Laser in situ keratomileusis (LASIK) is the most commonly performed corneal refractive surgery worldwide1,2 and is used for the correction of myopia, hyperopia, and astigmatism.3 The LASIK procedure begins with the creation of a corneal flap followed by excimer stromal ablation on the corneal bed that corrects the refractive error. The first step, creation of the hinged flap, is the most critical step of the LASIK procedure because it affects safety and efficacy of the final visual outcome. It is important to produce a uniform flap with a narrow standard deviation (SD) to obtain a proper stromal bed thickness and reduce the likelihood of corneal ectasia.4
Corneal flaps were initially created using a microkeratome blade. Microkeratome flap creation subsequently evolved from manually guided mechanical microkeratomes to automated microkeratomes and single-use microkeratomes; however, despite refinements in the technology, complications such as buttonhole flaps and irregular incision planes can still affect the outcome of the procedure.5,6
The use of a femtosecond laser for flap creation has been commercially available since 2002, and it is the most common application of the femtosecond laser.7 The theoretical advantages of femtosecond lasers include increased precision in flap creation, a decrease in flap imperfections, and lower procedural intraocular pressure (IOP).8 Femtosecond lasers create an incision through photodisruption. The laser produces pockets of plasma with each shot that expands, displacing the surrounding tissues and leading to the formation of cavitation bubbles.9 An opaque bubble layer (OBL) is produced by gas bubbles that accumulate in the superficial layers of the stromal bed and an excessive OBL might interfere with flap creation.9 Some unique potential complications associated with flap creation using the femtosecond laser include suction failure during the laser treatment resulting in an incomplete cut, OBL formation, vertical gas breakthrough, and transient light sensitivity syndrome.10 The new generation of femtosecond lasers use higher frequency and lower energy than their predecessors that allow for the creation of a better cleavage plane and easier flap lift. Commercially available femtosecond lasers differ with respect to pulse energy, duration, distance, and pattern and therefore must be evaluated empirically.11
Historically, different femtosecond laser systems have been used for either cornea or refractive applications (Intralase, Abbott Medical Optics, Inc.; the FS200, Alcon Laboratories, Inc.; the Femto LDV Z6, Ziemer Ophthalmic Systems AG; and the Visumax, Carl Zeiss Meditec AG) or cataract surgery (Lensar, Lensar, Inc. and the Catalys, Abbot Medical Optics, Inc.), which increases the difficulty and cost of making both procedures available to patients in a single clinic. At present, a few systems are being used for both applications (Femto LDV Z8, Ziemer Ophthalmic Systems AG and Victus, Technolas Perfect Vision GmbH). However, no clinical data have been published regarding the performance of either system with respect to corneal flap creation.
The femtosecond laser for the current study (Lensx, Alcon Laboratories, Inc.) has been in use for cataract surgery since 2010. The laser system uses tightly focused ultrashort femtosecond pulses (10 to 15 seconds) to create a continuous incision or tissue separation of the cornea. Previously, a pilot study to assess flap creation in 38 eyes of 20 patients was performed using a prototype that showed no statistically significant difference between the planned and postoperatively measured flap thickness, and with no associated adverse events.12 Herein we report the results of the first study using the commercially available femtosecond laser system with flap creation added as a capability, which evaluated the creation of LASIK flaps in 58 eyes for accuracy, precision, and safety.
PATIENTS AND METHODS
Study Design and Enrollment
The trial was a prospective nonrandomized dual-center open-label pilot study designed to evaluate the thickness accuracy, defined as achieved flap thickness versus desired flap thickness, of LASIK flaps created with a femtosecond laser system. Patients were enrolled at 2 investigative sites (Slade & Baker Vision Center, Houston, Texas, and Spector Eye Care, Norwalk, Connecticut, USA) with 2 investigators (S. Slade and S. Spector, respectively). The patients were required to provide written informed consent before enrollment in the trial and the conduct of any trial-related procedures. The final protocol was approved by the institutional review board. This trial adhered to the provisions of the guidelines of the World Medical Association Declaration of Helsinki. This trial was performed in compliance with all federal, local, and/or regional requirements, including with the U.S. Health Insurance Portability and Accountability Act.
Inclusion and Exclusion Criteria
Inclusion criteria allowed patients older than 21 years with myopia or hyperopia to be eligible for femtosecond laser–initiated surgery, with corrected distance visual acuity (CDVA) correctable to at least 20/25 in each eye. Exclusion criteria included previous corneal surgery, corneal lesions that would impede laser treatment, corneal edema, hypotony, glaucoma, existing corneal implant, keratoconus, irregular astigmatism, and corneal thickness values that would result in a residual stromal bed less than 280 μm when flap resection and excimer ablation were calculated.
Study Treatment and Plan
The planned scheduled visits for the study included the screening (day −30 to −1), surgery (day 0), and 2 postoperative visits at 1-month (day 30 to 45) and 3-month (day 90 to 105) intervals. Unscheduled visits were completed if additional follow-up was deemed necessary by the investigator. The total expected duration of participation for each patient was up to 5 months depending on the time of surgery after the preoperative/screening visit and the timing of each postoperative visit thereafter. Patients were enrolled sequentially based on the informed consent form date and time. Eligible patients who signed an informed consent form completed the screening assessments and returned to the clinic within 30 days to have bilateral LASIK surgery.
Primary and Secondary Effectiveness Endpoints
The primary endpoint of the study was flap thickness accuracy within the central zone at 3 months postoperatively. The secondary endpoints included flap thickness precision within the central zone at 1 month and 3 months postoperatively (variability of the achieved flap thickness), ease of flap dissection, stromal bed quality, OBL assessment, uncorrected distance visual acuity (UDVA) and CDVA, manifest refraction spherical equivalent, and prediction error between target versus achieved refraction. The results for UDVA and CDVA measurements are presented using the standard refractive graphs for reporting refractive surgery outcomes.13 An exploratory effectiveness endpoint was variability of flap thickness measured at 3 points across the central and peripheral zones of the flaps at 3 months postoperatively.
Safety endpoints included reporting adverse events, findings from slitlamp evaluation, significant IOP measurement, decrease in CDVA, and reporting surgical events and device deficiencies.
Flap Thickness Measurements
Flap thickness was calculated by subtracting the anterior segment optical coherence tomography (AS-OCT) (Visante, Carl Zeiss Meditec AG and iVue, Optovue, Inc.) measurement from the programmed (desired) flap thickness. Each AS-OCT measurement was performed separately by 2 different technicians to ensure accuracy. They took 1 measurement at the center and then 4 measurements peripherally (6.0 mm from center) at 0-degree, 90-degree, 180-degree, and 270-degree orientations at 1 month and 3 months postoperatively. These measurements were performed by placing the cursor at the appropriate points and visualizing the edge of the flap to manually mark the thickness to be measured by the AS-OCT. This was repeated 3 times for each measurement and the mean was reported. Software centration and live AS-OCT visualization allowed for accurate centration of the flap.
Assessment of Flap Dissection Quality
Flap dissection quality was assessed using a scale created by the authors ranging from 0 to 5 based on the difficulty in lifting the flap and the amount of resistance encountered. Grades were indicated as follows: 0 = unable to lift flap, 1 = able to lift flap with aid of sharp instrument, 2 = able to lift flap with difficulty using blunt instrument, 3 = able to lift flap with moderate resistance using blunt instrument, 4 = able to lift flap with minimal resistance using blunt instrument, 5 = able to lift flap without any resistance using blunt instrument.
Stromal Bed Quality Assessment
The quality of the stromal bed was assessed using a scale created by the authors ranging from 0 to 5 based on roughness of the stromal bed. Grades were indicated as follows: 0 = very rough, 1 = moderately rough, 2 = rough, 3 = smooth, 4 = moderately smooth, 5 = very smooth.
Assessment of Opaque Bubble Layer
The presence and severity of an OBL was evaluated by the investigators during surgery. Grades were indicated as follows: 0 = no OBL, 1 = between 1% and 24% of stromal bed area, 2 = between 25% and 49% of stromal bed area, 3 = between 50% and 74% of stromal bed area, 4 = between 75% and 99% of stromal bed area, 5 = 100% of stromal bed area.
The investigational femtosecond laser (Lensx Laser System) uses tightly focused ultrashort femtosecond pulses (10 to 15 seconds) to create a continuous incision or tissue separation of the cornea. The laser pulses are delivered through a patient interface, a sterile disposable applanation lens, and suction ring assembly that contacts the cornea and fixes the eye with respect to the delivery system. A small volume of tissue (a few microns in diameter) is photodisrupted at the laser focus. A computer-controlled scanning system directs the laser beam throughout a 3-dimensional pattern to the desired target location to produce the incision through photodisruption. The Wavelight laser system and the Visx laser were used to perform the corneal ablation. The femtosecond-laser settings were line spot separation, 7.0 μm and layer separation, and 7.0 μm.
The safety analysis set was the primary analysis set, and included all patients/eyes that were exposed to the device during the study. No formal statistical hypothesis testing was planned in support of the performance objectives. All baseline, performance, and safety data were summarized using descriptive statistics. A sample size of 50 eyes was considered sufficient for assessment of flap thickness accuracy.
Demographics and Baseline Characteristics
A total of 34 patients (68 eyes) were initially enrolled. Thirty patients (4 did not meet eligibility criteria) had bilateral LASIK surgery and 58 eyes were available upon completion of the study. Of the 30 patients who had bilateral LASIK surgery, 29 completed the study (96.7%) and 1 patient (3.3%) was lost to follow-up before the 1-month visit. Table 1 shows the demographics and baseline characteristics of the study population. The distribution of men to women was balanced and the majority of the patients were identified as white and non-Hispanic or Latino.
Analysis of Flap Thickness and Precision
Table 2 shows the mean flap thickness within the central zone, the flap thickness accuracy (defined as the mean difference between the achieved and desired flap thickness within the central zone), and the flap thickness precision (defined as the variation in flap thickness measured by the SD) at 1 month and 3 months postoperatively.
Flap Dissection Quality
Of the 60 flaps graded, the majority (47 [78.3%]) were graded 5 (able to lift flap without any resistance using blunt instrument), whereas only 10 (16.7%) were graded 4 (able to lift flap with minimal resistance using blunt instrument and 3 (5.0%) were graded 3 (able to lift flap with moderate resistance using blunt instrument) (Figure 1).
Anterior segment OCT (AS-OCT) measurements of the flap thickness were recorded within the peripheral zone (6.0 mm diameter), at 0-degree, 90-degree, 180-degree, and 270-degree orientations. Similar means for flap thickness were observed within the 4 sectors, indicating uniformity of flap thickness across the peripheral zone (Table 3).
Stromal Bed Quality
Surface quality of the stromal bed after flap creation was assessed using a 6-point grading scale ranging from 0 (very rough surface) to 5 (very smooth surface). All 60 stromal beds were graded as 5 by the investigators (Figure 2).
Opaque Bubble Layer
No OBL was observed in 44 eyes whereas 16 eyes showed an OBL occurring on less than 24% of the stromal bed surface (grade 1) (Figure 3). Furthermore, no surgical complications were reported in any eyes as a result of OBL formation.
The UDVA was assessed for the 58 eyes that completed the study. At 1 month postoperatively, 47 eyes had a UDVA of 20/20, and at 3 months postoperatively, 49 eyes had a UDVA of 20/20 (Figure 4). The CDVA was assessed for all 60 eyes; patients were manually refracted to their best correction before CDVA testing. At 1 month postoperatively, 53 eyes were 20/20, and at 3 months postoperatively, 57 eyes were 20/20 (Figure 5). On average, low residual refractive error was observed starting at 1 month postoperatively, with a mean MRSE of −0.17 diopters (D) 3 months postoperatively.
For 1 patient, a UDVA worse than 20/40 and a 2-line decrease in CDVA were reported in both eyes at the 1-month visit. This patient recovered to 20/25 by the 3-month visit. The decrease in visual acuity was attributed to a bilateral adverse event of IOP increase caused by a steroid response and conjunctivitis that led to a series of other complications throughout the study. No other eye in the study had a clinically significant decrease in CDVA.
Prediction Refraction Error
Figure 6 shows the results of the prediction refraction error analysis (defined as the difference between the actual postoperative refractive error and the intended formula-derived refractive target). The prediction error was 0.5 D or less in 54 eyes at 1 month postoperatively, and in 53 eyes at 3 months postoperatively. Furthermore, the prediction error was 1.0 D in 57 eyes at 1 month postoperatively, and in all 58 eyes at 3 months postoperatively.
The safety analysis set included all patients exposed to the device during the study. Table 4 shows the ocular treatment-emergent adverse events. No adverse event or serious adverse event related to the device was reported. The 1 serious adverse event that did occur was flap microstriae of mild severity, which required a surgical intervention of flap refloat. The investigator reported that the corneal flap microstriae had resolved at an unscheduled visit 2 days postoperatively. Table 5 shows the incidence and details of the ocular treatment-emergent adverse events.
Surgical Events and Device Deficiencies
Two incidences of surgical events were reported, both of which related to a patient interface suction failure. In both cases the patient interface was replaced and the surgery completed.
Femtosecond lasers have been shown to reduce postoperative complications and improve the smoothness and accuracy of flap creation compared with mechanical microkeratome use.10 Following the initial data on a femtosecond laser prototype, the current study was conducted to characterize the accuracy, precision, and safety of the commercially available system (differences between the 2 systems include the patient interface and software). The current study was designed for 3 months of follow-up, in contrast to similar studies that were followed for 1 month.14,15
In this study, AS-OCT measurements of flap thickness were 127.8 ± 3.7 μm at 1 month postoperatively, and 125.8 ± 4.8 μm at 3 months postoperatively, which were comparable to femtosecond lasers dedicated only to corneal and refractive applications. A previous pilot study using the same laser system reported a mean postoperative flap thickness of 140.28 ± 8.0 μm.12 Two other studies using another femtosecond laser system (LDV Z6)14,15 found mean postoperative flap thicknesses of 90.1 ± 2.7 μm and 89.6 ± 2.0 μm, respectively.
In the current study, the measurements of flap thickness accuracy within the central zone at 1 and 3 months were 3.3 ± 3.8 μm and 1.3 ± 2.6 μm, respectively, showing that flaps can be created accurately and precisely with a multiplatform femtosecond laser. The advantages of creating an accurate flap are well documented. Thick flaps can increase the probability of residual corneal stroma less than 250 μm, which increases the risk for postoperative corneal ectasia. In addition to accuracy, flaps in this study were shown to be very uniform across all 4 sectors of the peripheral zone. More planar flap morphology has been shown to improve LASIK outcomes.16,17
The visual acuity results were also comparable to other flap creation studies, although it is unclear whether those studies used the same excimer laser to perform the corneal ablation. At 1 month postoperatively, 81% of the patients in our study had a UDVA of 20/20 or better, compared with a study showing 82.2% (LDV Z6) at 3 months.18 The average efficacy (visual acuity ≤20/20) for femtosecond lasers tested in multiple studies was 79.1% (Visumax, average of 3 studies), 83.6% (FS200, average of 2 studies), and 85.1% (Intralase 60 kHz, average of 7 studies), systems that are dedicated to corneal and refractive applications.19
No serious adverse events were reported in the current study. Only 1 adverse event was reported to occur in more than 4% of patients (punctate keratitis, 11.7%), and no serious complications occurred, as has been reported in other studies.14,18 There were 2 instances of increased IOP because of a bilateral steroid response in 1 patient; the patient's IOP was controlled after the steroid was discontinued. The serious adverse event (flap microstriae) was reported to be of mild severity and had resolved spontaneously by 2 days postoperatively. Only 2 incidences of surgical events were reported that were related to suction failure, with no complications such as flap tears, corneal ectasia, buttonholes, and incomplete passes reported. A metaanalysis of femtosecond laser use in LASIK flap creation19 found that intraoperative and postoperative complication rates ranged from 0% to 37.5%, depending on the system and the study.
In the current study, stromal bed quality was uniformly rated very smooth, with approximately three-quarters of the eyes showing no OBL and no eye had an OBL occurring on more than one fourth of the stromal bed surface. Published literature supports that the quality of the stromal bed in terms of smoothness correlates positively with better visual outcomes and limiting higher-order aberrations.16 Real-time OCT visualization aided in centering the flap to guarantee that the horizontal overlap was in contact with the limbus, allowing gas to evacuate in a timely manner. Because an OBL is generally formed from gas that cannot escape, this placement helped avoid OBL formation. Other femtosecond laser systems use different methods for gas evacuation to minimize OBL appearance. For example, the FS200 laser uses a chimney-like tunnel system for gas evacuation in which a venting dissection corridor is created by the surgeon within the flap hinge.20 The Intralase creates a vertical gas pocket for gas removal; however, this might incur a risk for gas breakthrough into the anterior chamber.21
Strengths of the study include a 3-month follow-up (versus only 1 month), the use of AS-OCT rather than pachymetry to measure flap thickness, and having 2 independent observers perform the AS-OCT readings. Limitations of the study include the difficulty in using objective standards to measure the ease of flap lifting and the standardization of evaluation between different surgeons. The only way to perform an objective assessment for these parameters would involve in vitro testing. Therefore, subjective measurements were used for evaluation of flap dissection quality.
Limitations of AS-OCT measurements include decreased accuracy after surgery, overestimation of flap thickness, and difficulty in achieving the same position with the OCT during each measurement.22–24 In addition, the use of 3 different OCT units (Visante, iVue, and Optovue) introduces the possibility for variation in flap thickness measurements. To account for these limitations and maximize accuracy, measurements were repeated 3 times for each assessment. Software centration and live OCT visualization were important for centration of the flap during OCT measurement; however, it was not within the scope of this study to record the centration of every flap. Future studies might address this by evaluating the location of each flap.
The femtosecond laser in the current study can create flaps that are accurate, precise, uniform, and easy to lift, with the creation of a smooth stromal bed with minimum OBL. The expanded capability to include cornea and refractive applications in addition to cataract procedures facilitates patient access within a single clinic and creates economic value. The results from this study can be used to plan further comparative studies in the future.
WHAT WAS KNOWN
- Femtosecond lasers are commonly used for LASIK flap creation; however, few femtosecond lasers are in use for both corneal/refractive and cataract applications.
WHAT THIS PAPER ADDS
- A multifunctional, commercially available femtosecond laser system safely and effectively created LASIK flaps that were high quality, accurate, and precise.
- The majority of the flaps were lifted with no or minimal resistance.
- All the flaps had a very smooth stromal bed with minimum OBL.
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Disclosures:Dr. Slade is a consultant to Alcon Laboratories, Inc. Dr. Ignacio was an Alcon employee at the time of the study. Dr. Spector receives personal fees from Alcon Laboratories, Inc.