Cataract Surgery Alone Lowers Intraocular Pressure

Cataract Surgery Alone Lowers Intraocular Pressure

Does cataract surgery lower intraocular pressure (IOP)? How does this work? Is cataract surgery a stand-alone glaucoma treatment? These are the provocative questions that have lingered for the last few decades based upon surgeon experience and anecdotal report. Today, the relationship between cataract surgery and IOP reduction is clear. This has been documented in closed- and open-angle cases. Uniquely, there are now Level 1 randomized clinical trials (RCTs) that have provided high-level evidence that cataract surgery does lower IOP.

Does Cataract Surgery Lower IOP?

This question ends up being quite complex because cataract surgeries are done in different patients with different types of eyes. This is even true in glaucoma. Glaucoma patients routinely undergo cataract surgery similar to non-glaucomatous patients for the same reasons, including visual significance that impacts activities of daily living. However, glaucoma is a constellation of diseases and etiologies that just share the definition of optic neuropathy with associated visual field defects. Some patients have open-angle glaucoma and others have closed-angle glaucoma. Further, within each broad category (open versus closed) many subtypes exist.

The anecdotal experience that cataract surgery lowers IOP has been strongest for closed angles, even after removal of clear lenses.1 Thus, greater study was needed. A pair of influential studies were born, leading to a large RCT.

In a small, prospective RCT, medically uncontrolled, chronic angle-closure glaucoma Asian patients with cataracts received cataract surgery alone (n = 27) or combined cataract surgery and trabeculectomy (n = 24).2 Combined surgery outperformed cataract surgery alone in terms of final IOP (13.6 versus 15.9 mm Hg at 18 months; P=.01) and number of required glaucoma medications (1.25 fewer drops; P<.001).2 However, cataract surgery alone still lowered IOP (24.2 to 15.9 mm Hg at 18 months; P=.01) and reduced medication burden (3.3 to 1.6 drops at 18 months; P<.001) in a statistically significant fashion.2 Further, combined surgery had more complications (P<.001) and slightly greater glaucoma progression (P<.03) compared to cataract surgery alone.2

In a sibling small prospective RCT, medically uncontrolled chronic angle-closure glaucoma Asian patients without cataract received trabeculectomy (n = 24) or cataract surgery alone (n = 26).3 In this case, there was no difference in IOP lowering between trabeculectomy (8.9 mm Hg) and cataract surgery (8.4 mm Hg).3 Trabeculectomy eyes did require fewer postoperative glaucoma medicines (1.1 fewer; P<.001).3 However, similar to above with combined surgery, trabeculectomy resulted in more complications. One-third of the trabeculectomy patients developed cataracts within 2 years on their own, which necessitated cataract surgery.

Thus, the idea that cataract surgery lowered IOP was there, and the need for a large Level 1 RCT to directly address this question was raised. Fueled by these observations, the landmark EAGLE trial was performed4 to compare cataract surgery to medical management (Table). Aimed at cataract surgery in angle closure, EAGLE also tackled clears lens extraction (CLE). In 419 subjects with primary-angle closure or primary-angle closure glaucoma, subjects were randomized to receive CLE (n = 208) versus standard care (n = 211), including laser iridotomy and medical treatment.4 EAGLE trial results showed that compared to standard care, CLE resulted in lower IOP (16.6 ± 3.5 versus 17.9 ± 4.1 mm Hg; P=.004) with fewer medications (0.4 ± 0.8 versus 1.3 ± 1.0 drops; P<.001).4

Table: Impact of Cataract Surgery Alone in Large RCTs4,10,11

Name of Large RCT

Angle

Cataract Type

Approximate IOP Reduction
(Cataract Surgery Alone)

Approximate Medication Burden Reduction
(Cataract Surgery Alone)

EAGLE

Narrow

Clear Lens

~ 13 mm Hg

~ 0.6 drops

COMPASS

Open

Visually Significant

~ 5 mm Hg

~ 0.7 drops

HORIZON

Open

Visually Significant

~ 6 mm Hg

~ 1 drop


Using these data, researchers then asked if the difference seen in EAGLE was worth it?5 Markov models were created to extrapolate results at 5-year and 10-year horizons. Outcomes were (a) cost, (b) quality of life, and (c) cost-effectiveness ratio (assessed by combining cost and quality of life metrics). Naturally, the initial cost of CLE (~2500 British Pounds) was greater than that of medical management alone (~1500 British Pounds).5 Surgeries obviously cost more than lasers and drugs.5 However, extrapolated into the future, there was a calculated 67% to 89% chance that CLE was more cost-effective at 3 years.5 This was due to better quality of life. Further, simple cost savings could be realized at approximately 10 years because further surgeries and additional medications were not required.5 Thus, a cost and quality of life benefit was seen in cataract surgery compared to medical management.

Open Angles Too?

The question of whether cataract surgery lowered IOP in open angles was first tackled using retrospective analysis from the Ocular Hypertension Treatment Study (OHTS).6 OHTS was a prospective trial in which ocular hypertensive patients were randomized to receiving IOP-lowering therapy or not (control).7 The study was established to question the importance of IOP lowering, and the results showed that with IOP reduction there was a relative risk reduction for glaucoma of nearly 50%, with absolute risk reduction of ~5% (from ~10% untreated to ~5% treated).7 Then, within the control arm, patients received ocular standard-of-care and a subset of these patients (n = 63) underwent routine cataract surgery for visual significance.6 Retrospectively studied, after cataract surgery there was statistically significant IOP reduction (preoperative IOP: 23.9 ± 3.2 mm Hg and postoperative IOP: 19.8 ± 3.2; P<.001).6 Overall, there was an average 16.5% reduction in IOP, and 39.7% of subjects had ≥20% reduction. Control eyes not undergoing cataract surgery over the same time frame did not show IOP reduction (n = 743 eyes; 23.8 ± 3.6 mm Hg versus 23.4 ± 3.9).6 One major limit in this analysis was its retrospective nature, and mentally carried out it appeared that the IOP reduction may have begun to wane with time.

The advent of minimally invasive glaucoma surgeries (MIGS) provided a tidal wave of additional data. MIGS represent an explosion of small, safe, and rapid surgical options for IOP lowering in glaucoma. Most MIGS are coupled with cataract surgery and target the conventional outflow pathways by ablating or bypassing the trabecular meshwork (TM). During US Food and Drug Administration (FDA)-approval studies, cataract surgery alone arms were established.

The iStent was one of the original MIGS and used a snorkel-like device to bypass the TM, thereby creating a direct communication between the anterior chamber and Schlemm’s canal. Combined with cataract surgeries, initial landmark trials compared combined iStent and cataract surgery to cataract surgery alone. Using primary endpoints of IOP less than 21 mm Hg and greater than 20% IOP reduction, 72% (combined) and 66% (cataract surgery alone) of patients reached each of these endpoints at 1 year, respectively.8 By 2 years, the number of patients dropped to 50% and 44%, respectively.9 The number of glaucoma medications, while statistically significantly reduced in combined surgery compared to cataract surgery alone at 1 year (P=.001),8 was no longer significant at 2 years.9 Thus, the results showed that both cataract surgery and combined cataract plus MIGS were successful in lowering IOP. What was missing was a direct unmedicated IOP assessment in both arms at the end of the trial to isolate and separate the IOP lowering impact of the MIGS and cataract surgery alone.

Because early MIGS trials did not include unmedicated IOP measurements, the COMPASS and HORIZON studies were the first two RCTs to include at least 500 total eyes (MIGS and control groups combined) with terminal washout IOP measurements (Table).10,11 In the COMPASS multicenter RCT studying a supraciliary microstent, 187 subjects received cataract surgery alone.10 Unmedicated baseline IOP (24.5 ± 3.0 mm Hg) dropped after cataract surgery alone (19.3 ± 3.3 mm Hg; P<.001) at 2 years.10 Sixty percent of subjects had IOP reduction ≥20%.10

In the HORIZON multicenter RCT studying a Schlemm’s canal microstent, 131 subjects received cataract surgery alone (Table).11 Unmedicated baseline IOP (25.4 ± 2.9 mm Hg) dropped after cataract surgery alone (19.2 ± 3.8 mm Hg; P<.001) at 2 years.11 Fifty-eight percent of subjects had IOP reduction ≥20%. In both trials, there was also a significant decrease in medication burden after cataract surgery alone.11

The pivotal study results for iStent Inject (a third major MIGS RCT) are pending publication and have been reported at national meetings,12 also demonstrating significant IOP reduction in cataract surgery control arms in a large number of subjects with unmedicated IOP assessments.

On August 29, 2018, the CyPass Micro-Stent was voluntarily withdrawn from the global market, based on 5-year post-surgery data from the COMPASS-XT long-term safety study, which demonstrated a clinically and statistically significant increase in corneal endothelial cell loss reported in the CyPass Micro-Stent group compared to the cataract surgery-only control group.13

So How Does This Work?

Although observing IOP reduction is necessary to conclude that cataract surgery can lower IOP, understanding the mechanism reassures this observation while providing an opportunity to discover new mechanisms to target for IOP lowering in the future. The Goldman equation calculates IOP: (Fin - Fout)(R) + EVP (IOP = intraocular pressure [mm Hg]; Fin = aqueous production [µl/min]; Fout = unconventional outflow [µl/min]; R = conventional outflow resistance [mm Hg*min/µl]; and EVP = episcleral venous pressure [mm Hg]).14,15 For cataract surgery, IOP reduction must occur via change to at least one of these parameters. Recently, aqueous humor dynamic assessment has shown an increase in tonographic outflow facility (or decrease in resistance) after cataract surgery.16,17 Additionally, the level of tonographic outflow facility improvement fully accounted for the IOP reduction that was seen in some cases.18 However, the mechanism by which cataract surgery leads to improved outflow facility is still unclear. Hypotheses include mechanical ones where the angle is physically more expanded after cataract surgery. Molecular explanations exist, akin to trabeculoplasty,19 where cytokine alterations (possibly from the phacoemulsification ultrasound energy) could change trabecular biology.

So, Is Cataract Surgery a Treatment for Glaucoma?

To ultimately consider treating an optic neuropathy with associated visual field defects using phacoemulsification of a lens (cataract or otherwise) alone is provocative. In a case of progressing optic neuropathy from IOP that is too high, the priority is still to lower IOP effectively first, and cataract surgery in open angles alone is likely insufficient. The magnitude of IOP reduction (~5-6 mm Hg) does not rival that of conventional glaucoma surgeries, and thus cataract surgery is insufficient to replace glaucoma surgeries as the primary surgical option for patients with IOP too high for their optic nerves in advanced open-angle cases. However, in mild and moderate open-angle glaucoma cases, the story may be different. A modest IOP reduction in these cases may yield long-term benefit and limitation complications associated with any future glaucoma surgery. Let’s face it, there is a reason why in every case of complicated glaucoma surgery, one of the first questions asked is: “Tell me if the patient is still phakic?”

For closed-angle glaucomas, cataract surgery alone may be a real consideration now. The EAGLE study has shown that cataract surgery can be first-line care and cost effective.4 Further, all anterior segment surgeons know that cataract surgery has fewer severe complications compared to traditional glaucoma surgeries.3 Armed with these data, the time to alter the standard of care and initiate an open discussion with health care payers and regulators may be at hand.

To look at this argument from a different perspective, it may be helpful to consider the benefits of phakic status and why should it be protected. In the young, maintained accommodation is a real and positive benefit. In the old, the only benefit of phakic status may be a benefit of exclusion, the exclusion of having avoided risks of one of the safest surgeries in the world. Thus, outside of the young, there really isn’t that much benefit or reason to insist on maintaining phakic status.

The next step is to obtain longer-term follow-up of patients from previous high-quality RCTs. Further, better understanding of the exact mechanisms of how cataract surgery lowers IOP will be important. By fully comprehending the underlying mechanism of how cataract surgery works, future novel directed therapies could be devised to lower IOP even better than something we already know works today—cataract surgery alone.

References

  1. Barbosa DT, Levison AL, Lin SC. Clear lens extraction in angle-closure glaucoma patients. Int J Ophthalmol. 2013;6(3):406-8.
  2. Tham CC, Kwong YY, Leung DY, et al. Phacoemulsification versus combined phacotrabeculectomy in medically uncontrolled chronic angle closure glaucoma with cataracts. Ophthalmology. 2009;116(4):725-31, 31.e1-3.
  3. Tham CC, Kwong YY, Baig N, et al. Phacoemulsification versus trabeculectomy in medically uncontrolled chronic angle-closure glaucoma without cataract. Ophthalmology. 2013;120(1):62-7.
  4. Azuara-Blanco A, Burr J, Ramsay C, et al. Effectiveness of early lens extraction for the treatment of primary angle-closure glaucoma (EAGLE): a randomised controlled trial. Lancet. 2016;388(10052):1389-97.
  5. Javanbakht M, Azuara-Blanco A, Burr JM, et al. Early lens extraction with intraocular lens implantation for the treatment of primary angle closure glaucoma: an economic evaluation based on data from the EAGLE trial. BMJ Open. 2017;7(1):e013254.
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  7. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-13; discussion 829-30.
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  10. Vold S, Ahmed II, Craven ER, et al. Two-Year COMPASS Trial Results: Supraciliary Microstenting with Phacoemulsification in Patients with Open-Angle Glaucoma and Cataracts. Ophthalmology. 2016;123(10):2103-12.
  11. Samuelson TW, Chang DF, Marquis R, et al. A Schlemm Canal Microstent for Intraocular Pressure Reduction in Primary Open-Angle Glaucoma and Cataract: The HORIZON Study. Ophthalmology. 2019;126(1):29-37.
  12. Samuelson T. Second-Generation Trabecular Microbypass Stents Implanted in Conjunction with Cataract Surgery: Prospective Randomized Study. Presented at: ASCRS 2018. April 14, 2018. Available at: https://ascrs.confex.com/ascrs/18am/meetingapp.cgi/Paper/45148.
  13. US FDA. Alcon Research, LTD. Recalls CyPass Micro-Stent Systems Due to Risk of Endothelial Cell Loss https://www.fda.gov/MedicalDevices/Safety/ListofRecalls/ucm624282.htm. Accessed January 2, 2019.
  14. Brubaker RF. Goldmann's equation and clinical measures of aqueous dynamics. Exp Eye Res. 2004;78(3):633-7.
  15. Larsson L-I, Alm A. Clinical Aspects of Uveoscleral Outflow. In: Alm A, Kaufman PL, Kitazawa Y, et al., eds. Uveoscleral Outflow: Biology and Clinical Aspects. London: Mosby-Wolfe.
  16. Alaghband P, Beltran-Agulló L, Galvis EA, et al. Effect of phacoemulsification on facility of outflow. Br J Ophthalmol. 2018;102(11):1520-6.
  17. Meyer MA, Savitt ML, Kopitas E. The effect of phacoemulsification on aqueous outflow facility. Ophthalmology. 1997;104(8):1221-7.
  18. Overby DR, Stamer WD, Johnson M. The changing paradigm of outflow resistance generation: towards synergistic models of the JCT and inner wall endothelium. Exp Eye Res. 2009;88(4):656-70.
  19. Kagan DB, Gorfinkel NS, Hutnik CM. Mechanisms of selective laser trabeculoplasty: a review. Clin Exp Ophthalmol. 2014;42(7):675-81.
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