clinical characteristics of post LASIK ectasia: a review of over 30,000 LASIK cases. Semin Ophthalmol. 2018;33(7–8):869–877 [DOI] [PubMed] [Google Scholar]
- 12.Moshirfar M, Tukan AN, Bundogji N, Liu HY, McCabe SE, Ronquillo YC, Hoopes PC. Ectasia after corneal refractive surgery: a systematic review. Ophthalmol Ther. 2021;10(4):753–776 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Rad AS, Jabbarvand M, Saifi N. Progressive keratectasia after laser in situ keratomileusis. J Refract Surg. 2004;20(5 suppl):S718–S722 [DOI] [PubMed] [Google Scholar]
- 14.Randleman JB, Russell B, Ward MA, Thompson KP, Stulting RD. Risk factors and prognosis for corneal ectasia after LASIK. Ophthalmology. 2003;110(2):267–275 [DOI] [PubMed] [Google Scholar]
- 15.Seiler TG, Fischinger I, Koller T, Derhartunian V, Seiler T. Superficial corneal crosslinking during laser in situ keratomileusis. J Cataract Refract Surg. 2015;41(10):2165–2170 [DOI] [PubMed] [Google Scholar]
- 16.Ganesh S, Brar S. Clinical outcomes of small incision lenticule extraction with accelerated cross-linking (ReLEx SMILE Xtra) in patients with thin corneas and borderline topography. J Ophthalmol. 2015;2015:263412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kohnen T, Lwowski C, Hemkeppler E, de'Lorenzo N, Petermann K, Forster R, Herzog M, Böhm M. Comparison of femto-LASIK with combined accelerated cross-linking to femto-LASIK in high myopic eyes: a prospective randomized trial. Am J Ophthalmol. 2020;211:42–55 [DOI] [PubMed] [Google Scholar]
- 18.Zhang H, Roozbahani M, Piccinini AL, Hafezi F, Scarcelli G, Randleman JB. Brillouin microscopic depth-dependent analysis of corneal crosslinking performed over or under the LASIK flap. J Cataract Refract Surg. 2020;46(11):1543–1547 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620–627 [DOI] [PubMed] [Google Scholar]
- 20.Kanellopoulos AJ, Pamel GJ. Review of current indications for combined very high fluence collagen cross-linking and laser in situ keratomileusis surgery. Indian J Ophthalmol. 2013;61(8):430–432 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Raiskup F, Herber R, Lenk J, Ramm L, Wittig D, Pillunat LE, Spoerl E. Corneal crosslinking with riboflavin and UVA light in progressive keratoconus: fifteen-year results. Am J Ophthalmol. 2023;250:95–102 [DOI] [PubMed] [Google Scholar]
- 22.Lim EWL, Lim L. Review of laser vision correction (LASIK, PRK and SMILE) with simultaneous accelerated corneal crosslinking: long-term results. Curr Eye Res. 2019;44(11):1171–1180 [DOI] [PubMed] [Google Scholar]
- 23.Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(4):691–700 [DOI] [PubMed] [Google Scholar]
- 24.Subasinghe SK, Ogbuehi KC, Dias GJ. Current perspectives on corneal collagen crosslinking (CXL). Graefes Arch Clin Exp Ophthalmol. 2018;256(8):1363–1384 [DOI] [PubMed] [Google Scholar]
- 25.Dong R, Zhang Y, Yuan Y, Liu Y, Wang Y, Chen Y. A prospective randomized self-controlled study of LASIK combined with accelerated cross-linking for high myopia in Chinese: 24-month follow-up. BMC Ophthalmol. 2022;22(1):280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Low JR, Lim L, Koh JCW, Chua DKP, Rosman M. Simultaneous accelerated corneal crosslinking and laser in situ keratomileusis for the treatment of high myopia in Asian eyes. Open Ophthalmol J. 2018;12:143–153 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Chan TCY, Yu MCY, Ng ALK, Cheng GPM, Zhang J, Wang Y, Jhanji V. Short-term variance of refractive outcomes after simultaneous LASIK and high-fluence cross-linking in high myopic correction. J Refract Surg. 2016;32(10):664–670 [DOI] [PubMed] [Google Scholar]
- 28.Hashemi H, Asgari S, Mortazavi M, Ghaffari R. Evaluation of corneal biomechanics after excimer laser corneal refractive surgery in high myopic patients using dynamic Scheimpflug technology. Eye Contact Lens. 2017;43(6):371–377 [DOI] [PubMed] [Google Scholar]
- 29.Eliasy A, Chen KJ, Vinciguerra R, Lopes BT, Abass A, Vinciguerra P, Ambrósio R, Jr, Roberts CJ, Elsheikh A. Determination of corneal biomechanical behavior in-vivo for healthy eyes using CorVis ST tonometry: stress-strain index. Front Bioeng Biotechnol. 2019;7:105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg. 2009;35(3):540–546 [DOI] [PubMed] [Google Scholar]