European Journal of Cardiovascular Medicine

Cataract surgery is the most commonly performed surgical procedure globally, with millions of surgeries conducted annually to restore vision in patients suffering from cataract-induced visual impairment [1]. Despite its high success rate and advancements in surgical techniques, the long-term postoperative complication of posterior capsule opacification (PCO) remains a significant challenge. PCO, often referred to as "after-cataract," occurs in up to 50% of patients within five years following cataract surgery, with many requiring Nd:YAG laser capsulotomy to restore clear vision [1]. This secondary procedure, while effective, is not without risks, including retinal detachment, elevated intraocular pressure, and increased healthcare costs [1]. The pathogenesis of PCO involves the proliferation, migration, and metaplasia of residual lens epithelial cells (LECs) from the anterior subcapsular epithelium and remnants of lenticular fibers. These cells transform into fibroblasts and myofibroblasts, leading to the formation of opaque scar tissue along the posterior lens capsule [2-4]. Despite significant advancements in surgical techniques, such as meticulous cortical cleanup, and improvements in intraocular lens (IOL) design, material, and edge configuration, PCO remains a persistent issue, highlighting the need for additional preventive measures [2-4]. In recent years, pharmacological interventions have gained attention as a promising strategy to reduce PCO incidence. Both in vivo and in vitro studies, including our own, have demonstrated that various pharmacological agents with antimitotic, antifibrotic, or antineoplastic properties can inhibit LEC activity and prevent PCO formation [5-7]. Additionally, molecular biology and gene therapy approaches have shown potential in targeting the underlying mechanisms of LEC proliferation and transformation [5-7]. Among pharmacological agents, non-steroidal anti-inflammatory drugs (NSAIDs) have emerged as particularly effective due to their ability to inhibit cell division, metaplasia, and collagen synthesis in LECs [8]. Animal studies and clinical trials have further validated the efficacy of NSAIDs in reducing PCO rates. For example, NSAID-coated IOLs have been shown to significantly lower PCO incidence compared to uncoated IOLs [9]. Previous research has also demonstrated the effectiveness of NSAIDs in PCO prevention. Specifically, they found that the long-term postoperative use of topical ketorolac in paediatric cataract patients with intact posterior capsules effectively prevented PCO formation [10]. Similarly, hydro dissection using diclofenac sodium has been shown to reduce PCO rates for up to two years postoperatively [11]. Recent in vitro and in vivo studies have further highlighted the potential of ketorolac-loaded IOLs to inhibit LEC adhesion and prevent PCO development, offering a novel approach to PCO prevention [12].

Corticosteroids, such as dexamethasone, have traditionally been used postoperatively to control inflammation and reduce the risk of complications. However, their role in PCO prevention remains less clear. While corticosteroids effectively manage postoperative inflammation, they may not sufficiently address the underlying mechanisms of LEC proliferation and transformation contributing to PCO. This has led to the exploration of combination therapies, where corticosteroids are used alongside NSAIDs, to leverage the anti-inflammatory properties of corticosteroids and the anti-fibrotic effects of NSAIDs. Such combination therapies have shown promise in preclinical studies, but their clinical efficacy in preventing PCO remains under investigation. Given the compelling evidence supporting the role of NSAIDs in PCO prevention and the potential synergistic effects of combining NSAIDs with corticosteroids, this study aims to compare the efficacy of a combined regimen of topical dexamethasone 0.1% and ketorolac tromethamine 0.5% eye drops versus dexamethasone 0.1% alone in preventing PCO formation two years after phacoemulsification with primary posterior chamber IOL (PC-IOL) implantation. By evaluating the synergistic effects of these agents, this investigation seeks to contribute to the development of more effective postoperative strategies to minimize PCO and improve long-term visual outcomes for cataract surgery patients. Therefore, the aim of the present investigation was to compare the efficacy of topical dexamethasone 0.1% plus ketorolac tromethamine 0.5% eye drops versus dexamethasone alone regarding the prevention of PCO two years after phacoemulsification with primary implantation of a posterior chamber IOL (PC-IOL).

This prospective, observational clinical study was conducted at the Department of Ophthalmology, Government Medical College and Hospital, Bettiah, Bihar, India, over a period of two years. The study enrolled 100 patients admitted for elective cataract surgery with primary implantation of a posterior chamber intraocular lens (PC-IOL). Written informed consent was obtained from all participants prior to their inclusion in the study.

Inclusion Criteria:

• Patients aged 21 years or older with a visually significant cataract in the study eye.
• Patients scheduled for elective cataract surgery with primary implantation of a posterior chamber intraocular lens (PC-IOL).
• Patients willing to provide written informed consent and comply with the study protocol, including follow-up visits.
• Patients with no history of ocular trauma or previous intraocular surgery in the study eye.
• Patients with no contraindications to the use of topical dexamethasone or ketorolac.

Exclusion Criteria:

• Patients with a history of glaucoma, uveitis, or other inflammatory eye diseases.
• Patients with corneal opacities or other corneal diseases that prevent adequate visualization of the posterior capsule.
• Patients with a history of topical or systemic use of corticosteroids or NSAIDs within the previous month.
• Patients with known allergies to NSAIDs or any components of the study medications.
• Patients with intraoperative complications, such as posterior capsule rupture, vitreous prolapse, or zonular dehiscence.
• Patients with significant systemic diseases that may interfere with wound healing or follow-up adherence.
• Patients with preexisting retinal pathologies or other conditions that may affect visual outcomes independently of PCO.

Study Design and Group Allocation:

Patients were divided into two groups based on the postoperative treatment regimen:

• Group 1:Received a combination of topical dexamethasone 0.1% and ketorolac tromethamine 0.5% eye drops.
• Group 2 (Control):Received topical dexamethasone 0.1% eye drops alone.

The use of ketorolac in Group 1 was based on its potential to prevent posterior capsule opacification (PCO), while Group 2 served as the control to evaluate the additional benefit of ketorolac.

Preoperative Evaluation:

A comprehensive preoperative assessment was performed, including:

• Detailed medical and ocular history.
• Best-corrected visual acuity (BCVA) measurement using a Snellen chart.
• Slit-lamp biomicroscopic examination to assess the anterior and posterior segments.
• Intraocular pressure (IOP) measurement using Goldmann applanation tonometry.
• Dilated fundus examination to rule out retinal pathologies.

Surgical Procedure:

All surgeries were performed by experienced ophthalmologists using a standardized phacoemulsification technique:

• Pupillary dilation was achieved using a combination of topical cyclopentolate 0.5%, tropicamide 0.5%, and phenylephrine 2.5% one hour before surgery.
• A 2.8-mm clear corneal incision was made, followed by the injection of viscoelastic material into the anterior chamber.
• A continuous curvilinear capsulorhexis was performed using a needle and completed with capsulorhexis forceps.
• Hydrodissection and hydrodelineation were performed to separate the nucleus from the cortex.
• The nucleus was emulsified using a phaco probe, and residual cortical material was aspirated.
• A foldable monofocal hydrophobic acrylic IOL was implanted in the capsular bag.
• Viscoelastic material was removed using an irrigation-aspiration probe, and the wound was hydrated to ensure self-sealing.
• Intracameral antibiotics were administered at the end of the procedure to prevent infection.

Postoperative Regimen:

• Group 1: Patients received topical ketorolac 0.5% eye drops four times daily for four weeks, in addition to dexamethasone 0.1% eye drops six times daily for the first week, tapered to four times daily for the remaining three weeks.
• Group 2: Patients received only dexamethasone 0.1% eye drops on the same schedule as Group 1.
• Both groups received topical antibiotic drops four to six times daily for one month to prevent postoperative infection.

Follow-up and posterior capsule opacification assessment:

Patients were followed up on postoperative days 1, 3, and 7, at the end of the first month, and six-month intervals thereafter. Additional visits were scheduled if patients reported a gradual decline in visual acuity. At each visit, the following assessments were performed:

• Slit-lamp examination under mydriasis (using cyclopentolate 1% and tropicamide 0.5%) to evaluate the posterior capsule for opacification.
• Documentation of PCO severity, including fibrotic changes and Elschnig pearl formation.
• Nd:YAG laser capsulotomy was performed in cases where PCO significantly reduced visual acuity or obscured the red reflex.

Outcome Measures: The primary outcome measure was the incidence and severity of PCO in both groups at the end of two years. Secondary outcomes included the need for Nd:YAG laser capsulotomy, visual acuity, and any adverse effects related to the study medications.

Statistical Analysis: The collected data was organized into a table using Microsoft Excel 2019. Next, the data was transferred to GraphPad version 8.4.3 for further statistical analysis. A P-value of less than 0.05 was considered statistically significant.

All patients underwent identical surgical procedures, which included a superotemporal clear corneal incision, phacoemulsification, standard posterior capsular polishing, and insertion of a posterior chamber intraocular lens (PC-IOL). The demographic characteristics of the patients in both groups were comparable, with no statistically significant differences (Table 1). Group 1 (dexamethasone + ketorolac) comprised 30 males (30%) and 20 females (20%), while Group 2 (dexamethasone alone) included 28 males (28%) and 22 females (22%). The mean age of patients in Group 1 was 61.85 ± 2.76 years, with an age range of 21–81 years, whereas in Group 2, the mean age was 58.97 ± 3.34 years, with a range of 21–85 years. The difference in mean age between the two groups was not statistically significant (p > 0.05). Additionally, the distribution of operated eyes (right vs. left) and the mean follow-up duration (23.2 ± 1.3 months in Group 1 and 23.9 ± 2.1 months in Group 2) were similar, with no significant differences (p > 0.05). These findings confirm that the two groups were well-matched in terms of baseline characteristics, ensuring the validity of the comparative analysis. The incidence of posterior capsule opacification (PCO) requiring Nd:YAG laser capsulotomy was slightly lower in Group 1 (4%, 2/50 eyes) compared to Group 2 (6%, 3/50 eyes). However, this difference was not statistically significant (p > 0.05). Similarly, the mean time to capsulotomy was comparable between the two groups, with Group 1 showing a mean of 23.56 ± 1.45 months and Group 2 showing a mean of 24.18 ± 2.76 months (p > 0.05). These results suggest that the addition of ketorolac to dexamethasone did not significantly reduce the incidence of PCO or delay the need for capsulotomy compared to dexamethasone alone.

Table 1: Showing the different demographic profiles of the patients of both groups.

Table 2: Showing the comparison of posterior capsule opacification (PCO) incidence and mean time to capsulotomy between both groups

Posterior capsule opacification (PCO) remains one of the most common long-term complications following cataract surgery, with reported incidence rates as high as 50% in some studies. Despite advancements in surgical techniques and intraocular lens (IOL) design, PCO continues to pose a significant challenge, often necessitating Nd:YAG laser capsulotomy, which carries its own risks, including cystoid macular edema, retinal detachment, and IOL damage or subluxation [1-7]. Given these risks, there is a pressing need for effective strategies to prevent PCO formation. Non-steroidal anti-inflammatory drugs (NSAIDs) have shown promise in reducing PCO incidence by inhibiting lens epithelial cell (LEC) proliferation, migration, and metaplasia, as demonstrated in both in vivo and in vitro studies [12,13]. However, the clinical efficacy of NSAIDs, particularly in combination with corticosteroids, remains a topic of debate. Previous studies have explored the role of NSAIDs in PCO prevention with mixed results. Flach and Dolan [14] reported a lower incidence of PCO with ketorolac compared to diclofenac, though the difference was not statistically significant at three years postoperatively. However, the absence of a control group in their study makes it difficult to draw definitive conclusions about the specific effects of ketorolac. Similarly, other studies have found no significant difference in PCO incidence between eyes treated with diclofenac and those treated with betamethasone [15]. Zaczek et al. [16] compared diclofenac, dexamethasone, and placebo in the immediate postoperative period but did not include ketorolac in their analysis, leaving its role in PCO prevention unclear. These conflicting findings highlight the need for further research to determine the efficacy of NSAIDs, particularly ketorolac, in combination with corticosteroids for PCO prevention.

In this study, we aimed to address this gap by comparing the incidence of PCO in patients treated with a combination of dexamethasone and ketorolac versus dexamethasone alone. Our findings revealed no significant difference in PCO incidence or the mean time to capsulotomy between the two groups. The overall incidence of PCO was 4% in Group 1 (dexamethasone + ketorolac) and 6% in Group 2 (dexamethasone alone), with no statistically significant difference (p > 0.05). These results align with previous studies that found no significant reduction in PCO incidence with the use of NSAIDs alone or in combination with corticosteroids [17-19]. This suggests that the addition of ketorolac to dexamethasone does not provide a significant advantage in preventing PCO following cataract surgery.

The role of IOL design and material in PCO prevention has also been widely studied. Hydrophobic acrylic IOLs with sharp-edged optics have been associated with lower PCO rates compared to round-edged IOLs [20,21]. However, the results remain controversial, with some studies reporting higher PCO rates with hydrophobic acrylic IOLs compared to silicone IOLs [4]. To minimize the influence of these factors, we used a single type of IOL for all patients and ensured meticulous surgical techniques, including continuous curvilinear capsulorhexis and complete cortical cleanup, to reduce the risk of PCO formation [22]. Despite these measures, the incidence of PCO in our study was consistent with previous reports, further underscoring the need for effective pharmacological interventions.

This study has several limitations. First, the duration of ketorolac treatment was limited to four weeks postoperatively. A longer treatment duration or more frequent dosing may yield different results, as suggested by previous studies [10]. Second, the follow-up period of two years, while sufficient for initial conclusions, may not capture long-term PCO development. Extended follow-up studies are needed to assess the durability of the observed outcomes. Third, PCO assessment was based on slit-lamp bio-microscopy, which, while commonly used, may lack the precision of more advanced imaging techniques such as high-resolution digital retro illumination imaging with a Scheimpflug camera.

This study demonstrates that the addition of ketorolac to dexamethasone does not significantly reduce the incidence of PCO or delay the need for Nd:YAG capsulotomy compared to dexamethasone alone. These findings suggest that dexamethasone remains a viable option for postoperative management, with no significant added benefit from the inclusion of ketorolac. However, further research with longer treatment durations, extended follow-up periods, and advanced imaging techniques is warranted to explore the potential benefits of NSAIDs in PCO prevention. This study contributes to the growing body of evidence on PCO prevention and highlights the need for continued innovation in both pharmacological and surgical strategies to improve long-term visual outcomes following cataract surgery.

1. Donachie PH, Barnes BL, Olaitan M, Sparrow JM, Buchan JC. The Royal College of Ophthalmologists National Ophthalmology Database study of cataract surgery: Report 9, Risk factors for posterior capsule opacification. Eye. 2023 Jun;37(8):1633-9.
2. Wu Q, Li Y, Wu L, Wang CY: Hydrophobic versus hydrophilic acrylic intraocular lens on posterior capsule opacification: a meta-analysis. Int J Ophthalmol. 2022;15:997-1004.
3. Horn JD, Fisher BL, Terveen D, Fevrier H, Merchea M, Gu X: Academy Iris(®) registry analysis of incidence of laser capsulotomy due to posterior capsule opacification after intraocular lens implantation. Clin Ophthalmol. 2022, 16:1721-30.
4. Kwon YR, Hwang YN, Kim SM: Posterior capsule opacification after cataract surgery via implantation with hydrophobic acrylic lens compared with silicone intraocular lens: a systematic review and meta-analysis. J Ophthalmol. 2022, 2022:3570399.
5. Maedel S, Buehl W, Findl O: Intraocular lens optic edge design for the prevention of posterior capsule opacification after cataract surgery. Cochrane Database Syst Rev. 2017, 2017:CD012516.
6. Mylona I, Tsinopoulos I: A critical appraisal of new developments in intraocular lens modifications and drug delivery systems for the Prevention of cataract surgery complications. Pharmaceuticals (Basel). 2020, 13:448.
7. Hepsen IF, Bayramlar H, Gultek A, et al.: Caffeic acid phenethyl ester to inhibit posterior capsule opacification in rabbits. J Cataract Refract Surg. 1997, 23:1572-6.
8. Nishi O, Nishi K, Fujiwara T, Shirasawa E: Effects of diclofenac sodium and indomethacin on proliferation and collagen synthesis of lens epithelial cells in vitro. J Cataract Refract Surg. 1995, 21:461-5.
9. Nishi O, Nishi K, Yamada Y, Mizumoto Y: Effect of indomethacin-coated posterior chamber intraocular lenses on postoperative inflammation and posterior capsule opacification. J Cataract Refract Surg. 1995, 21:574-8.
10. Ozkul Y, Evereklioglu C, Borlu M, Taheri S, Calis M, Dündar M, Ilhan O: 5,10-Methylenetetrahydrofolate reductase C677T gene polymorphism in Behcet's patients with or without ocular involvement. Br J Ophthalmol. 2005, 89:1634-7.
11. Yao Y, Shao J, Tan X, et al.: Effect of diclofenac sodium combined with nuclear rotation on the prevention of posterior capsule opacification: two-year follow-up. J Cataract Refract Surg. 2011, 37:733-9.
12. Topete A, Tang J, Ding X, et al.: Dual drug delivery from hydrophobic and hydrophilic intraocular lenses: in- vitro and in-vivo studies. J Control Release. 2020, 326:245-55.
13. Lu D, Wang H, Feng C, et al.: Spin-coating-based facile annular photodynamic intraocular lens fabrication for efficient and safer posterior capsular opacification prevention. ACS Appl Mater Interfaces. 2022, 14:48341-55.
14. Flach AJ, Dolan BJ: Incidence of postoperative posterior capsular opacification following treatment with diclofenac 0.1% and ketorolac 0.5% ophthalmic solutions: 3-year randomized, double-masked, prospective clinical investigation. Trans Am Ophthalmol Soc. 2000, 98:101-7.
15. Tsuchiya T, Ayaki M, Onishi T, Kageyama T, Yaguchi S: Three-year prospective randomized study of incidence of posterior capsule opacification in eyes treated with topical diclofenac and betamethasone. Ophthalmic Res. 2003, 35:67-70.
16. Zaczek A, Laurell CG, Zetterström C: Posterior capsule opacification after phacoemulsification in patients with postoperative steroidal and nonsteroidal treatment. J Cataract Refract Surg. 2004, 30:316-20.
17. Borkenstein AF, Borkenstein EM: Geometry of acrylic, hydrophobic IOLs and changes in haptic-capsular bag relationship according to compression and different well diameters: a bench study using computed tomography. Ophthalmol Ther. 2022, 11:711-27.
18. Rajesh SJ: Study on buckling of intraocular lens haptic in 2 types of intraocular lens material and its effect on vision. Rom J Ophthalmol. 2020, 64:387-95.
19. Bose KS, Sarma RH: Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution. Biochem Biophys Res Commun. 1975, 66:1173-9.
20. Er H, Doganay S, Evereklioglu C, Erten A, Cumurcu T, Bayramlar H: Retrospective comparison of surgical techniques to prevent secondary opacification in pediatric cataracts. J Pediatr Ophthalmol Strabismus. 2000, 37:294-8.
21. Leydolt C, Schartmüller D, Schwarzenbacher L, Röggla V, Schriefl S, Menapace R: Posterior capsule opacification with two hydrophobic acrylic intraocular lenses: 3-year results of a randomized trial. Am J Ophthalmol. 2020, 217:224-31.
22. Darian-Smith E, Safran SG, Coroneo MT: Lens epithelial cell removal in routine phacoemulsification: is it worth the bother? Am J Ophthalmol. 2022, 239:1-10.