# SMILE for Hyperopia With and Without Astigmatism: Results of a Prospective Multicenter 12-Month Study

Dan Z Reinstein, Walter Sekundo, Timothy J Archer, Pavel Stodulka, Sri Ganesh, Beatrice Cochener, Marcus Blum, Yan Wang, Xingtao Zhou

## ► To cite this version:

Dan Z Reinstein, Walter Sekundo, Timothy J Archer, Pavel Stodulka, Sri Ganesh, et al., SMILE for Hyperopia With and Without Astigmatism: Results of a Prospective Multicenter 12-Month Study. Journal of Refractive Surgery, 2022, 38 (12), pp.760 - 769. 10.3928/1081597x-20221102-02. hal-04737684

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<figure><img src="image_1.png" /></figure>
# SMILE for Hyperopia With and Without Astigmatism: Results of a Prospective Multicenter 12-Month Study

Dan Z. Reinstein, MD, MA(Cantab), FRCOphth; Walter Sekundo, MD, PhD; Timothy J. Archer, MA(Oxon), DipCompSci(Cantab), PhD; Pavel Stodulka, MD; Sri Ganesh, MD; Beatrice Cochener, MD, PhD; Marcus Blum, MD, PhD; Yan Wang, MD, PhD; Xingtao Zhou, MD, PhD

## ABSTRACT

**PURPOSE:** To investigate the safety and effectiveness of small incision lenticule extraction (SMILE) in patients who have hyperopia with or without astigmatism.

**METHODS:** This was a prospective multicenter trial including 374 eyes of 199 patients treated by SMILE for hyperopia using the VisuMax femtosecond laser (Carl Zeiss Meditec AG). Inclusion criteria were sphere up to +6.00 diopters (D), cylinder up to 5.00 D, and maximum hyperopic meridian up to +7.00 D, with preoperative corrected distance visual acuity (CDVA) of 20/25 or better. The optical zone was 6.3 mm with a transition zone of 2 mm. The minimum lenticule thickness was set at 25 µm in the center and at 10 µm at the edge. Patients were examined at 1 day, 1 week, and 1, 3, 6, 9, and 12 months after surgery. Standard refractive surgery outcomes analysis was performed.

**RESULTS:** The preoperative spherical equivalent was +3.20 ± 1.48 D [range: +0.25 to +6.50 D]. At the 12-month follow-up visit, 81% of eyes treated were within ±0.50 D and 93% of eyes were within ±1.00 D of intended correction. A total of 1.2% of eyes lost two or more lines of CDVA at the 12-month follow-up visit, and 83% were at least 20/20, corresponding to a safety index of 1.005 at 12 months. Of the 219 eyes with plano target, 68.8% had an uncorrected distance visual acuity of 20/20 or better and 88% were at least 20/25 uncorrected at 12 months. There were no statistically significant changes in contrast sensitivity.

**CONCLUSIONS:** SMILE was found to be an effective treatment method for the correction of compound hyperopic astigmatism, demonstrating a high level of efficacy, predictability, safety, and stability.

[J Refract Surg. 2022;38(12):760-769.]

From Reinstein Vision, London, United Kingdom (DZR, TJA); London Vision Clinic, EuroEyes Group, London, United Kingdom (DZR, TJA); the Department of Ophthalmology, Phillips University of Marburg, Germany (WS); Gemini Eye Clinic, Zlín and Gemini Eye Clinic, Prague, Czech Republic (PS); Nethradhama Superspeciality Eye Hospital, Bangalore Jayanagar, India (SG); University Brest Hospital, Brest, France (BC); the Department of Ophthalmology, HELIOS-Hospital Erfurt, Erfurt, Germany (MB); Tianjin Eye Hospital, Heping District, Tianjin, China (YW); and EYE & ENT Hospital, Fudan University, Shanghai, China (XZ).

© 2022 Reinstein, Sekundo, Archer, et al; licensee SLACK Incorporated. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0). This license allows users to copy and distribute, to remix, transform, and build upon the article, for any purpose, even commercially, provided the author is attributed and is not represented as endorsing the use made of the work.

Submitted: July 26, 2022; Accepted: November 2, 2022

Supported by Carl Zeiss Meditec AG, Jena, Germany. The sponsor participated in the design of the study, data management, data analysis, interpretation of the data, and review of the manuscript.

Disclosure: Drs. Reinstein, Blum, Ganesh, Sekundo, and Zhou are consultants for Carl Zeiss Meditec AG. Dr. Cochener reports that University Brest Hospital received funding for the study. Dr. Stodulka received funding for the study from Carl Zeiss Meditech AG. Dr. Reinstein has a proprietary interest in the Artemis Insight 100 technology (ArcScan, Inc, Golden, Colorado) through patents administered by the Cornell Center for Technology Enterprise and Commercialization (CCTEC), Ithaca, New York. The remaining authors have no proprietary or financial interest in the materials presented herein.

Drs. Reinstein and Sekundo contributed equally to this work and should be considered as equal first authors.

Clinical Trial No. NCT03431571.

Correspondence: Dan Z. Reinstein, MD, MA(Cantab), FRCOphth, Reinstein Vision, London Vision Clinic, EuroEyes Group, 138 Harley Street, London W1G 7LA, United Kingdom. Email: dzr@reinsteinvision.com

doi:10.3928/1081597X-20221102-02
With more than 6 million treatments worldwide, small incision lenticule extraction (SMILE) has been established as a modern, minimally invasive, and reliable procedure for the treatment of myopia and myopic astigmatism since the first publications in 2011.¹,² SMILE for hyperopia has also been developed and preliminary studies published.³⁻⁹ The initial feasibility study of hyperopia treatment using femtosecond lenticule extraction, published in 2013, showed promising initial results, but was associated with refractive regression and loss of corrected distance visual acuity (CDVA).³ As a consequence of this investigation, the lenticule profile was redesigned to have both a larger optical zone and a larger transition zone, which was shown to improve safety and stability, and centration was applied to the corneal vertex rather than the pupil center.⁴,⁵

This updated large transition zone profile was first investigated for hyperopic SMILE treatment by Reinstein et al⁶⁻⁸ and Pradhan et al⁹ at the Tilganga Institute of Ophthalmology. This study found that optical zone centration was similar to hyperopic LASIK and that the achieved optical zone diameter after SMILE with a 6.3-mm optical zone (and 2-mm transition zone) was larger than for laser in situ keratomileusis (LASIK) with a 7-mm optical zone with corresponding improvement in the induction in spherical aberration with SMILE compared to the same zone LASIK.⁶,⁷ This study also showed promising visual and refractive results at 3⁸ and 12⁹ months, demonstrating refractive stability despite the high refractive average correction in the patients recruited for study.

Following these early studies, a large scale, multicenter, international, prospective study was executed for hyperopic SMILE using the VisuMax femtosecond laser (Carl Zeiss Meditec AG).

## PATIENTS AND METHODS

This prospective, multicenter study was conducted between July 2017 and October 2020 at the following sites: Department of Ophthalmology, Phillips University of Marburg, Marburg, Germany (Sekundo); London Vision Clinic, London, United Kingdom (Reinstein); Gemini Eye Clinic, Zlín and Prague, Czech Republic (Stodulka); Nethradhama Superspeciality Eye Hospital, Bangalore, India (Ganesh); Hôpital Morvan, Brest, France (Cochener); Department of Ophthalmology, HELIOS-Hospital Erfurt, Erfurt, Germany (Blum); Tianjin Eye Hospital, Heping District, Tianjin, China (Wang); and EYE & ENT Hospital, Fudan University, Shanghai, China (Zhou). The study was listed on clinicaltrials.gov (NCT03431571), was approved by the respective Ethics Committees/Institutional Review Boards at each participating institution, and adhered to the tenets of the Declaration of Helsinki.

The inclusion criteria were as follows: (1) patient age of 18 years or older; (2) preoperative CDVA of 20/25 or better in both eyes; (3) central corneal thickness of greater than 500 µm and calculated postoperative residual stromal thickness of 250 µm or greater; (4) normal corneal topography; (5) no preceding refractive surgery; (6) subjective hyperopic sphere up to +6.00 D; (7) subjective astigmatism up to +5.00 D; (8) refraction at the maximum hyperopic meridian up to +7.00 D; (9) a difference in spherical equivalent refraction (SEQ) between cycloplegic and manifest refractions up to 1.00 D; (10) predicted postoperative keratometry less than 51.00 D (calculated by adding the maximum hyperopia treated to the preoperative keratometry); (11) no contact lens wear before baseline measurements for at least 1 week (soft lenses), 2 weeks (soft toric lenses), or 1 month (rigid gas permeable lenses); (12) patients able to understand the patient information and willing to sign an informed consent; and (13) patients willing to comply with all follow-up visits and the respective examinations.

The exclusion criteria were identical to the strict general exclusion criteria for corneal laser refractive surgery, such as autoimmune dermal and/or collagen vascular diseases, diabetes, ocular comorbidities (eg, glaucoma, keratoconus, pellucid marginal degeneration, or cataract), pregnancy/nursing, systemic or topical medications with steroids/antimetabolites/retinoids and other drugs, inability to stay still in a supine position, and/or weight greater than 135 kg (weight limitation of the VisuMax laser bed).

The preoperative examination was identical to the previous hyperopic femtosecond lenticule extraction study.⁴,⁵ Visual acuity was measured to the nearest letter (0.02 logMAR) using the CSV-1000 standardized Early Treatment of Diabetic Retinopathy Study chart (VectorVision). Manifest refraction and cycloplegic refraction were performed according to a standardized protocol to push maximum plus and maximum cylinder.¹⁰ The manifest refraction was repeated at a separate visit before the day of surgery, with the advantage of being able to refer to the previous manifest, cycloplegic, and aberrometry refractions. This final manifest refraction was used to plan the treatment. The CSV-1000 chart with four rows of sine-wave gratings was used to measure contrast sensitivity at spatial frequencies of 3, 6, 12, and 18 cycles/degree (cpd). Corneal topography was measured using the Atlas 9000 topography system (Carl Zeiss Meditec AG) to monitor keratometry and higher order aberrations.

In patients with bilateral ametropia, a bilateral simultaneous procedure was performed on the day of surgery. In cases where only one eye fulfilled the inclusion criteria, the fellow eye was either left untreat-
ed or received a standard femtosecond laser-assisted LASIK treatment.

**Figure A** (available in the online version of this article) summarizes the parameters, geometry, and cutting order of the lenticule, as has already been described in detail in previous publications.⁴,⁵ The standard protocol was to use an optical zone of 6.3 mm with a transition zone of 2 mm (corresponding to a total lenticule diameter of 8.3 mm), although the zone was adjusted between 6 and 7 mm for some cases. A medium-sized (M) contact glass was used in all cases with sufficient white-to-white horizontal diameter (11.7 mm) to accommodate the large optical zone and transition zone. The minimum lenticule thickness used was fixed at 25 µm centrally and between 10 and 24 µm peripherally. A cap thickness of 120 µm was used. The femtosecond laser energy and spot spacing settings were optimized for each individual laser.¹¹ The energy was usually approximately 130 nJ (VisuMax software setting 26) with a fixed laser spot and tracking distance of 4.5 µm. The small incision width ranged from 2 to 4 mm and was placed superotemporally or superiorly. At some sites, a reserve small incision was created superonasally according to the Standard Operating Procedure.¹¹ The approximate suction time for the average case of hyperopic SMILE was 31 seconds (± approximately 3 seconds). After suction was applied, the centration achieved was confirmed to be on the corneal vertex with reference to the topography eye image, as described previously.¹¹ For eyes with a cylinder of 2.00 D or greater, marks were placed on the cornea to adjust for cyclotorsion by rotating the contact glass after suction was applied.¹²

## SURGICAL TECHNIQUE

Due to the use of the M size contact glass and larger cap diameter, a modified version of the Reinstein SMILE Separator was used that has a longer 9-mm separating arm (compared to 8 mm for the similar myopic instrument). This enables the safe separation of the interfaces without the instrument stressing the small incision. The lenticule was separated using the same technique as each surgeon used for myopic SMILE, but here ensuring that the lenticule interface separation was first conducted peripherally followed by the central cornea where the lenticule is thinnest (25 µm).

## POSTOPERATIVE EVALUATION

Patients were given antibiotic and steroid eye drops according to the standard routine protocol at each site. Patients were observed for 12 months with postoperative visits at 1 week and 1, 3, 6, 9, and 12 months. The postoperative examination included measurement of uncorrected distance visual acuity (UDVA), CDVA,

manifest refraction, contrast sensitivity using the CSV-1000, slit-lamp examination, corneal topography using the Atlas, corneal tomography using the MS-39 OCT (CSO Italia), corneal aberrations, and intraocular pressure using the Ocular Response Analyzer (Reichert).

## STATISTICAL ANALYSIS

A sample size calculation was performed using an exact binomial test including seven approval criteria for safety, efficacy, predictability, stability, and cylinder correction. Including a drop-out rate of 20%, the total sample size was calculated as 374 eyes with an α error probability of 0.05 and a statistical power (1-β error probability) of 0.8. The sample size calculation also took into account the variance inflation due to partial correlation between right and left eyes. The impact of this correlation was calculated based on a previous hyperopic data set. Because binomial criteria refer to rates, the intraclass correlation (ICC) was considered.¹³,¹⁴ For all performance criteria that allow the calculation of the ICC, a correction factor was applied. The correction factor was calculated as $D_{\text{eff}} = (2n_1 + n_2) / [2n_1 / (1 + \text{ICC}) + n_2]$, where $n_1$ was the number of patients treated bilaterally and $n_2$ was the number of patients treated monocularly. Because the numbers $n_1$ and $n_2$ were not known in advance, it was conservatively assumed that all patients would be treated bilaterally (ie, $n_2 = 0$). This resulted in a simplified formula: $D_{\text{eff}} = 1 + \text{ICC}$.¹³,¹⁴ The correction was applied if a clear correlation was present (ie, if ICC was greater than 0.3).¹⁵ The sample size was multiplied by the correction factor for the respective criteria. The final sample size was chosen as the largest sample size required across all criteria. Full details of the sample size calculation are included in the Clinical Investigation Report (data on file, Carl Zeiss Meditec AG).

All measured data were entered and collected using an electronic case report form for a centralized analysis. Regular monitoring visits were performed by an independent clinical research organization according to the International Organization for Standardization standard ISO 14155 and clinical guidelines. In addition, the Marburg site as a Leading Investigator was monitored by the Government Authority of the Federal State of Hesse (Germany). A comprehensive and detailed 230-page Clinical Investigation Report was produced and provided to the European authorities.

Outcome analysis was performed according to the Standard Graphs for Reporting Refractive Surgery¹⁶ and vector analysis was performed using the Alpins method.¹⁷ Data from the 12-month visit were used for analysis. Eyes where the intended postoperative
refraction was not emmetropia were excluded in the efficacy analysis. For the calculation of lost/gained lines of visual acuity, logMAR values were converted to Snellen lines. Unchanged was considered to be between -0.9 and +0.9 lines, and gained/lost a line +1.0 to +1.9 and -1.0 to -1.9, respectively. Accordingly, gain/loss of two lines was considered as +2.0 to +2.9 lines and -2.0 to -2.9 lines. For statistical analysis, the values of the CSV-1000 were converted to logarithmic units. All statistics were calculated using SAS (SAS Institute) and Microsoft Excel 2019 (Microsoft Corporation) software.

# RESULTS

## PATIENT POPULATION

A total of 199 patients (374 eyes) were recruited for the study, as per the sample size calculation, of whom 175 patients were treated binocularly and 24 patients were treated monocularly. Data were available at 3 months in 352 eyes (94.1%), 6 months in 338 eyes (90.4%), 9 months in 315 eyes (84.2%), and 12 months in 323 eyes (86.4%). Follow-up percentages were slightly lower than projected due to the coronavirus disease 2019 (COVID-19) pandemic. **Table 1** shows demographic data for the study population. The mean age was 38.8 ± 12.5 years with the oldest patients treated in London, United Kingdom (mean: 52.3 ± 11.6 years) and the youngest patients treated in Zlín, Czech Republic (mean: 27.3 ± 6.7 years). The highest hyperopia was treated in Zlín, Czech Republic (SEQ: +4.26 ± 1.31 D) and the lowest in Marburg, Germany (SEQ: +2.56 ± 1.20 D). **Table 2** shows the number of eyes by each diopter combination of maximum hyperopia and cylinder treated. The optical zone used was 6 to 6.2 mm in 21 eyes (5.6%), 6.3 mm in 352 eyes (94.1%), and 7 mm in 1 eye (0.27%). The minimum peripheral lenticule thickness was 10 µm in 263 eyes (70.3%), 11 to 15 µm in 72 eyes (19.3%), and 20 to

24 µm in 39 eyes (10.4%). All lenticules were created with a central minimum thickness of 25 µm.

## EFFICACY

**Figure 1** shows the Standard Graphs for Reporting Refractive Surgery for the data from the 12-month visit. As shown in **Figure 1A**, UDVA was 20/20 or better in 68% of eyes, relative to 85% with preoperative CDVA of 20/20 or better. UDVA was 20/16 or better in 28% and was 20/40 or better in all eyes at the 12-month visit. UDVA was within one line of preoperative CDVA in 93% of eyes (**Figure 1B**).

<table><caption>TABLE 2
Distribution of Eyes by Sphere and Cylinder Treated (Positive Cylinder Notation)</caption><thead><tr><th rowspan="2">Bin Distribution<br>Cylinder</th><th colspan="7">Sphere (D)</th></tr><tr><th>0.00 to +1.00</th><th>+1.01 to +2.00</th><th>+2.01 to +3.00</th><th>+3.01 to +4.00</th><th>+4.01 to +5.00</th><th>+5.01 to +6.00</th><th>Total</th></tr></thead><tbody><tr><td>0.00 to +1.00</td><td>38 (10.16%)</td><td>70 (18.72%)</td><td>66 (17.65%)</td><td>44 (11.76%)</td><td>34 (9.09%)</td><td>2 (5.88%)</td><td>274 (73.26%)</td></tr><tr><td>+1.01 to +2.00</td><td>2 (0.53%)</td><td>14 (3.74%)</td><td>7 (1.87%)</td><td>21 (5.61%)</td><td>8 (2.14%)</td><td>5 (1.34%)</td><td>57 (15.24%)</td></tr><tr><td>+2.01 to +3.00</td><td>5 (1.34%)</td><td>8 (2.14%)</td><td>7 (1.87%)</td><td>7 (1.87%)</td><td>4 (1.07%)</td><td>0 (0%)</td><td>31 (8.29%)</td></tr><tr><td>+3.01 to +4.00</td><td>5 (1.34%)</td><td>4 (1.07%)</td><td>1 (0.27%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>10 (2.67%)</td></tr><tr><td>+4.01 to +5.00</td><td>2 (0.53%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>0 (0%)</td><td>2 (0.53%)</td></tr><tr><td>Total</td><td>52 (13.90%)</td><td>96 (25.67%)</td><td>81 (21.66%)</td><td>72 (19.25%)</td><td>46 (12.30%)</td><td>27 (7.22%)</td><td>374 (100%)</td></tr></tbody></table>

D = diopters
<figure><img src="image_2.png" /><figcaption>Uncorrected Distance Visual Acuity</figcaption></figure>

<figure><img src="image_3.png" /><figcaption>Uncorrected Distance Visual Acuity
vs. Corrected Distance Visual Acuity</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>Change in Corrected Distance Visual Acuity</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>Spherical Equivalent Refraction
Attempted vs Achieved</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>Spherical Equivalent Refraction
Accuracy</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>Spherical Equivalent Refraction
Stability</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>Refractive Astigmatism</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>Target Induced Astigmatism vs
Surgically Induced Astigmatism</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>Refractive Astigmatism Angle of
Error</figcaption></figure>

**Figure 1.** Nine standard graphs for reporting refractive surgery showing the visual and refractive outcomes 12 months after hyperopic small incision lenticule extraction using the VisuMax femtosecond laser (Carl Zeiss Meditec AG). (A) UDVA; (B) UDVA vs CDVA; (C) change in CDVA; (D) SEQ attempted vs achieved; (E) SEQ accuracy; (F) SEQ stability; (G) refractive astigmatism; (H) TIA vs SIA; (I) refractive astigmatism angle of error. CDVA = corrected distance visual acuity; D = diopters; Postop = postoperative; Preop = preoperative; SEQ = spherical equivalent refraction; SIA = surgically induced astigmatism; TIA = target induced astigmatism; UDVA = uncorrected distance visual acuity
<table><caption>TABLE 3
Stability of Spherical Equivalent Refraction and Atlas Keratometry</caption><thead><tr><th>Parameter</th><th>Preoperative</th><th>3 Months</th><th>12 Months</th><th>3 to 12 Months Change</th><th>Mean Change per Month</th><th>3 to 12 Months Change Within ±0.50 D</th><th>3 to 12 Months Change Within ±1.00 D</th></tr></thead><tbody><tr><td>Eyes with refractive data, n</td><td>374</td><td>352</td><td>323</td><td>316</td><td>316</td><td>316</td><td>316</td></tr><tr><td>Spherical equivalent refraction adjusted for intended target (D), mean ± SD (range)</td><td>+3.49 ± 1.34 (+0.75 to +6.50)</td><td>-0.02 ± 0.57 (-2.00 to +3.75)</td><td>+0.12 ± 0.56 (-1.75 to +3.00)</td><td>+0.12 ± 0.46 (-1.88 to +1.75); P &lt; .001</td><td>0.013</td><td>72.15%</td><td>93.35%</td></tr><tr><td>Refractive cylinder (D), mean ± SD (range)</td><td>+0.88 ± 0.87 (0.00 to +4.75)</td><td>+0.42 ± 0.41 (0.00 to +2.25)</td><td>+0.40 ± 0.44 (0.00 to +2.00)</td><td>-0.02 ± 0.38 (-1.00 to +1.25); P = .319</td><td>-0.002</td><td>67.72%</td><td>96.84%</td></tr><tr><td>Eyes with keratometry data, n</td><td>373</td><td>352</td><td>320</td><td>313</td><td>313</td><td>313</td><td>313</td></tr><tr><td>Average keratometry (D), mean ± SD (range)</td><td>42.79 ± 1.51 (38.79 to 46.59)</td><td>45.23 ± 1.93 (40.13 to 50.03)</td><td>45.15 ± 1.95 (39.88 to 49.74)</td><td>-0.15 ± 0.62 (-3.35 to +5.13); P = .024</td><td>-0.017</td><td>75.40%</td><td>93.93%</td></tr><tr><td>Corneal astigmatism (D), mean ± SD (range)</td><td>1.23 ± 0.88 (0.02 to 4.16)</td><td>1.24 ± 0.62 (0.03 to 3.45)</td><td>1.23 ± 0.64 (0.04 to 3.87)</td><td>-0.002 ± 0.40 (-1.60 to +1.98); P = .671</td><td>-0.0002</td><td>81.47%</td><td>97.44%</td></tr></tbody></table>

D = diopters; SD = standard deviation

The Atlas is manufactured by Carl Zeiss Meditec AG.

## SAFETY

There was a gain of one line of CDVA in 10% of eyes, whereas there was one line loss in 11% and two or more lines loss in 1.2% at the 12-month visit (Figure 1C). For eyes with preoperative CDVA of 20/25 or better, none had a final postoperative CDVA worse than 20/40.

**Table A** (available in the online version of this article) includes the photopic contrast sensitivity data before and at the 12-month visit after the surgery. At 12 months, there was a statistically significant decrease at 6 cpd (P = .0018), 12 cpd (P < .0001), and 18 cpd (P < .0001). There was a decrease by more than 0.25 log units in more than 30% of eyes for the 12 and 18 cpd frequencies.

## PREDICTABILITY

SEQ predictability was within ±0.50 D in 81% and within ±1.00 D in 93% of eyes at the 12-month visit (Figure 1E). The mean SEQ improved from +3.49 ± 1.38 D (range: 2.11 to 4.87 D) to +0.12 ± 0.56 D (range: -0.44 to +0.68 D) at 12 months. The attempted versus achieved scatter plot (Figure 1D) shows that there was a trend for undercorrection to a small degree in low hyperopia, with the undercorrection more significant above +4.00 D. The slope of the attempted versus achieved plot was 0.9079, indicating that further no-mogram adjustments would have produced even better predictability for higher hyperopia.

## ASTIGMATISM

Postoperatively, the cylinder improved in all cases and was 1.00 D or less in 93% and 0.50 D or less in 75% of eyes (Figure 1G). There were no eyes with induced cylinder greater than 2.00 D. The scatter plot for surgically induced astigmatism vector (SIA) versus target induced astigmatism vector (TIA) shows that the refractive cylinder correction was on target in terms of magnitude (Figure 1H). The angle of error histogram (Figure 1I) shows that the refractive correction was placed accurately on the intended meridian for the majority of eyes, with 76% within ±15 degrees. Figure B (available in the online version of this article) shows the vector analysis for refractive cylinder, and the main outcome measures are shown in Table B (available in the online version of this article).

## REFRACTIVE AND CORNEAL STABILITY

Figure 1F displays the change in SEQ over time. Table 3 shows SEQ, refractive cylinder, and Atlas average keratometry and corneal astigmatism before surgery and change between 3 and 12 months after surgery. As expected for hyperopic treatments, there was an initial overcorrection that healed to the final SEQ from -0.17 ± 0.53 D at 1 month to -0.02 ± 0.57 D at 3 months after surgery. There was a small further average hyperopic shift of +0.12 D between 3 months and 1 year (P < .001). This change was deemed to be corneal rather than lenticular as it correlated to the change in
average corneal keratometry of -0.14 D between 3 and 12 months (P = .024).

## CORNEAL HIGHER ORDER ABERRATIONS

**Table C** (available in the online version of this article) shows the Atlas corneal higher order aberrations, assessed based on the vertex of the topography in a 6-mm zone using the Optical Society of America notation, for RMS, spherical aberration, and coma before surgery and change between 3 and 12 months after surgery. The average increases in corneal aberrations were within expected ranges: higher order RMS by +0.36 µm, spherical aberration by +0.50 µm, and coma by 0.32 µm.

## COMPLICATIONS

Intraoperative complications that occurred during this study were all previously described and at rates observed for routine myopic SMILE.¹¹ Suction loss leading to the abortion of procedure occurred in 5 of 374 eyes (1.34%), and incomplete removal of the lenticule in 7 eyes (1.87%), where all were small and peripheral, without adversely affecting CDVA. The procedure was aborted due to the inability to remove the lenticule in one eye (0.27%). The occurrence of an epithelial defect or corneal erosion was reported in 22 eyes (5.88%), mostly at the incision site. These were managed by the application of a bandaged contact lens until the defect was healed, usually within 24 hours.

The least anticipated postoperative complication was interface haze, seen more frequently than expected for myopic SMILE. Interface haze occurred with a peak of 17% at the 6-month follow-up visit (**Table D**, available in the online version of this article), of which 66% were grade 0.5 (trace or faint haze seen only by indirect broad tangential illumination), 25% were grade 1 (haze of minimal density seen with difficulty with direct and diffuse illumination), and 9% were grade 2 (a mild haze easily visible with direct focal slit illumination) and associated with reduction in contrast sensitivity. By the 12-month follow-up visit, the overall rate of interface haze reported decreased to 6.5%, which is still higher than seen in myopic SMILE.¹¹ A VisuMax CIRCLE retreatment procedure (converting the cap to a flap) was performed at 9 months for 1 eye with recalcitrant visually significant grade 1 haze despite topical corticosteroid therapy. The small residual refraction of -0.50 -0.25 x 113 was simultaneously corrected by excimer laser ablation (MEL 90; Carl Zeiss Meditec AG) and mitomycin C was applied to the underside of the flap and stromal bed, which subsequently resolved all haze.

In other expected postoperative complications, dry eye signs such as corneal punctate epithelial staining

and/or reduced tear meniscus at the slit lamp were seen in 1.24% of eyes at the end of the follow-up period. Epithelial ingrowth occurred in 1 eye (0.27%) at the incision site in an eye with a 4-mm temporal incision, in which a significant epithelial defect occurred at the time of the primary surgery. This was managed conclusively by opening the incision, epithelial removal, and wound closure by a 10.0 cross-suture, removed 2 weeks later.

## DISCUSSION

This was a prospective multicenter trial of hyperopic SMILE with and without astigmatism and achieved refractive results comparable to modern hyperopic corneal refractive surgery outcomes. Complications were minor and manageable, most of which were expected from myopic SMILE experience, with the exception of a higher rate of interface haze. As we know from photorefractive keratectomy,¹⁸ haze prevention by using topical corticosteroids for longer than the standard of 1 week used in myopic SMILE may mitigate this and is the subject of further investigation.

This study built on the first hyperopic SMILE studies by Reinstein et al⁶⁻⁸ and Pradhan et al,⁹ which demonstrated similar centration accuracy to hyperopic LASIK,⁶ improved aberration control compared to hyperopic LASIK,⁷ and comparable refractive accuracy.⁸ The Pradhan et al study,⁹ for considerably higher hyperopia (mean: +5.61 ± 1.21 D), achieved 76% of eyes within ±1.00 D and 53% within ±0.50 D of intended SEQ at 12 months. In a population with lower hyperopia (mean: +3.49 ± 1.38 D), the current study achieved comparable accuracy with 93% of eyes within ±1.00 D and 81% within ±0.50 D of intended correction at 12 months.

Both the current and previous SMILE studies demonstrated superiority over the previous hyperopic femtosecond lenticule extraction study,⁴ despite an even lower hyperopic population (mean: +1.96 ± 1.04 D); 90% of eyes within ±1.00 D and 69% within ±0.50 D of intended correction. This improvement was partly due to the use of nomogram adjustments, based on the aggregate data from the previous femtosecond lenticule extraction⁴ and SMILE studies.⁹

In the current study, there was a loss of one line of CDVA in 11% of eyes and two lines in 1.2% eyes at 12 months of 374 eyes. **Table E** (available in the online version of this article) includes a summary of the cause and clinical course for each of the eyes that lost two lines of CDVA. This safety was comparable to the previous SMILE study where 16% lost one line of CDVA and no eyes lost two lines of CDVA in 93 eyes.⁹ In the lower hyperopic femtosecond lenticule extraction study, there
was loss of one line in 10% of eyes and no eyes lost two lines in 39 eyes.⁴ Although the incidence of one line loss of CDVA was similar between studies, the current study produced a small but measurable 1.2% loss of two lines of CDVA (95% confidence interval: 0.34% to 3.14%). For comparison, the 95% confidence interval for two lines loss was 0.00% to 3.97% for the SMILE study⁹ and 0.00% to 8.97% for the femtosecond lenticule extraction study,⁴ implying that the current study was no worse. The inclusion criteria for the current study was preoperative CDVA of 20/25 or better, and CDVA was 20/16 or better in 43% of eyes. In comparison, the inclusion criteria in the previous SMILE study was preoperative CDVA of 20/40 or better, and CDVA was 20/25 or better in only 35% of eyes. Therefore, the safety statistics must be considered in this context and are probably not directly comparable.

The most commonly observed postoperative complication was interface haze, which peaked in 17% of eyes (1.5% with grade 2) at 6 months and persisted in 6.5% of eyes (0.31% with grade 2) at 12 months. This was similar to the previous femtosecond lenticule extraction study where trace haze was reported for 20% of eyes at 9 months.⁴ On the other hand, interface haze was not reported in the previous SMILE study.⁹ This difference may be related to the age of patients treated because the average age in the previous SMILE study was 27 years, compared to 38 years in the current study. Another contributing factor might be an observer-dependent bias in recording these trace levels of haze; a higher rate of transient haze was reported at the sites in Marburg, Germany, and London, United Kingdom.

It is known that interface haze is related to the degree of interface dissection trauma, which in turn is related to the optimization of SMILE energy setting parameters. The potential influence of energy and spot spacing was discussed for the previous femtosecond lenticule extraction study⁴ and it was suggested that wound healing might differ from myopic SMILE.¹⁹ Energy setting optimization has been extensively studied¹¹,²⁰⁻²² and is the subject of future investigation for hyperopic SMILE.

It might be expected for the incidence of suction loss in hyperopic SMILE to be higher than for myopic SMILE because of the longer suction time required. For example, a myopic lenticule with a 6.5-mm optical zone within an 8-mm cap takes approximately 28 seconds of cutting time, whereas a hyperopic lenticule with a 6.3-mm optical zone and transition of 2 mm takes approximately 31 seconds of cutting time. In the current study, suction loss occurred in 5 eyes (1.3%), and incomplete removal of the lenticule occurred in 7 eyes (1.87%).

This suction loss rate was slightly higher than for the majority of myopic SMILE studies, where suction loss is usually in the region of 0.50%,²³ but this may be expected to be the case given the longer lenticule cutting time (31 seconds). The newly CE-marked VISUMAX 800 laser creates the same lenticular cuts in hyperopic SMILE in a much shorter time, and can be expected to greatly reduce this suction rate to even less than that of current VisuMax myopic SMILE. The retained lenticule rate is usually in the region of 0.18%.¹¹,²⁴

Centration represents one of the more unique potential differences regarding patient selection for hyperopic SMILE versus LASIK because this involves the interplay between the corneal white-to-white horizontal diameter and the angle kappa of the eye. In the prior hyperopic SMILE study, the mean optical zone decentration was found to be 0.23 mm from the corneal vertex,⁶ compared to 0.20 mm for myopic SMILE using an identical docking technique and centration protocol.²⁵ Although ideally the patient interface contact glass applies suction to the corneolimbal junction, smaller eyes may result in suction ports being applied onto the conjunctiva. In the case of a smaller eye and small angle kappa, this may not be an issue. However, even an eye with an acceptable white-to-white horizontal diameter for an M glass (eg, 11.7 mm), in the presence of a large angle kappa, may still lead to significant conjunctival application of suction ports. In a series of 404 consecutive myopic eyes treated by LASIK, in which the M contact glass was used for eyes with a white-to-white horizontal diameter of 11.7 mm or less, there were 3 (0.74%) suction losses observed (Dan Z. Reinstein, MD, MA(Cantab), FRCOphth, personal communication, April 2022). The issue with conjunctival encroachment of suction ports also relates to centration once suction is achieved because the application of a spherical contact glass to an asymmetric aspheric cornea (tilted cornea by angle kappa) can sometimes result in the inability to achieve suction on the corneal vertex of the coaxially fixating eye as intended. This means that patient selection criteria for hyperopic SMILE will need to be studied based on more than just white-to-white horizontal diameter, but also including angle kappa, to ensure that suction is sufficiently close to the visual axis. This problem does not arise as much with LASIK because a slightly temporally decentered flap due to this scenario has little impact on centration of the excimer laser ablation, because this is locked by an eye tracker based on the coaxially fixating corneal vertex.²⁶

Most of the participating surgeons (both highly experienced and less experienced in myopic SMILE) reported a distinct learning curve to the surgical process
of hyperopic SMILE. Lenticule removal was reported to be initially more surgically challenging. Because no set surgical technique was defined in the study protocol, we may expect this to be improved had the Standard Operating Protocol been applied across all sites.¹¹ For example, the use of the longer 9-mm instrument shaft meant that those using a superior incision would find it more difficult to separate the lenticule in deep-set eyes without stressing the wound. A superotemporal incision provided a more ergonomic location to access the lenticule. Additionally, the clearance zone between the edge of the cap and the edge of the lenticule is smaller (down to 0.2 mm in some cases) than for myopic treatments to accommodate the larger transition zone. This created more challenges to locate the lenticule interface and increased the chance of false plane dissection. Following the Standard Operating Procedures employing specific instrumentation and angulation, as well as partial tunnelling and the “double-edge confirmation” technique, reduces the probability of false plane creation. Finally, implementing the “cap recovery technique”²⁷ eliminates the difficulties encountered when the lenticule interface is inadvertently separated first.

The results of early hyperopic corneal subtractive procedures were less than ideal, but modern published LASIK outcomes rival those of phacoemulsification and intraocular lens implantation.²⁸,²⁹ To compare the current study to modern studies in the past 5 years (excluding presbyopic profiles), a literature review was performed using the search terms “LASIK” and “hyperopia” or “hyperopic” in PubMed, as well as extracting the U.S. Food and Drug Administration pre-market approval study data for reference. It is important to note that studies reporting hyperopic LASIK outcomes for the MEL 80 and MEL 90 lasers are most comparable because the ablation profile is similar to the hyperopic SMILE lenticule profile used in the current study. Table F (available in the online version of this article) summarizes the key outcome measures of the studies that were identified (see reference list with the table) The UDVA results in the current study were similar to the results of modern hyperopic LASIK treatments. For studies with at least 75% of eyes with CDVA of 20/20 or better, UDVA varied between 67% and 90% for UDVA of 20/20 or better and 84% and 100% for UDVA of 20/40 or better compared to 68% and 100% in the current study. Predictability of spherical equivalent refraction within ±0.50 D varied between 47% (for high hyperopic populations) and 95% compared to 81% in the current study.

The strength of the study was that it was a prospective controlled trial, with full clinical research orga-

nization monitoring, that included multiple surgeons and laser devices, located across the world, incorporating a wide range of ethnicity. One potential weakness of the study was that there was unequal recruitment between the nine sites; 69% of patients were treated at three sites. There was also a range of previous experience in myopic SMILE between surgeons, which could have led to centration, cyclotorsion, and lenticule extraction variability and thus may negatively impact visual recovery and quality of vision parameters. It was not possible to statistically evaluate this due to the small sample size at some sites.

This multicenter study revealed that hyperopic SMILE performed in a broader refractive surgical community with refractive outcomes that match the current state of the art in hyperopic LASIK. SMILE and LASIK each possess inherent advantages and disadvantages. The benefits of SMILE over LASIK with reduced aberration induction³⁰,³¹ and dry eye symptoms³²⁻³⁴ have been demonstrated for myopic SMILE. The current study adds to the evidence that these benefits carry over to hyperopic SMILE, providing improved treatment options for the treatment of hyperopic refractive error.

## AUTHOR CONTRIBUTIONS

Study concept and design (DZR, WS, TJA); data collection (DZR, WS, TJA, PS, SG, BC, MB, YW, XZ); analysis and interpretation of data (DZR, WS, TJA, SG, MB); writing the manuscript (DZR, WS, TJA); critical revision of the manuscript (WS, PS, SG, BC, MB, YW, XZ); statistical expertise (DZR, TJA)

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<figure><img src="image_11.png" /><figcaption>**Figure A.** Hyperopic lenticule geometry and the cutting order shown by arrows: the lenticule interface is created first (from out-to-in), followed by the lenticule side cut, the cap interface (from in-to-out), and finally the small incision of 2 to 4 mm.</figcaption></figure>
<table><caption>TABLE A

**Change in Photopic Contrast Sensitivity (CSV-1000) in Log Units**</caption><thead><tr><th>Group</th><th>Preop</th><th>3 m</th><th>6 m</th><th>9 m</th><th>12 m</th><th>12m to Pre Change</th><th>P</th><th>Decrease > 0.25 Log Units</th><th>12m to 3m Change</th><th>P</th><th>Decrease > 0.25 Log Units</th></tr></thead><tbody><tr><td>A (3 cpd)</td><td>1.70 ± 0.17</td><td>1.70 ± 0.18</td><td>1.71 ± 0.18</td><td>1.73 ± 0.19</td><td>1.72 ± 0.17</td><td>+0.01 ± 0.19</td><td>.220</td><td>9.3%</td><td>+0.02 ± 0.19</td><td>.440</td><td>11.3%</td></tr><tr><td>B (6 cpd)</td><td>1.90 ± 0.17</td><td>1.82 ± 0.21</td><td>1.86 ± 0.22</td><td>1.89 ± 0.21</td><td>1.87 ± 0.21</td><td>-0.04 ± 0.23</td><td>.002</td><td>19.8%</td><td>+0.04 ± 0.21</td><td>&lt; .001</td><td>16.7%</td></tr><tr><td>C (12 cpd)</td><td>1.56 ± 0.22</td><td>1.42 ± 0.28</td><td>1.47 ± 0.27</td><td>1.47 ± 0.28</td><td>1.45 ± 0.27</td><td>-0.11 ± 0.33</td><td>&lt; .001</td><td>35.6%</td><td>+0.03 ± 0.29</td><td>.035</td><td>21.4%</td></tr><tr><td>D (18 cpd)</td><td>1.08 ± 0.25</td><td>0.93 ± 0.26</td><td>0.99 ± 0.26</td><td>0.98 ± 0.25</td><td>0.98 ± 0.27</td><td>-0.11 ± 0.32</td><td>&lt; .001</td><td>33.4%</td><td>+0.05 ± 0.27</td><td>.002</td><td>24.8%</td></tr></tbody></table>

cpd = cycles per degree

The CSV-1000 is manufactured by VectorVision.
<table><caption>**Figure B.** Vector analysis of refractive cylinder displayed as polar plots for target induced astigmatism vector (TIA), surgically induced astigmatism vector (SIA), difference vector (DV), and correction index (CI).</caption><thead><tr><th>TIA</th><th>SIA</th></tr></thead><tbody><tr><td><img src="tia Vector mean.png" alt="Vector mean of TIA data"></td><td><img src="sia Vector mean.png" alt="Vector mean of SIA data"></td></tr><tr><td><img src="dv Vector mean.png" alt="Vector mean of DV data"></td><td><img src="ci Vector mean.png" alt="Vector mean of CI data"></td></tr></tbody></table>
<table><caption>TABLE B
Vector Analysis of Refractive Cylinder</caption><thead><tr><th>Parameter</th><th>Spherical Treatments</th><th>All Eyes With Cylinder</th></tr></thead><tbody><tr><td>Eyes</td><td>29</td><td>294</td></tr><tr><td>Target induced astigmatism vector (D)</td><td></td><td></td></tr><tr><td>Arithmetic mean ± SD (range)</td><td>-0.98 ± 0.85 (0.25 to 4.75)</td><td></td></tr><tr><td>Summated vector mean</td><td>-</td><td>0.38 Ax 89°</td></tr><tr><td>Surgically induced astigmatism vector (D)</td><td></td><td></td></tr><tr><td>Arithmetic mean ± SD (range)</td><td>0.29 ± 0.41 (0.00 to 1.50)</td><td>0.96 ± 0.70 (0.09 to 4.91)</td></tr><tr><td>Summated vector mean</td><td>0.14 Ax 162°</td><td>0.25 Ax 88°</td></tr><tr><td>Correction index-geometric mean ± SD (range)</td><td>-</td><td>1.21 ± 0.79 (0.14 to 6.72)</td></tr><tr><td>Difference vector (D)</td><td></td><td></td></tr><tr><td>Arithmetic mean ± SD (range)</td><td>0.29 ± 0.41 (0.00 to 1.50)</td><td>0.41 ± 0.44 (0 to 2)</td></tr><tr><td>Summated vector mean</td><td>0.14 Ax 72°</td><td>0.13 Ax 91°</td></tr><tr><td>Index of success-geometric mean ± SD (range)</td><td>-</td><td>0.65 ± 0.95 (0 to 7)</td></tr><tr><td>Angle of error (°)</td><td></td><td></td></tr><tr><td>Arithmetic mean ± SD (range)</td><td>-</td><td>0.65 ± 21.17 (-71.06 to 84.03)</td></tr><tr><td>Absolute mean ± SD (range)</td><td>-</td><td>12.2 ± 19.43 (0 to 90)</td></tr><tr><td>Postop cylinder magnitude ≤ 0.25 D</td><td>62%</td><td>52%</td></tr><tr><td>Postop cylinder magnitude ≤ 0.50 D</td><td>83%</td><td>74%</td></tr><tr><td>Postop cylinder magnitude ≤ 1.00 D</td><td>93%</td><td>93%</td></tr><tr><td>Postop cylinder magnitude ≤ 2.00 D</td><td>100%</td><td>100%</td></tr><tr><td>Cylinder induced ≥ 0.50 D</td><td>38%</td><td>63%</td></tr><tr><td>Cylinder induced ≥ 1.00 D</td><td>7%</td><td>31%</td></tr><tr><td>Cylinder induced ≥ 2.00 D</td><td>0%</td><td>10%</td></tr><tr><td colspan="3">D = diopters</td></tr></tbody></table>
<table><caption>TABLE C
Atlas Corneal HOAs</caption><thead><tr><th>Parameter</th><th>Preoperative</th><th>3 Months</th><th>12 Months</th><th>Preop to 3 Months Change</th><th>Preop to 12 Months Change</th></tr></thead><tbody><tr><td>Eyes, n</td><td>374</td><td>352</td><td>323</td><td>352</td><td>323</td></tr><tr><td>HOAs RMS (µm), mean</td><td>+0.51 ± 0.21</td><td>+0.86 ± 0.42</td><td>+0.86 ± 0.44</td><td>+0.36 ± 0.45</td><td>+0.36 ± 0.46</td></tr><tr><td>± SD (range)</td><td>(+0.20 to +2.00)</td><td>(+0.28 to +2.60)</td><td>(+0.20 to +3.30)</td><td>(-1.50 to +2.00); P &lt; .001</td><td>(-1.40 to +2.90); P &lt; .001</td></tr><tr><td>Spherical aberration (µm), mean ± SD (range)</td><td>+0.22 ± 0.10<br>(-0.47 to +0.67)</td><td>-0.28 ± 0.22<br>(-0.97 to +0.32)</td><td>-0.29 ± 0.25<br>(-2.45 to +0.33)</td><td>-0.50 ± 0.22<br>(-1.26 to +0.10); P &lt; .001</td><td>-0.52 ± 0.24<br>(-2.59 to +0.10); P &lt; .001</td></tr><tr><td>Coma (µm)</td><td>+0.29 ± 0.16<br>(+0.02 to +1.30)</td><td>+0.61 ± 0.40<br>(+0.03 to +2.02)</td><td>+0.61 ± 0.40<br>(+0.03 to +2.41)</td><td>+0.32 ± 0.39<br>(-0.61 to +1.67); P &lt; .001</td><td>+0.33 ± 0.39<br>(-0.54 to +2.22); P &lt; .001</td></tr></tbody></table>

HOAs = higher order aberrations; RMS = root mean square; SD = standard deviation

The Atlas is manufactured by Carl Zeiss Meditec AG.
<table><caption>TABLE D
Incidence of Interface Haze</caption><thead><tr><th rowspan="2">Parameter</th><th colspan="2">1 Month</th><th colspan="2">3 Months</th><th colspan="2">6 Months</th><th colspan="2">9 Months</th><th colspan="2">12 Months</th><th rowspan="2">No. of Eyes<br>Affected</th></tr><tr><th>n/N</th><th>%</th><th>n/N</th><th>%</th><th>n/N</th><th>%</th><th>n/N</th><th>%</th><th>n/N</th><th>%</th></tr></thead><tbody><tr><td>Corneal haze overall</td><td>11/368</td><td>3.26%</td><td>36/352</td><td>10.51%</td><td>56/338</td><td>16.86%</td><td>46/315</td><td>14.92%</td><td>21/323</td><td>6.5%</td><td>96</td></tr><tr><td>Grade 0.5</td><td>7/368</td><td>1.9%</td><td>20/352</td><td>5.68%</td><td>37/338</td><td>10.95%</td><td>36/315</td><td>11.43%</td><td>15/323</td><td>4.64%</td><td>60</td></tr><tr><td>Grade 1</td><td>1/368</td><td>0.27%</td><td>10/352</td><td>2.84%</td><td>14/338</td><td>4.14%</td><td>9/315</td><td>2.86%</td><td>5/323</td><td>1.55%</td><td>26</td></tr><tr><td>Grade 2</td><td>3/368</td><td>0.82%</td><td>6/352</td><td>1.7%</td><td>5/338</td><td>1.48%</td><td>1/315</td><td>0.32%</td><td>1/323</td><td>0.31%</td><td>10</td></tr></tbody></table>
<table><caption>TABLE E
Summary of Eyes That Lost 2 Lines of CDVA</caption><thead><tr><td>Eye ID</td><td>Preop CDVA</td><td>12m CDVA</td><td>Notes</td></tr></thead><tbody><tr><td>Case 1</td><td>-0.18</td><td>0.04</td><td>Lost 2 lines of CDVA at 12 months due to mild interface haze associated with high Objective Scatter Index of 2.7, combined with elevated total higher order aberrations of 0.7 µm consisting mainly of trefoil and coma.</td></tr><tr><td>Case 2</td><td>-0.08</td><td>0.12</td><td>Lost 2 lines of CDVA at 12 months due to dry eye and tear film instability. The patient was being treated with Thealoz Duo lubricant eye drops (Thea Pharmaceuticals) to improve the tear film quality and symptoms.</td></tr><tr><td>Case 3</td><td>-0.10</td><td>0.18</td><td>Lost 2 lines of CDVA at 12 months. However, on retrospective review of the patient chart, the preoperative CDVA was found to have been entered incorrectly into the database. Because this was found after the database had been checked by the clinical research organization and locked, it was not possible to update the value.</td></tr><tr><td>Case 4</td><td>0.00</td><td>0.22</td><td>Lost 2 lines of CDVA, initially due to preoperatively identified anterior basement membrane disorder, resulting in an intraoperative epithelial slide that delayed healing under a bandage contact lens. This was further accompanied by delayed stromal deturgescence producing intrastromal and interface scatter with very high Objective Scatter Index that took 6 months to return to preoperative levels (6.2, 5.5, 4.4, and 2.7 at 1 week, 1 month, 3 months, and 6 months, respectively). Grade 1 stromal interface haze developed between 3 and 12 months with loss of 2 lines of CDVA. A circle cap-to-flap enhancement was performed as a topography-guided re-treatment assuming this would decrease interface haze and light scatter, so a further surface ablation re-treatment was carried out including MMC application. At 1 year after the re-treatment, CDVA had returned to within 1 line from preoperative levels.</td></tr></tbody></table>

CDVA = corrected distance visual acuity; MMC = mitomycin C
<table><caption>TABLE F
Literature Review of Hyperopic LASIK Studies</caption><thead><tr><th rowspan="2">First Author</th><th rowspan="2">Year</th><th rowspan="2">N (Eyes)</th><th rowspan="2">Technique</th><th rowspan="2">Preop SEQ (D)</th><th rowspan="2">Age (Years)</th><th rowspan="2">Timepoint</th><th rowspan="2">Mean ± SD (Range)</th><th colspan="2">Accuracy</th><th colspan="2">CDVA Preop</th><th colspan="2">UDVA</th><th colspan="2">Safety</th></tr><tr><th>± 0.50D</th><th>± 1.00D</th><th>&lt;20/20</th><th>&lt;20/20</th><th>&lt;20/40</th><th>1 line</th><th>&gt;2 lines</th></tr></thead><tbody><tr><td>Sekundo¹</td><td>2018</td><td>39</td><td>FLEx</td><td>+1.96 ± 1.04 (+0.63 to +4.50)</td><td>49 (27 to 56)</td><td>9 months</td><td>-0.40 ± 0.61 (-1.50 to +0.75)</td><td>70</td><td>89</td><td>50</td><td>6</td><td>88</td><td>10</td><td>0.0</td><td></td></tr><tr><td>Pradhan²</td><td>2019</td><td>93</td><td>SMILE</td><td>+5.61 ± 1.21 (+1.00 to +6.90)</td><td>27 ± 6 (21 to 50)</td><td>12 months</td><td>-0.22 ± 0.88 (-2.20 to +3.00)</td><td>53</td><td>76</td><td>24</td><td>27</td><td>95</td><td>16</td><td>0.0</td><td></td></tr><tr><td>Current Study</td><td>2022</td><td>374</td><td>SMILE</td><td>+3.49 ± 1.38 (0.75 to +6.50)</td><td>39 ± 12 (18 to 69)</td><td>12 months</td><td>+0.12 ± 0.56 (-1.75 to +3.00)</td><td>81</td><td>93</td><td>85</td><td>68</td><td>100</td><td>11</td><td>1.2</td><td></td></tr><tr><td>Reinstein³</td><td>2009</td><td>258</td><td>MEL 80<br>Hansatome zero compression</td><td>+2.54 ± 1.16 (+0.25 to +5.75)</td><td>56 (44 to 66)</td><td>12 months</td><td>+0.09 ± 0.48</td><td>79</td><td>95</td><td>94</td><td>81</td><td>98</td><td>14</td><td>0.5</td><td></td></tr><tr><td>FDA⁴</td><td>2016</td><td>160</td><td>MEL 80</td><td>2.70 ± 1.07 (+0.88 to +6.38)</td><td>47 ± 9 (22 to 69)</td><td>12 months</td><td>-0.023 ± 0.541</td><td>78</td><td>92</td><td>-</td><td>67</td><td>97</td><td>-</td><td>0.3</td><td></td></tr><tr><td>Reinstein⁵</td><td>2013</td><td>30</td><td>MEL 80<br>Hansatome zero compression<br>Small angle kappa</td><td>+4.15 ± 1.10 (+2.50 to +5.88)</td><td>51 ± 9 (22 to 60)</td><td>12 months</td><td>+0.40 ± 0.78 (-1.38 to +2.29)</td><td>53</td><td>77</td><td>93</td><td>80</td><td>100</td><td>20</td><td>0.0</td><td></td></tr><tr><td>Reinstein⁵</td><td>2013</td><td>30</td><td>MEL 80<br>Hansatome zero compression<br>Large angle kappa</td><td>+4.33 ± 0.89 (+2.75 to +5.75)</td><td>43 ± 12 (18 to 60)</td><td>12 months</td><td>+0.45 ± 0.74 (-1.13 to +1.87)</td><td>47</td><td>70</td><td>93</td><td>77</td><td>100</td><td>20</td><td>0.0</td><td></td></tr><tr><td>Alio⁶</td><td>2013</td><td>27</td><td>Intralase &amp;<br>500kHz Amaris excimer<br>OZ 6.2-6.9mm</td><td>+6.33 ± 0.83 (+5.00 to +8.50)</td><td>Not reported</td><td>6 months</td><td>+0.55 ± 1.09 (-0.50 to +3.38)</td><td>-</td><td>70</td><td>57</td><td>44</td><td>92</td><td>8</td><td>0.0</td><td></td></tr><tr><td>Leccisotti⁷</td><td>2014</td><td>800</td><td>Ziemer LDV Z2<br>Technolas 217P</td><td>+3.41 ± 1.16 (+1.00 to +6.50)</td><td>41 ± 9</td><td>9 months</td><td>-0.06 ± 0.26</td><td>74</td><td>88</td><td>-</td><td>-</td><td>95</td><td>7.3</td><td>0.3</td><td></td></tr><tr><td>Plaza-Puche⁸</td><td>2015</td><td>86</td><td>Intralase &amp;<br>500kHz Amaris excimer<br>OZ 6.3-7.0mm</td><td>+2.66 ± 1.68 (-1.38 to +5.75)</td><td>40 ± 10 (23 to 64)</td><td>36 months</td><td>+0.40 ± 0.65 (-1.63 to +2.00)</td><td>70</td><td>85</td><td>77</td><td>76</td><td>99</td><td>6.2</td><td>1.2</td><td></td></tr><tr><td>Amigo⁹</td><td>2015</td><td>24</td><td>Wavelight Allegretto 400<br>Hz &amp; Hansatome<br>Wavefront Optimized</td><td>+3.66 ± 0.61 (+2.75 to +5.00)</td><td>39 ± 9 (20 to 49)</td><td>6 months</td><td>+0.08 ± 0.56 (-0.75 to +1.25)</td><td>57</td><td>96</td><td>79</td><td>67</td><td>92</td><td>21</td><td>4</td><td></td></tr><tr><td>Amigo⁹</td><td>2015</td><td>16</td><td>Wavelight Allegretto 400<br>Hz &amp; Hansatome<br>Aspheric Customized<br>Profile</td><td>+4.05 ± 0.59 (+2.75 to +5.13)</td><td>39 ± 9 (20 to 49)</td><td>6 months</td><td>+0.21 ± 0.44 (-0.50 to +1.00)</td><td>87</td><td>100</td><td>81</td><td>81</td><td>100</td><td>12</td><td>0.0</td><td></td></tr><tr><td>Antonios¹⁰</td><td>2015</td><td>53</td><td>Amaris<br>M2</td><td>+2.25 ± 1.06 (+0.75 to +5.00)</td><td>45 ± 12 (19 to 61)</td><td>6 months</td><td>+0.22 ± 0.75 (-1.25 to +1.75)</td><td>43</td><td>72</td><td>90</td><td>85</td><td>92</td><td>0.0</td><td>0.0</td><td></td></tr><tr><td>Antonios¹⁰</td><td>2015</td><td>72</td><td>Amaris<br>LDV femto</td><td>+2.24 ± 0.95 (+0.50 to +4.75)</td><td>46 ± 10 (18 to 66)</td><td>6 months</td><td>-0.32 ± 0.76 (-2.13 to +1.50)</td><td>65</td><td>90</td><td>96</td><td>87</td><td>100</td><td>0.0</td><td>0.0</td><td></td></tr><tr><td>de Ortueta¹¹</td><td>2017</td><td>38</td><td>Amaris<br>Carriazo-Pendular</td><td>+4.07 ± 0.90 (+2.38 to +5.75)</td><td>40 ± 10 (18 to 57)</td><td>6 months</td><td>+0.28 ± 0.58</td><td>61</td><td>96</td><td>33</td><td>18</td><td>84</td><td>8</td><td>8</td><td></td></tr><tr><td>Plaza-Puche¹²</td><td>2016</td><td>51</td><td>Intralase &amp; Amaris<br>OZ 6.2-6.9mm</td><td>+6.33 ± 0.83 (+5.00 to +8.50)</td><td>33 ± 9 (21 to 54)</td><td>6 months</td><td>+0.50 ± 1.06 (-0.50 to +3.38)</td><td>-</td><td>71</td><td>92</td><td>53</td><td>98</td><td>11</td><td>6.5</td><td></td></tr><tr><td>Arba-Mosquera¹³</td><td>2016</td><td>46</td><td>AMARIS 750S<br>Carriazo-Pendular</td><td>+3.64 ± 1.42 (+1.27 to +6.18)</td><td>45 ± 11 (18 to 62)</td><td>6 months</td><td>+0.19 ± 0.61</td><td>61</td><td>93</td><td>52</td><td>30</td><td>85</td><td>13</td><td>6.5</td><td></td></tr></tbody></table>
<table><tr><td>Reinstein<sup>14</sup></td><td>2017</td><td>785</td><td>MEL80<br>VisuMax or Hansatome<br>zero compression</td><td>+4.52 ± 0.84<br>(+2.00 to +6.96)</td><td>50 ± 12<br>(18 to 70)</td><td>24 months</td><td>+0.30 ± 0.85<br>(-3.63 to +4.25)</td><td>50</td><td>77</td><td>100</td><td>62</td><td>96</td><td>22</td><td>0.5</td></tr><tr><td>El-Naggar<sup>15</sup></td><td>2017</td><td>20</td><td>Wavelight FS200<br>Wavelight EX500</td><td>+2.55 ± 1.17<br>(+1.00 to +6.00)</td><td>47 ± 4<br>(42 to 56)</td><td>12 months</td><td>+0.10</td><td>95</td><td>100</td><td>85</td><td>90</td><td>100</td><td>0.0</td><td>0.0</td></tr><tr><td>Garcia-Gonzalez<sup>16</sup></td><td>2018</td><td>76</td><td>Esiris<br>Intralase 60kHz<br>With mitomycin-C</td><td>+2.71 ± 1.30<br>(+2.00 to +6.25)</td><td>45 ± 1<br>(41 to 55)</td><td>6 months</td><td>+0.18</td><td>87</td><td>97</td><td>-</td><td>71</td><td>100</td><td>6.6</td><td>2.6</td></tr><tr><td>Garcia-Gonzalez<sup>16</sup></td><td>2018</td><td>76</td><td>Esiris<br>Intralase 60kHz<br>No mitomycin-C</td><td>+2.90 ± 1.10<br>(+2.00 to +6.25)</td><td>44 ± 1<br>(41 to 55)</td><td>6 months</td><td>+0.42</td><td>75</td><td>91</td><td>-</td><td>54</td><td>100</td><td>9.2</td><td>6.6</td></tr><tr><td>Reinstein<sup>17</sup></td><td>2018</td><td>1,350</td><td>MEL 90<br>VisuMax</td><td>+2.77 ± 1.34<br>(+0.13 to +6.50)</td><td>54 ± 11<br>(21 to 75)</td><td>12 months</td><td>-0.11 ± 0.55<br>(-2.13 to +2.50)</td><td>73</td><td>93</td><td>93</td><td>75</td><td>99</td><td>17</td><td>0.6</td></tr><tr><td>Gauthier-Fournet<sup>18</sup></td><td>2019</td><td>146</td><td>Amaris 750S<br>Moria</td><td>+6.64 ± 1.01<br>(+5.25 to +9.50)</td><td>-</td><td>6 months</td><td>-0.06 ± 0.83</td><td>66</td><td>87</td><td>86</td><td>60</td><td>97</td><td>10</td><td>0.0</td></tr><tr><td>Moshirfar<sup>19</sup></td><td>2021</td><td>189</td><td>EX500<br>Intralase 150kHz</td><td>+1.79 ± 0.90<br>(+0.13 to +4.38)</td><td>46 ± 11<br>(18 to 72)</td><td>12 months</td><td>-0.46 ± 0.79<br>(-2.13 to +1.25)</td><td>78</td><td>96</td><td>90</td><td>69</td><td>97</td><td>4.8</td><td>1.1</td></tr><tr><td>Tăbăcaru<sup>20</sup></td><td>2021</td><td>593</td><td>MEL 80<br>VisuMax</td><td>+4.08 ± 1.57<br>(+1.50 to +6.00)</td><td>33 ± 8<br>(22 to 49)</td><td>12 months</td><td>+0.50 ± 0.83</td><td>49</td><td>74</td><td>56</td><td>59</td><td>96</td><td>1.0</td><td>0.0</td></tr></table>

FLEx = femtosecond lenticule extraction; LASIK = laser in situ keratomileusis; SMILE = small incision lenticule extraction

REFERENCES

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16. Garcia-Gonzalez M, Iglesias-Iglesias M, Drake Rodriguez-Casanova P, Gros-Otero J, Teus MA. Femtosecond laser-assisted LASIK with and without the adjuvant use of mitomycin C to correct hyperopia. *J Refract Surg*. 2018;34(1):23-28. https://doi.org/10.3928/1081597X-20171116-01 PMID:29315438

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18. Gauthier-Fournet L, Penin F, Arba Mosquera S. Six-month outcomes after high hyperopia correction using laser-assisted in situ keratomileusis with a large ablation zone. *Cornea*. 2019;38(9):1147-1153. https://doi.org/10.1097/ICO.0000000000002011 PMID:31169605

19. Moshirfar M, Megerdichian A, West WB, et al. Comparison of visual outcome after hyperopic LASIK using a wavefront-optimized platform versus other excimer lasers in the past two decades. *Ophthalmol Ther*. 2021;10(3):547-563. https://doi.org/10.1007/s40123-021-00346-1 PMID:34009511

20. Tăbăcaru B, Stanca HT, Pîrvulescu RA, et al. Femtosecond-LASIK outcomes using the VisuMax®-MEL® 80 platform for hyperopia and hyperopic astigmatism refractive surgery. *Exp Ther Med*. 2021;21(3):288. https://doi.org/10.3892/etm.2021.9719 PMID:33603895