Treat and extend: An international view

Treat-and-extend has emerged as the preferred method for treating neovascular age-related macular degeneration with anti-VEGF drugs. Here, three internationally recognized experts on T&E—Anat Loewenstein, MD, of Tel Aviv, Israel; Peter Kertes, MD, of the University of Toronto and lead author of the landmark CANTREAT study; and Justus Garweg, MD, of Bern, Switzerland, and one of the international EyeCOPE study investigators—share their thoughts on clinical trial guidance, what types of patients are best suited to T&E, and the potential impact of emerging therapies that would enable even longer treatment intervals. 

Q: What can retina specialists take away from the clinical trials and apply in the clinic when it comes to treat-and-extend?

No tolerance for intraretinal fluid 

Dr. Garweg: Luckily, the majority of patients respond well to anti-VEGF therapy, whichever drug you choose. So the drug choice is critical mainly for patients with advanced disease and poor responders, whom you don’t know beforehand. But clearly, if the patients already have macular destruction at diagnosis, then they are not likely to have significant visual gains. If there’s already subretinal fibrovascular tissue and the ellipsoid zone is destroyed, then whatever you do may stabilize but not improve vision.

What we’ve learned in real life is to tell our patients that we cannot predict how much vision they will gain. After the three-injection loading phase, we can then see how a patient has gained vision. The aim would be the long term, which means maintaining the visual gain that was reached by the end of the loading phase for five years or more. 

One of the important learnings involves the appearance of the macula. It can look quite damaged, and you can be surprised at how much vision it gains. Therefore we should know about the patients’ visual expectations before initiating treatment, as patients have to learn that it’s not always granted that they’ll achieve reading or driving vision, even under consequent treatment. Predicting treatment outcomes is very important for long-term patient compliance. 

Adherence to the treatment protocol is the one key issue that leads to good long-term outcomes. And we have learned that intraretinal fluid shouldn’t be tolerated. This is at the discretion of the treating physician, but if the macula isn’t significantly drier after six months and not dry after 12 months, then we would want to switch the agent.

Patients appreciate predictability

Dr. Kertes: AMD is a heterogeneous disease and patients have different responses to treatment. A treat-and-extend regimen allows us to pair a patient’s treatment needs with their treatment frequency. It allows them to retain their vision as long as possible, and I think it improves compliance. 

My sense is that patients like knowing beforehand that they’re getting an injection, as opposed to a pro re nata regimen, when patients don’t know if they’re going to need an injection before the visit. There’s some peace that comes from knowing what’s going to happen when they go to see a doctor. 

The COVID-19 pandemic has really highlighted the value of the treat-and-extend regimen, so we can see patients less often. If they have an established treatment interval, we can get them in and out relatively quickly and not expose them to any undue risk.

Extending by two or four weeks

Dr. Loewenstein: There aren’t many trials that were done regarding the treat-and-extend regimen. The main one is the ALTAIR¹ trial; also the ARIES trial looked at early and late treat-and-extend.² Some small studies had been conducted in Spain. There aren’t a lot of prospective, level I data, but from the existing data, it seems that the treat-and-extend regimen is as effective as the PRN treatment with fewer non-injection visits. Theoretically, I think we can conclude that using treat-and-extend is a feasible regimen. 

The other thing that we can conclude from the trials is, that we can consider extending some injections by four weeks rather than by two weeks. This is based on the ALTAIR study, in which both of the study arms reported similar results whether the injections were extended to two-week or to four-week intervals. However, I think that in clinical practice, most of us are using an extended regimen of two weeks. 

We can also conclude from the trials that the treat-and-extend regimen is beneficial both for aflibercept and ranibizumab. This is an important finding, and I think it’s obvious to everyone that it decreases the patient’s burden and still maintains the visual acuity outcome by avoiding non-injection visits. 

Another lesson that we can learn from the trials, specifically the ARIES trial,² is that it’s more beneficial to start treat-and-extend early in the course of the process. You don’t have to maintain a year of fixed regimen and only then initiate a treat-and-extend approach. 

Q: What type of patient is best-suited for a T&E regimen?

nAMD patients only

Dr. Kertes: Neovascular AMD is especially well-suited for treat-and-extend. We know these patients for the most part will need to be treated long-term, unlike the other indications for anti-VEGF agents such as diabetic macular edema or vein occlusions. Many of those patients don’t need treatment in perpetuity, although some do. Whereas AMD patients really do generally need treatment long-term.

As we get agents that last longer and longer—as we get more and more durable agents—we’ll be able to establish very reasonable, very long treatment intervals that I think  will be very well tolerated by patients and their caregivers, and make our lives and clinics a little less crazy.

Sometimes PRN first

Dr. Loewenstein: For me, every type of patient is suited for a treat-and-extend regimen. I find it difficult to explain the treat-and-extend regimen to patients that were initially treated with a PRN regimen, so a switch is difficult. The reason is that patients, once I educate them that when intraretinal fluid appears they need an injection, don’t really understand why they need to be injected when they don’t have any fluid. 

Other than that, for me treat-and-extend is the best way to go. We usually do a loading phase of three injections. Usually we have to start with bevacizumab, and then once we determine that it doesn’t work, we can move to one of the registered drugs. Sometimes I try a PRN regimen first just to give the patients a chance; maybe they’re in the group that doesn’t need so many injections. But most of the time, I go straight a to treat-and-extend approach. I actually offer patients both options, but for me the preference is to go ahead with the treat-and-extend regimen. 

I will attempt a PRN regimen first, if this is the patient’s choice, mainly if there’s an early lesion. Some patients need only a few injections; though it’s not common. I will give one PRN injection to see if the patient can go without injections for a longer period of time. But I only give them one chance. When they need to be injected the first time, I go to the treat-and-extend regimen. 

Exceptions to any AMD patient

Dr. Garweg: Any patient with macular neovascularization may undergo a treat-and-extend protocol, with some exceptions: patients with myopic choroidal neovascularization, for example, or with a secondary CNV in uveitis.

Formerly we would extend to 12 weeks, but nowadays we routinely extend to 16 weeks, and in some cases even to 20 weeks without interim follow-up. If patients are completely stable, as we have shown in a recent publication, then we might discuss pausing treatment.³

I don’t say stop treatment. If we pause treatment, then we go for two months with controls. Many of our patients prefer to go on with continuous treatment every 14 to 16 weeks compared to having a consult every eight weeks and not knowing what to expect. 

The advantage of being consequently under-treated isn’t that you avoid recurrences. However, even if recurrences do occur, they do so with less vision loss and a lower risk of macular hemorrhages than they would otherwise. 

If you stop treatment and the patient has a recurrence, then there’s a distinct risk of macular hemorrhage. I think patients with an only eye and those in whom the fellow eye is already scarred would benefit from going on with this treatment, just for the safety considerations. 

Q: Are there any lessons from the COVID-19 pandemic for keeping T&E patients adherent to follow-up and monitoring?

Remote clinic, home visits

Dr. Loewenstein: During the pandemic, we called patients and made sure that we were providing them with a safe environment. Also, in our clinic we were very lucky because we had a remote clinic outside of the hospital where we could perform injections and evaluations, which was very beneficial for the patients. 

Moreover, we reached out to patients at home. If patients were in the loading phase or had an optical coherence tomography scan done elsewhere, we even performed the injections in their homes. We don’t have the resources to do that now, but we do go out and inject in elderly home shelters for patients who are reluctant to come to the clinic. However, we don’t have a suitable system and the resources to call every patient that didn’t come in to be examined. 

Flexibility on missed visits

Dr. Garweg: AMD patients can be prone to forgetting their appointments. So, we have to fit the appointments in not with only the patients, but also with their relatives. And we have to fit in new appointments if a patient forgot about the scheduled meeting. We have a nurse who specifically cares for patients who aren’t showing up. She calls them and arranges for new appointments so that every patient has a chance to get the treatment they need. 

It’s worth adding that patients who come with a new diagnosis of exudative AMD are very unhappy and they have no idea about treatment. They expect that they get one  injection and the problem is solved, like with a cataract; you get cataract surgery and the problem is solved. 

They have to learn that they have a chronic disease, and the treatment plan is very high in the beginning, but that it lessens over time. In the majority of cases, they will get along with three-and-a-half to four injections in years three, four and five, and so on, but in single cases, many more injections might be needed to maintain vision. 

It’s also important that you meet patient expectations in terms of functional gains or functional needs. For example, if you have a patient who has a significant increase in his vision but aims at reaching a driving vision and fails to do so, this patient will be unhappy. So, you have to first educate the patient—what they have to expect. But you also have to learn what the patients expect from their treatment, and you have to bring them back to a realistic level in order to maintain treatment adherence. 

Quick follow-up, longer intervals

Dr. Kertes: As the intervals between treatments become longer, the risk of patients missing their appointments becomes greater. But there are many ways to engage them. There are patients who do forget and need to be reminded of their appointments, so my staff can call them and remind them. 

If they do miss an appointment, we follow up carefully, make sure they’re well, and give them another appointment very soon. During the pandemic there were patients that wouldn’t even come into the hospital, with the uncertainty and the fear of the pandemic looming. Patients certainly did fall off the wagon and miss their appointments but, fortunately, most of those patients did OK and were able to regain whatever vision was lost. 

Sometimes we were able to establish a longer interval because they missed appointments due to COVID-19, but a small number came back with severe vision loss that we haven’t been able to recover. We’re lucky as ophthalmologists; our patients really do value their vision—particularly a patient who’s lost vision in one eye and needs treatment in their fellow eye. They’re pretty diligent. They want to get their eyes treated. They don’t want to risk losing vision. 

Q: Any closing thoughts?

Managing high-treatment cases

Dr. Garweg: Two-thirds of the cases end up with a low treatment burden, which is every 12 to 16 weeks. One-third of cases have a high treatment demand. These are the more critical cases because they have chronic, slowly progressive active disease. If they don’t comply with treatment, then they usually have severe lesions over three to five years. Those are the cases where we consequently switch to another drug. 

If you have a low responder in one eye, that doesn’t necessarily predict low response or poor response in the fellow eye. If it’s treated early, then the risk for poor response is low. If you catch an eye late or with very prominent scarring, then the risk for poor response is higher, but even then, consequently switching is very important. Also, this gives patients the notion that you’ll try anything to maintain their vision, which, again, supports their compliance. 

Monthly injections are not failures 

Dr. Kertes: This is obviously an active area of investigation. There are a variety of different strategies that have been developed and different agents that are in clinical trials. Most of these agents are tested in a fixed-dosing regimen and are compared to monthly or bimonthly injections, so to assess the real durability and efficacy of an agent, it’s a little bit disingenuous to compare our current agents and how they’ve been approved on label with regular frequent intervals. Every agent will stand on its own merits based on how well it performs in a treat-and-extend regimen, which obviously takes time and usually happens post-approval; but those are the more relevant comparisons.

With newer agents and longer durations, it’s realistic to expect that many of our patients will need maybe as few as one or two injections a year and be able to maintain their vision. I think most patients and caregivers and practitioners can tolerate that. I think that’s much more manageable than monthly or every two-month injections.

Keep in mind that there are patients who need more frequent injections. As difficult as that is, we found many of those patients in the CANTREAT study who needed monthly injections maintained good vision.^4,5 I think there’s a tendency for us to think of those patients as treatment failures, but they’re not. They’re just patients that need more anti-VEGF than others. We should pair our treatments with the patients’ needs to maintain them at the best vision that we can.

Adopting emerging agents

Dr. Loewenstein: We will need to change the way we treat patients with some of the newer drugs that can extend treatments out to three and four months. I think if you need to perform an injection every three or four months, you might not need a treat-and-extend regimen. Although, maybe you would because if you can extend to three or four months, maybe you could go out to three-and-a-half months, maybe four-and-a-half months. 

Also, the new emerging technology of the Port Delivery System containing ranibizumab requires a refill only once every six months. The port is not something that I would want to extend. I would like to see my patients at least once in six months. RS

REFERENCES

^{1. Ohji M, Takahashi K, Okada AA, Kobayashi M, Matsuda Y, Terano Y; ALTAIR Investigators. Efficacy and safety of intravitreal aflibercept treat-and-extend regimens in exudative age-related macular degeneration: 52- and 96-week findings from ALTAIR: A randomized controlled trial. Adv Ther. 2020;37:1173-1187.} 

^{2. Mitchell P, Holz FG, Hykin P, et al; ARIES study investigators. Efficacy and safety of intravitreal aflibercept using a treat-and-extend regimen for neovascular age-related macular degeneration: The ARIES study: A randomized clinical trial. Retina. 2021;41:1911-1920.} 

^{3. Garweg JG, Traine PG, Garweg RA, Wons J, Gerhardt C, Pfister IB. Continued anti-VEGF treatment does not prevent recurrences in eyes with stable neovascular age-related macular degeneration using a treat-and-extend regimen: a retrospective case series. Eye (Lond). Published online May 3, 2021. doi: 10.1038/s41433-021-01562-6.} 

^{4. Kertes PJ, Sheidow T, Williams G, et al. CANTREAT Study 24-month results: The ability to extend treatment and associated visual outcomes in the treat and extend group. Paper presented at: 19th EURETINA Congress. September 8, 2019. Paris, France.}

^{5. Kertes PJ, Galic IJ, Greve M, et al. Efficacy of a treat-and-extend regimen with ranibizumab in patients with neovascular age-related macular disease: A randomized clinical trial. JAMA Ophthalmol. 2020;138:244-250.}