Three prestigious races comprise the Triple Crown of Motorsport: the Indy 500, the 24 hours of Le Mans and the Monaco Grand Prix. Winning all three during a driver’s career is considered an unofficial racing achievement – and it’s only happened once (Fun fact: Graham Hill is the driver that won all three).
Each of the three Triple Crown courses varies widely. Winding through the streets of Monaco, the Grand Prix is a slower race (average speed 97mph or 156km/h) with a lot of twists and turns (19 to be exact); the Indy 500 is much faster (average speed 227mph or 365km/h) with only four turns; and the 24 hours of Le Mans has been called the ‘Grand Prix of Endurance and Efficiency’ – where racers must balance the demand for speed while maintaining the car’s ability to run for 24 hours without mechanical failure.
Certainly, this is a lot of information about car racing for an ophthalmology magazine. However, here at PIE Magazine, we’re always keen to take a deeper (or perhaps a more metaphorical) look ‘under the hood’ – and as it turns out, car racing and ophthalmology might have more in common than meets the eye . . .
In fact, we think the posterior segment has a ‘triple crown’ of its own: imaging for diagnosis and management, and laser and anti-VEGF for therapy. Together, these create the ‘triple crown’ of treatment in the posterior segment, leading to championship wins by improving outcomes for patients.
Imaging: The Grand Prix of diagnosis and management
Held on a narrow course on the streets of Monaco, the Grand Prix has many elevation changes, tight corners and a tunnel – making it one of the most demanding tracks in Formula One.
The anatomy of the posterior segment has some similarities with the Monaco Grand Prix: With all its twists and turns, it provides a complicated course for surgeons to navigate. Without accurate roadmaps – or images – finding the correct course would be impossible.
Thankfully today, surgeons have access to the ultimate in eye ‘road-mapping’. Since its introduction, spectral domain optical coherence tomography (SD-OCT) has led the pack in imaging and diagnostics, due to its low cost and high-resolution imaging.
But now, there is a new car in the race: swept-source OCT (SS-OCT). With faster scanning speeds and longer wavelengths for deeper imaging, is SS-OCT gearing up to overtake SD-OCT? Is a new champion to be crowned?
According to Dr. Judy Kim, a tenured professor at the Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin (USA), there are different factors to consider – and for each, a different winner. Here’s how she says the SD-OCT vs. SS-OCT races breakdown:
For vitreoretinal interface and showing intra- and subretinal fluid: It’s a tie. “Both SS-OCT and SD-OCT are excellent at showing intra- and subretinal fluid as well as vitreoretinal interface,” said Dr. Kim. “Since much of our treatment decisions for retinovascular diseases are based on the presence or absence of fluid, and surgical decisions for vitreoretinal interface disorders are assisted by OCT, both OCTs are incredibly helpful in our daily management of patients . . . and the race may be a tie.”
On speed: SS-OCT wins. Dr. Kim says if the race was purely based on speed, there is no question that SS-OCT would win – simply because it’s faster. She explained: “The faster scanning speed of SS-OCT allows for denser scanning and a wider scanning area for a given image acquisition time compared to SD-OCT.”
On imaging deeper structures: SS-OCT wins. Compared to SD-OCT, SS-OCT has a longer wavelength and reduced sensitivity roll-off. “These characteristics of SS-OCT allow better imaging of deeper structures and better penetration through RPE (retinal pigment epithelium),” explained
Dr. Kim. “As a result, one area that SS-OCT excels over SD-OCT is in OCT Angiography (OCTA). There are studies that show better detection and delineation of type 1 choroidal neovascularization (CNV) with SS-OCTA compared to SD-OCTA.”
One such study was published in 2017 by Miller et al.1 There, the investigators found that “SS-OCTA imaging provided a more accurate representation of the CNV compared with SD-OCTA imaging, in particular the SS-OCTA measurements are more consistent across the different scan sizes”.
Overall: Cost wins for SD-OCT. Like in the Monaco Grand Prix – where the race is won at much lower speeds – faster doesn’t always win in imaging. And despite the benefits of SS-OCTA, Dr. Kim currently believes that SD-OCT is way ahead in the race.
“While SS-OCT is fast, it has a huge problem that drags and slows down its adaptation by the masses and that’s the cost,” she explained. “It is highly expensive compared to SD-OCT and, until the cost comes down – or its limited drivers who race with SS-OCT can demonstrate that it significantly improves our patient outcomes compared to what we can achieve currently with SD-OCT – I believe that most retina specialists will continue to drive with SD-OCT.”
So, what navigation system does Dr. Kim use in her practice? They use SD-OCT.
“Being at an academic setting, we try to get the latest and best . . . however, the definition of ‘best’ also includes ‘most cost-effective’,” she said, noting that SD-OCT allows them to care for patients well without the significant downsides posed by cost.
“[With SD-OCT] we do not have to worry about added costs of buying more expensive imaging equipment that may not add further to management of our patients, we believe SD-OCT is an excellent choice,” continued Dr. Kim, adding that she has systems from Carl Zeiss Meditec (Jena, Germany) and Heidelberg Engineering (Heidelberg, Germany), but most of the time, she uses the latter.
She says the Heidelberg system’s image averaging, eye tracking and image registration provides excellent images from visit to visit: “I appreciate that I can get a widefield B-scan OCT with a special lens in this system, which I often use to study the vitreoretinal interface,” she said, noting that it also has other features, including autofluorescence which helps to follow geographic atrophy; and ICG (indocyanine green) angiography, which is useful in detection of various diseases such as polypoidal choroidopathy and central serous choroidopathy.
On the side of SD-OCT, Dr. Kim continued that in clinical practice, qualitative data (such as the presence or absence and relative growth of CNV compared to previous visits) is often used – rather than exact measurements of CNV size, which is needed in research.
Given its imaging capabilities, Dr. Kim says she would love to have SS-OCT in her clinic, but cost remains a huge limiting factor.
“Until we can solve that issue, and also demonstrate that SS-OCT can significantly alter the care of our patients relative to how we are doing currently, SD-OCT should suffice for now,” she said. “However, algorithms and instrumentation are continually changing in this imaging field; I eagerly await its every day clinical utility over SD-OCT.”
Final Score: While SS-OCT provides faster and deeper images,
it remains too cost-prohibitive for widespread clinical use. Therefore, the current victor remains SD-OCT. But how long will it remain in the lead? Only time will tell . . .
Anti-VEGF: A race of ‘endurance and efficiency’
Like the 24 Hours of Le Mans, those using anti-VEGF are in for the theoretical (and literal) long-haul – and like the race, finding the agent and treatment regimen that balances ‘endurance’ and ‘efficiency’ continues to challenge doctors.
Dr. Kim believes that all currently available anti-VEGF agents provide significant efficacy for most patients, however she finds that there are some patients who may respond better to one agent versus another, possibly due to pharmacogenetics. She also says that a ‘good response’ can also mean different things for different patients.
“In some patients, we can successfully stabilize the condition and no further injections are needed. In another, continuous chronic monthly treatment may be necessary to keep the retina dry. Yet in another, the retina remains with fluid despite frequent dosing, but the visual acuity can be maintained,” she explained, adding that different diseases respond differently to anti-VEGF agents.
Selecting the ‘Right’ Fuel for High Performance Results
The first variable to determine – and pardon the metaphor – is what gas to put into the car (or which anti-VEGF agent to inject). Across the board, there are three commonly used agents: bevacizumab (Avastin, Genentech); aflibercept (Eylea, Bayer); and ranibizumab (Lucentis, Novartis).
“The development of anti-VEGF is revolutionary in our management of various retinovascular disorders,” said Dr. Kim. These agents are used to treat conditions like macular edema due to retinal vein occlusion (RVO), diabetic retinopathy (and associated edema), and neovascular age-related macular degeneration (nAMD).
Fueling with bevacizumab. Avastin, which is used in cancer therapy, is the ‘parent’ molecule from which ranibizumab was derived for the treatment of nAMD; the cost per dose of bevacizumab is about 5-10% that of ranibizumab.2 Avastin is often used off-label to treat nAMD based on efficacy and cost-effectiveness.
In most cases of nAMD, Dr. Kim starts with Avastin. This is due to several factors including the fact that it’s readily available in her office, and its pre-authorization is not required by insurance companies. But perhaps most importantly, she notes that trial results (like those from IVAN and CATT) showed similar efficacy of bevacizumab and ranibizumab when given accordingly.
“As a result, I can treat on the same day of a new patient visit or at the evaluation visit with Avastin. And while most patients respond favorably to Avastin, if there is no improvement, or worsening in the amount of fluid in or under the retina, my next line of treatment is Eylea . . . and many patients end up continuing on it,” explained Dr. Kim. “If the patient does not respond to Eylea, or if there is that rare patient with inflammation with Eylea, I then switch over to Lucentis.”
“Likewise, for eyes with macular edema from central retinal vein occlusion or hemi-retinal vein occlusion, I also begin with Avastin and switch to Eylea if needed,” she continued, noting that this treatment is based on SCORE2 study findings.
[Ed. Note: For more on SCORE2 trial results, see the full story on page 38.]
“For central-involved diabetic macular edema, I try to follow DRCR. net Protocol T data, which showed no significant difference between the three anti-VEGF agents when visual acuity was 20/32 to 20/40, but Eylea was better for visual acuity and OCT outcomes for eyes with 20/50 or worse,” said Dr. Kim.
“Therefore, depending on the disease and its severity, we are fortunate to be able to choose different anti-VEGF agents, guided by clinical trial findings. While most patients can be started with Avastin and stay the course with Avastin if they are responding well, some end up switching over to a “different lane” and different drug – usually Eylea – during the course of the ‘race’,” she said.
“While multi-center randomized clinical trials guide my treatment decisions, the final decision of which anti-VEGF agent to initiate the therapy, treatment frequency, and possible switching or even cessation of treatment, are based on my discussion with each patient, according to his or her clinical and social situations and other needs,” concluded Dr. Kim.
Clinical trial results and cost are also two guiding factors for Dr. Anil Arora, medical director of the Central Coast Eye Specialists in Gosford, NSW, Australia. He says the three main anti-VEGF agents (Avastin, Eylea and Lucentis) are very similar – and this is supported by numerous studies and trials.
“I tend to use Avastin as my first line agent as it is less of a burden to the taxpayer and health care system,” said Dr. Arora, noting that while Lucentis and Eylea are subsidized by the Australian government, they cost the healthcare system about $500 million annually, a cost that he says could be better served in other health initiatives like cancer treatment or building new hospitals.
“I think that if the drugs are equally effective (as the trials suggest), then eye doctors have a responsibility to the greater health care system to do their bit to not see the cost of health care blow out and become unaffordable – hence my ‘philosophical’ bias for using Avastin,” explained Dr. Arora.
The duration of anti-VEGF treatment regimens
Like the 24 Hours of Le Mans, treatment with anti-VEGF is not a short race – often injections will be maintained for years to preserve visual acuity and anatomical benefits. Recent studies have shed light on determining how often anti-VEGF injections should be given to provide the optimal benefit to patients – and one regimen, treat-and-extend or T&E, is quickly becoming a fan favorite for treating nAMD.
Finding balance with T&E.
Dr. Gemmy Cheung from Singapore National Eye Centre (SNEC) uses T&E as her preferred regimen. She says the advantage of T&E is that it addresses long-term needs, to the second and third year and beyond.
Because nAMD is a chronic condition with no current cure, Dr. Cheung stresses that it’s important to have an open discussion with patients. “Anti-VEGF controls the condition, so therefore long-term treatment is necessary in most cases,” she said.
“In fact, we have cumulating data that suggest that if treatment is not continued at adequate retreatment frequency, much of the initial visual gain will be eroded in subsequent years,” continued Dr. Cheung. “Once we have accepted that fact, the next challenge is to make the treatment regimen and frequency practical and logistically acceptable – in other words, we need to find ways to reduce the number of return visits and injections.”
Dr. Cheung says this is where individualization is the key: “We know that some patients only need retreatment every 12 weeks or so, but this is not for everyone. There is currently no accurate way to predict this at the outset – therefore T&E fits into this need very well.”
“Although many clinicians have been using T&E for a while, we have not had very robust clinical trials until recently,” explained Dr. Cheung. “Now studies like ALTAIR or Trend have demonstrated that T&E can deliver good visual gain, while reducing retreatment burden. Concurrently, real world data, such as those from the Fight Retinal Blindness Registry, have also reported encouraging results using T&E.”
Dr. Kim is also an advocate of using T&E in nAMD for several reasons. Firstly, clinical trial results (like those mentioned by Dr. Cheung) show that the T&E regimen can yield similar visual acuity outcomes as monthly dosing for up to two years. “This greatly reduces treatment burden on the patient, as well as on the physicians, without compromising visual acuity outcomes,” she said.
Lowering the number of injections, and thus the treatment burden, is another reason. “The HARBOR and CATT studies have shown that the number of injections required by a patient can vary greatly. Some patients required only few injections, while others required monthly injections over two years,” said Dr. Kim.
“Furthermore, we currently do not have good biomarkers to know at baseline which patient is going to require more injections,” continued Dr. Kim, adding that if all patients are treated monthly, many will be overtreated. Alternately, even if patients are not treated monthly, they would still require monthly follow-up to check for changes in OCT and visual acuity – and thus, this does not alleviate the burden of number of clinic visits.
“Also, a monthly visit with PRN (pro re nata or as needed) treatment is a reactive treatment rather than proactive treatment and risks recurrences with irreversible loss of visual acuity,” said Dr. Kim. “Many studies have shown that under-treatment is common in real-world data and is most likely the reason for poorer real-world visual acuity outcomes when compared to clinical trial outcomes.”
Dr. Arora says that while he tends to take a PRN approach, multiple factors are taken into consideration. This includes: the state of the other eye (if other eye is bad, he will be far more likely to treat, even if there is little or no evidence of active disease); the patient’s ability to travel and attend treatment; stability of vision and ocular findings; and what has happened in the past if treatment was delayed or withheld.
“If the situation is very stable, the macula looks dry and the OCT looks good, then I’ll often go to a treat-and-extend protocol,” said Dr. Arora, adding that currently there are no standardized rules regarding anti-VEGF treatment regimens. “If you ask 10 different ophthalmologists, you will get 10 different opinions.”
“Studies show that patients who get regular monthly injections no matter what (e.g. even if their retina looks completely normal with no evidence of fluid or blood and vision has returned to normal) do the best in the long-term, but it is often difficult in the real world to justify the cost and the anxiety, and the low, but ever-present risk of endophthalmitis, to a patient when everything is normal,” said Dr. Arora.
Overall: Preferred regimen to last for the long haul is T&E. “In my opinion, the T&E regimen is currently the best we have to offer that can minimize treatment and visit burdens to our patients, while personalizing the injection and visit frequency, avoiding under-treatment and not compromising the visual acuity,” concluded Dr. Kim.
Laser: Finding its place in the pack
The Indy 500 is the world’s oldest major automobile race. And laser has been investigated and used for ophthalmic purposes since the 1960s and 70s – making it one of the older, yet still effective technologies for treating certain posterior segment conditions.
“Laser treatments have been with us for decades, and they can be useful in the management of localized non-center involving diabetic macular edema (DME) and proliferative retinopathies, such as sickle cell retinopathy, neovascular glaucoma, retinopathy of prematurity, proliferative diabetic retinopathy (PDR), and neovascularization following retinal vein occlusions,” said Dr. Kim. “I also use laser to treat retinal tears, limited retinal detachment, symptomatic macroaneurysm, Coat’s disease, among other conditions.”
In her practice, Dr. Kim uses a Nidek (Gamagori, Japan) pattern laser system – she says that in patients who are cooperative, the pattern laser allows for faster treatment for PRP (panretinal photocoagulation). “There can be variations in uptake of laser in different parts of the eye, and the pattern laser seems to result in less intense PRP in some patients,” she said, noting that the pattern laser is also slightly more sensitive to media opacity.
“Therefore, in many patients, I perform PRP with single spots or with an indirect laser,” said Dr. Kim. “Even in cooperative patients, I do not perform focal grid laser treatment with pattern, but with single spots for accuracy and safety.”
In his clinic, Dr. Arora says he uses a green diode laser for extrafoveal lesions: “I think [laser] can reduce the frequency of [anti-VEGF] injections, if used in conjunction with injections for conditions like retinal vein occlusion and diabetic retinopathy.”
So, why is a newer treatment like anti-VEGF speeding past an old remedy like laser? According to Dr. Kim, there are downsides to laser: “Focal grid laser can result in inadvertent treatment of the fovea, or expansion of the laser scar over time, that encroaches into the fovea and causes loss of visual acuity,” she said, adding that PRP is excellent as a treatment for PDR, but it has shown to reduce visual field and night vision.
In addition, Dr. Arora says that laser therapy is a controversial topic, and doctors may use it in different degrees instead of, or in conjunction with, anti-VEGFs.
According to Dr. Kim, recent studies suggest anti-VEGF’s superiority to laser, either as a monotherapy or in combination, for conditions like DME and PDR. She said that for management of eyes with central-involved DME with vision loss, Protocol I from DRCR.net showed that anti-VEGF was superior to focal/grid laser. In eyes with DME and PDR, Protocol J found that a combination of anti-VEGF and PRP can reduce vision loss from DME worsening after PRP.
Meanwhile, she said that Protocol S of DRCR.net showed a two-year benefit of anti-VEGF therapy for PDR: “There was greater area under the curve for visual acuity, less visual field loss, and less need for vitrectomy in the anti-VEGF group compared to PRP group,” said Dr. Kim. “However, the 5-year data was not as strong and there was significant number of subjects who were lost to follow-up, which I believe is a significant issue.”
She continued: “Furthermore, while anti-VEGF injections can even improve diabetic retinopathy severity score, after the first year of intense therapy with frequent injections, the subjects continued to require average of 3 injections, even at year 5, suggesting some eyes may require chronic intravitreal injections.”
But are there cases where laser may produce a more favorable outcome? In certain instances, and while this differs from the Protocol I and T findings, Dr. Kim says there is an advantage to laser: “Since one or two PRP sessions can stabilize PDR in most patients for the long-term – and diabetic patients tend to be sicker and are at higher risk for being lost to follow-up – I am concerned by chronic therapy with anti-VEGF for PDR, and have decided to use PRP more to give these eyes a chance for persistent stabilization.”
Overall: While it’s played second fiddle to anti-VEGF as of late, laser still plays a vital role in treating certain conditions – and its role as a mono- or combination therapy will continue to be studied to further positive outcomes for patients. And the Triple Crown goes to…As diagnostic and imaging technology speeds forward, therapy options and treatment regimens remain under evaluation – and time will tell as long-term trial results help dictate the course of treatment for the various sight-threatening conditions affecting the posterior segment. Until then, the race for better outcomes will be propelled forward by the continued work of researchers, ophthalmologists and those involved in the industry – and in our humble PIE opinion, it’s those people that are the ultimate ‘Ophthalmic Triple Crown’ winners.
References:
1 Miller A, Roisman L, Zhang Q, et al. Comparison Between Spectral-Domain and Swept-Source Optical Coherence Tomography Angiographic Imaging of Choroidal Neovascularization. Invest Ophthalmol Vis Sci. 2017;58(3):1499-1505.
2 Chakravarthy U, Harding SP, Rogers CA, et al. A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN). Health Technol Assess. 2015;19(78):1-298.
3 Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398.
4 Wai KM, Singh RP. Treat and Extend Dosing Regimen with Anti-vascular Endothelial Growth Factor Agents for Neovascular Age-related Macular Degeneration. Am J Ophthalmic Clin Trials. 2018;1(1):1-6.5 HARBOR Study Group, Ho AC, Busbee BG, Regillo CD, et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014;121(11):2181-2192.
“While SS-OCT is fast, it has a huge problem that drags and slows down its adaptation by the masses and that’s the cost. It is highly expensive compared to SD-OCT and, until the cost comes down – or its limited drivers who race with SS-OCT can demonstrate that it significantly improves our patient outcomes compared to what we can achieve currently with SD-OCT.”
– Dr. Judy Kim
IVAN Study
The IVAN (Inhibit VEGF in Age-related choroidal Neovascularization) trial was a head-to-head comparison between bevacizumab and ranibizumab. The investigators found that ranibizumab and bevacizumab have similar efficacy.2
CATT Study
The Comparison of Age-related Macular Degeneration Treatments Trials (or CATT) described the effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years. They found that ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period.3
“Although many clinicians have been using T&E for a while, we have not had very robust clinical trials until recently. Now studies like ALTAIR or Trend have demonstrated that T&E can deliver good visual gain, while reducing retreatment burden.”
– Dr. Gemmy Cheung
Trend
The Trend study showed that T&E dosing with ranibizumab was non-inferior to monthly dosing and had clinically comparable results in visual acuity compared to monthly dosing after 52 weeks.4
ALTAIR
The ALTAIR study is the first to critically compare different T&E protocols and showed that both the 2- and 4-week extension protocols for T&E regimens improved visual and anatomical outcomes through week 52.4
HARBOR Trial
The HARBOR trial evaluated the 24-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly or as needed (PRN) in patients with nAMD. Investigators reported the mean number of ranibizumab injections through month 24 was 21.4 (0.5 mg monthly), 13.3 (0.5 mg PRN), 21.6 (2.0 mg monthly), and 11.2 (2.0 mg PRN). At month 24, the mean change from baseline in BCVA was (letters) +9.1, +7.9, +8.0, and +7.6, respectively.5 These results led investigators to conclude that physicians should be comfortable optimizing treatment strategies on an individual basis.
“Studies show that patients who get regular monthly injections no matter what (e.g. even if their retina looks completely normal with no evidence of fluid or blood and vision has returned to normal) do the best in the long-term, but it is often difficult in the real world to justify the cost and the anxiety, and the low, but ever-present risk of endophthalmitis, to a patient when everything is normal.”
– Dr. Anil Arora
A Summary of the Treat-and-Extend Approach from Dr. Gemmy Cheung
When starting patients on a T&E regimen for nAMD, there are several steps to consider:
- Initial counseling: Physicians should outline the need for long-term treatment – and consequences of suboptimal follow-up treatment – with patients before beginning the T&E treatment regimen.
- Start with intensive treatment phase: Give monthly injections with the aim of establishing maximal improvement in visual acuity and anatomical response.
- Once maximal improvement has been reached, explain the transition to the ‘maintenance phase’ to the patient. The aim is not to improve any further, but to maintain gains while reducing retreatment visits.
3a. Titration phase: During this phase, provide injections during every visit, while lengthening the return visit (if there are no signs of recurrence of disease activity). Stop further extension once recurrence occurs and return to the previous ‘dry’ interval.
3b. Stable maintenance phase: Most patients will establish their optimal retreatment interval after a period of titration. I would continue retreatment using this interval as a ‘fixed’ regimen for a minimum of 1 year.
3c. Re-challenge: For patients who have ‘failed’ a certain extension interval, I would consider re-challenging once or twice if they become stable for a couple of cycles.
Dr. Cheung notes that these are general principles: “Each clinician will need to evaluate individual patients further according to their needs, their visual potential and their disease phenotype.”
