• ZAP, LiGHT & SALT

    Written By: Annie Stuart, Contributing Writer

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    Should prophylactic laser peripheral iridotomy (LPI) be used extensively for primary angle-closure suspects (PACS)? Are eye drops and selective laser trabeculoplasty (SLT) comparable first-line treatments for primary open-angle glaucoma or ocular hypertension? Is inflammation helpful or a hin­drance after SLT?

    In 2019, three glaucoma studies—ZAP, LiGHT, and SALT—addressed these very issues.1-3 “We’re lucky to have some high-quality studies on questions that are hard to answer,” said Jo Ann A. Giaconi, MD, at the University of California, Los Angeles. “Whether simply confirming what we already thought to be true or exploring new areas, they’re very helpful,” added L. Jay Katz, MD, of the Wills Eye Glaucoma Service in Philadelphia.

    ZAP: Prophylactic LPI for Primary Angle-Closure Suspects

    In the early 1900s, researchers found that an iridectomy could relieve acute attacks of high pressure in eyes of patients with narrow-angle glaucoma, said David S. Friedman, MD, PhD, MPH, at Harvard Medical School in Boston. Ophthalmolo­gists also performed this procedure in the fellow eye, which had a very high chance of getting an acute attack, he said.

    Laser peripheral iridotomy. In the mid-1970s, LPI became the first-line treat­ment for primary angle-closure glaucoma. With the advent of laser, the risk-bene­fit ratio favored treatment over observation, so LPI also became a common treat­ment for patients with narrow angles, said H. George Tanaka, MD, at Vold Vision in Fayetteville, Arkansas. These primary angle-closure suspects have an increased risk of an acute attack but have healthy nerves, normal intraocular pressure (IOP), no peripheral anterior synechiae (PAS), and no other symptoms.

    “We’re always balancing risks and benefits with patients,” said Dr. Katz. “What’s the worst-case scenario if you develop angle-closure glaucoma? Pretty awful.” On the other side of the coin, “What’s the worst-case scenario with an iridotomy? A little inflammation, bleeding, or corneal edema, usually temporary,” he said. Although less common, the main long-term problem is glare. “Out of an abun­dance of caution, we’ve been erring on the side of doing an LPI because you just never know,” said Dr. Giaconi, adding that the risk of angle-closure glaucoma is higher for patients who don’t follow up regularly.

    The downside of this approach? There have been no guidelines or clinical evidence to support using LPI for all primary angle-closure suspects, said Dr. Tanaka. “That’s why studies like ZAP are so important.”

    ZAP study design. In this six-year, randomized controlled trial, bilateral PACS patients between 50 and 70 years old were enrolled at a tertiary specialized hospital in Guangzhou, China. Eligible patients received LPI in one randomly selected eye, with an untreated contralateral control.

    The primary outcome was PAC disease, a com­posite of three different endpoints: an increase in IOP, PAS, or acute angle closure. “In untreated eyes, PAS was by far the most common,” said Dr. Friedman, a ZAP coauthor. “But PAS is a slow, benign process that doesn’t result in visual loss or affect the patient’s life if pressures remain normal.”

    Fewer attacks than expected. This study reaf­firmed that acute angle closure is less common in at-risk eyes than previously thought and that the rate of developing PAS and elevated IOP is rela­tively slow, said Dr. Giaconi.

    “Most attacks occurred after dilation,” said Dr. Friedman, “which was a part of our protocol to allow observation of any impact iridotomy had on the devel­opment of cataract. Without dilation, only two cases of acute attacks occurred in nearly 900 untreated eyes followed for six years.”

    Older studies. “A similar earlier study reported nearly three times the rate of acute attacks,” said Dr. Friedman. “We based our sample size on the assumption of more events, which just didn’t happen.” Why the differ­ence? One possible reason, said Dr. Giaconi, is that the ZAP study screened many patients in the community instead of at tertiary clinics, where patients who show up may already have subtle signs and symp­toms such as headache.

    Another reason could be that past definitions of PACS and PAC have lacked precision, said Dr. Tanaka. And studies have used different criteria for occlusion, measured by gonioscopy, a some­what subjective assessment resulting in variations in grading, added Dr. Katz.

    Risk-benefit ratio: a new view. This study revealed that you needed to treat 44 PACS patients to prevent one case of primary angle closure in six years, said David Garway-Heath, MD, MBBS, FRCOphth, at Moorfields Eye Hospital in London. “One would imagine you’d need to treat even more to prevent one significant case of visual loss as a consequence of primary angle closure.”

    The conversion rate was much lower than pre­viously reported, said Dr. Tanaka. “This really sup­ports the notion that observing low-risk primary angle-closure suspects is usually fine. Conversely, treating all primary angle-closure suspects with laser iridotomy is definitely overtreatment.”

    LPI risks. As for LPI risks, the findings were mostly confirmatory, said Dr. Giaconi. In addition to assessing the more common side effects, the researchers also specifically looked at the endothe­lial cell count of the cornea, which didn’t change, said Dr. Friedman. The study also didn’t find an increased risk for cataract progression, but at least one other study4 has, said Dr. Tanaka, who has also seen this in his practice.

    Study strengths and limitations. Dr. Giaconi called ZAP a very strong study, but she would have liked to see data on the measurement of lens vault, which is a risk factor for pupillary block and acute angle attacks in other Asian studies. Overall, she said, “The researchers really thought about their inclusion and exclusion criteria and how to gather data.” The study also verified endpoints with a second observer, said Dr. Friedman.

    Dr. Tanaka pointed to three major strengths of the study: 1) Each patient served as his or her own control. 2) Follow-up was six years—extend­ed to recruit more patients because the number of endpoints met at three years was so low. 3) All patients essentially received a provocative test: dilation.

    The main limitation of the study is the inability to generalize results to other populations. “Angle closure in China may not be the same as in the United States, for example,” said Dr. Katz, citing different demographics and eye anatomies, and potentially different mechanisms of action. On the plus side, Dr. Friedman doesn’t think the rates would be higher elsewhere. That’s because Chinese have among the highest rates of acute attacks.

    “Along with others in the United Kingdom, the Working Group for the Royal College of Oph­thalmologists will make recommendations for how to implement the results of this study in our population,” said Prof. Garway-Heath. And the Academy’s updated Preferred Practice Patterns for glaucoma are expected to be published in early 2021.

    Practice implications? “ZAP has made me think that I don’t want to search for angle-closure sus­pects because I’m not sure we benefit tremendous­ly by finding them,” said Dr. Friedman. “From a public health standpoint, I think we should change what we are doing.”

    Dr. Katz agrees that the public health mes­sage is clear, and that it’s reassuring most people will be fine, even if never diagnosed. “But I’m a physician, and once I have a patient with a narrow angle in front of me, it’s my obligation to describe the risks, options, warning signs of acute angle closure, and need for follow-up. Then it’s the patient’s right to decide what to do.”

    However, this study makes it easier to reassure primary angle-closure suspects that observation is often a reasonable approach, said Dr. Tanaka. “If you don’t have LPI, your actual risk of an acute attack is on the order of 1% or less over six years.” Dr. Tanaka would only recommend a laser iridoto­my in a subset of patients, specifically those who:

    • have symptoms such as headaches or eye pain that suggest the onset of primary angle closure,
    • have a family history of angle closure,
    • may need dilated exams for diabetes, and/or
    • may not follow up or may travel to remote areas.

    In addition, Dr. Giaconi recommends an iri­dotomy for patients with signs such as PAS, high IOP, or an anterior lens surface that vaults into the anterior chamber.

    When to Do LPI

    Consider LPI in patients who have the following:

    • symptoms such as headaches or eye pain that suggest the onset of primary angle closure,
    • a family history of angle closure,
    • signs such as PAS, high IOP, or an anterior lens surface that vaults into the anterior cham­ber.

    Or those who may need dilated exams for diabetes and/or may not follow up or may travel to remote areas.

    LiGHT: SLT or Eyedrops as First-Line Treatment

    In 1990, the multicenter, NEI-funded Glaucoma Laser Trial evaluated argon laser trabeculoplasty (ALT), a predecessor to selective laser trabecu­loplasty (SLT).5 “The large study showed that it [ALT] was equally, if not more, effective than timolol in controlling the pressure in patients with glaucoma,” said Dr. Katz, “but it never really changed our practice.”

    Smaller trials leading up to LiGHT showed similar results with SLT: It worked as well as lat­anoprost as a first-line therapy to lower pressure with minimal side effects, he said. But still there was little movement away from drops. “About 15 years ago, our Medicare billing study6 showed that SLT was being done in less than 5% of people with glaucoma,” said Dr. Friedman.

    An eyedrops bias? Why the continued reluc­tance to use SLT? There are likely many contribu­tors, ranging from provider inertia to patient fears and misconceptions. “When you say ‘laser’ to patients, it can conjure up James Bond being cut in half,” said Prof. Garway-Heath. “Some clinicians also refer to laser as surgery. We tend not to in the United Kingdom, lump­ing it in with medical, rather than surgical, treatment.”

    Although the literature has made a fairly compelling case for laser trabeculoplas­ty as a first-line treatment, Prof. Garway-Heath said it’s often been reserved as an add-on treatment in patients who have IOP that’s been difficult to control with medication. “And in gener­al, add-on treatments are less effective than primary treatments,” he said, indicating that this may be an important reason laser has been perceived as having low efficacy in the real world.

    Not only is SLT less effective when used as an add-on treatment, said Dr. Katz, but these patients are more likely to experience pressure spikes, inflammation, and other problems. “These are people who are already hanging onto the cliff with their fingernails,” he said. “Zapping them with laser might push them over the edge.”

    LiGHT study design. With help from patients, LiGHT compared SLT with latanoprost eyedrops as first-line treatments for ocular hypertension and glaucoma. “In the United Kingdom, we involve patients in the design of studies and ask them about their outcomes of interest,” said Prof. Garway-Heath, a LiGHT coauthor. “The advice we get from patients is very helpful.”

    Before conducting the LiGHT study, patients told the researchers that being drop free was im­portant to them, he said. This helped the research­ers craft a different kind of study than had been done in the past, one where the main outcomes were related to patient quality-of-life (QoL) measures and cost effectiveness; an important outcome was achieving target pressures without the need for eyedrops.

    Efficacy and safety of SLT. “This study con­firmed what we knew from our clinical experience—that SLT is about as effective as one drop of latanoprost,” said Dr. Tanaka. “I have offered it as a first-line treatment for a while, even before studies like LiGHT.” Although the study also reaffirmed Dr. Giaconi’s thinking and approach, the side effects of SLT were fewer and the benefits greater than she’d previously described for her patients.

    “In the LiGHT trial, lack of compliance might account for the higher rate of progression in the medically treated patients,” said Dr. Tanaka. “Based on some studies, compliance rates at best may be 50% with a once-a-day drop. If you add a second drop, compliance goes down even further.”

    Based on previous literature, Prof. Garway-Heath was also not surprised by the efficacy and safety of the laser. “However, I was a little dis­appointed that we didn’t see more on the quali­ty-of-life outcomes, which all slightly favored the laser but were not statistically significant,” he said. “The larger differences were, as expected, with the ocular surface questionnaire. The main QoL outcome was chosen to allow the calculation of quality-adjusted life years, but it is a fairly blunt QoL instrument.”

    Cost-effectiveness of drops versus laser. “Giv­en that we were expecting more or less equivalence between the two types of treatment in effective­ness, the superiority in SLT’s cost-effectiveness re­ally stood out,” said Prof. Garway-Heath. However, Dr. Tanaka would expect an even larger difference in the United States because patient co-pays and deductibles can be high. If the laser doesn’t have longevity, it won’t save much, said Dr. Tanaka. But if bilateral SLT lasts four years, that’s the equiva­lent of nearly 3,000 drops of medication.

    Repeat treatments. “In LiGHT, repeated treatment ended up working in a lot of people,” said Dr. Friedman, adding that his past practice has been to stop if the laser didn’t work the first time. “I will now likely change my algorithm and try again after six to eight weeks if it doesn’t work the first time.” In LiGHT, the second treatment actually lowered pressures relatively more than the first treatment, Dr. Giaconi pointed out.

    Unlike its predecessor, SLT seems to be much more amenable to repeat treatment, said Dr. Katz. This study had a defined protocol of treating 360 degrees, but in the “real world,” practices may vary, making it harder to know exactly how effec­tive retreatment will be and for how long.

    Study strengths and limitations. “Funded by the U.K.’s National Institute for Health Research, LiGHT was a large, well monitored, and very well implemented study—pretty definitive,” said Dr. Friedman.

    Dr. Tanaka pointed out one caveat. “The pro­tocol doesn’t reflect what U.S. ophthalmologists do in real life,” he said. In the laser arm, patients received laser and a second laser if the first didn’t work. If that was unsuccessful, patients were put on drops and received surgery if drops didn’t control pressures. In the eyedrops arm, doctors immediately offered patients surgery if medical treatment failed.

    “In the United States, we offer patients laser before surgery if they choose not to use eyedrops or if eyedrops fail,” said Dr. Tanaka. “This has been the traditional paradigm for 20 years.” The LiGHT protocol largely explains why 11 patients in the medically treated group needed surgery, he said. If they had been offered laser before surgery, this number might be lower.

    Change practice? “Like many other ophthal­mologists, I often didn’t think of laser as part of the first-line treatment conversation,” said Prof. Garway-Heath. “Now I do. It’s routine for me to tell patients that they have three options—either to be observed, have laser, or have drops.”

    If you are a public health official, the results of the study would suggest laser for everybody with early-to-moderate open-angle glaucoma, said Dr. Katz, and the addition of medications and other surgery as needed. “But talking to an individual is different than looking at this from a public health perspective,” he said, adding that he doesn’t like to push patients against the wall. However, the study does help with these conversations. “I feel more confident telling patients that we have a study strongly supporting laser as a first-line therapy.”

    Dr. Giaconi agrees, and she uses the study results to reassure patients not only about laser’s efficacy, but also its safety. “I explain that it reju­venates the drain, like laser rejuvenates the skin.” She also works in a VA glaucoma clinic, where SLT is often used as a last step before surgery. “I shared this paper with our residents and optometry ser­vice,” she said, explaining that it often makes sense to refer patients for SLT, rather than prescribing drops and holding on to patients.

    SALT: Improving SLT Outcomes With Anti-Inflammatories

    SLT is relatively benign, said Dr. Tanaka. However, using more energy with certain patients, such as those with less pigment in the angle, can cause photophobia or discomfort in the hours or days after the laser—which can be bothersome in some people, he noted.

    “Because they don’t want to get the phone call, some physicians automatically put SLT patients on steroids or NSAIDs after SLT,” said Dr. Tanaka. Others have been concerned that reducing the postlaser inflammatory response might lessen the efficacy of the laser, interfering in some way with its mechanism of action. “Nobody knew who was right,” said Dr. Tanaka.

    Results of the study. The purpose of SALT was to examine whether short-term topical steroids or nonsteroi­dal anti-inflammatory drugs (NSAIDs) after SLT could improve its efficacy.

    In fact, patients in this study who used steroids or NSAIDs did better at three months than those who did not. Compared with place­bo, the steroid group had a 2 mm Hg IOP decrease, and the NSAID group had a more than 3 mm Hg IOP decrease. Dr. Tanaka found it striking that im­mediate postoperative treatment given only four times a day for four days could produce such a large effect at 12 weeks. There was no difference in response at six weeks. A blunting of the inflamma­tory response might explain why, said Dr. Tanaka.

    Study limitations and strengths. “SALT is the sort of study that is indicative, rather than definitive,” said Prof. Garway-Heath. “It is quite small with only about 30 patients per group. And, even though it was randomized, there was quite a difference in the number of eyes treated—28 in the NSAIDS group and 37 in the steroid group.”

    Because it was left up to the clinician, there were also fairly large differences between the groups in the intensity of treatment given, he said. “In the NSAIDs group, only 25% had a 180-de­gree treatment and in the saline group, it was 45%,” said Prof. Garway-Heath. “This might partly explain pressure differences.”

    This study also had a limited follow-up peri­od. However, Prof. Garway-Heath said that the LiGHT study found two-month post-treatment pressures were a good indicator of future pressure control, suggesting that ophthalmologists should not automatically dismiss the 12-week results in SALT.

    Time to change practice? Professor Garway-Heath and Dr. Katz aren’t quite there yet. “I think this is good evidence but not sufficient to change practice,” said Prof. Garway-Heath. Dr. Katz also has concerns about the size and length of the study, as well as questions about how clini­cians’ different laser practices—number of shots, amount of energy, or degree of treatment—might produce different outcomes.

    On the other hand, Drs. Friedman, Tanaka, and Giaconi are less circumspect. “A short course of medication after SLT is not risky,” said Dr. Giaconi, “and it is beneficial if it gains patients a few extra millimeters of mercury.”

    Dr. Friedman found the effect “a little biologi­cally hard to believe. “But does it influence how I will behave?” he asked. “Yes. In my view, providing a steroid or NSAID is probably the better decision. Given the strong findings in favor of treatment, it is unlikely that a second study will show that treat­ment adversely affects the procedure.”

    Dr. Tanaka is also reassured. “This shows us that we can treat patients for comfort following a pretty benign procedure and not worry it will limit its effectiveness,” he said. “It works hand in hand with LiGHT: Be generous in offering patients laser and afterward, feel free to give an anti-inflammatory.”

    ZAP, LiGHT, and SALT

      Participants Length Outcomes Results
    ZAP 889 primary angle-closure suspects Contralateral eyes as controls 72 months Primary angle closure disease as a composite endpoint of increased IOP, PAS, or acute angle closure

    A primary outcome event occurred in:

    • 19 treated eyes
    • 36 untreated eyes No serious adverse events
    LiGHT

    718 participants with:

    • 356 in the SLT group
    • 362 in the eyedrops group
    36 months

    Primary outcome: HRQoL assessed by EQ-5D

    Secondary outcome: 

    • Cost and cost-effectiveness
    • Disease-specific HRQoL
    • Clinical effectiveness
    • Safety

    Primary outcome: No significant difference between the two groups

    Secondary outcome: 

    • 97% probability of SLT as first treatment being more cost-effective than eyedrops
    • 74.2% in SLT group required no drops to maintain IOP at target
    • Eyes in SLT group were within IOP targets at more visits than eye in eyedrops group
    • Surgery required in 11 of eyedrops group vs. zero in SLT group
    SALT 96 eyes of 85 individuals randomized to one of three groups before SLT: ketorolac 0.5%, prednisolone 1%, or saline. Drops were used 4x/day for five days, starting the day of SLT. 12 weeks

    Primary outcome: IOP at 12 week

    Secondary outcome: 

    • IOP at 1 and 6 weeks
    • Patient-reported pain
    • Detectable anterior chamber inflammation

    Primary outcome: Statistically significant decrease in IOP in both steroid and NSAIDs groups compared to placebo

    Secondary outcome: No statistically significant differences between groups:

    • In IOP at 6 weeks
    • In discomfort at 1 hour and 1 week
    • In inflammation at 1 hour and weeks 1, 6, and 12
    EQ-5D: EuroQOL-5D; HRQoL: Health-related quality of life.

    ___________________________

    1 He M et al. Lancet. 2019;393(10181):1609-1618.

    2 Gazzard G et al. Lancet. 2019;393(10180):1505-1516.

    3 Groth SL et al. Ophthalmology. 2019;126(11):1511-1516.

    4 Vijaya L et al. Br J Ophthalmol. 2017;101(5):665-670.

    5 The Glaucoma Laser Trial Research Group. Ophthalmology. 1990;97(11):1403-1413.

    6 Jampel H et al. JAMA Ophthalmol. 2014;132(6):685-690.

    Meet the Experts

    David S. Friedman, MD, PhD, MPH Chair and director of glaucoma and medical director for clinical research at Massachusetts Eye and Ear and codirector of the Glau­coma Center of Excellence at Harvard Medical School, in Boston. Relevant financial disclo­sures: None.

    David Garway-Heath, BSc, MBBS, MD, FRCOphth IGA Professor of ophthalmology for glaucoma and allied studies at the Institute of Ophthalmology, University College London, and consultant ophthalmic surgeon at Moorfields Eye Hospital in London. He is also the president of the European Glaucoma Society. Relevant financial disclosures: Aerie: C; Alcon: S; Aller­gan: C; Bausch + Lomb: C; Pfizer: C,L; Santen: C,L,S.

    Jo Ann A. Giaconi, MD Health sciences profes­sor of ophthalmology, Stein Eye Institute, David Geffen School of Medicine, University of Cali­fornia, Los Angeles. She is also chief of ophthal­mology for the Greater Los Angeles Veterans Administration. Relevant financial disclosures: None.

    L. Jay Katz, MD Director Emeritus Wills Eye Hospital Glaucoma Service and professor of ophthalmology at Thomas Jefferson University in Philadelphia. Relevant financial disclosures: None.

    H. George Tanaka, MD Ophthalmologist at Vold Vision, Fayetteville, Ark. Dr. Tanaka is also former codirector of the Glaucoma Service at California Pacific Medical Center in San Fran­cisco. Relevant financial disclosures: None.

    Full Financial Disclosures

    David S. Friedman, MD, PhD, MPH Aerie: C; Bausch + Lomb: C; Jobson Publishing: C.

    David Garway-Heath, BSc, MBBS, MD, FRCOphth CenterVue: C; Heidelberg Engineering: S; Topcon: S.

    Jo Ann A. Giaconi, MD Allergan: C,L.

    L. Jay Katz, MD Aerie Pharmaceutical: O; Allergan: L; Bausch + Lomb: L; Glaukos: E,O; Heidelberg: S; Mati Pharmaceutical: O; Olleyes: O; Zeiss: S.

    H. George Tanaka, MD Aerie: L; Allergan: C,L; Bausch + Lomb: L; Ellex: C; New World Medical: C; Sight Sciences: L.

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