Clinical Outcomes after Implantation of a Novel Binocular Complementary Extended Depth-of-Focus Intraocular Lens Compared to Bilateral Low Near-Add Multifocal Intraocular Lenses

Improvement in surgical technique and intraocular lens (IOL) design paved the way for even better refractive outcomes after cataract surgery. Patients as well as surgeons seek for optimal optical performance with less spectacle dependence from distance to near, ideally with limited functional compromise. With the growing use of tablets and computers, intermediate vision has become of increasing importance. Several presbyopia correcting strategies have been described to compensate for the loss of accommodation after lens surgery.

The option commonly used to reduce postoperative spectacle dependence is multifocal IOLs (MIOLs). The principle of these lenses is to split light between multiple focal points providing good distance and near as well as some intermediate vision. However, negative effects like blurred vision, photic phenomena (e.g., halo, glare, starburst), or decreased contrast sensitivity might arise with these IOLs. To overcome these problems, several other strategies have been developed.

Insertion of EDOF (enhanced depth-of-focus) IOLs offers a further possibility to gain less spectacle dependence after cataract surgery. Contrary to MIOLs, EDOF lenses do not induce multiple distinct foci but rather produce an elongated focus [1‒3]. This type of IOLs could therefore provide improved visual acuity (VA) in the intermediate distance, less photic phenomena, and less reduction in contrast sensitivity. A further approach for presbyopia correction, without induction of multiple foci, is monovision or mini-monovision, aiming for emmetropia in the dominant eye and a more myopic outcome in the fellow eye to gain a broader binocular depth of focus [4]. This concept may also be used when inserting EDOF or MIOLs [5].

Another solution, often described as mix and match in literature, uses MIOLs with different near additions for each eye. The idea behind this approach is to improve the contrast in the intermediate distance compared to trifocal IOLs. Yoon et al. [6] investigated patients after implantation of a diffractive MIOL (Tecnis ZM900) with a near addition of +4D in one eye and a refractive MIOL (Rezoom NXG1) with a near addition of +3D in the fellow eye, which showed comparable results to patients who received unilateral implantation of a diffractive MIOL (Tecnis ZM900) only. A study by Gundersen and Potvin included patients who received the AcrySof IQ ReSTOR +2.5D in the dominant eye and the ReSTOR +3D in the nondominant eye. Compared to the other group, which received the same MIOLs (AT LISA tri) in both eyes, there was no difference regarding near and distance vision with similar visual disturbances [7]. Nuijts et al. [8] also demonstrated similar results when implanting the ReSTOR +2.5D MIOL in one eye and ReSTOR +3D in the fellow eye compared to bilateral implantation of the ReSTOR +2.D lens. Other mix-and-match modalities, also combining MIOLs with EDOF IOLs, have been published [9‒12]. Originally, the intended use of MIOLs was designed for binocular application with equal IOL models and all these examples do not follow a standardized principle.

A novel concept consists of two IOLs with different diffractive properties who match each other to gain a broader depth of field. This binocular complementary IOL approach uses two diffractive IOLs (ARTIS SYMBIOSE, Cristalens, France) with a “Mid” model that offers foci at distance and intermediate and a “Plus” model for distance and more near [13]. Through this combination, in binocular vision the ARTIS SYMBIOSE covers an addition from 1.5 to 3.75 diopters. Recently published clinical data showed good visual performance and a large depth of field that resulted in high patient satisfaction [14, 15]. Besides, the lens system was also investigated in the laboratory setting, showing promising outcomes also compared to established MIOLs [16, 17]. Purpose of this study was to assess the clinical outcomes of this novel multifocal complementary lens system and to compare it with an established low near-add MIOL.

This randomized, patient- and examiner-masked, controlled trial included 56 eyes of 28 patients who were scheduled for cataract surgery at the Hanusch Hospital, Vienna, Austria. Patients were allocated into two groups using Research Randomizer (randomizer.org). All had bilateral cataract surgery either receiving ARTIS SYMBIOSE Mid and Plus (Cristalens, France) or the AT LARA (Carl Zeiss Meditec AG, Germany) in both eyes. The ARTIS SYMBIOSE Mid and Plus (Cristalens, France) are hydrophobic acrylic IOLs with a tetraloop design. These lenses have two different diffractive profiles, which are complementary for binocular insertion. The ARTIS SYMBIOSE Mid is designed for a continuum for distance and intermediate vision and is implanted in the dominant eye, while the ARTIS SYMBIOSE Plus is designed for distance and near vision. The AT LARA (Zeiss, Germany) is a hydrophilic acrylic IOL with a hydrophobic surface and a plate haptics design with diffractive properties for far and intermediate distances.

Enrollment took place between March 2019 and May 2021 and inclusion criteria were bilateral age-related cataract, expected postoperative astigmatism of 0.75 diopters (D) or less, and an interest in postoperative spectacle independence. Exclusion criteria were prior refractive or ocular surgery, any acute or chronic disease, which could compromise visual function, extreme shallow anterior chamber, amblyopia, strabismus, capsule, zonular or pupil abnormalities, as well as incompatibility with multifocality (e.g., patients with increased night work like pilots or truck drivers, patients demanding perfect visual needs).

The study was conducted in adherence to the Declaration of Helsinki and procedures were followed by Good Clinical Practice. Study documents were reviewed and approved by the local Ethics Committee and patients signed consent prior to study entry. The study is registered on ClinicalTrials.gov (Identifier: NCT03921762). The CONSORT checklist was used for this manuscript [18].

All patients received a comprehensive examination before cataract surgery including slit-lamp biomicroscopy and fundoscopy, measurement of intraocular pressure (IOP), monocular and binocular corrected distance visual acuity (CDVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at 4 m, and biometry using the IOL Master 700 (Carl Zeiss Meditec AG, Germany) for axial length measurement, keratometry (K), and anterior chamber depth measurements. The IOL power and the expected spherical equivalent was calculated using the Haigis and Barrett True K formula, whereby the surgeon ultimately selected the IOL power. Furthermore, corneal topography (Atlas, Carl Zeiss Meditec AG, Germany) was performed to rule out irregular astigmatism.

Postoperatively, patients were examined at 1 week, 6 weeks, and 6 months. All follow-up examinations included slit-lamp evaluation, IOP, and binocular as well as monocular CDVA assessment. At 6 weeks postoperatively, also monocular and binocular uncorrected distance visual acuity (UCDVA), monocular and binocular defocus curve, binocular reading performance evaluation using Salzburg Reading Desk at near distance, binocular contrast sensitivity with and without glare (OPTEC 6500 Vision Tester; Stereo Optical, Chicago, IL, USA), and binocular measurement of halos using Aston Halometer by Wolffsohn were performed. At the final visit at 6 months, UCDVA as well as uncorrected and distance-corrected intermediate visual acuity (UCIVA and DCIVA) using ETDRS charts at 70 cm and uncorrected and distance-corrected near visual acuity (UCNVA and DCNVA) using ETDRS chart at 40 cm were each performed monocularly and binocularly. Defocus curves were assessed with distance correction as a three-step procedure to ensure better patient compliance. In the first step, the defocus curve started from +1.00D to −4.00D in 1.00D steps, followed by the second beginning with +0.50D to −3.50D in 1.00D steps. The third step started with −1.25D to −2.75D in 0.50D intervals. Between each test, other examinations (e.g., corneal topography) were performed.

Cataract surgery was conducted following local standard procedures by three experienced surgeons. Surgery was performed under topical anesthesia, with a temporal clear corneal incision, injection of ophthalmic viscoelastic device, capsulorhexis, phacoemulsification, and removement of cortical material using coaxial irrigation and aspiration. After IOL implantation, the ophthalmic viscoelastic device was removed and stromal hydration for wound sealing was performed at the end of surgery. Postoperative standard treatment regimen consisted of bromfenac eye drops and additionally prednisolone acetate eye drops in case of diabetic patients for 4 weeks.

For statistical analysis, descriptive testing (median, mean, range) was used for VA data. Main outcome analysis for comparison of VA between the groups was done using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare matched data. Similarly, contrast sensitivity, IOP, and mean absolute error were compared between the groups performing Mann-Whitney U test. Halometer, refraction, and Salzburg Reading Desk were analyzed using the paired and unpaired t test. Data analysis was conducted via Excel (Microsoft Corp., USA) and SPSS (IBM, USA). A p value lower than 0.05 was considered statistically significant.

The sample size calculation was based on data of binocular DCNVA at 40 cm under photopic conditions, assuming a difference of 0.1 logarithm of the minimum angle of resolution (logMAR) to be clinically significant. Based on these assumptions (α of 0.05, power of 0.9) and a 25% dropout rate, it was calculated that 14 subjects in each group needed to be included.

In total, 56 eyes of 28 patients with 14 patients in each group were included in this study. Of these, 5 patients were excluded and 6 patients were lost to follow-up. Reasons for exclusion were the following: IOL power not available (1), protocol noncompliance (1), cancelled surgery (2), and a posterior capsule rupture during cataract surgery (1).

Table 1 shows the patient characteristics at inclusion. Table 2 shows the binocular postoperative results including subjective refraction, CDVA, UCDVA, DCIVA, UCIVA, DCNVA, UCNVA, as well as mean absolute error. There were no statistically significant differences between the ARTIS SYMBIOSE or the AT LARA. At 6 months, CDVA was −0.1 logMAR in both groups, UCDVA was 0.0 logMAR in the ARTIS SYMBIOSE, and −0.1 logMAR in the AT LARA group. DCIVA and UCIVA at 70 cm was 0.1 logMAR in both groups. DCNVA at 40 cm was 0.1 logMAR with the ARTIS SYMBIOSE and 0.2 logMAR with the AT LARA (p = 0.093). The mean absolute error of the calculated spherical equivalent at 6 months showed no statistically significant difference between the IOLs (0.20 for the ARTIS SYMBIOSE and 0.16 for the AT LARA groups, p > 0.05).

Binocular defocus curves 1–2 months postoperatively showed no statistically significant difference between both IOL groups (shown in Fig. 1). Binocular defocus curves showed best median VA of 0.0 logMAR at +0.5D to −0.5D with the ARTIS SYMBIOSE and −0.1 logMAR at 0.0D with the AT LARA. There were no statistically significant differences in the defocus curves between the ARTIS SYMBIOSE Mid and Plus.

Subjective refraction at the last follow-up visit at 6 months showed no difference between the IOLs. All patients of the ARTIS SYMBIOSE group had a spherical equivalent within ±0.5D compared to 94% in the AT LARA group. A total of 81% had a spherical equivalent within ±0.25D with the ARTIS SYMBIOSE and 83% with the AT LARA.

Figure 2 shows the binocular contrast sensitivity (logCS) with and without glare under photopic and mesopic conditions at different spatial frequencies (cycles per degree, cpd). The ARTIS SYMBIOSE showed statistically significant better mean contrast sensitivity compared to the AT LARA at 1.5 cpd under photopic conditions without glare (1.54 logCS vs. 1.43 logCS, p = 0.046) and under mesopic conditions with glare at 1.5 cpd and 3 cpd (1.31 logCS vs. 0.58 logCS, p = 0.002; 1.28 logCS vs. 0.51 logCS, p = 0.006).

Figure 3 represents the mean postoperative binocularly perceived halo eccentricity using the Aston Halometer by Wolffsohn. No statistically significant difference was found comparing halos of the ARTIS SYMBIOSE group to the AT LARA group, as well as comparing the ARTIS SYMBIOSE Mid and Plus.

There was no statistically significant difference when measuring binocular reading performance using the Salzburg Reading Desk. In the ARTIS SYMBIOSE group, patients had in median 120 words per minute (WPM) with a reading time of 8 min compared to the AT LARA with 146 WPM at 6.6 min reading time (p > 0.05). Similarly, no difference between the ARTIS SYMBIOSE Mid and Plus was observed (median 95 WMP vs. 107 WMP, p > 0.05; 10.5 vs. 9.25 min reading time, p > 0.05). Monocular reading performance with the AT LARA was 107.5 WPM at 9.4 min.

The aim of this randomized controlled trial was to compare the performance of a commonly used low near-add MIOL with a novel twinset system of MIOLs, which is based on the binocular complementarity to achieve a continuous range of binocular vision from distance to near [13]. To our knowledge, this is the first published clinical study comparing the ARTIS SYMBIOSE IOLs with a commonly used low near-add MIOL. Both lenses, the ARTIS SYMBIOSE and AT LARA, have diffractive lens designs [13, 19]. Binocular implantation of the ARTIS SYMBIOSE twinset with two different diffractive profiles is aimed to offer a wider depth of focus from 40 to 90 cm [13].

In this study, there was no significant difference regarding binocular corrected and uncorrected distance VA between both groups, although the mean UCDVA was slightly better in the AT LARA group at 1–2 months and 6 months postoperatively. VA at 70 cm was similar in both groups. DCNVA showed slightly better results in favor of the ARTIS SYMBIOSE, however not statistically significant, and no differences regarding UCNVA were found. Previous data of the ARTIS SYMBIOSE showed similar VAs postoperatively [14, 15, 20].

The defocus curve showed no difference despite that the AT LARA group had a slightly better VA at emmetropia and the decline in the ARTIS SYMBIOSE group was less steep in the near range. Laraja-Blesa et al. [15] showed defocus curves results of the ARTIS SYMBIOSE with a VA of 0.0 logMAR from 0.5D to −2.5D. In their study, the ARTIS SYMBIOSE Mid had a further peak at around −1.75D and the Plus at −2.25D. Previous data by McNeely et al. showed secondary peaks at −2D to −2.5D with the ARTIS SYMBIOSE Mid and −2.5D with the Plus, whereas Whang et al. had a peak at −2D with the Plus IOL [14, 20]. Laboratory studies could simulate similar results [16, 21]. In contrast, patients implanted with the ARTIS SYMBIOSE in our cohort had a lower functional vision amplitude compared to those in the clinical study by Laraja-Blesa et al. [15]. In addition, defocus curves of the Mid and Plus showed no distinct second peak, rather a broader plateau compared to the studies mentioned above. In prior clinical trials, VA with the AT LARA of better than 0.1 logMAR at intermediate range of 60–90 cm has been demonstrated [22, 23].

In our cohort, good results were found in terms of refractive predictability and postoperative subjective refraction in both, the ARTIS SYMBIOSE and AT LARA group. Although the data regarding postoperative spherical equivalent following AT LARA lens implantation were consistent with those of Poyales et al., the results with the ARTIS SYMBIOSE were even better compared to the values shown by McNeely et al. [14, 24].

Concerning contrast sensitivity, the ARTIS SYMBIOSE performed superior under mesopic conditions with glare at 1.5 and 3 cpd and under photopic conditions without glare at 1.5 cpd compared to the AT LARA. Both lenses showed stable contrast sensitivity when comparing photopic and mesopic curves without glare, but decreased remarkably at light situations with glare, which is also consistent with previous reports among phakic healthy participants [25]. Contrast sensitivity is known to be reduced with MIOLs compared to monofocal IOLs, although a systematic review comparing monofocal and MIOLs showed smaller differences than expected [26]. With the ARTIS SYMBIOSE, contrast sensitivity in the study by McNeely et al. using Pelli-Robson chart was 1.72 and Lajara-Blesa et al. described photopic contrast sensitivity without glare within normal range [14, 15]. Poyales et al. [24] showed good results with the AT LARA with regard to mesopic contrast sensitivity. Ganesh et al. [27] maintained better photopic contrast sensitivity than in our cohort (1.47 logMAR ± 0.18 at 3 cpd to 1.66 logMAR ± 0.18 at 6 cpd), although it was measured using another instrument, the CSV-1000 system. In the study by Reinhard et al. [28], mesopic and photopic contrast sensitivity was, respectively, slightly and distinctly better when compared to the AT LARA group of our study.

In this current study, the amount of dysphotopsias was similar between both groups and between the ARTIS SYMBIOSE Mid and Plus. The Aston Halometer was used to measure dysphotopsias, which consists of an LED glare source in front of an iPad, where letters circulate around the light source with varying radius. The size of photopic scotoma is measured in degrees [29]. Dysphotopsia assessment in a study conducted by Buckhurst et al. [30] revealed, as expected, a larger extent of photopic scotomas of a MIOL (Tecnis ZM900) compared to a monofocal IOL (Softec-1). Dissatisfaction due to halos is among the major factors for MIOL and EDOF IOLs explantation. It is described that neural adaptation to dysphotopsias can take several months [2, 31].

The Salzburg Reading Desk is a standardized system to evaluate reading performance [32, 33]. Improvement of uncorrected reading acuity after implantation of diffractive MIOLs has been described [34]. Another study by Alio et al. [35] showed significantly better reading acuity with diffractive MIOLs compared to monofocal IOLs as well as smaller print size also compared to refractive MIOLs. Ganesh et al. [27] showed an improvement of reading capability throughout the study up to 1 year, having the best uncorrected results at 60 cm with 170 ± 42 wpm. Reading performance in the study by McNeely et al. [14] showed 115 WMP and 104 WMP at 40 cm and 66 cm, respectively, with the ARTIS SYMBIOSE, which is lower than in our cohort.

Exclusion was necessary in 5 patients and 6 patients were lost to follow-up, the latter mostly due to COVID-19 restrictions and national lockdown regulations. The resulting rather small sample size is one of the main limitations of this study. Therefore, questionnaire data concerning spectacle independence, subjective rating of dysphotopsias, or overall patient satisfaction were not analyzed. In a previous study using the Visual Function Index (VF-14) questionnaire, high patient satisfaction with a score of 95.99 was found and another study showed as well satisfying results with a Quality of Vision questionnaire and 93.2% being spectacle independent after 1 year of ARTIS SYMBIOSE implantation [14, 15].

In conclusion, data of the current study demonstrated promising results of the novel ARTIS SYMBIOSE system, which are comparable to the previously well-studied AT LARA regarding VA at different distances, the defocus curves, and size of halos. The ARTIS SYMBIOSE IOL showed a better contrast sensitivity at low spatial frequencies especially under mesopic conditions with glare.

This study protocol was reviewed and approved by the local Ethics Committee of the city of Vienna, Vienna, Austria (Approval No. EK 18-205-1018). All research and measurements followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from all patients before enrollment in the study and before any study measures were performed.

None of the authors have any financial or personal interest related to the study. Prof. Findl is a scientific advisor to Alcon, BVI, Carl Zeiss Meditec AG, Croma, and Johnson & Johnson.

This study was an investigator-initiated trial supported by a grant from Cristalens.

H. Ivellio-Vellin and M. Ruiss conceptualized the study, performed data acquisition and statistical analysis, and prepared the manuscript; J. Hienert conceptualized the study, performed data acquisition, and critically reviewed and gave final approval of the manuscript to be published; S. Georgiev, C. Pilwachs, and A. Fisus performed data acquisition and critically reviewed and gave final approval of the manuscript to be published; and O. Findl conceptualized the study, critically reviewed and gave final approval of the manuscript to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Hannah Ivellio-Vellin and Manuel Ruiss contributed equally to this work.The study was registered at ClinicalTrials.gov (https://clinicaltrials.gov) with the clinical trial registration number NCT03921762.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.