Phacoemulsification cataract surgery (phaco) is a potential approach for reducing IOP in glaucoma patients. The effect is typically mild in those without glaucoma, and appears to be greater in eyes with glaucoma, particularly with angle closure disease.

Angle closure disease is a clinical spectrum that encompasses patients in three categories: primary angle closure suspect (PACS), primary angle closure (PAC), and primary angle closure glaucoma (PACG). PACS is defined in an eye that has 180 degrees or more of occludable angle. An occludable angle is present when the gonioscopy examination shows grade 1 or less (Shaffer classification system). PAC is defined in those eyes that meet PACS criteria and also have presence of peripheral anterior synechiae and/or IOP greater than 21 mmHg. PACG is PAC with optic nerve and/or visual field abnormalities that define glaucoma. The term ‘acute angle closure glaucoma’ (acute ACG) is used to represent angle closure eyes with rapid IOP elevation.

A growing body of evidence demonstrates that IOP is significantly reduced after phaco.¹ Data from a recent review paper showed that the IOP lowering is modest in primary open-angle glaucoma with a 13% IOP reduction, and the reduction in number of medications is modest as well. Results are significantly better in eyes with angle closure disease. PACG provides a nearly 30% reduction in IOP and 53% decrease in number of medications. For acute ACG, the pressure goes down substantially (71%), and there is almost no need for post-phaco medications. Among open- and closed-angle glaucomas, subsequent trabeculectomy was found to be uncommon after phaco in this review.²

Is cataract extraction safe and effective for patients with angle closure disease?

With aging, the crystalline lens thickens and loses its clarity, becoming a cataract. The thick cataractous lens could worsen the preexisting narrow anterior chamber angle in an angle closure patient. Hence, it seems reasonable that cataract extraction would be an option for the management of PACG. Numerous studies over the past decade also support this idea.

Anatomical studies using ophthalmic imaging have demonstrated that the angle deepens substantially after lens extraction in eyes with angle closure, even with an existing laser peripheral iridotomy (LPI). A Japanese group evaluated more than 100 patients who had residual angle closure. After undergoing cataract surgery, all eyes experienced improvement of the angle as assessed by ultrasound biomicroscopy (UBM).³ Likewise, a study from India showed an increase in angle parameters measured by anterior segment optical coherence tomography (AS-OCT).⁴ Thus, mechanically, the angle improves significantly after phaco.

For the IOP-lowering aspect, a research group in Hong Kong conducted a trial in people who had cataract when presenting with acute ACG. They compared outcomes between early phaco versus standard care including LPI, and phaco showed far greater success (defined as pressure less than 21 mmHg after treatment). At 18 months, phaco was more effective than LPI, particularly in acute attacks with IOP > 55 mmHg. From the same study, the phaco group also outperformed in three categories: medication, IOP, and gonioscopy grading.⁵

Another study focused on eyes having PACG with controlled IOP and a coexisting cataract and aimed to compare the effect of phaco alone versus combined phaco-trabeculectomy. Although the combined group was shown to be more effective in IOP control, the study also demonstrated that IOP and number of medications decreased substantially after phaco alone. Furthermore, the phaco group had significantly less complications. Interestingly, no significant differences in visual acuity and visual field (VF) progression were observed during the 2-year study period.⁶

What about clear lens extraction?

There are many studies that support cataract extraction as a method to improve IOP control in situations of concomitant cataract and angle closure. However, what about performing phaco in an eye without a visually significant cataract? Is this approach the optimal first-line therapy for angle closure instead of standard LPI?

Data from a case series in 2013 suggested a benefit of performing clear lens extraction.⁷ They reported five cases of acute ACG or PACG. All patients were using maximally tolerated medications with IOP ≥ 21 mmHg. All cases were on the verge of trabeculectomy or tube surgery. None of them had a visually significant cataract, and best-corrected vision was close to or equal to 20/20. Clear lens extraction was performed. Four of the cases were considered successes, with fewer medications, well-controlled IOP, and no need for additional surgery. Three out of the four were essentially "complete successes" and did not need any glaucoma medications afterward. Only one of the five cases was unsuccessful, with unchanged IOP, medications, and visual acuity after surgery, and required a trabeculectomy.

Learnings from the EAGLE Study

The best evidence so far that supports the role of initial clear lens extraction is the recently published EAGLE (Effectiveness in Angle Closure Glaucoma of Lens Extraction) study.⁸ The authors reported the effectiveness of performing phacoemulsification in patients with a clear lens and concomitant PAC/PACG. This was a multicenter, randomized, controlled trial in 30 hospitals in five countries: Australia, mainland China, Hong Kong, Malaysia, Singapore, and the United Kingdom. Randomization was to clear lens extraction versus standard care, including LPI and topical medication, as first-line therapy. The study included people who were 50 years or older without symptomatic cataract and they had to be newly diagnosed PAC with IOP > 30 mmHg or PACG. Main outcomes were evaluated for three co-primary endpoints: patient-reported health status, IOP, and cost-effectiveness ratio. Of 419 total subjects, most were PACG (263), and enrollees were randomized into clear lens extraction (208) and standard care (211). The final outcomes were assessed at 3 years.

Health status was evaluated using the European Quality of Life 5 Dimensions (EQ-5D) survey, which includes mobility, self care, usual activity, pain/discomfort, and anxiety/depression. The group that had clear lens extraction had overall better results. However, although the clear lens extraction group had better outcomes, it may be interpreted that the actual differences in terms of absolute values seem mild, e.g., with a EQ-5D difference in post-treatment change between the two groups of 0.052 (95% CI 0.015 to 0.088) (Table 1).

IOPs at the 3-year follow-up were improved in both groups. IOP decreased from 29.5 mmHg to 16.6 mmHg in the clear lens extraction group and from 30.3 mmHg to 17.9 mmHg in the standard care group. Though IOP reductions were better in the clear lens extraction group, the actual difference was not that substantial (1.18 mmHg with 95% CI 0.38 to 1.99). There was also a difference between the two groups in terms of fewer medications in the clear lens extraction group.

For the cost-effectiveness analysis, the cost was higher in the surgical group. Also, the quality adjusted life year (QALY) value was greater in the surgery group. The incremental cost effectiveness ratio (ICER), which is the difference of the cost divided by the difference of treatment effect, was GBP 14,284 per QALY. This result met the criteria for level of acceptable incremental cost. It should be noted that although the clear lens extraction group started off with high initial procedure costs, the incremental costs in this group are partly offset over the follow-up period. It can be assumed that there would be a trend of improvement in cost effectiveness of clear lens extraction over longer-term follow-up. However, the ICER reported here was calculated only for the subsets in the UK, thus, it may not be applicable to other geographical settings, such as third world countries.

Besides these three primary endpoints, the EAGLE study also reported other outcomes including additional measures of quality of life, vision, and safety of each treatment. For the vision-related quality of life assessment, the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) as well as Glaucoma Utility Index outcomes were assessed and found to be better in the clear lens extraction cohort. Best-corrected visual acuity was tested with ETDRS charts, and also showed better results in the clear lens extraction group. However, the visual field data demonstrated no significant difference, which is not surprising due to the relatively short follow-up. Longer-term follow up, such as 5 years, may be necessary to realize the benefit of performing clear lens extraction compared with standard care.

In terms of adverse effects, there were no serious adverse events in either group. Notably, there was only 1 out of 208 cases in the surgery arm that required additional glaucoma surgery, while the control group had about 10% of participants needing additional surgery, most of which were lens extraction and trabeculectomy.

The EAGLE study provides answers to long-awaited questions regarding the benefit of using phaco as a first-line treatment for primary angle closure disease. The study has the advantages of being multicenter, with a pragmatic design and large sample size. Along with the safety of performing primary phaco, the study reported the relatively consistent superiority of clear lens extraction in terms of clinical benefits and quality of life. Nevertheless, the generalizability of the compelling results is something we need to bear in mind. First, the study population was limited to individuals aged 50 years and older. To perform phaco in younger subjects who may still have their accommodation preserved could result in negative effects on their quality of life. Second, the study excluded advanced glaucoma cases and most of subjects in the trial were in the mild stage of glaucoma with an average MD -3 to -4 dB. Additional benefits and safety of clear lens extraction in moderate and advanced cases have not yet been proven. Third, it should be emphasized that only the PAC subjects who had IOP > 30 mmHg were recruited for the study. This subset is likely not very common in routine practice. Ultimately, the investigators in the EAGLE study should be congratulated for providing important data regarding the treatment of angle closure glaucoma that can have practical and far-reaching applications in the real world.

Promising Results

Cataract surgery is a safe and effective surgical option for PACG patients with coexisting cataract. The EAGLE study provides excellent evidence to support clear lens extraction in PAC and PACG patients in terms of efficacy, safety, quality of life, and cost effectiveness. Future studies and analyses will provide additional answers regarding clear lens extraction in younger subjects and earlier and later forms of angle closure disease. GP

References

1. Armstrong, et al. J Glaucoma. E-pub ahead of print: March 22, 2017.
2. Chen PP, et al. Ophthalmology. 2015;122(7):1294-1307.
3. Nonaka A, et al. Ophthalmology. 2005;112(6):974-979.
4. Dada T, et al. J Cataract Refract Surg. 2015;41(7):1470-1477.
5. Lam DS, et al. Ophthalmology. 2008;115(7):1134-1140.
6. Tham CC, et al. 2008;115(12):2167-2173.
7. Barbosa DT, et al. Int J Ophthalmol. 2013;6(3):406-408.
8. Azuara-Blanco A, et al. Lancet. 2016;388(10052):1389-1397.

Dr. Chansangpetch is an instructor at Chulalongkorn University and King Chulalongkorn Memorial Hospital and a visiting assistant professor of ophthalmology at the University of California, San Francisco. She can be reached at sunee.ch@chula.ac.th.

Dr. Lin is a professor of ophthalmology and director of the glaucoma service at the University of California, San Francisco. He can be reached at shan.lin@ucsf.edu.